INTERDISCIPLINARY CANCER THERAPY: ADJUVANTTHERAPY EVERETT V. SUGARBAKER ALFRED S. KETCHAM GORDON F. ZUBROD

TABLE OF CONTENTS HISTORICAL C O N C E P T OF C A N C E R C U R R E N T CONCEPTS IN T U M O R

SURGERY AND THERAPY

7

B I O L O G Y A N D R A T I O N A L E FOR

INTERDISCIPLINARY C A N C E R T H E R A P Y

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9

C H E M O T H E R A P Y : BASIC PRINCIPLES A N D

APPLICATIONS. . . . . . . . . . . . . . .

ADJUVANT

RADIOTHERAPY: BASIC PRINCIPLES A N D APPLICATIONS "IMMUNOTHERAPY" OR "IMMUNOMODULATION" DEVELOPMENT MALIGNANT SARCOMAS CARCINOMA

OF A D J U V A N T

TUMORS

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THERAPY PROGRAMS

OF C H I L D H O O D

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. . . . . . . . . . . . . . . . . . . . . OF T H E C O L O N A N D R E C T U M

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BREAST CANCER . . . . . . . . . . . . . . . . . . . SQUAMOUS MALIGNANT ADJUVANT

CELL CARCINOMA MELANOMA

OF H E A D

A N D NECK

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T H E R A P Y OF O T H E R M A L I G N A N C I E S

IMPLICATIONS OF EFFECTIVE A D J U V A N T PRACTICE OF C A N C E R

SURGERY

22 31 36 38 41 42 46 50

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54

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57

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58

T H E R A P Y FOR T H E

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59

is Associate Professor of Surgery and Oncology at the University of Miami and is a diplomate of the American Board of Surgery and the American Board of Thoracic Surgery. H e received his M.D. degree from Cornell University and completed training in General and Thoracic Surgery at the Massachusetts General Hospital. H e was Clinical Associate at the National Cancer Institute for two years. After completing Chief Residency at Massachusetts General Hospital, he spent one year as a Fellow in Surgical Oncology at the M. D. Anderson Hospital and Tumor Institute in Houston. Doctor Sugarbaker's clinicalresearch interests relate to the controlled clinicaltrialsutilizingadjuvant therapy and his laboratory research interests center around experimental metastasis formation.

ALFRED

S. K E T C H A M is Clinical Director and Chief of the Surgery Branch at the National Cancer Institute, and Associate Scientific Director for Clinical Research, Division of Cancer Biology and Diagnosis, National Cancer Institute. He is a Diplomate of the American Board of Surgery. Doctor Ketcham completed his medical education at the University of Rochester School of Medicine, served an internship at the National Naval Medical Center, Bethesda, Maryland and completed his surgical training at the U.S.P.H.S. Hospital in San Francisco and Seattle. His research interests include experimental metastases and therapeutic results of clinical cancer investigations.

cA fis Director of the Comprehensive Cancer Center for the State of Florida at the University of Miami School of Medicine where he is, in addition, Professor and Chief of the Department of 0ncology. He is President of the American Association for Cancer Research and Vice President and Chairman of Task 10 of the Association of American Cancer Institutes. Doctor Zubrod received his M.D. from Columbia University, College of Physicians and Surgeons in New York City and served an internship at Jersey City Hospital, then in Presbyterian Hospital, New York. His interests include chemotherapeutic drug investigations and the, methodology necessary to carry out the most effective programs for the clinical management of cancer.

DUE TO SYSTEMIC METASTASES, more than 50% of all human cancers are incurable at the time of diagnosis by radical local treatment only. Occult m e t a s t a s e s - p r e s e n t at the time of d i a g n o s i s - e v e n t u a l l y cause treatment failure and the patient succumbs only too frequently. Death due to recurrent cancer, often associated with a painful, malodorous, septic focus, continues to be a gruesome fact for the oncologist and lay public alike. Survival statistics of 1 0 - 3 0 % for patients with advanced disease clearly are unsatisfactory as a therapeutic end 'point. There are four basic approaches to correct these inadequate survival statistics (Table 1). Since the risk for dissemination increases with primary tumor size, early diagnosis will improve the survival statistics in some tumors. However, the limitations of early diagnosis are apparent. A palpable 1-cm tumor contains approximately 10 '~ cells. Therefore, the preclinical period of growth is 8 logs in terms of cell numbers, with only 3 more logs needed to reach a preterminal size and weight (approximately 1012 cells). The preclinical period of growth is indeed the iceberg below sea level. During this period of indeterminate duration, the risk for lymphatic or vascular dissemination undoubtedly is present. Witness the fact that in patients with nonpalpable, mammographically detected breast cancer, 22% have positive axillary nodes in their mastectomy specimen. Most women with positive nodes eventually will succumb to cancer. Other cancers, such as oat cell carcinoma of the lung or undifferentiated carcinoma of the thyroid, must disseminate nearly from the time of inception. The net result is that all such patients are incurable. AdNOTE: This work was supported by CCC Core Grant # NCI CA14395, NCI: 1PO1CA-1932101 and American Cancer Society Grant J F C F # 373. 4

TABLE 1.-APPROACHES OR STRATEGIES FOR IMPROVING CANCER CONTROL 1. Early diagnosis 2. Prevention 3. Silver bullet 4. Interdisciplinarycancer therapy NOTE: The combinationof treatments under the term interdisciplinarycancer therapy is one of the four strategies in improvingcancer results. The importance of this approach is emphasized,for it seems difficultto prevent cancer, and early diagnostic programs may be thwarted by significant socioeconomicfactors, particularly in the indigent patient population.

ditionally, early diagnostic programs assume a concerned and responsive patient population. To the clinician treating illinformed or misinformed segments of the population, it has become apparent t h a t significant psycho-socioeconomic impediments to early diagnostic screening programs exist, which are beyond the scope of his influence. Therefore, early diagnosis m a y not provide a major incremental advance in cancer survival statistics. Carcinoma of the lung, the leading cancer in men, is caused by cigarette smoking in 90% of cases. One-third of these cases arise as "oat cell" carcinoma and the prognosis is essentially hopeless. Squamous cell lesions carry a 60% mortality even if the lesion is localized at the time of diagnosis. It is a national tragedy t h a t our society a n d those who lead it cannot effect control of the noncontributory industry producing cigarettes and the contained cancerogenic substances. However, these are political realities t h a t reinforce the problems of preventive medicine. The third approach is the search for the "silver bullet" or a specific metabolic therapy t h a t would reverse the basic mechanism of cancer. This is the ultimate goal of much research. However, it has become clear t h a t multiple factors and cofactors are involved in the etiology and dissemination of cancer. Additionally, m a n y technical problems must be overcome before specific meaningful questions can be asked. The fourth approach, and the central subject of this monograph, is the use of combined modalities through interdisciplinary cancer therapy (Fig. 1). Based on a statistical projection of subclinical cancer dissemination, it can be predicted t h a t surgical extirpation alone will result in inadequate survival statistics, particularly in advanced neoplastic disease. Therefore, other modalities with general efficacy must be directed at occult systemic metastases present at the time of primary treatment. The concept of considering the primary lesion and distant micrometastases separately for therapeutic purposes is at the core of interdisciplinary cancer therapy. This means t h a t the primary lesion is treated by a lo5

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Fig 1.-Interdisciplinary cancer therapy. Surgery, radiation therapy, chemotherapy and "immunotherapy" are the primary current modalities for the planning of interdisciplinary treatment programs. However, other adjuvant approaches may evolve based on a better future understanding of tumor growth and metastasis.

cal modality (i.e., excision, radiation or a combination of both) and the distant subclinical metastases, whose potential existence is :defined by past statistical experience, are treated by chemot h J r a p y or by "immunotherapy." INFINITE THERAPEUTIC COMBINATIONS (Table 2 ) . - F o r m o s t primary cancers there exists a choice of possible surgical techniques, different from one another by the extent of tissue removed. The radiation therapist has an extensive array of particle energies, ports, fields and dosimetry at his command. The chemoTABLE 2 . - I N F I N I T E THERAPEUTIC COMBINATIONS 1. 2. 3. 4. 5.

50 drugs active in man Infinite drug combinations Radiotherapy: Range of portslfieldsldosimetrylparticle energies Surgery: Conservative to radical Hormonal manipulations in certain cancers: Inhibition of prostaglandinmediated osteotropism, estrogens, androgens, corticosteroids 6. Immunotherapy: Specific versus nonspecific applications 7. Unexplored adjuvant possibilities: Anticoagulants, antiangiogenesis, IRCF, platelet inhibitors, exploit differences between primary tumors and. metastases

NOTE: For any given stage of any given metastasizing cancer, theoretically there are infinite treatment possibilities. The need for well-controlled studies that increase the information gained in the treatment of "limited" patient material is apparent. "

therapist has more than 50 drugs proved active in man. In addition, combinations of these drugs are even more active. The "immunotherapist" still is defining the place of this modality. The net result is that an almost infinite number of therapeutic possibilities exist for nearly every stage of cancer. The challenge of the next decade will be to coordinate therapeutic efforts so that optimal t r e a t m e n t combinations can be devised as rapidly as possible. In this new and explosively developing field, few t r e a t m e n t results are available, and many current treatment programs will undergo modifications with time. Therefore, it is important to review the principles and the rationale underlying each one of the therapeutic modalities, so as to give the trainee or clinician an understanding of the "blends" of therapy that are the substance of interdisciplinary cancer treatment. This monograph will (1) review the history of the single-modality approach to cancer and the reasons for failure, (2) review the current concepts in tumor biology that provide the rationale for interdisciplinary cancer therapy, (3) outline the basic principles of the application of the major therapeutic modalities, (4) outline current guidelines for the logical combinations of therapy and (5) provide a review of the early interdisciplinary t r e a t m e n t results in selected disease categories and indicate some ongoing studies that are not ready for assessment of results at the time of this writing.

HISTORICAL CONCEPT OF CANCER SURGERY AND THERAPY TIME/SPACE PROGRESSION OF T U M O R G R O W T H

The concept of cancer growth and dissemination that was formulated in the late nineteenth and early twentieth centuries dictated the therapeutic approach to the disease process. Cancer was thought to be a mass of propagating cells that, over a period of time, invaded surrounding tissues, permeated lymphatics with "toothpaste-like" extensions of tumor, embolized to regional lymph nodes and later entered the bloodstream. Using these morphologic observations as a basis for therapy led to important assumptions: (1) time was important, i.e.,cancer caught early enough would not have spread so far and (2) lymph nodes were effective "filters"for cancer cells, at least on a time-limited basis. Therefore, en bloc resection of the primary tumor, the regional lymphatic channels and the first echelon of lymph nodes would provide cure in most patients. Initially applied to breast cancer by Moore '39 and later by Halsted, 8~ this concept was quickly applied to carcinoma of the rectum by Miles, '33to oral cancer metastatic to the neck by Crile3s'and to m e l a n o m a by Pringle '53 and 7

Handley. 8' In these procedures, the inclusion of lymphatics and regional lymph nodes that were not grossly involved in the disease process was advocated. Treatment for subclinical (nonpalpable) metastatic disease was by operation alone, for no other modalities were available nor were they thought to be necessary. EXTENDING THE SURGICAL PERIMETER

When recurrences and metastases were noted, despite en bloc resection, a major direction in cancer t h e r a p y - f r o m 1910 to the 1 9 6 0 s - w a s to extend the surgical perimeter to include more tissue. With the well-known advances in surgical technique, blood replacement, antibiotics and intensive care over this period, super-radical extirpation became feasible. The Whipple procedure (pancreaticoduodenectomy), 2~ extended radical gastrectomy, ~29 super-radical mastectomy 2~ and hemicorporectomy were all devised within this conceptual framework and are tributes to the ingenuity and daring of surgical innovators, as well as to their concern for the survival of their patients.

CONCEPT OF DIFFUSE SUBCLINICAL DISEASE However, despite these extensions of the surgical perimeter to the absolute anatomic limits, many patients still died from systen:ic metastases. Surgery alone, although successful in eradicating the primary, often failed to "trap" the disease in a regionalized state. The cellular theory of systemic metastasis, which initially established the concept o f e n bloc resection, now has become the explanation for surgical failures and has provided the impetus for current interdisciplinary approaches to cancer management. DOSE

RESPONSE AND THRESHOLD FOR TUMOR "TAKE" AS THE CONTINUING RATIONALE FOR ABLATIVE CANCER SURGERY

The "take" of tumor implants in both h u m a n and experimental situations is close dependent. 's~ The threshold dose of cells for true tumor "take" is represented by the balance of host-defense mechanisms and innate aggressiveness of the cancer in question. Although it is true that absolute prevention of cancer contamination in a surgical wound probably is not possible, it is equally true that a positive tumor margin or gross violation of a tumor space very frequently results in local failure. Therefore, we adhere to en bloc resection wherever technically feasible and practical. In addition, tumor cell contamination is reduced to a minimum by frequent instrument and glove changes and thor8

ough irrigation of the operative wounds with sterile water (this m a y have some osmotic destructive effect on residual cancer cells). The goal of these maneuvers is not as ambitious as the initial concepts of cancer surgery led one to believe, since it is now realized that many patients have systemic disease at the time of surgical intervention. However, every therapeutic modality has a dose-response aspect and it is important to eliminate iatrogenic tumor dissemination during operation and to provide wide, clean margins of resection. The efficacy of adjuvant modalities is optimal when the tumor burden is reduced to a minimum. RADIATION THERAPY

As a local t r e a t m e n t modality, radiation therapy has been subject to the same limitations as surgery. It is limited by the extent of established subclinical metastasis. Although significant technical advances in therapeutic ratio are possible, radiation also faces the problem of existing systemic subclinical disease. One of the difficulties of combining chemotherapy with radiation therapy is that m a n y of the side-effects are additive. Particularly with the alkylating agents, immunosuppression m a y be enhanced. In addition, the antibiotics create severe radiation "recall reactions" in the ports of therapy and m a y severely limit the dosage of chemotherapy that can be utilized. '97

CURRENT CONCEPTS IN TUMOR BIOLOGY AND RATIONALE FOR INTERDISCIPLINARY CANCER THERAPY In the last analysis, it is the crude growth of cancer that kills the patient. The surgical attack on cancer is a forthright one and is designed to extirpate the tumor. However, the mechanisms of chemo-, immuno- and radiation therapy are more complex. An understanding of how these modalities affect the cancer cell(s) is important to the surgeon in his "adjuvant" use of these treatments, which bear directly on future cure statistics of the traditional s u r g i c a l patient. It is important to review the pertinent aspects of tumor biology to understand the mode of action of the adjuvant modalities and the potential for creating new "adjuvants." The pertinent areas in tumor biology are (1) the kinetics of tumor growth and (2) tumor invasion and metastasis. TUMOR GROWTH AND THE GOMPERTZ EQUATION

First let us consider observations on crude tumor growth rates. The'grossly measured growth rate of nearly all experimental and the studied h u m a n tumors is characterized by a progressive slow9

105

E

,-0

EXPONENTIALGROWTH GOMPERTZIAN GROWTH - - -

///

i,.a,J

'"

10-5 0

W/Wo: Wo= INITIAL TUMOR SIZE W = TUMOR AT TIME I T

I

2 4 TIME (Days)

I

6

Fig 2.-Gompertzian growth vs simple exponential tumor doubling. As both experimental and clinical tumors increase in size, their growth rate progressively slows. The reasons for this observation in tumor biology are extremely important and form the basis for many concepts in adjuvant therapy.

ing in grossly observed growth, with increasing tumor size.,,s, ,,5. ,ss This type of growth is best described mathematically by the Gompertz equation (Fig. 2). A typical Gompertzian growth curve of a solid tumor versus a theoi~etic exponential curve of progressive and constant tumor doubling are contrasted in Figure 2. This is an extremely important distinction in tumor biology, for the mechanisms involved in the progressive retardation of tumor growth with increasing tumor size have profound implications for the use of adjuvant treatment modalities or for the primary therapeutic use of either radiation therapy or chemotherapy. T H E PRIMARY T U M O R AS A METABOLIC AND KINETIC MOSAIC: T H E CAUSE OF GOMPERTZIAN G R O W T H

The results of the classic studies by Tannock '9~, ,96 have been represented diagramatically in Figure 3 and contribute significantly to the understanding of why the tumor "slows down" as it increases in size. As proliferating cells push others to a greater distance from the tumor's capillary blood supply, a diffusion gradient of essential metabolites is established. When this distance reaches greater than 150/~67 to 169 ~20o nutritional support is inadequate and necrosis develops. Therefore, since the cells that become necrotic cannot divide and are resorbed, they attenuate the theoretic exponential gr~wth curve and are lost to the total of 10

1:)02 Gradier

Labelinginc

esidual onogenic

Fig 3 . - P r i m a r y tumor as a metabolic and kinetic mosaic; explanation for Gompertzian growth. Studies by Tannock have defined both metabolic (Po2) and kinetic gradients within growing malignant tumors. The high growth fraction of well-vascularized tissues vs the I o w g r o w t h fraction of hypoxic central tissues affects the response of neoplasia to chemotherapy and radiation therapy and may contribute to a selection process in the dissemination of cancer.

grossly measured tumor volume. Necrosis, however, represents only the bitter end of this internal metabolic derangement of cancer growth. Tannock has shown (Fig. 3) that the percentage of tumor cells that are synthesizing DNA diminishes as the distance from the capillary interface increases. 195 Therefore, as cells are pushed toward the zone of necrosis, the number of these cells initiating cell division diminishes. Tannock 195 also studied the length of the cell cycle in dividing cells and found that it was essentially unchanged; however, others have found some prolongation of cell cycle times with hypoxic growth conditions. In other terms, the growth fraction, or the percentage of cells actually in the cell cycle and synthesizing DNA, diminishes as the distance from capillary perfusion increases. Measurements of oxygen tension with Po 2 microelectrode~ document the direct correlation of 11

hypoxia to diminished growth fraction. 3~ As the growth fraction falls, a population ofnondividing b u t viable cells is established. TM Although these cells contribute to grossly measured tumor volume, they do not add to grossly measured tumor growth rate, a fact that confirms the Gompertzian growth curve. Although the growth fraction diminishes with increasing tumor size, SimpsonHerren et al. in have demonstrated that transplantation to normal experimental animals of small bits of tumor from large tumors with small growth fractions rapidly reverses this trend. With rev~scularization, a high percentage of cells enter the cell cycle and incorporate radioactive DNA label. Cells other than those lost by necrosis are shed into the circulation itself. Butler and Guillino 22 quantitated cell loss into the circulation by isolating the vascular pedicles of a tumor implant in the mouse ovary. They demonstrated 3 - 4 • l0 G cells shed per gram of tumor in a 24-hour period. This volume of cell loss is a significant contribution to the Gompertzian curve. Of theoretic importance is the potential accrual o f ilzhibitory substances released by a growing tumor, which eventually retards the rate of growth of both the primary tumor and distant metastases. This subject recently has been reviewed extensively by us, 186 with the conclusion that it is a significant mechanism in tumor biology. In summary, from an analysis of the grossly measured Gompertzian growth of tumors, we can conclude t h e presence of a metabolic diffusion gradient, the existence of a diminishing growth fraction with increasing hypoxia and t h e development of a nondividing ~'Go" or "resting" tumor cell population. Cell loss due to exfoliation centrally into areas of necrosis or into the venous or lymphatic circulation, in the form of circulating tumor cells, is also important. These observations in tumor biology have significant therapeutic implications for the use of adjuvant therapeutic modalities. TUMOR CELL KINETICS T h e specifics of the cellular events by which a tumor cell reproduces itself are of great importance. The data of Tannock '95, 196 and those reviewed by B a s e r g a " and Lamerton '1~ suggest that the cell cycle time in solid tumors is relatively unchanged, and that factors that determine the growth fraction (i.e., the number of cells actually in the cell cycle) are most important in contributing to the growth characteristics of a given tumor. In h u m a n tumors, however, Steele '75 has observed a broad range of intermitotic times and it is clear that a difference between cycling and noncycling cells m a y be difficult to determine. It is also important to emphasize that tumor .cells are dividing asynchronously, with 12

probable variations in the times of each of the cell cycle events, as has been shown by Steele. 175The specific events of the tumor cell cycle, however, are of great importance in understanding how chemotherapeutic drugs and a combination of drugs work. THE CELL CYCLE AND THE GROWTH FRACTION.--The length of the cell cycle is measured from mitosis to mitosis (the intermitotic time, Tr as demonstrated in Figure 4. Tumor cells that are active in the cell cycle constitute the proliferating pool or the Fig 4.-The events of the cell cycle. The cell cycle is characterized by discrete phases, each one with dominant macromolecular events.

TWO CELLS PRODUCED

;1

G

PROLIFERATINGPOOL

CELL LOSS !. HECROSIS 2, CIRCULATING TUMOR CELLS 3. IMMUNE DESTRUCTION 4. GENETIC ERRORS

(GROWTH FRACTION)

? MECHkNISM RECRUITMENT............. ? MECHANISM

1. tIUTRITIOH, HYPOXIA 2. MIIOIIC iNHIBITORS

CHALONES OR NONSPECIFIC 3.[POLYAMINE]

NONPROLiFERATiHG POOL ("Go" or "Resting Cells")

1. CLONOGENICvs. NONCLONOGENIC 2. MATURATION/SUBLETHALGENETIC ERRORS

DOMINANTMOLECULAREVENTSOF CELLCYCLE(Tc) 1,GvRNA, Protein synthesis, maximum expression tumor antigen, expressions of cell function " 2uS - DNA synthesis . RNA, protein synthesis .,

3 , G 2- Protein synthesis "silent pre.mitotic period" ,4, M - Tubular protein synthesis RNA synthesis 13

growth fraction. After mitosis, a new cell cycle begins and tumor cells enter G,. During G 1 (first gap period), RNA and protein synthesis occur and in normal cells the specific cell functions are accomplished. In normal cell populations, maturation may occur from G, and these maturing cells lose reproductive capacities. They, however, produce enzymes (pancreas), hormones (adrenals), proteins (liver) and metabolize foodstuffs (liver, gut mucosa), excrete foreign substances (kidneys and sweat glands) or, indeed, initiate mechanical events (skeletal and cardiac musculature). Cell replication in adult somatic cell populations is tightly controlled and proliferation does not occur except under circumstances of injury or other metabolic conditions. However, in tumor systems, cell maturation does not occur and cell replication is uncontrolled, or certainly less controlled. In tumor cell populations, a percentage (although variable) of cells pass on through G, and reinitiate DNA synthesis. An at least partial control of tumor growth is apparent in G, phases. Through mechanisms that are only partially understood, many tumor cells pass out of the proliferating pool into a nonproliferating ("Go" or "resting" cells) pool. At least a high percentage of these "Go" cells retain the ability to re-enter the cell cycle at a future date, in response to poorly understood stimuli. This re-entry into the cell cycle is termed "recruitment." One of the potential mechanisms by which G~ cells enter the nonproliferating pool are suggested by Tannock's studies195,,9~ documenting both a metabolic and a kinetic gradient from the hypoxic central cells to the normally oxygenated periphery. Goldacre and Sylven67 have shown that even the central and apparently necrotic areas of experimental tumors contain clonogenic cells that can be transplanted and produce tumors in bioassay experiments. However, other investigations are needed to totally explain such nonproliferation in tumor cells. Negative feedback mechanisms on tumor growth related to tumor mass have been hypothesized'32 and reviewed recently. ~s6 Also poorly understood are the mechanisms of recruitment of the "Go" cells back into the proliferating pool. Other questions remain, such as: How is the duration of the nonproliferating state of a "Go" cell determined? Do these cells qualitatively or quantitatively differ from those of the G~ period? Does a gray zone in the distinction of these populations explain some of the observed very long intermitotic times? '75 As will become more apparent subsequently, these mechanisms represent some of the critical aspects for the future of adjuvant therapy. The cells that pass through G~ then enter S, or the phase of DNA synthesis. Thetriggering events for entry into DNA synthesis are not understood but correlate with changing concentrations of cellular enzymes. Many of these enzyme changes have been reviewed by Baserga." Both protein and RNA synthesis occur during the S phase, but the dominant molecular event is 14

DNA synthesis. During DNA synthesis, the standard diploid chromosome number (2N) is doubled to the tetraploid number (4N) before mitosis occurs. Interestingly, in many malignant tumor cells there is variation in DNA synthesis, and changes in ploidy result in chromosomal aberrations in daughter cells. Mechanisms involved in such genetic variation are not known but seem related to the frenetic, uncontrolled growth of many malignant tumors. After completion of DNA synthesis (i.e., 4N amount of DNA has been synthesized), cells enter a brief and poorly understood premitotic period (G2), where additional RNA and protein synthesis occurs. With organization of anatomically identifiable chromosomes, the prophase of mitosis begins and rapidly proceeds through metaphase. During metaphase, tubular proteins are synthesized and form the mitotic spindle. Anaphase ensues as chromosomes separate and telophase is the end point of cell division. The daughter cells then enter G, or may be variably lost into the circulation or enter the nonproliferating "Go" pool. CELL CYCLE DEPENDENT EXPRESSION OF TUMOR A N T I G E N S . B u r k e and Drewinko2~recently have studied the relative strength

of antigenic expression in a human neurosarcoma maintained in tissue culture. The tissue culture line was "synchronized" so that the entire population of cells was passing through the cell cycle simultaneously. Then sarcoma antisera absorption experiments were performed at all phases of the cell cycle. The fascinating result was that maximal antigenic expression (demonstrated by absorption of antisera) occurred in the G~ phase of the cell cycle. This observation would be in keeping with the general observation that the most sophisticated cell functions occur in the G, phase of the cell cycle. The relevance of this observation for combined immunochemotherapeutic regimens remains as a possible future avenue for treatment. CLONOGENIC VERSUS NONCLONOGENIC CELLS.--In most tumor systems, many thousands of cells must be injected to produce a tumor "take." It has been hypothesized that only a small percenta g e of the cells in a tumor actually are such "clonogenic cells" similar to the small number of stem cells in normal human bone marrow. Bersagel and Valeriote 14 found that only 4.4% of tumor cells in a mouse plasmacytoma were clonogenic, as compared to a much higher growth fraction. The implic/ttions of this finding are particularly significant in that it has been shown that only a small percentage of tumor cells that enter the bloodstream actually form metastases. ~s5 Obviously, cells must be clonogenic to form metastases but, as will be discussed, a more complex picture is present in the process of metastasis, for other selection factors influence this event. In summary, tl~en, the growth of tumors cannot be thought of 15

as an uncontrolled exponential doubling process. In fact, solid tumor growth slows as a function of increasing tumor volume. Metabolic and Po 2 gradients can contribute to this process, 1~'~,,gG but an inhibitory or negative feedback mechanism is also likely. ls6 These factors make the analysis of tumor cell kinetics in tumor growth a more complex problem than the outmoded concept of simple exponential doubling. Likewise, tumor cell popula' tions are asynchronously passing through the cell cycle. The concept of the "Go" or "resting" cell, a variable growth fraction, cell loss, clonogenic versus nonclonogenic cells, variations in intermitotic times and the cell cycle specific expression of tumor antigens are all important modifications of the previous simplistic model of tumor growth. All of these concepts interrelate with the basic rationale and limitations of cancer adjuvant therapeutic modalities. CANCER INVASION AND METASTASIS The unrestrained local growth of cancer cells is the most obvious gross event in the neoplastic disease history of an untreated patient. However, with the evolution of successful surgical extirpation of cancer, disease dissemination becomes the most significant cause of failure. Indeed, it is th.e failure of en bloc surgical resections, even with maximal extensions of the surgical perimeter, that has dictated the need for adjuvant therapy through interdisciplinary cancer care. Therefore, a brief review of the current status of the events of invasion and metastasis is clearly pertinent to a better understanding of the use of adjuvant therapeutic modalities. INVASION.--At the periphery of a growing cancer, tumor cells can be seen extending into adjacent normal tissues (Fig. 5). These microscopic fingers of invasion often extend well beyond the clinically apparent tumor margin. Some tissues, such as bone, fascia, nerves and arterial blood vessels are more resistant to cancer invasion and mold or direct cancer spread along adjacent tissue planes. Other factors correlated with invasion, such as increased tumor cell motility in vitro, '4r loss of contact inhibition, which results in tumor cells crawling over other tumor cells or normal cells in tissue culture, I and secretion of proteolytic enzymes, 192 m a y act in concert with these resistant structures in producing peripheral distribution of cancer cells. Importantly, these peripheral extensions of tumor induce neovascularization in m a n y tumor systems by release of an angiogenesis factor. 5s The host contributes a collagenous stroma. TM It is not clear whether stroma induction is an abortive host defense mechanism or whether it is an attempt of partially dedifferentiated tumor cells to develop an organoid microstructure.'The invasion of adjacent tissues is not 16

enIctivzt~r.Ilc,]

L~eTIc~ncn]lesion ,icati0ns sl~nglissnepl~n~s in lumnr d Sil~usoids

AL[XTEItSIQH$OXIC, I |RADII011

Fig 5 . - C a n c e r invasion and entrance into the bloodstream- T h r o u g h a number of possible mechanisms, cancer cells gain entrance to the bloodstream or lymphatics. Both cell characteristics a n d / o r the pattern of t u m o r vascularization influence this event.

unique t5 the neoplastic process. In fact, the release of an ovum, its circulation during which fertilization takes place, followed by the invasion of the endometrium by the trophoblastic component of the morula is not, conceptually or histologically, dissimilar from invasion and metastasis of cancer. Reich e t a l . 1~ have found that these events in the reproductive cycle correlate with enzymatic induction of high levels of plasminogen activator. Since plasmin is a proteolytic enzyme with broad substrate activity, it is tempting to speculate that invasion is facilitated by this enzyme. Studies in such model systems might help define the molecular events of invasion. Interestingly, Kleinerman e t a l . t ' ~ have found that tumor cells entering the veins of a tumor-bearing extremity have higher levels of plasminogen activator than do cells from the bulk of the primary tumor. This would suggest that they were selected by virtue of special invasive properties for entrance into the bloodstream. ENTRANCE

INTO THE

BLOODSTREAM

(see

Figure

5).-Many

tumor cells enter the bloodstream, as documented by Butler and. Guillino ~2 and as documented by m a n y bioassay experimentsY4, m , ~46 In fact, this may be a significant factor in calculat17

ing the cell loss fraction in the analysis of growth kinetics in a given cancer. It m a y be that the occult oat cell cancer of the lung, which presents with diffuse metastases, is shedding cells as fast as they are produced and therefore it m a y never appear as a clinically apparent primary cancer. All the factors correlated with tissue invasion can also contribute to the neoplastic invasion ofcapi'llaries, venules or lymphatics. Other factors, however, m a y also contribute. Of particular importance is the formation of tumorcell-lined vascular sinusoids in some tumor systems, as illustrated in Figure 5. Warren and Shubik 2~ showed that after initial neovascularization of an experimental melanoma, some necrosis occurred and tumor cells per se lined vascular sinusoids or lakes. These cells, in direct contact with blood, require no special properties for entrance into the bloodstream. Minor changes in tissue pressure or tumor manipulation would facilitate the release of large numbers of cells and cell clumps. In other models/47 increased tumor tissue pressure causes cells to enter between capillary endothelial c e l l s - a process termed intravasation. Some differences in the biologic potential of cells entering the circulation might be expected based on the prime mode of entry, i.e., the hypoxic central cells entering as clumps from areas of tumor-sinusoids versus the oxic, rapidly dividing cells entering vascular conduits by the process of invasion. Selection of cells at the primary site by such differing mechanisms of entrance into the bloodstream might well affect the eventual development of true metastases. The results reported by Kleinerman e t al. ~i~ suggert that some cells with high levels of plasmino.gen activators m a y be "selected" for entrance into the bloodstream by virtue of special proteolytic properties. Other selection factors obviously must be important. Particularly in cells near the hypoxic areas, attempting to replicate under borderline metabolic conditions, genetic defects commonly are seen. These areas of tumor growth may be "tidal pools" for neoplastic progression producing genetic variants with a greater potential for survival in the host when they are selected for metastasis formation. POTENTIAL

ADJUVANT

THERAPEUTIC

APPROACHES

T O I N V A S I O N . --

The molecular events of tumor invasion are not well understood. However, the identification and isolation of a tumor angiogenesis factor by Folkman 5s is of great interest. T u m o r cells have been shown to release a substance ( M W 70,000) that induces formation of capillary ingrowth from adjacent vessels. Possible development of an antiangioge'nesis antibody or of an inhibitor of angiogenesis factor has been suggested by Folkman. 5s It has been shown that the substance ICRF-159 "normalizes" abnormal tumor vessels and diminishes experimental metastasis formation, s3 However, the clinical use of this substance has not been very rewarding so 'far.a~ The use of antiproteolytic enzymes (Trasylol) 18

has been tried in an in vitro model system to reduce invasiveness, ''G but has not been used in clinical trials. The high levels of plasminogen activator in tumor cells released into the circulation ''~ make this potential use a riot totally unreasonable suggestion. Obviously there are other molecular events in tumor invasion, the inhibition of which eventually could be exploited as adjuvant therapeutic modalities for the control ofinvasiveness in distant micrometastatic foci. TUMOR CELL CIRCULATION.--The presence of viable circulating tumor cells now is known to be a frequent event early in the disease course; however, only a few select tumor cells form metastases. Since only a few cells are destined to form metastases, it is not surprising t h a t the simple observation of tumor cells in hum a n peripheral blood does not correlate with prognosis. 1c'4 The selection of tumor cells from the m a n y circulating cells is an imFig 6 . - T u m o r cell circulation. Tumor cells circulate in the blood, where most of them are killed. Only a few survive to form metastases. A number of theoretic and/or experimentally demonstrable phenomena may affect the selection of the few cells selected for true metastasis formation.

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portant dynamic factor in tumor biology. The circulation is a hostile environment for the circulating tumor cell, since most cells never survive to form metastases. ]64Those that survive m a y do so by virtue of altered antigenicity, 7~ ]79 consumption of cytotoxic antibody by free tumor antigen 3T and sublethal immune clumping, which promotes arrest of clumps in the capillary bed. 52 In some instances, survival m a y be an entirely random event in which clonogenic cells with a kinetic advantage rapidly divide in a distant organ system. These events in the selection of cells for true metastases are summarized in Figure 6. ARREST AND GROWTH OF 1VIETASTASIZING CEL~.--The process of arrest, entrapment, transcapillary migration and growth of metastases has been anatomically observed by Wood ~~ and is outlined in Figure 7. Single cells or small clumps first must adhere to the capillary endothelium. For some cells, this is a transi-

Fig 7 . - A r r e s t and growth of true metastases. As observed under phase cinemicroscopy, a series of events occurs after a tumor cell reaches the distant capillary bed. Again, only a few that reach this bed actually survive as metastases.

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tory event, and subsequently they are swept into the hostile circulation. Others are trapped in fibrin/platelet microthrombi. Subsequently, transendothelial migration occurs and cells begin to divide, induce capillary ingrowth and stroma, forming a new distant focus of neoplastic g r o w t h - t h e micrometastasis. Details of these events have been reviewed elsewhere, ls5 Interference with the process of metastasis is possible by anticoagulating experimental animals before tumor cells circulate, and has been proposed as an adjuvant to surgical resection. Since thrombocytopenia also inhibits experimental metastasis formation, 63 inhibitors of platelet adhesiveness have had appeal and clinical studies have been initiated. ~4s As at the primary tumor site, antiangiogenesis has been suggested as a possible future therapeutic modality. 5s K I N E T I C S OF MICROMETASTATIC GROWTH. - - A s shown previously, a large primary tumor m a y have a small growth fraction. On the other hand, the small micrometastasis is well provided with vessels and probably has a very high growth fraction, leG,172,~3 This may, however, be manifest only after removal of the large primary tumor. 1s6 Since these micrometastases are rapidly dividing, they are more susceptible to the effect of chemotherapeutic agents. This quantitative difference in the kinetics of the primary tumor versus the micrometastasis constitutes the basic rationale for adjuvant chemotherapy after surgical resection, for these small foci should be maximally sensitive to cell cycle specific chemotherapeutic agents. This difference in kinetics m a y persist even though the metastases grow in size. ~6s There are several other fascinating aspects ofmetastasis that are poorly understood. However, future studies of the phenomena of tumor cell dormancy, 1s2 organ selection of metastasis, ~46,1s~ metastasis from metastases Is~ and a deeper understanding of the inhibitory influence of the primary tumor on metastasis ~s6 m a y well uncover other mechanisms that can be exploited as future adjuvants to surgical treatment.

IMPORTANCE

OF CELL SELECTION IN METASTASIS F O R M A T I O N . -

The establishment of a true metastasis represents the end stage of several highly selective processes. B y virtue of special invasive properties u~ or their juxtaposition to vascular lakes in the primary tumor, 2~ some cells are selected for entry into the circulation. In the blood or lymph, most cells are destroyed. A few selected cells (which must also be "clonogenic") adhere to the capillary endothelium and penetrate into the extravascular spaces. Those that are clonogenic are further selected by their angiogenic and stroma-inducing capabilities for the development of a true metastasis. In the primary tumor, the central areas of borderline vascularity near areas of necrosis ~nay be the "tidal pools of neoplastic evolution" where many genetic mutations occur. The selective 21

events may, in effect, clone the "fittest" cells for true metastasis formation. The severe prognosis associated with small recurrent tumors, even though apparently localized, may relate to the selection of such "super cells" for metastasis formation. The selection process, therefore, may result in metastases with properties different from the primary. Such differences could also be exploited therapeutically and therefore are the goal of much current research. THE CENTRAL THERAPEUTIC PROBLEM DEFINED.--This brief review of the process of neoplastic tumor growth, invasion and metastasis has provided several potential mechanisms for tumor destruction. Since the surgeon is asked to treat patients whose cancers already are established, the subclinical tumor dissemination is a fair accompli in a statistically predictable percentage of patients, based on clinical disease staging. Therefore, measures to absolutely prevent tumor dissemination are impractical, for this event already has occurred at the time of clinical diagnosis. Therefore, the cancer treatment team must address itself to the therapy of distant and/or local-regional subclinical metastases. Therapeutic modalities with a ubiquitous scope of efficacy are needed. Any basic biologic differences between primary tumors and metastases must be exploited to therapeutic advantage. Such differences currently are (1) the higher growth fraction and therefore greater drug sensitivity of micrometastases, (2) the better vascularity and better oxygenation of micrometastases, which establishes radiosensitivity, and (3) the lesser antigen burden present after removal of the primary tumor mass by surgery. Other differences, either qualitative or quantitative, may find future applications.

CHEMOTHERAPY: BASIC PRINCIPLES AND ADJUVANT APPLICATIONS EARLY OBSERVATIONS The early applications of chemotherapeutic agents to cancer stemmed from the World W a r II accidental use of the mustard gases,~,,,56 although as early as 1919 the profound effect of rnus9tard gas on bone marrow had been noted. '~ In 1955, a comprehensive drug synthesis and screening program was initiated by the N C I T M and the efficacyof animal systems for preclinical testing of drugs was established thereafter.6s,69 The basic methodology was truly empirical, with laborious trial and error schemes in the clinical area. Subsequently, the basic modes of action of most of the effective chemotherapeutic agents have been elucidated and it is the tylJe of interaction with cell kinetics and metabolism that establishes the basic classification of these drugs (Fig. 8). 22

VINCA ALKALOIDS.... [MITOTIC INHIBITORS)

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ANTIMETABOLITES

L-ASPARAGINASE TRIAZ[N( DERIVA11VES[011C) HORMONES-?]GROWTH FRACTION [inhibits protein synthesis) Fig 8.--Classification of drugs based on interactions with the cell cycle. Drugs may act in all phases of the cell cycle and therefore are termed non-cell cycle specific. Other categories, which include the antimetabolites and the mitotic inhibitors, interact specifically in certain phases of the cell cycle. The differing sites of interaction form a central philosophy for the combination of drugs for increased oncolytic effect.

Zubrod~H. 212 has emphasized that one of the earliest clinical observations in the therapy of cancer was that the most rapidly growing tumors were the most sensitive to chemotherapeutic agents. Indeed, the cancers that are curable with single chemotherapeutic drugs are those with high growth fractions and grossly measured doubling times of only a few days. These, in man, are choriocarcinoma and Burkitt's lymphoma (Table 3). This kinetic clue was rapidly investigated and the importance of tumor cell kinetics and drug effect rapidly expanded. 16G,173 23

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chemotherapeutic modalities. Initially, single drugs were screened for efficacy in a wide variety of tumors and a response percentage obtained. A rigid definition of"response" requires that all measurable lesions diminish in size by 50% or more and no disease progression occur. Combinations of drugs increased the response percentage and, importantly, markedly increased the numbers of complete responses. When no tumor exists after a complete response, the important parameter for measurement is the response duration. The response duration is a measure of the success in managing a micrometastatic or subclinical population. Consolidating drug combinations, maintenance drugs and changes in drug regimens have been applied during this period of treatment for subclinical disease, in hopes of eventually treating this phantom disease predictably present in a statistically defined percentage of patients. The postoperative use of adjuvant drugs begins at the point of the chemotherapist's complete remission. Surgery rapidly effects the removal of all identifiable tumor, yet the subclinical disease persists. The interdisciplinary team must concentrate on treating this statistical shadow-subclinical disease. Since this population is kinetically different from the primary, better drug efficacy is to be expected. These concepts are represented in Figure 9 and demonstrate that the postoperative patient essentially starts from the point of a complete remission after primary chemotherapeutic response. HORMONES

It now is well established that the growth of some breast and prostatic cancers is at least hormone dependent. Hormone withdrawal in premenopausal women or additions of hormones in postmenopausal women can cause significant disease regressions. Adjuvant use of hormone manipulations, based on in vitro analysis of estrogen receptor activity, l~s has been proposed and will be discussed in more detail under the section on breast cancer. It has been suggested that the kinetic effects of hormones are to establish a larger "Go" or "resting" population, which could interfere with the action of combination chemotherapy by reducing the growth fraction. No clinical proof is available for this concern. LIMITATIONS ON CHEMOTHERAPY BY FIRST-ORDER KINETICS AND THE GROWTH FRACTION

The administration of a given drug or drug combination reduces the existing cancer population by a constant percentage. TM This means that there always will be a theoretic lower limit of any drug effect or, alternatively stated, some cancer cells theoretically always will survive chemotherapy alone. For instance, a 129

cm nodule m a y contain approximately 10 ~ cells. An effective combination of drugs is given to this nodule, which has a growth fraction of 100% and which kills 99.99% of the cells. Thus, this drug therapy has effected a four log kill, leaving yet 10 ~ remaining cells for regrowth. Host defenses, or tumor immunity, have no such lower limit of efficacy, and presumably this is why so many cancer operations are truly effective. However, in model systems such as the L-1210 leukemia, this effect of firstorder kinetics is readily quantifiable. 173Likewise, the growth fraction is of critical importance. Nondividing or resting cells are more resistant, even to the alkylating agents, and totally resisFig lO.-Cell cycle specific chemotherapy-cancer of the cervix. If the specific events of the cell cycle for a given tumor can be obtained, it is possible to administer chemotherapeutic agents so that they interact with specific aspects of the cell cycle at the appropriate times. Development of such cell cycle specific drug combinations is the goal of much current research. ( ~ VIN.CRISTINE KILLS CELLSTHAT

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tant to cell cycle specific agents. Therefore, the poorly understood factors controlling the growth fraction of tumors are of critical importance. CELL CYCLE SPECIFIC CHEMOTHERAPY. -- A special application of drugs may improve therapeutic results. The cell cycle is composed of a series of discrete time-limited events m (see Fig. 4). Since chemotherapeutic dru~s interact .in specific phases of the cell cycle, it is theoretically possible to time the use of drug combinations to obtain maximal effect. As Zubrod2~2has stated, there probably is no class of pharmacologic agents in which the therapeutic effect is so influenced by the time-dose scheduling. Specifically timed combinations based on kinetic analysis have been termed cell cycle specific chemotherapy. The details of such a program for the management of squamous cell carcinoma of the cervix have been reported by Averette et a l / a n d are summarized in Figure 10. First, methotrexate is given by infusion into the regional arterial supply. It is given for 96 hours based on an autoradiographic analysis of the cell cycle kinetics of the carcinoma of the cervix. Cells in S are killed by inhibition of DNA synthesis. In addition, cells in other phases of the cell cycle cannot enter DNA synthesis and therefore "back up" at the G~-S interface. Second, leucovorin rescue reverses this G~-S block and the cycled cells enter DNA synthesis. 6~In the third step, hydroxyurea, which has its specific cytotoxic effect on those cells flooding DNA synthesis, is administered. In the fourth step, vincristine is given some 8 hours later to produce mitotic arrest of any cells that escape the cytotoxid effects of hydroxyurea during DNA synthesis. With repetitive cycles of this cell cycle specific combination, "Go" cells should be recruited into the cell cycle and thereby become amenable to therapy. Averette et a l / h a v e demonstrated improved disease regression and survival using this approach. It is likely that future refinements in the use of adjuvant chemotherapy will utilize kinetic analyses of tumors and tailored cell cycle specific combinations of drugs. ~~ ~gs

RADIOTHERAPY: BASIC PRINCIPLES AND APPLICATIONS DETERMINANTS OF TUMOR RESPONSE TO RADIATION THERAPY

An older concept in therapy categorized some tumors as radiosensitive and others as radioresistant. A corollary of this concept was that a given cancer had a specific cancericidal dose of radiation. These concepts no longer are valid in the original sense. Strandqvist ~7 and later Fletcherz5 correlated clinical responses with the delivered dose in rhds. A sigmoid dose response curve 31

was demonstrated (Fig. 11). Therefore, since an increasing dose in rads correlated with better cancer cure, the concept of a specific cancericidal dose was dismissed. Additionally, it was found that larger tumor sizes required higher doses for control. 8,55 Therefore, contrary to earlier beliefs, the response of h u m a n cancers to irradiation therapy was both dose and tumor size dependent. In vitro radiobiologic investigations confirmed the fact that the number of tumor cells was important in the response to radiation therapy. These investigations documented the fact that the relative degree of oxygenation of tumor cells influences the radiation ki11.55, 56 As tumor size increases, the central regions of a tumor become hypoxic; therefore, radiation resistance in the hypoxic core of cancers is the reason for the failure of even high doses of radiation to cure bulky cancers. The growth fraction and, to a lesser extent, the intermitotic time (Tr of a given cancer are also important in assessing the timing of the observed "shrinkage" or response after radiation therapy. The ionizing radiation works by creating lethal injury to the cell genome (DNA). The lethality of this injury m a y not be expressed until the cell attempts to synFi9 11.-Determinants of the therapeutic ratio in radiation therapy. The susceptibility of tumors to radiation therapy and also the injury of somatic tissues are influenced by several determinants. The relationship of tumor response to tissue injury has been termed the therapeutic ratio and can be manipulated to the patient's advantage through the understanding of these determinants as illustrated.

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thesize DNA or proceed into mitosis. Therefore, i f a tumor, is composed largely of"Go" or "resting" cells, a dramatic effect on tumor size m a y never be seen, or m a y occur only very slowly as thin nondividing population is recruited back into the active cell cycle. Once back in the cell cycle, an attempt to synthesize DNA-or perform other metabolic functions m a y r e s u l t in immediate death or several generations of daughter cells may be produced before the radiation damage is expressed by tumor shrinkage. Another important consideration in assessing the "radiation shrinkage" of a given clinical cancer is the stromal component of the cancer. Many scirrhous lesions contain much collagen, which must be cleared before shrinkage will be observed. The apparent responsiveness of the rapidly growing and highly cellular anaplastic tumors to radiation therapy and the "resistance" of the slower growing and scirrhous tumors is explainable in part as it is related to these differences in growth fraction and stromal component. Another determinant of the response to radiation therapy is dose fractionation. 8 After a given dose of radiation therapy, a certain percentage of cancer cells and normal cells are killed or damaged. Radiation damage initiates a cycle of repair in both tumor cells (termed repopulation) and in normal tissues (repair). In addition, since the cells at the tumor periphery are the wellvascularized and oxygenated cell populations, they are most sensitive to radiation therapy and a large percentage of these cells are killed. With their death, the tumor shrinks and its periphery is reva:~cularized by capillary ingrowth, making another layer of tumor cells more sensitive to radiation. Thus, dose fractionation allows for "reoxygenation" and increases the susceptibility of cancer cells to radiation therapy. It is difficult to predict from experimental work what is the optimal dose fractionation of a given tumor. In clinical practice, it has been determined that standard dose fractionation is 200 rads per day, 5 days per week. 55, 5G THERAPEUTIC RATIO (SEE FiR. 11)

The determinants of injury to normal somatic tissue are identical to those that specify the therapeutic tumor response, i.e., (1) dose of x-ray therapy delivered, (2) state of oxygenation, (3) growth fraction and (4) dose fractionation. In addition, the volume of tissue irradiated is important, probably because damage to blood vessels that leads to thrombosis can add injury to the established radiation damage. Any demands on the clonogenic potential of normal somatic tissues, such as is incurred with a surgical incision or infection o r with chemotherapeutic drug usage, can accentuate the damage to somatic tissues. As in tumor cells, often the lethal effect is not seen dntil the cell attempts to divide. Simi33

larly, the mitotic demands of wound healing may initiate a process of necrosis in the irradiated field. The central goal of radiation therapy obviously is to control cancer while somatic tissue complications are kept to a minimum. This cure-to-injury ratio has been termed the therapeutic ratio (see Fig.ll). Special techniques such as the "shrinking field of Baclesse, ''8 wherein the port size gradually is decreased as the tumor size diminishes in response to therapy, reduces the volume of tissues receiving high radiation doses. Interstitial implants of radium or other radioactive material can boost doses to small residual tumor masses after conventional dose limits have been reached in surrounding tissues. Electron beam technique can focus radiation effect in superficial tissues and cobalt gamma rays tend to spare skin while more densely irradiating deeper structures. Rotational techniques can be used for pelvic cancers, minimizing the dose of radiation therapy to noninvolved pelvic organs. ADJUVANT RADIOTHERAPY: THE TUMOR PERIPHERY AND SUBCLINICAL DISEASE

Since key determinants of radiation responsiveness are the degree of oxygenation and the number of tumor cells to be killed, it is at the well-vascularized/oxygenated tumor periphery that moderate doses of radiation therapy have maximal tumoricidal effect. These peripheral fingers of invasion a#e the aspects of the ncoplastic process that most frequently defeat the surgeon. In adclition, these cells are more likely to be released at the time of operation into the open lymphatics or into the systemic circulation. Thus, the addition of radiation therapy to surgery has been proposed to effect a better control of the primary cancer and, to a lesser extent, reduce the implantability of cells locally or in distant organs25 In addition, a ~'tumor bed effect" has been shown to diminish the implantability of normal tumor cells when injected into an irradiated field. ~7 Subclinical disease deposits, which have high vascularity/oxygenation and which obviously are small in size with a high growth fraction, should be very sensitive to moderate doses of radiation therapy. Experimental data substantiate this concept j69 and, most important, extensive clinical observations show that doses of 4500-5000 rads delivered in 41/2- 5 weeks (standard fractionation) control greater than 90% of predicted subclinical regional nodal metastases in breast cancer and squamous carcinoma of the head and neck. 55,56 Fortunately, it is quite possible to operate after doses in the 4000-5000 rad range (assuming that they have been given with standard fractionation) without incurring any increased morbidity, particularly since the surgical pro34

cedure can safely be modified through the use of thicker skin flaps, etc. This modification in the extent of surgery is possible because radiation therapy has controlled regional subclinical disease extensions. In addition, in highly selected disease categories, a less extensive surgicalprocedure may indeed be possible with radiation control of subclinical disease extensions. The use of wide local excision plus regional irradiation for the t r e a t m e n t of soft tissue sarcomas has greatly reduced (but not entirely eliminated) the need for major amputations, ls7 In addition, it has been demonstrated that wide excision plus regional irradiation produces the same survival statistics in early-stage breast carcinoma (using strict and appropriate staging criteria) as do the standard radical surgical procedures. 84Thus, if one is to argue for one form of t r e a t m e n t versus another in breast cancer, it must be based on the relative morbidity of the techniques rather than on their cure statistics. The cosmetic result after the combined therapy in breast cancer certainly seems more acceptable. An additional application of "adjuvant" radiation therapy is in the conversion of irresectable cancers to resectable ones by preoperative radiation therapy. 3, s7 Some inoperable rectal cancers, by virtue of posterior fixation, or head and neck cancers, by virtue of extensive involvement, can be shrunken by radiation therapy, which removes the well-vascularized periphery, and excision is possible after moderate doses ( 4 0 0 0 - 5 0 0 0 rads). Whether cure statistics can b e improved by such "conversions" remains to be demonstrated. PREOPERATIVE VERSUS POSTOPERATIVE RADIATION THERAPY

Should radiation be given preoperatively or postoperatively remains a topic of discussion. The advocates of preoperative therapy believe that any tumor cells released at the time of operation m a y be less able to establish distant foci of metastatic growth. However, the opposite concept is that these micrometastases already are established, go that the advantage of preoperative therapy is not significant2 TM The use of radiation therapy after the surgical wound has completely healed possibly lessens the effect of radiation therapy in impairing wound healing and may reduce postoperative complication rates. In our hands, these decisions are based largely on the projected extent of the surgical procedure, for, when long mucosal suture lines will be required in reconstruction, we prefer postoperative radiation therapy after the wound had healed. However, because some cancer cells could be trapped in oxygenated scar tissue postoperatively, some radiation therapists deliver 6000 rads in 6 weeks postoperatively versus t h e 4 5 0 0 - 500.0 rads given preoperatively. The higher postoperative dosage m a y interfere'with wound healing. 1~ 35

LIMITING FACTORS FoR ADJUVANT RADIATION THERAPY Unfortunately, the effect of radiation therapy on host tissues is permanent. Mature cell populations of somatic tissues may have sustained a lethal injury, which can result in necrosis many years later when minor trauma stresses their clonogenic potential. Additionally, the oncogenic effects, although not frequent, have been well documented and constitute a lifelong risk in the cured adult cancer population. '3s Ifwe become successful in curing a large percentage of our current high-risk malignancies, these late effects will greatly increase in significance,m Another limiting factor is the potentiation of irradiation effect by chemotherapeutic agents, particularly the antibiotics. Severe toxicity can result from combinations of radiation therapy and adriamycin or actinomycin D. 197 Radiation also has an acute and lasting effect on T cell populations, 29. 176 suggesting that an immunosuppressive effect may be present. Indeed, postoperative radiation therapy in breast cancer patients may diminish 3-year survivals.176 Combinations of radiation and surgery are further limited by the fact that the net therapeutic goals are only in the local-regional area. Systemic subclinical disease extensions are not approached by this treatment, and, if antibiotics are indicated for systemic disease control, seuere local tissue toxicity may result.

"IMMUNOTHERAPY" OR "'IMMUNOMODULATION" BACKGROUND It is known that many experimental tumors contain tumor antigens and that exposure to these antigens protects the animals from subsequent tumor inoculations. The hope that human host immunity to cancer could be used therapeutically, however, has not been realized to the extent of our initial expectations. The immune response and the regulation of it in man has provedto be an extremely complex mechanism, to the extent that therapeutic manipulation has been difficult to establish and, so far, has been impossible to monitor effectively26 Nevertheless, the concept of immunotherapy, even if premature in its application, has a solid scientific foundation. Therefore, we will attempt to briefly categorize various types of immunotherapy and explain their rationale: (1) tumor transplantation antigens do exist, at least in rodent tumor model systems, and specific cell-mediated cytotoxicity to tumors can be demonstrated; (2) these antigens probably also exist in human neoplasms'4~ (3) as tumors increase in size, anergy frequently develops in the human, i.e., the ability to develop any cell-mediated immune reactions is lost. The presence of anergy in man denotes a poor prognosis, even though the lesion is resectable by standard surgical criteria. 29,4G.202 Other correlates of this 36

anergic state are suppressed T cell counts and loss of lymphocyte and macrophage functions as monitored in vitro. 2~ These depressed immunologic functions can, in some patients, be reversed by surgical excision of the tumor. 46The specific approaches in the current field of"immunotherapy" relate to these general concepts in tumor immunology. SPECIFIC IMMUNOTHERAPY Tumor cells or vaccines produced by extracting tumor antigens have been used in an attempt to augment the destruction of cancer. In malignant melanoma, Zeigler et al. 2~ have demonstrated a common tumor antigen that elicits a cytotoxic antibody response and they have developed extensive experience with specific immunotherapy in malignant melanoma. NONSPECIFIC IMMUNOTHERAPY A number of bacterial agents can greatly stimulate the reactivity of the immune response. Initially, the use of Coley's toxin attempted to exploit this type of immunostimulation. Currently, BCG (bacillus Calmette-Gu~rin)in many forms, including a methanol-extracted residue of BCG (MER), is in widespread use as a nonspecific immunostimulant. The hope is that the anergy of patients with advanced cancer can be reversed by this type of nonspecific immunostimulation. C o r y n e b a c t e r i u m p a r v u m is another bi~cterial preparation that produces nonspecific stimulation of the immune response. It has been difficult to explain exactly how this type of stimulation might affect tumor cell destruction, since there is no antigenic similarity between the stimulants and the tumor. However, it is possible that reconstitution of the iramune response by stimulation can result in the eventual development of immune reactivity toward the tumor antigens per se. In addition, stimulation of maerophages, which are the nonspecific arm of the immune response and the site of initial antigen production, may indeed be the most important effect of nonspecific immunostimulation. Activated or "killer" macrophages are the most destructive cells known in biology, 'and they react to a broad spectrum of biologic materials, such as senescent red cells, white cells, bacteria and foreign particles of all typos, including coal tar and inhaled microparticles. When stimulated, they may recognize and react to tumor cells. ADOPTIVE IMMUNOTHERAPY I t i s possible to sensitize other species or other individuals to tumors and then retransfer these oncolytic products back to the 37

patient afflicted with cancer. A transfer factor ''2 should confer the donor's immunity to the patient with cancer; clinical trials so far have been negative. Sensitized lymphoid cells have been used, but a difficulty here is in the transplantation differences that result in rapid cell destruction, except with identical twins. Immune R N A fractions have also been used for adoptive immunotherapy experiments.39 At present, all of these cumbersome techniques are in an experimental stage only. AGENTS THAT RECONSTITUTE THE ANERGIC IMMUNE SYSTEM OF THE CANCER PATIENT "

Two substances, levamisole and ihymosi n, stimulate T cell populations. Thymosin is a thymic hormone that causes precursor T lymphocytes to become functionally mature lymphocytes. This hormone can increase T cell levels in patients whose T cell level has been suppressed by radiation therapy or by a large cancer burden. Levamisole is an anthelmintic substance that also has a biologic activity in stimulating T cell production. Preliminary studies suggest an improvement in cancer therapy results and are part of several current treatment protocols. The role of immunotherapy remains to be defined. A recent comprehensive review of the results of immunotherapeutic protocols nationwide left many unanswered questions and no definite positive therapeutic results stand out. In all studies, questions about patient selection, completeness of staging, etc. have plagued the analysis of end results. Precise randomized studies by interested investigators with accurate clinical and experimental monitoring willbe required to evaluate the therapeutic place of these various types of immunomodulation. It is possible that tumor immunology will remain a fascinating expression of tumor biology but will not become a therapeutic tool..

DEVELOPMENT OF ADJUVANT THERAPY PROGRAMS FAILURE PROFILE

The question now arises: How to best design adjuvant therapeutic programs? The most important treatment standard is patient survival and, indeed, all therapies must stand this ultimate test of success. However, the survival criterion ignores the fact that a disease may have recurred and been re-treated successfully. In addition, it ignores the prolonged survivals of some patients with k n o w n recurrent disease. For the common malignancies that afflict the older, population, survival from the cancer under treatment must be assessed against a background of diseases that 38

TABLE 5 . - F A I L U R E PROFILE AFTER STANDARD THERAPY 1. 2. 3. 4.

Local recurrence Regional lymphatic metastasis Systemic metastasis New primaries

NovE: After standard surgical management, a percentage of patients fail treatment. An analysis of the sites and timing of treatment failure is extremely important for planning an improved interdisciplinary cancer treatment. If local recurrence is the salient failure, irradiation and surgery may be optimal. If systemic metastases are the rule, combinations of surgery and chemotherapy may be indicated.

affect many other organ systems and make survival a relatively obscure end point for evaluating a cancer therapy program. Therefore, a careful analysis of the sites and timing of failures after initial treatment, which we have designated the failure profile (Table 5), can provide the best guideline for analyzing treatment results. In addition, as one looks at the failure profile after standard traditional therapy modalities, one can see the areas for which new approaches must be added to effect total cure. As indicated in Table 5, the cancer can fail by breaking through locally, into regional lymph nodes and lymphatics and into the systemic circulation. An important dimension also includes the formation of new primary cancers, after cure of the initial disease. If local recurrence is the central reason for treatment failures, a',combination of surgery and radiation therapy m a y provide better local-regional control than surgery alone. This is the case with low-grade fibrosarcomas of soft tissues and in patients with neck metastasis from squamous cell carcinoma of the head and neck. If systemic metastasis is the central reason for failure, surgery m a y combine best with chemotherapy in order to control widespread subclinical deposits of disease. In breast cancer and other cancers, the combination of surgery and chemotherapy seems most promising if systemic metastases are a significant part of the failure profile. For most common cancers, both local recurrence a n d s y s t e m i c metastases represent the prevalent type of failure. It is possible that appropriate chemotherapy will be able to manage local-regional failure as well as systemic subclinical disease. Alternatively, in some neoplasias we m a y find that surgery plus radiation therapy is important for local-regional control whereas chemotherapy is needed for systemic disease. The problems of combining some types of chemotherapy with radiation therapy have been discussed. Failure profiles for ascending clinical stages of a given cancer often are quite different. Another ill-defined variable, which has been termed the "biologic potential" or the tendency for dissemination related to 39

the size of the tumor, also influences the planning for adjuvant therapies. RANGE OF THERAPEUTIC EFFECTIVENESS OF EACH MODALITY

In addition, it is important to consider what the efficacy of each modality is in planning adjuvant therapy programs. Excision works well for bulk disease whereas it fails to control the subclinical periphery or the micrometastases in distant organs. Radiation therapy can add to local regional control but is a poor agent for the central hypexic core of large tumors except at extremely high doses. Chemotherapy is effective for small deposits of cancer with a high growth fraction and, therefore, is most effective against either the "liquid" cancers or the systemic subclinical disease, metastatic from the common solid tumors. The spectrum of efficacy of immunotherapy is as yet difficult to define. Certainly gross spontaneous regressions of cancer have been noted,4s but, on the other hand, in experimental tumor systems only one or two logs improvement in kill can be expected with immunotherapy. Therefore, probably one must be working under the 10~ cancer cell burden for this to be effective. CONTROLLED STUDIES: HISTORICAL CONTROLS VERSUS RANDOMIZED STUDIES

With the nearly infinite number of therapeutic possibilities for any given cancer, it is important that logical thinking dictate the initial planning of adjuvant therapy programs. Significant questions must be asked. Even if all eligible patients are entered into protocols, there still will be insufficient material within the next few years to answer all the potential questions. Therefore, design of studies is extremely important. For certain types of cancer, such as those that carry a completely hopeless or nearly hopeless prognosis, the historical data base for the results of therapy is so strong that it is our belief that randomized studies need not be undertaken. However, when one is attempting a more modest improvement in statistics from, say, a 50% survival to 80-100% survivals, randomization of study groups is extremely important to ensure the pertinence of the clinical results. The potential benefits of all added modalities must be carefully weighed against toxic effects. Informed patient consent is necessary before randomization can be carried out. Unnecessary morbidity without reasonable chance for benefit must be avoided by careful peer review of all protocols. It is hoped that, with these principles in mind, major inroads on the cancer disease statistics can be made over the forthcoming decade, through the design and execution of interdisciplinary treatment protocols. 40

MALIGNANT TUMORS OF CHILDHOOD WILMS' TUMOR

The first convincing demonstration of the value of adjuvant therapy came from the use of combined modalities in the treatment of Wilms' tumor. Surgery alone salvaged only 17-23% of cases.'~ Farber~~showed that surgery plus actinomycinD chemotherapy and irradiation to the nephrectomy bed dramatically improved these statistics if no distant metastases were present. Even with metastases, a 50% survival was obtained with combined modality treatment.5~Vincristine was also found to be effective, and Sutow's9 combinedthis drug With actinomycinD and projected a 90% cure rate in localized Wilms' tumor therapy. The National Wilms' Tumor Study Group has broad affiliations with most of the major cancer centers participating and contributing patients, This group is attempting to refine treatment programs to reduce the toxicityofcombinedradiation therapy, surgery and chemotherapy.3s For instance, they have shown that postoperative radiation is not of demonstrable benefit in patients with small tumors confinedto the kidney, and especially in the very young patient. The late sequelae of combined radiation therapy and chemotherapyare severe,and since both moda]ities are not necessary,this findingis extremely important.'~, ,9, This group is also studying the possible adjuvant benefitsof adr!amycin,especially in patients with advanced disease on presentation.38 The initial~application of combined therapy, progressive improvements ~{ndrefinements with evolving experiencein this disease will, it is hoped, be a mode] for progress in the interdisciplinary therapy of the solid adult neoplasms. EMBRYONAL RHABDOMYOSARCOMA

This lesion, which is one of the three most common malignant neoplasms of childhood (about equal in incidence to that of Wilms' tumor and neuroblastoma), is the most frequent soft tissue tumor of childhood. Survival statistics after surgical excision or combined surgery and irradiation have been unacceptably low. The Children's Hospital in Cincinnati reports a 28% 2-year survival. Sutow et el. .9~ reviewed 78 children wit}, this disease seen at the M. D. Anderson Hospital between 1946 and 1966, and only 47% and 35% survived 2 and 5 years, respectively. A multicenter approach was initiated in November of 1972, with the Acute Leukemia Group B, the Children's Cancer Study Group and the Southwest Oncology Group joining forces to pool patient material. Analysis of the failures in previous series 42, ~2, ,49 allowed for the development of a staging system for this group's comprehensive 41

activities. Stage I patients were those with completely resectable localized disease without evidence of regional node metastasis. Most of these patients are under 2 years of age. Stage II constitutes a group with regional disease who have positive regional nodes or microscopically positive margins after surgical resection or invasion of adjacent organs. Stage III are those patients with distant metastases or gross disease remaining after operation. Between November of 1972 and the Spring of 1976, 265 cases were available for analysis. 8~ Stage I patients were treated with excision or irradiation plus vincristine, actinomycin D and cyclophosphamide (VAC). Ninety-two per cent in both groups remained without evidence of disease. Therefore, it is possible that irradiation therapy can be eliminated in the future. Stage II patients received surgery and radiation therapy plus vincristine and adriamycin intensively for 1 year or the entire VAC protocol less intensively for 2 years. Both groups had an 85% disease-free s'tatus at 2 years. Stage III treatment combined all modalities ail~adriamycin was added on a randomized basis. Much improved results were obtained, even in these advanced disease stages. :.Thus, in' this aggressive neoplasm of childhood, marked improvement in survival utilizing adjuvant therapy has been a~tiieVed. What remains to be demonstrated is the accomplishment of 100% survival statistics and the minimization of toxicity and long4erm effects Ofthe treatment program.

N ' EUROBLASTOMA On the other hand, neuroblastoma has been refractory to adjuvant therapy. A randomized study that utilized C y t o x a n - t h e best single drug in the treatment of neuroblastoma-showed no beneficial effect when used in the adjuvant setting. 4~

SARCOMAS Comprehensive generalizations about this; heterogeneous group of tumors are not possible. Sarcomas are characterized by their propensity for early and explosive lung metastases. Surprisingly, most patients with osteosarcoma and soft tissue sarcoma do not have identifiable metastatic disease at the time of initialpresentation. After surgical resection, however, early explosive pulmonary metastases occur in many patients and one must ~ k whether or not the surgical procedure produces or accelerates the growth of established distant micrometastases. Currently, adjuvant therapy relies on chemotherapeutic and/or immunotherapeutic methods. 42

OSTEOGENIC SARCOMA

FAILURE PROFILE.--The failure profile in this disease after standard surgical resection has been reviewed in detail.'~176 ,0,, ,52 By 24 months after amputation alone, 80% of patients develop metastases and by 36 months 80% are dead of their disease. A prominent site of metastases is the lung, for only 5% of patients die with only extrapulmonary sites of metastasis. For the planning of adjuvant therapy, it should be emphasizedthat extrapulmonary metastasis accompanies lung metastasis in more than 30% of patients, so that one cannot focus solely on the lung to improve survival statistics. Indeed, it has been demonstrated that prophylacticwhole-lungirradiation had no benefit when it was used as an adjuvant to surgical amputation.TM EFFICACY OF CHEMOTHERAPY AND ADJUVANT APPLICATIONS.Grossly metastatic osteogenicsarcoma was noted for its remark-

able resistance to the entire spectrum of chemotherapeutic agents until the introduction of the drug adriamyein.3' This drug produced a 35% response rate. Subsequently,the use of high-dose methotrexate with leucovorin rescue produced abouti~the same 35% response rate in grossly metastatic osteogenicsarcoma.6', 99 With more frequent sched.ulingof HDMTX-rescue therapy, the response rate was increasedto 85%.'ooAdjuvant use of these drug programs has been init{ated and preliminary results show an improvement in 2ryear survival to 80%.'~176 Rosen et/ai. '59 have combinedadriamycin and HDMTX-rescue,along with Vincristine preopel~atively, ancladded cycloph0sphamideto these three drugs in the postoperative adjuvant setting. The preoperative adjuvant therapy causes Sh1:inkage of the primary tumor, and ]0ng bone excision with prosthetic replacements rather than Complete amputations has been made possible.'5s The postoperative adjuvant therapy effectivelycontrolsboth local and systemic.subclinical disease, so that recurrences have been infrequent.'5s, !59 Even in patients with lung metastases on initial presentation, a large percentage apparently are cured by these programs plus resectionof any residual pulmonarymetastases.'2 ~ Because of the explosive pattern of early postoperative lung metastasis, many efforts have concentrated on reversing the dissemination~of tumor cells by surgical biopsy and/or surgical resection itself. Therefore, small groups of patients with osteogenic sarcorna have been treated with massive preoperative irradiation3 (I0,000 fads) or intra-arterial,adriamycin infusion with or witho[it irradiation therapy.:42I n t h e latter group of patients, preoperativeshrinkage of the tumor may have allowedfor some more limited tumor resections followed by allograft bone replacement. Immunotherapyhas.also been used in the management of osteogenicsarcoma,~but theresults are not clear at this 43

point. The immediate future in the adjuvant therapy of osteogenic sarcoma should see refinement in the numbers of drugs utilized and in their time-dose scheduling. Conservative surgical resections likely will become an integral part of their m a n a g e m e n t in the interdisciplinary cancer t r e a t m e n t erm EWING'S SARCOMA Combination chemotherapy plus radiation therapy for local control has changed completely the prognosis in Ewing's sarcoma. Historical data indicate that only 5 - 2 5 % of patients are a l i v e at 2 years, and with combination chemotherapy 80% are alive at 2 years. 77, 97, 98 This lesion no longer is considered a surgical problem except for the establishment of a biopsy diagnosis. SOFT TISSUE SARCOMAS FAILURE PROFILE.--The resection of any one tumor of this heterogeneous group of lesions has been attended by high local recurrence rates. In a detailed analysis from Memorial Hospital, Cantin e t al. 25 found local recurrence in 3 9 - 77% of patients after resection. This observation has tended to support more radical and extensive surgical procedures in an attempt to improve this unfortunate statistic. However, in another retrospective review that partially overlapped this same group of patients, Shiu e t ~al. 17~ found that the tissue type, histologic rate of malignancy, t u m o r size and location were in fact more important prognostic determinants than was the extent of the surgical procedure. Suit e t al. ~87 have made similar observations regarding the effect of histologic degree of differentiation, tumor size and tumor location on prognosis. These and other prognostic variables have been welded into a staging system that should bring more uniformity to the interpretation of therapeutic results in this heterogeneous group of tumors. ~ Distant metastases to the lung also follow the same prognostic factors and account for more deaths than do local recurrences. ADJUVANT RADIATION THERAPY.-Since local recurrence is such a prominent reason for failure, combinations of surgical and adjuvant radiation therapy were recommended '29 and studied extensively. 187Suit e t a l . ~87 reported the first 100 patients treated by wide excision of the soft tissue sarcoma, followed by radiotherapy, at the M. D. Anderson Hospital. Doses of 6 0 0 0 - 7 0 0 0 rads delivered in 61/2- 71/2 weeks were used and, in a later experience, a portion of the circumference of the extremity was spared the effects of radiation therapy. Thirteen per cent of patients eventually developed local r e c u r r e n c e - an improvement over the historical d a t a - and these were in those patients with histologic grades 44

2 and 3. For lesions located distal to the elbow or knee there were no local recurrences. Functional results were also satisfactory. The problem with this therapy is that the failure due to distant metastasis remains, for only 17% of those patients with grade 3 malignancies were free from systemic disease at the time of analysis. ' 8 ' A D J U V A N T PREOPERATIVE CHEMOTHERAPY: ISOLATION-PEP-FUsION OR ARTERIAL DRUG INFUSIONS. - - M c B r i d e has used preop-

erative isolation perfusion of a sarcoma-bearing extremity using L-phenylalanine mustard and actinomycin D. Surgical excision is performed 6 weeks later. Only a 9% local recurrence rate was noted. The 5-year survivals of 57%, however, reflect the death of m a n y patients due to systemic metastases. '27 Morton e t a l . m recently reported preoperative 3-day arterial infusions of adriamycin with or without localized radiation therapy. Although the tumors shrank significantly, most of the extremities still required amputation because of tissue complications, although some extremities were salvaged by this preoperative adjuvant approach. SYSTEMIC

ADJUVANT

APPROACHES:

CHEMOTHERAPY

AND IM-

MUNOTHERAPY.-Table 6 lists the drug effectiveness of the most effective single agents and combinations of agents in metastatic sarcoma. The potential of various drug combinations now is being explored in several adjuvant studies, b u t results are too preliminary fo~ definite statement. It would appear that disease-free intervals are being prolonged with the adjuvant use of chemotherapyY ~ The direction for the future seems to be in localized surgical excisions, the extent of which m a y be reduced by preoperative adjuvant radiotherapy followed by systemic adjuvant chemotherapy. Whether adjuvant radiotherapy will be continued for local control must be defined. The irradiation recall problems in the "adjuvant" x-ray port, with the systemic use of adriamycin, are serious problems that would be avoided if the systemic drug could achieve equal local control rates when added to surgical treatment. TABLE 6.-SINGLE DRUG AND COMBINATION CHEMOTHERAPY IN METASTATIC SARCOMA e'~ R E S P O N S E

Adriamycin (A) Dimethyl triazeno imidazole carboxamide (DTIC) A + DTIC + vincristine (V) + "'

NUMBERS

22

28, 72

17

72

46} 39

Cytoxan (C)

A + DTIC + V + actinomycin D A + C methotrexate _+C p a r v u m *Randomized comparisons.

REFERENCE

34

13" 150" 45

CARCINOMA OF THE COLON AND RECTUM FAILURE PROFILE.-- In 1975, it was estimated t h a t 99,000 new cases of carcinoma of the large bowel were diagnosed.'" The magnitude of this problem is accentuated by analysis of survival statistics of "all comers," i.e., analysis of all patients entering a given institution and not just those undergoing curative resections. Over-all 5-year results from several major reporting institutions are listed in Table 7.", ~, 60, 66, ,3, Only 3 0 - 4 0 % of patients survive 5 years. The cause of failure in 60-70% of patients is suggested by the status of these patients on presentation, as listed in Table 8. In addition, this analysis gives insight into the basic strategies needed for improvement of prognosis in carcinoma of the colon and rectum. Some of the reporting institutions are of a referral nature, so t h a t a more advanced disease status m a y be generated from these references, but at least an approximate estimate can be made. On presentation to the institutions t h a t have comprehensively analyzed their statistics, 7% of patients are inoperable because of distant metastases and are not explored for resection or palliation. T h i r t y per cent of patients are explored and resection for cure is not possible because of liver metastases (approximately 10%), local fixation, carcinomatosis, distant metastases or liver metastases (about 20% of the entire group). Palliative resections may have been performed for some of these patients. About 60-63% of patients are resectable for :'cure," i.e., all the grossly identifiable tumor can be removed by an appropriate surgical procedure. Unfortunately, only 50% of those resected for cure survive 5 years. Table 9 identifies a composite failure profile and the causes for failure in those undergoing curative colon resections. Operative mortality is not an insignificant event, and we should be able to continually improve on the reported 4 - 1 0 % s u r g i c a l m o r t a l i t y rate. Other failures in terms of disease recurrence occur in a broad spectrum of sites, which include the local resection s i t e i n 15-21%, liver metastaTABLE 7.-COLORECTAL CANCER: OVER-ALL 5-YEAR RESULTS NO. PATIENTS

Botsford e t al. '7 (1960-1965) Copeland e t a l . ~3 (1941- 1956) Franklin and McSwain6~ (1956-1963) Gilbertsen~,~ (194.0-1954) McSherry e t a l . m ., (1932- 1962) 46

"

C~ 5 - Y R . S U R V I V A L

222

39.2

1084

37.3

1022

40.2

840

32.0

1625

29.8

TABLE 8.-ADENOCARCINOMA OF COLON: STATUS OF "ALL COMERS" AT DIAGNOSIS PROGNOSIS TIME OR 5-YR SURVIVAL

%

Inoperable (no surgery) Inoperable (intraoperative) L.M. only = 10%, local fixation, carcinomatosis, D.M. _+ L.M. + 20% Resectable for cure Dukes A Dukes B Dukes C

7 3O

9.5 mos

63 5- 10 40-50 40-50

45- 50% 80% 40-60% 6-25%

L.M. = liver metastases ses in 15% a n d d i s t a n t m e t a s t a s e s w i t h a p p a r e n t local control in t h e a b d o m e n in 15%. N e w p r i m a r y a d e n o c a r c i n o m a s d e v e l o p in 4 - 6% of p a t i e n t s a n d a b o u t 50% of t h o s e r e s e c t e d for c u r e s u r v i v e w i t h o u t e v i d e n c e of d i s e a s e for a t l e a s t 5 y e a r s . As one b r e a k s d o w n t h e s e r e s u l t s b y s t a g e of colon cancer, o n l y 6 - 2 5 % of pat i e n t s w i t h D u k e s C lesions s u r v i v e 5 y e a r s . T h i s f a i l u r e profile, w h i c h e n c o m p a s s e s t h e p r o b l e m of colorect a l c a n c e r f r o m i n i t i a l d i s e a s e p r e s e n t a t i o n to t h e c a u s e s of failu r e a f t e r s u r g i c a l resection, o r i e n t s t h e b a s i c s t r a t e g y for f u t u r e i m p r o v e m e n t in s u r v i v a l r e s u l t s . I t is c l e a r t h a t m o r e t h a n onet h i r d of p a t i e n t s a r e i n o p e r a b l e b e c a u s e of t h e e x t e n t of t h e dise a s e a t t h e t i m e of p r e s e n t a t i o n . T h i s p o p u l a t i o n c a n n o t b e h e l p e d b y a n y " a d j u v a n t " t h e r a p y b e c a u s e t h e i r d i s e a s e is b e y o n d s u r g i cal r e s e c t i o n a t p r e s e n t a t i o n . E a r l i e r d i a g n o s t i c a n d / o r p r e v e n t i v e m e a s u r e s or t h e " s i l v e r b u l l e t " a r e n e e d e d to effect c u r e in t h i s p o p u l a t i o n . T h e r e m a i n i n g t w o - t h i r d s a r e r e s e c t e d for cure, in t h a t all gross d i s e a s e is r e m o v e d b y o p e r a t i o n . T h e incidence of f a i l u r e d u e to s u b c l i n i c a l d i s e a s e c a n b e s t a t i s t i c a l l y projected b y t h e D u k e s classification. T h e p e r c e n t a g e of pelvic r e c u r r e n c e aft e r r e s e c t i o n for r e c t a l c a r c i n o m a e s c a l a t e s w i t h t h e D u k e s classification, as h a s b e e n d o c u m e n t e d b y T h o m a s e t a l . 199 O t h e r a r e a s TABLE 9.-FAILURE PROFILE AF'FER RESECTION FOR CURE (50% SURVIVAL)* Operative mortality Local recurrence Liver metastases Distant metastases with control in abdomen Second primary cancer of colon No failure ,|

4-10% 15- 21%* 15% 15% 4 - 6% 50%

*Includes colon and rectum. 47

of recurrence follow this trend, although documentation is not so convincing as for local recurrence. This group, which is surgically resectable for cure, therefore fails because of subclinical disease not recognized preoperatively or intraoperatively. Thus, about one-half of patients undergoing resection for cure, or about onethird of the 99,000 patients newly diagnosed as having colorectal carcinoma in 1975 (33,000 patients), are the targets for improvem e n t in survival by the use of interdisciplinary therapeutic techniques. EFFICACY

OF CHEMOIMMUNORADIOTHERAPY

IN C O I L ) R E C T A L C A N -

CSR.--Table 10 summarizes the results of chemotherapeutic treatment of grossly metastatic colorectalcancer. Recently, three drug combinations have broken through the 20% barrier, which is the levelof response to 5-FU alone or 5-FU in combination with several other drugs. Current response rates of 32-43.5% are reported in well-controlledstudies2,49,13~ A combination of methyl CCNU and 5-FU is being utilized for adjuvant therapy (Gastrointestinal Study Group Protocols 6175 and 7175). Surprisingly, immunotherapy with Mer B C G alone has been found to cause regressions of metastases or stabilizationof metastatic disease.136 Radiotherapy has effectiveness in rectal cancer, since about 10% of resection specimens were histologicallysterilizedby a preoperative dose of 5000 rads in 5 weeks, and 26 of 27 patients showed regression in tumor size.3,5~ Thus~ these modalities all have effectiveness in gross disease and are-being applied to the management of subclinicaldisease aftersurgical resection. A D J U V A N T RADIOTHERAPY FOR CARCINOMA OF THE R E C T U M . Local recurrence is the initial cause of treatment failure in

1 5 - 2 0 % of patients undergoing abdominoperineal resections of TABLE 10.-ADENOCARCINOMA OF THE COLON: DRUG EFFECTIVENESS SINGLE DRUGS

e'~ RESPONSES

5-FUDR. 5-Fluorouracil (5-FU) Cyclophosphamide L-phenylalanine mustard Methyl CCNU BC'NU CCNU Mitomycin C DRUG COMBINATIONS 5-FU + many other drugs tested in combination 5-FU, methyl CCNU, vincristine

23 21 20- 27 17 17.5 12.5 10 12

20 43.5

5-FU, methyl CCNU 5-FU, mitomycinC

32 40

48

AUTHORS

Moertel et al. '37 Falkson et al. 49 Moertel et al. 137 Baker et al. 9 Kim

TABLE ll.-CARCINOMA OF RECTUM: 15-21% PELVIC RECURRENCE STAGE

% RECURRENCE 199

Dukes A Dukes B Dukes C

27 30 43

the r e c t u m (Table 11). It is well known to the surgeon t h a t significant manipulation of tumors often is required duri ng resection, and for large tumors the m ar gi n is limited by the pelvic sidewalls. In an analysis by Thomas et al., ~99 73% of the local recurrences were in Dukes B and C lesions. T he VA Surgical Adjuvant GrouplS~. 162 performed a randomized study of preoperative adjuv a n t radiation t h e r a p y to pr event such local recurrences after resections of carcinoma of the rectum. A dose of 2000 rads was delivered to the pelvis in 2 weeks and, for tumors less t h a n 8 cm from the anal verge, an additional dose of 500 rads was delivered to a perineal port. This irradiation was followed by immediate operation. In 414 patients undergoing abdominoperineal resection, the actuarial survival rate was 30% in the control group and significantly be t t e r at 46% (p < 0.05) in the preoperatively irradiated group. Significantly fewer positive regional nodes were found after this brief course o f i r r a d i a t i o n and this i s p r e s u m e d to be an effect of this small dose of irradiation. It is equally possible t h a t more Dukes C lesions were randomized to the control group and thus results are spurious. However, other nonrandomized studies have reported the beneficial effects of adjuvant radiation therapy.3, m Thus, recently several randomized studies (Table 12) have been initiated, investigating the value of preoperative and postoperative r a di ot he r apy in carcinoma of the rectum. Based on the previous review of the basic principles of radiation therapy, one would anticipate t h a t a dose of 4 5 0 0 - 5 0 0 0 rads would be TABLE 12.-ONGOING RANDOMIZED STUDIES OF ADJUVANT RADIATION IN CANCER OF RECTUM ORGANIZATION

DOSE*

PRE/POST

4500 r -+ other adjuvants 3150r 150 r fractions

Post

1975

Pre European Organization for Research Rx of 3450 r -+ 5-FU Pre Cancer ECOG 4000-5000 r -+ 5-FU Pre SEG 94500 r -+ other adjuvants Post *Standard fractions (200 r/day 5• unless noted.

1973

GI Study Group VA Adjuvant Study II

DATE BEGUN

1974 1975 1977 (planned)

49

required for maximal control of subclinical disease. 55,56 Since several of the ongoing studies use lesser doses, interesting comparisons will be possible when results become available. D I S S E M I N A T E D S U B C L I N I C A L DISEASE. - - Local recurrence is only part of the failure profile in carcinoma of the rectum. Metastases to the liver and other organs, as well as peritoneal seeding, are important aspects of failure. For lesions above the pelvic floor, local recurrence is not as common, and irradiation is impracticable because of damage to other intra-abdominal organs. Chemotherapy and immunotherapy therefore have appeal for higher lesions. The results of "pulse" chemotherapy given at the time of operation were unsatisfactory in studies performed in the 1950s. ss The most recently reported VA trial randomized patients to surgery alone or surgery plus 5-FU for a prolonged period. There is no significant difference between these two treatment groups; however, a nonsignificant trend toward improved survival in the drug-treated group has been noted, ss Grage et al., 73 reporting for the Central Oncology Group, also had negative results in a similar study. Another randomized study using intraluminal as well as intravenous 5-FU demonstrated no benefit with this singledrug adjuvant. 11s Since gross disease responds better to drug combinations, currently there are a number of ongoing surgical adjuvant studies that utilize drug combinations. A new VA study initiated in January of 1973 uses combinations of 5-FU and methyl CCNU. The Gastrointestinal Study Group Protocol for Colorectal Cancer also used 5-FU plus methyl CCNU with the addition of Mer BCG to one of these treatment arms for lesions above the pelvic floor. Mavligit e t al. 126 have reported results of nonrandomized trials that suggest that 5-FU plus BCG is a more effective adjuvant than 5-FU alone. The Southwest Oncology Group is studying the effect of this combined chemo-immunotherapy in the adjuvant setting. 12~ Lack of randomization in these last two studies, however, obscures their interpretation. As the results of these ongoing studies, particularly those with randomization, are reported, answers to the questions regarding the place of adjuvant therapy in the management of colorectal cancer should be clarified further.

BREAST CANCER FAILURE P R O F I L E . - - T h e failure profile after standard Halsted mastectomy first came into focus in 1943 when Haagensen and Stout TM retrospectively reviewed the courses of all patients treated by radical ma~tectomy between 1917 and 1943 at Columbia- Presbyterian Hospital. They showed that certain local signs 50

TABLE 1 3 . - F A I L U R E PROFILE AFTER MASTECTOMY IN PATIENTS WITH POSITIVE NODES* 18 mos Disease recurrence (low regional or systemic) 1 - 3 nodes positive 4 nodes positive Survival

27.4" 18.6 37.1 92.5

PER CENT 3 yrs 5 yrs 51.6 39.7 64.5 72.8

63.6 54.2 73.8 56.2

10 yrs 75.5 67.7 83.6 39.7

*Modified from Bonadonna et al. TM

were associated with disease recurrence and death, despite the absence of known dissemination. These prognostic determinants obtained by physical examination are the basis of the Columbia Classification of breast cancer. The value of this staging system was that unnecessary radical mastectomies were avoided; however, patients with these serious local signs were doomed to death with systemic disease, even though the lesion was localized on presentation by known diagnostic criteria. A composite picture of the failure profile after resections for breast cancer TM shows that even if one excludes patients with advanced local disease from curative resections, a significant incidence of local recurrence is noted (10-40%), parasternal and supraclavicular nodes become positive with time and distant metastases develop. The data generated by the National Surgical Adjuvant-Breast Project53, 54 and by Bonadonna e t al. ~6 detail the failure rate and survival of patients with positive nodes after standard radical or modified radical mastectomy. Table 13 is modified after data recently presented by Bonadonna e t a L ~6 In patients with positive nodes, only 25% over-all are disease-free after 10 years and only 40% are surviving. These data emphasize the extent of the uncontrolled subclinical disease problem in patients with positive nodes and dictate the need for the addition of some effective modality for control if the statistics are to be improved. Therefore, in breast cancer, the anatomic scope of the failure profile is locally about the surgical wound, regionally in lymph nodes and distally in systemic organs. Optimally, systemic adjuvant therapy must be used. EFFICACY OF CHEMOIMMUNORADIOTHERAPY AND HORMONAL MANIPULATIONS IN BREAST C A N C E R . - - T h e u s e o f chemotherapy in

advanced breast cancer has undergone remarkable advances with the use of drug combinations, as initially suggested by Greenspan. 75 Table 14 summarizes much of the currently available data on the res .ponsiveness of grossly metastatic breast Cancer. The maximal responsiveness to single agents has been in the 20-30% range, with short durations of remissions and a few 51

TABLE 14.-BREAST CANCER: DRUG EFFECTIVENESS IN GROSS DISEASE SYMBOL

Single Drugs Methotrexate Adriamycin Cyclophosphamide L-phenylalanine mustard 5-Fluorouracil Vincxistine Combinations CMFVP (prednisone) CMFP CMF randomized comparison CAF CA randomized comparison VA (no cross resistance with CMF) Sequential Combinations CMF VA Combined Chemoimmunotherapy CAF + BCG (longer remission duration)? CAMF • C. parvum Combined Chemo-Hormonal Therapy Oophorectomy > CMF

c~ RESPONSE

REF. NO(S).

M A C L-PAM F V

33 36 34 25 26 25

27 93 27 24, 27 27 27

P

60-90 63 49 72 80 50

27, 75 26

?

26

75 65

94 40

?

18

2, 105 26

complete remissions. C o m b i n a t i o n s h a v e i n c r e a s e d responses to 5 0 - 70% a n d m u c h c u r r e n t effort is directed a t finding r e g i m e n s t h a t r e s u l t in a h i g h e r p e r c e n t a g e of complete responses w i t h less toxicity. T h e s e q u e n t i a l use of two n o n c r o s s - r e s i s t a n t different d r u g c o m b i n a t i o n s , such as C M F followed b y VA, is also a c u r r e n t a v e n u e of i n v e s t i g a t i o n . 2s This use of s e q u e n t i a l c o m b i n a t i o n s parallels the a d v a n c e s m a d e in the conquest of l e u k e m i a a n d o t h e r "liquid" cancers. T h e e m p i r i c i s m of h o r m o n e ablations h a s b e e n s u p e r s e d e d b y t h e use of the e s t r o g e n receptor assay, w h i c h allows the clinician to predict w h i c h p a t i e n t s are m o s t likely to respond. 12s T h e scope of e n d o c r i n e m a n i p u l a t i o n s is s u m m a r i z e d in T a b l e 15. A d j u v a n t use of o o p h o r e c t o m y alone h a s b e e n s h o w n to be ineffective in TABLE 15.-BREAST CANCER: RESPONSE OF METASTATIC DISEASE TO HORMONAL MANIPULATIONS PREMENOPAUSAL

Oophorectomy12s Adrenalectomy 12s Hypophysectomy~2~ Estrogen therapy12S Aminoglutethimide ~65 Antiestrogens (nafoxidine/tamoxifen)~l~, ~93 52

PRE- OR POSTMENOPAUSAL

60-65% ER + 5O-6O% ER + 50% regardless of ER 50-60% ER + 38% regardless of ER 28- 35% regardless of ER

improving pure statistics, although the disease-free interval was slightly prolonged, 59' 10~.120 so that the most promising uses of adjuvant hormonal ablation are in combination with other adjuvant modalities. ~s' Hg. ~6~,193 The ~'medical adrenalectomy" with aminoglutethimide 165 and the use of antiestrogens 193 allow endocrine ablation without the need for open operation and, therefore, lead to a broader application of such manipulations in the adjuvant setting. ADJUVANT THERAPY OF BREAST C A N C E R . - T h e high incidence of local recurrence can be greatly improved, if not eliminated, by the adjuvant use of preoperative or postoperative radiotherapy. 55 However, as has been documented by Spratt ~74and by Donegan e t al., 43 local recurrence almost invariably is an indication of systemic disease in breast cancer and, therefore, survival has not been improved by this local-regional adjuvant modality. In fact, Stjernsward '76 has compiled significant evidence suggesting that the disease-free interval is diminished with adjuvant radiotherapy, possibly due to its immunosuppressive effect. The search, then, is for the most effective systemic medality. The National Surgical Adjuvant Breast Project pioneered studies in adjuvant chemotherapy. In 1958 a trial ofthiotepa, and later of 5-FU, given at the time of radical mastectomy and for several days thereafter was undertaken. 54 The time to first recurrence was delayed significantly in premenopausal women, but there was no difference in disease-free status or survival at 5 years. No differences were present at any time in the postmenopausal group. Analyzing subgroups, there was a significant improvement in survival (24% vs 57%) in premenopausal women with 4 or more positive nodes. However, the patient numbers in this subgroup were small. The difference of this particular subgroup in this early adjuvant trial has been emphasized, for, as we will see, it bears directly on the results of the most recent studies of adjuvant chemotherapy. 53 In 1972, the NSAPB, ECOG and the COG began to compare the adjuvant effects of L-phenylalanine mustard (L-PAM) to a placebo in the adjuvant therapy of women with positive axillary lymph nodes. Recent evaluation of these results shows a significant improvement in the disease-free interval in premenopausal women, an improvement that is most pronounced in those with greater than or equal to 4 positive nodes. ~ Although there was a temporary delay in recurrence in the postmenopausal women, the relapse curves overlapped by 2 years. 52 Bonadonna et al. '6 shortly thereafter began a similar adjuvant study comparing CMF to no treatment. Recent update of these results is seen in Table 16. Results paralleled those of the N S A B P in that a marked improvement in disease-free status is seen in premenopausal women with positive nodes, most m a r k e d ' i n those with 4 or more positive 53

TABLE 1 6 . - E A R L Y RESULTS OF CMF ADJUVANT THERAPY* (Per cent relapse at 36 months by life table analysis; 20 months mean follow-up) PREMENOPAUSAL N o d e Status 1-3 ~_ 4

Control 30 90

CMF 5 32

POSTMENOPAUSAL Control 34 48

CMF 32 45

*Modified from Bonadonna et al? 6

nodes, but no significant difference is observed in the postmenopausal group. Also, with time, the relapse curves in the treated groups seem to be slowly approaching those of the control groups. Although results at this time are better in these studies than in the earlier thiotepa trial, defnitive long-term improvement in patient survival remains to be demonstrated. A great number of breast adjuvant therapy trials currently are in progress. These trials are studying the effects of adjuvant antiestrogens (tamoxifen) in combination with chemotherapy, combinations of radiation therapy and chemotherapy and adjuvant immunotherapy with either nonspecific or specific tumor antigen preparations in combination with chemotherapy. The next 5 years will witness the accumulation of much interesting data and, it is hoped, give directions for solid improvement in patient survival statistics.

SQUAMOUS CELL CARCINOMA OF HEAD AND NECK FAILURE PROFILE AFTER SURGERY ALONE. - - A n a l y s e s of the results of surgery in the management of squamous cell carcinoma of the head and neck are closely tied to accurate clinical staging. For cancer of the oral cavity and oral pharynx, the smaller lesions such as T 1 and superficial or exophytic T 2 lesions are readily treated by either surgery alone or irradiation alone, with good cure statistics of about 7 5 - 80%. The infiltrative T 2 (greater than 2 cm but less than 4 cm) or T 3 lesions (greater than 4 cm) do poorly with surgery because of a high incidence of failure at the primary site. Radiotherapy likewise gives poor results because the hypoxic core of these large tumors is resistant to radiation at doses that are tolerated by the surrounding normal tissues. Surgery fails at the periphery, where subclinical disease extends into lymphatic, perineural or muscle tissue. In the control of neck metastases, the radical neck dissection alone has "an unacceptably high local recurrence rate. When a radical neck dissecti6n is performed because of pathologically proved metastatic disease, the local recurrence rate has been re54

ported at 47%, 85 50% '78 and 75%. T M After radical neck dissection for positive nodes, new nodes evolved in the opposite side of the neck in 27%. '0 Paradoxically, then, when radical neck dissection is performed for truly positive nodes, it is least effective in controlling the disease. Likewise, radiation therapy alone fails to control most metastatic disease in the neck. Failures are reported in 31%, 8239% 2~ and 46%. 5' Another important aspect of the failure profile in head and neck cancer relates to the development of new primary carcinoma, particularly in patients cured of their first lesion. In a recent analysis of "why we fail," Jesse and Sugarbaker '~ found that 37% of patients surviving 5 years have developed a new primary carcinoma of either the head and neck, esophagus or lung. Head and neck patients who are cured of their first primary cancer must be carefully and periodically screened for new primary disease. Most patients with head and neck cancer die of local or regional recurrence.'However, if the local-regional disease is controlled, a significant incidence of distant metastasis is noted. In a recent analysis of carcinoma of the oropharynx, 10% developed distant metastasis as the only manifestation of treatment failure. '~ Therefore, in head and neck cancer, adjuvant therapy must consider the failure at the primary site, failures in the neck, distant failure due to metastases and the evolution of new primary disease in the derivatives of the embryologic f o r e g u t - a l l of which have been exposed to the common etiologic agents, namely alcohol and tobacco. CHEM()THERAPY

IN

GROSS SQUAMOUS

CELL

CARCINOMA.--

Squamous cell carcinoma of the head and neck has been remarkably resistant to chemotherapeutic agents. The responses to many commonly used drugs '5, ,34 are listed in Table 17. Despite the reasonable percentage response rate, the duration of any response usually is very short and complete responses are almost nonexistent. The drug combinations may be extremely toxic and patient tolerance is poor, often because of the other consequences of longstanding alcohol and drug abuse, such as severe pulmonary disease and/or cirrhosis. A high mortality rate in the drug treatment of patients with grossly recurrent head and neck carcinoma,recently has been reported in patients treated with the Bacon combined regimen. T M Therefore, effective systemic chemotherapy is not currently available, although several programs are under studyY, 45 ADJUVANT THERAPY OF SQUAMOUS CELL CARCINOMA OF THE

HEAD AND NECK.-Since either surgery or radiation alone failed with advanced primary lesions and in patients with metastatic disease in the neck, .it was logical to combine these two modalities. Improved control of the primary site has been achieved by delivering 4500-5000 rads in 4'/2-5 weeks preoperatively or 55

TABLE 17.-SQUAMOUS CELL CANCER OF THE HEAD AND NECK: DRUG EFFECTIVENESS IN GROSS DISEASE SYI~IBOL

c'~ R E S P O N S E

REF. NO.

H M C B "ON"

39 38 36 31 29 20 25 60

15 15 15 15 15 15 15 6

50 52 50 ?

15 15 15 157

Single Drugs* Hydroxyurea Methotrexate Cyclophosphamide Bleomycin Vinblastine CCNU Adriamycin HDMTX-rescue

A

Combinationst BM

MV BA BACON

*Higher responses have been reported with intra-arterial infusions. t Small numbers of patients reported.

6000 rads postoperatively. 1~ io3 In the neck, the combination of radiation therapy and surgery has been studied in randomized series. Strong '78 and Henschke, s~ at Memorial Hospital, used 2000 rads delivered in 1 week prior to radical neck dissection. Local recurrence in the neck was significantly diminished in patients with p o s i t i v e nodes from 50% without radiation-therapy to 31% with this small dose given preoperatively. When 2 or more nodes were positive, the local recurrence rate was diminished from 60% with surgery alone to 32% with combined therapy, s~ Millburn and Hendrickson TM reported similar data, with recurrence diminished from 75% with surgery alone to 10% with the use of a higher dose of adjuvant radiation therapy. Extensive data obtained by retrospective review of the experience at the M. D. Anderson Hospital has shown that the local recurrence in the neck can be diminished to 3% with an adequate dose of 4 5 0 0 - 5 0 0 0 rads in 41/2- 5 weeks. '~ 5G,102,,o3,122 Lymph nodes evolving in the contralateral neck were controlled by irradiation of the contralateral neck. i~ 56 Adjuvant immunotherapy may be important in the management of head and neck cancer. Squamous cell carcinoma frequently produces profound systemic anergy, and such anergy is associated with a poor prognosis, even for small lesionsY 9, 46. 202 Attempts at reconstitution of the immune system, therefore, are part of m a n y current protocols for adjuvant immunotherapy in head and neck cancer. 45. 157 No effective adjuvant chemotherapeutic programs have yet been reported. The use of cell cycle specific combination programs delivered by arterial infusions have significant appeal for shrinking large le56

sions, preoperatively, but better cure statistics are dependent on effective systemic therapy.

MALIGNANT MELANOMA FAILURE PROFILE.-- Malignant melanoma is recognized as a disease with a great propensity for local recurrence, metastasis to regional lymph nodes and systemic hematogenous metastasis. In addition, in melanoma of the extremities, a peculiar type of"intransit recurrence" occurs. The specific failure profile for melanoma must be related to the initial anatomic location of the primary tumor. The details of the failure profile for melanoma of the extremities, trunk, head and neck recently have been documented in detail by Sugarbaker e t a l 2 , 1~, 18~ In summary, it is possible to state that if the primary tumor only is removed, 20-38% of patients eventually evolve gross metastatic deposits in regional lymph nodes. On the other hand, if clinically negative nodes are removed by elective regional node dissection, 20- 50% are found to contain microscopically positive nodes. If lymph nodes are grossly positive at the time of presentation, the 5-year survival is between 20% and 30%. If the lymph nodes are microscopically positive, the 5-year survival is between 43% and 60%. If the lymph nodes are microscopically negative, the 5-year survival ranges between 75% and 87%. Therefore, this brief look at the failure profile in malignant melanoma establishes the high risk of patients with positive regional nodes for systemic or local occult disease. It is this group of patients with positive regional nodes that must be treated with some effective systemic adjuvant therapy if these extremely poor survival statistics are to be improved. CHEMOTHERAPY

AND

CHEMOIMMUNOTHERAPY

OF

GROSSLY

MALIGNANT MELANOMA.--Table 18 lists the drug effectiveness in grossly metastatic melanoma. Melanoma is characterized by resistance to chemotherapeutic agents and by short durations of remission should responses occur. It is possible that future cell cycle specific drug combinations may have better efficacy in metastatic melanoma than any reported to date. There are more "spontaneous regressions" in metastatic malignant melanoma than in any other malignancy.4s This type of host defense has suggested that tumor immune reactions may be important in the control of microscopic malignant melanoma. Therefore, many studies have used either specific or nonspecific types ofimmunotherapyYs' 134,m It has been quite difficult to assess the results of many studies, for it is clear that the route of administration of BCG, the type of strain of BCG used and the site of administrati'on all have influenced the therapeutic results. TM The addition of BCG to chemotherapy has also been re57 METASTATIC

TABLE 18.-MALIGNANT MELANOMA: DRUG EFFECTIVENESS IN GROSS DISEASE

Single Drugs Dimethyl triazeno imidazole carboxamide Methyl CCNU Cyclophosphamide Procarbazine Actinomycin D BCNU L-phenylalanine mustards Hydroxyurea Vincristine Combinations DTIC, Me DTIC, V, B DTIC, BCNU *B, H, DTIC *CV, VS, CVPV, HDMTX-rescue tCombinations with BCG *C, DTIC • C. parvum

SYMBOL

r RESPONSE

DTIC hie C P D B L-PAM H V

20-25 23 22 18-28 18 18 9 9 - -

20-25 28 19 33 30-33 36 40 27-33

REF. NOiS).

181 181 181 181 181 181 181 181 181 181 181 181 35 23 44 78,135 151

*Randomized studies with large numbers of patients. ~Nonrandomized study. $60% response by isolation-perfusion.

norted to provide additive benefits, although the study design that utilizes historical controls makes this interpretation impossible to reach with assurance/s. 134 ADJUVANT THERAPY OF MALIGNANT MELANOMA. -- A d j u v a n t

use of DTIC has been accomplished in the Central Oncology Group. 89 There was a prolongation of the duration of the diseasefree status in patients in whom toxicity developed but no improvement in survival. These studies suggest that only high toxic levels of DTIC are of any benefit, and this only transiently. The use of adjuvant BCG has been reported by Morton et al. T M to improve the disease-free interval in patients with positive regional nodes. There are numerous ongoing studies utilizing Corynebacterium parvum, adjuvant chemotherapeutic regimens and other types of immunostimulants. Results are all preliminary or not available at this time. Adjuvant isolation-perfusion for extremity melanoma has improved the local-regional control, but a definitive addition to survival is not demonstrable because of study design. ~s3 ADJUVANT THERAPY OF OTHER MALIGNANCIES A major improvement is required in lung cancer, where death frequently is caused by subclinical disease. However, drug pro58

grams currently are largely ineffectual and severely 'toxic in this disease process. '23 Adjuvant radiation therapy has not proved to be beneficial and, in fact, was statistically detrimental to survival in the VA study. The Veterans Surgical Adjuvant Study Group has investigated drugs (Cytoxan and CCNU) used as single adjuvant agents with negative results to date. Adjuvant intrapleural BCG has shown early promising results. Treatment of carcinoma of the pancreas frequently fails because of systemic subclinical disease. An ongoing study of adjuvant radiation therapy with or without adjuvant 5-FU in carcinoma of the pancreas is being conducted by the Gastrointestinal Study Group. Carcinoma of the stomach and many other tumors are also being studied, but results are either preliminary or not available at the time of this writing. IMPLICATIONS OF EFFECTIVE ADJUVANT THERAPY FOR THE PRACTICE OF CANCER SURGERY MORE CONSERVATIVE RESECTIONS. When extensive surgery is performed for control of subclinical disease, a lesser operation combined with an adjuvant modality may be equally effective. This has proved to be the case in the management of soft tissue sarcomas, in which wide local excision plus irradiation therapy actually gives better results in terms of local control than does extensive amputation. 1s7 The important difference is the preservation of function. It is also possible that wide local excision plus appropriate radiation therapy can provide equal local-regional control rates in carcinoma of the breast. 83 This may mean that when effective systemic adjuvant modalities are available in other disease categories, less extensive cancer procedures will be effective and preserve function and/or cosmesis. -

-

STAGING PARALLELS THE THERAPEUTIC GOAL IN NODE DISSECTIONS. - In the case of adjuvant management of carcinoma of the

breast, the pathologic staging of regional lymph nodes is of paramount importance. Therefore, an operative approach that plans to select patients for adjuvant therapy, based on positive regional lymph nodes, must remove these for accurate pathologic staging. In this circumstance, the goal of staging parallels the therapeutic objective of lymph node removal. An analogous situation pertains to elective regional node dissection in patients with malignant melanoma. Here, knowledge of nodal positivity dictates that a patient enter an appropriate adjuvant therapeutic protocol. A parallel rationale pertains to the lymphatic involvement in carcinoma of the colon and lung and other tumors. HEROIC PROCEDURES MAY HAVE A STRONGER R A T I O N A L E . - - T h e

extensive procedures done for the gross presence of neoplastic disease have faced high failure statistics. These extended pro59

cedures often failed not because of inadequate surgical resection but because of systemic subclinical disease. If effective adjuvant therapy is available there is a stronger rationale for these extensive surgical procedures. Therefore, some of the extensive local cancers of the breast may be resected in years to come, even if the chest wall is involved, since adjuvant modalities may be able to manage the subclinical disease problem that dictated failure in Haagensen and Stout's analysis3 9 CYTOREDUCTIVE PROCEDURES MAY BE PERFORMED IN SELECTED

1NSTANCES.--The presence of a solitary metastasis or a limited number of systemic metastases may not be a hopeless situation in the future. If these lesions are resected and if effective adjuvant modalities are available, selected "debulking" or cytoreductive procedures may have merit. THE PROBLEMS OF ADJUVANT THERAPY. -- W h e n multiple subspecialties become involved in patient treatment, the efficacy of patient evaluation and decision making may be impaired. Therefore, it is important that the interdisciplinary cancer treatment team function well and efficiently together. Additionally, the adjuvant programs must have minimal toxicity, for a certain percentage of patients would have been cured by surgery alone. It is hard to justify extremely toxic or potentially lethal treatments in a group of patients in whom many would be cured without such therapy. The patient must be thoroughly informed of study de,~ign and randomization procedures, and this requires some sophistication in patient understanding. The randomized approach may not be applicable in some patient situations. However, even with these problems and the c u r r e n t limitations of drug efficacy, it is difficult to stem one's enthusiasm for the adjuvant therapeutic approach. With the separation of the primary tumor from micrometastases for therapeutic purposes, we may witness a major improvement in current cancer survival statistics in the next decade. REFERENCEs 1. Abercrombie, M., and Ambres, E. J.: The surface properties of cancer cells: A review, Cancer Res. 22:525, 1962. 2. Ahmann, D. C., O'Connell, M. J., and Bisel, H. F.: An evaluation of Cytoxan/adriamycin (CA) vs. Cytoxan/adriamycin/5-FU(CAF) in advanced breast cancer, Proc. Am. Soc. Clin. Oncol. 17:278, 1976. 3. Allen, C. V., and Fletcher, W. S.: Observations on preoperative irradiation of rectosigmoid carcinoma, Am. J. Roentgenol. 108:136, 1970. 4. Allen, C. V., and Stevens, K. R.: Preoperative irradiation for osteogenic sarcoma, Cancer 6:1364: 1973. 5. Ames, F., Sugarbaker, E. V., and Ballantyne, A. J.: Analysis of survival and disease control in stage I melanoma of the head and neck, Am. J. Surg. 132: 484, 1976. 6. Arlen, hi.: Combin~h radiation-methotrexate therapy in preoperative management of carcinoma of the head and neck, Am. J. Surg. 132:536, 1976. 60

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