HEMATOLOGICALONCOLOGY, VOL. 10,3-6 (1992)
ADVANCES IN CURRENT CANCER TREATMENT: A N OVERVIEW GARY H. LYMAN AND ALEXANDER S. D . SPIERS
Division of Medical Oncology Department of Internal Medicine University of South Florida College of Medicine, U.S.A. H. Lee Mojitt Cancer Center and Research Institute at University of Soulh Florida Tampa, Florida, U . S . A .
More than one million cases of invasive malignancy are diagnosed each year in the United States with in excess of 500 000 deaths (Table 1). The National Cancer Institute reports that the average annual age adjusted cancer mortality for the period 19861987 was 171 per 100 000/year for an increase of 5 per cent over comparable rates for the period of 1973-1974 (Silverberg et al., 1990). Most of the increase in cancer mortality rates has been in the elderly with an actual decrease in cancer mortality rates in those under 55 years of age of 1 1 per cent. If lung cancer is excluded, the decrease in cancer mortality rates between 1973-1974 and 1986-1987 in those under 55 was 14.3 per cent. Mortality rates have decreased for gastric and invasive cervical carcinoma over this time period paralleling decreases in incidence rates for these disease sites. An apparent improvement in prostate cancer survival may be attributed to improved technology or changing diagnostic criteria. However, the decrease in mortality for other sites appears to be at least in part related to improved survival rates. Data provided by the Surveillance, Epidemiology and End Results (SEER) Report demonstrates a small but significant increase in five-year relative survival rates for cancer patients between the periods of 1974-1976 and 1981-1986 (National Cancer Institute, 1990).This increase in five-year relative survival is apparent for most tumour sites (Table 2). The Symposium presented here summarizes several of the treatment advances that have served as a basis for progress against selected malignancies. The articles that follow also provide a foundation and perspective for future progress in the therapy of adult cancer. The topics presented were selected to provide a spectrum of neoplastic disease and antineoplastic therapy that has obvious extensions to the majority of such disorders and modalities. The discipline of Hematology/Oncology and our understanding of the pathophysiology and therapeutics of malignancy are dynamic, requiring constant review and update. We hope to have an opportunity to revisit these and other issues at the forefront of modern cancer treatment in a future symposium. The first three papers address the current therapy of lung cancer. Lung cancer accounts for more than one-third of invasive cancers in men and is the leading cause of cancer mortality in both men and women, killing nearly 150 000 in the United States annually. Current therapeutic approaches to small cell lung cancer are summarized in the paper by Joseph Aisner (1991). Great excitement about the responsive nature of this lethal form of lung cancer in the 1970’s and 1980’s has given way to reasoned efforts to address many of the remaining important issues. The use of new agents such as etoposide, carboplatinum and ifosfamide along with an improved understanding of the schedule dependency of available treatment regimens offer continued reason for optimism in the long term control of this disease. The optimal use of multimodality approaches in the treatment of small cell lung cancer is also yet to be defined. 0278-0232/92/0 10003-04 $05.00 0 1992 by John Wiley & Sons, Ltd.
4
G. H. LYMAN AND A. S. D. SPIERS
Table 1. Estimated cancer incidence, U S . 1990*
All sites Gastric Lung Bone and soft tissue Cervix uterus Corpus uterus Ovary Breast Hodgkin disease Non-Hodgkins lymphoma Leukemia
Total
Males
Females
1040000 23 200 157 000 7800 I3 500 33 000 20 500 150 900 7400 35 600 27 800
520 000 13 900 102 000 4200
520 000 9300 55 000 3600 13 500 33 000 20 500 150 900 3200 17 000 12 100
-
900 4200 18 600 15 700
~
*Silverberg et al., 1990.
Surgery remains the only known curative modality for non small cell lung cancer. Approximately one-half of patients presenting with non small cell lung cancer will have disease confined to the chest on careful staging. While many patients in this group will be considered resectable, the vast majority of patients with nodal involvement at the time of resection will recur and die of their disease. E. Carmack Holmes describes recent studies of the Lung Cancer Study Group utilizing adjunctive chemotherapy and radiation therapy in this group of non small cell lung cancer patients (Holmes, 1991). The observed improvement in disease-free survival holds promise for the improved survival of such patients in future studies. The majority of patients with non small cell lung cancer will develop advanced metastatic disease. This disease continues to be a model system for testing new agents, regimens and modalities. John Ruckdeschel summarizes trials in this group of patients conducted by the Eastern Cooperative Oncology Group (Ruckdeschel, 1991). These studies support a recommendation that suitable patients with non small lung cancer be offered one or two courses of systemic chemotherapy with assessment of response and continued therapy in those demonstrating objective improvement. Algorithms are presented as a suggested approach to patients with this disease. Such patients should be offered participation in controlled clinical trials. Ultimately the decision on whether to proceed with treatment depends on recognized prognostic factors, the studies or regimens available and careful informed consent. As a group, cancer affects the digestive organs more often than any other body system, accounting for approximately one-fourth of all malignancies. For the first half of the century gastric carcinoma was the most common malignancy of this system and in fact was the most lethal malignancy among all Americans. For poorly defined reasons, the incidence of gastric carcinoma has fallen considerably over the last few decades. Nevertheless, approximately 23 000 new cases of gastric cancer occurred in 1990 with nearly 14 000 deaths. Surgery remains the only known curative modality for gastric cancer. James Weese concisely summarizes the current surgical approach to gastric carcinoma (Weese and Nussbaum, 199 1). While surgical techniques have clearly improved, the vast majority of patients are destined to recur locally or develop distant metastasis. Gastric carcinoma has been shown to be the most responsive of the gastrointestinal malignancies to systemic chemotherapy. John MacDonald summarizes chemotherapy results in patients with advanced gastric cancer (MacDonald, 1991). While several new agents are of promise, most interest has focused on combination regimens including those
5
CURRENT CANCER TREATMENT
Table 2. Five-year relative survival (percentage)* SEER Programme 1960-1963
1974-1976
1981-1986
White Black White Black White Black All sites
Gastric Lung
Cervix uterus Corpus uterus Ovary Breast Hodgkin disease Non-Hodgkinslymphoma Leukemia
39 11 8 58 73 32 63 40 31 14
27 8 5 47 31 32 46 -
-
50 14 12 69 89 36 75 71 47 34
39 16 11 63 62 41 63 68 48 30
52 16 13 67 84 39 78 76 51 36
38 18 11 57 55 38
64 74 45 29
*National Cancer Institute, 1990.
incorporating cisplatin and etoposide. Regimens with response rates in excess of 50 per cent with a substantial number of complete responses now appear available. The gynaecologic malignancies represent the third leading group of malignancies in women with more than 70 000 invasive cancers of the female organs diagnosed annually in this country. While surgery remains the mainstay of therapy for this group of malignancies, advances in the chemotherapy of patients with advanced disease are summarized in the paper by Robert Ozols (1991). Several new agents of promise in the treatment of gynaecologic malignancies are discussed. The importance of dose intensity and the role of drug resistance in treatment planning are discussed. Among the gynaecologic malignancies, the role of combination systemic chemotherapy, regional chemotherapy and combined modality regimens has been best defined in ovarian cancer. Malignancies of bone and connective tissue constitute a relatively small proportion of cancers, accounting for less than 8000 cases in the United States annually. The importance of this group of diseases, however, exceeds these numbers. The loco-regional management of these cancers has served as a model system for the treatment of other localized solid tumours. In the article by Anthony Elias, the use of chemotherapy in patients with advanced disease as well as the role of chemotherapy as an adjunct to surgery for the sarcomas is discussed (Elias, 1991). While the value of adjunctive chemotherapy in patients with osteogenic sarcoma, Ewings sarcoma and rhabdomyosarcoma appears established, the role of chemotherapy in the soft tissue sarcomas is yet to be fully defined. The role of dose intensity in remission induction and prolongation of disease-free survival appears well demonstrated in several malignancies. The steep dose response curve for the leukemias and lymphomas and for certain solid tumours can be best tested by the use of autologous bone marrow transplantation following very high intensity regimens. In the study by Karen Fields et al. (1991), an innovative induction regimen (mini ICE) was followed by very high dose therapy with autologous marrow transplantation in those demonstrating an objective response. While longer follow-up is needed, the potential value of this approach in the malignant lymphomas and patients with breast cancer is attested to by the high proportion of individuals progression free following the transplantation programme. Other potential methods for exploiting the dose dependency of resposivenessmalignancies includes peripheral stem cell replacement and the use of hematopoietic growth factors as aids to marrow recovery.
6
G . H. LYMAN A N D A. S. D. SPIERS
Clearly, substantial progress has been made in the treatment of selected malignancies over the past decade. We await yet additional classes of agents with improved antineoplastic activity and safety to complement our enhanced supportive care of patients on more intensive and complex regimens. Nevertheless, we have defined a firm basis upon which to take the next step in our progress against a variety of malignant diseases. REFERENCES Aisner, J. (1991). Current approaches to small cell lung cancer. Hematol. Oncol. Elias, A. D. (1991). Future directions in the management o f soft tissue sarcomas. Hematol. Oncol. Fields, K. K., Elfenbein, G. J., Saleh, R. A., Zorsky, P. E . , Janssen, W. E., Perkins, J. B., Saleh, T. G., Piazza, J . T., Kronish, L. E., Machak, M. C., Lyman, G. H. (1991). Ifosfamide carboplatin, and etoposide in combination for induction and high-dose chemotherapy: Focus on breast cancer and lymphoma. Hematol. Oncol. Holmes, E. C. (1991). Adjuvant therapy of non small cell lung cancer. Hematol. Oncol. MacDonald, J. S. (1991) Gastric cancer: Chemotherapy o f advanced disease. Hematol. Oncol. National Cancer Institute Surveillance Program, Division of Cancer Prevention and Control. Cancer Statistics Review, 1Y73-1987. U.S. Department of Health and Rehabilitative Services, Public Health Service, NIH Publication No. 90-2789. Ozols, R. F. (1991). Advances in the chemotherapy of gynaecologic malignancies. Hematol. Oncol. Ruckdeschel, J. C. (1 99 1). Chemotherapy ofmetastatic non-small cell carcinoma of the lung. Hematol. Oncol. Silverberg, E., Boring, C. C., Squires T. S. (1990). Cancer Statistics, 1990. Ca-A Cancer J . Clin., 40,9-26. Weese, J. L., Nussbaum, M. L. (1991). Gastric cancer-surgical approach. Hematol. Oncol.
ADVANCES IN CURRENT CANCER TREATMENT: A N OVERVIEW GARY H. LYMAN AND ALEXANDER S. D . SPIERS
Division of Medical Oncology Department of Internal Medicine University of South Florida College of Medicine, U.S.A. H. Lee Mojitt Cancer Center and Research Institute at University of Soulh Florida Tampa, Florida, U . S . A .
More than one million cases of invasive malignancy are diagnosed each year in the United States with in excess of 500 000 deaths (Table 1). The National Cancer Institute reports that the average annual age adjusted cancer mortality for the period 19861987 was 171 per 100 000/year for an increase of 5 per cent over comparable rates for the period of 1973-1974 (Silverberg et al., 1990). Most of the increase in cancer mortality rates has been in the elderly with an actual decrease in cancer mortality rates in those under 55 years of age of 1 1 per cent. If lung cancer is excluded, the decrease in cancer mortality rates between 1973-1974 and 1986-1987 in those under 55 was 14.3 per cent. Mortality rates have decreased for gastric and invasive cervical carcinoma over this time period paralleling decreases in incidence rates for these disease sites. An apparent improvement in prostate cancer survival may be attributed to improved technology or changing diagnostic criteria. However, the decrease in mortality for other sites appears to be at least in part related to improved survival rates. Data provided by the Surveillance, Epidemiology and End Results (SEER) Report demonstrates a small but significant increase in five-year relative survival rates for cancer patients between the periods of 1974-1976 and 1981-1986 (National Cancer Institute, 1990).This increase in five-year relative survival is apparent for most tumour sites (Table 2). The Symposium presented here summarizes several of the treatment advances that have served as a basis for progress against selected malignancies. The articles that follow also provide a foundation and perspective for future progress in the therapy of adult cancer. The topics presented were selected to provide a spectrum of neoplastic disease and antineoplastic therapy that has obvious extensions to the majority of such disorders and modalities. The discipline of Hematology/Oncology and our understanding of the pathophysiology and therapeutics of malignancy are dynamic, requiring constant review and update. We hope to have an opportunity to revisit these and other issues at the forefront of modern cancer treatment in a future symposium. The first three papers address the current therapy of lung cancer. Lung cancer accounts for more than one-third of invasive cancers in men and is the leading cause of cancer mortality in both men and women, killing nearly 150 000 in the United States annually. Current therapeutic approaches to small cell lung cancer are summarized in the paper by Joseph Aisner (1991). Great excitement about the responsive nature of this lethal form of lung cancer in the 1970’s and 1980’s has given way to reasoned efforts to address many of the remaining important issues. The use of new agents such as etoposide, carboplatinum and ifosfamide along with an improved understanding of the schedule dependency of available treatment regimens offer continued reason for optimism in the long term control of this disease. The optimal use of multimodality approaches in the treatment of small cell lung cancer is also yet to be defined. 0278-0232/92/0 10003-04 $05.00 0 1992 by John Wiley & Sons, Ltd.
4
G. H. LYMAN AND A. S. D. SPIERS
Table 1. Estimated cancer incidence, U S . 1990*
All sites Gastric Lung Bone and soft tissue Cervix uterus Corpus uterus Ovary Breast Hodgkin disease Non-Hodgkins lymphoma Leukemia
Total
Males
Females
1040000 23 200 157 000 7800 I3 500 33 000 20 500 150 900 7400 35 600 27 800
520 000 13 900 102 000 4200
520 000 9300 55 000 3600 13 500 33 000 20 500 150 900 3200 17 000 12 100
-
900 4200 18 600 15 700
~
*Silverberg et al., 1990.
Surgery remains the only known curative modality for non small cell lung cancer. Approximately one-half of patients presenting with non small cell lung cancer will have disease confined to the chest on careful staging. While many patients in this group will be considered resectable, the vast majority of patients with nodal involvement at the time of resection will recur and die of their disease. E. Carmack Holmes describes recent studies of the Lung Cancer Study Group utilizing adjunctive chemotherapy and radiation therapy in this group of non small cell lung cancer patients (Holmes, 1991). The observed improvement in disease-free survival holds promise for the improved survival of such patients in future studies. The majority of patients with non small cell lung cancer will develop advanced metastatic disease. This disease continues to be a model system for testing new agents, regimens and modalities. John Ruckdeschel summarizes trials in this group of patients conducted by the Eastern Cooperative Oncology Group (Ruckdeschel, 1991). These studies support a recommendation that suitable patients with non small lung cancer be offered one or two courses of systemic chemotherapy with assessment of response and continued therapy in those demonstrating objective improvement. Algorithms are presented as a suggested approach to patients with this disease. Such patients should be offered participation in controlled clinical trials. Ultimately the decision on whether to proceed with treatment depends on recognized prognostic factors, the studies or regimens available and careful informed consent. As a group, cancer affects the digestive organs more often than any other body system, accounting for approximately one-fourth of all malignancies. For the first half of the century gastric carcinoma was the most common malignancy of this system and in fact was the most lethal malignancy among all Americans. For poorly defined reasons, the incidence of gastric carcinoma has fallen considerably over the last few decades. Nevertheless, approximately 23 000 new cases of gastric cancer occurred in 1990 with nearly 14 000 deaths. Surgery remains the only known curative modality for gastric cancer. James Weese concisely summarizes the current surgical approach to gastric carcinoma (Weese and Nussbaum, 199 1). While surgical techniques have clearly improved, the vast majority of patients are destined to recur locally or develop distant metastasis. Gastric carcinoma has been shown to be the most responsive of the gastrointestinal malignancies to systemic chemotherapy. John MacDonald summarizes chemotherapy results in patients with advanced gastric cancer (MacDonald, 1991). While several new agents are of promise, most interest has focused on combination regimens including those
5
CURRENT CANCER TREATMENT
Table 2. Five-year relative survival (percentage)* SEER Programme 1960-1963
1974-1976
1981-1986
White Black White Black White Black All sites
Gastric Lung
Cervix uterus Corpus uterus Ovary Breast Hodgkin disease Non-Hodgkinslymphoma Leukemia
39 11 8 58 73 32 63 40 31 14
27 8 5 47 31 32 46 -
-
50 14 12 69 89 36 75 71 47 34
39 16 11 63 62 41 63 68 48 30
52 16 13 67 84 39 78 76 51 36
38 18 11 57 55 38
64 74 45 29
*National Cancer Institute, 1990.
incorporating cisplatin and etoposide. Regimens with response rates in excess of 50 per cent with a substantial number of complete responses now appear available. The gynaecologic malignancies represent the third leading group of malignancies in women with more than 70 000 invasive cancers of the female organs diagnosed annually in this country. While surgery remains the mainstay of therapy for this group of malignancies, advances in the chemotherapy of patients with advanced disease are summarized in the paper by Robert Ozols (1991). Several new agents of promise in the treatment of gynaecologic malignancies are discussed. The importance of dose intensity and the role of drug resistance in treatment planning are discussed. Among the gynaecologic malignancies, the role of combination systemic chemotherapy, regional chemotherapy and combined modality regimens has been best defined in ovarian cancer. Malignancies of bone and connective tissue constitute a relatively small proportion of cancers, accounting for less than 8000 cases in the United States annually. The importance of this group of diseases, however, exceeds these numbers. The loco-regional management of these cancers has served as a model system for the treatment of other localized solid tumours. In the article by Anthony Elias, the use of chemotherapy in patients with advanced disease as well as the role of chemotherapy as an adjunct to surgery for the sarcomas is discussed (Elias, 1991). While the value of adjunctive chemotherapy in patients with osteogenic sarcoma, Ewings sarcoma and rhabdomyosarcoma appears established, the role of chemotherapy in the soft tissue sarcomas is yet to be fully defined. The role of dose intensity in remission induction and prolongation of disease-free survival appears well demonstrated in several malignancies. The steep dose response curve for the leukemias and lymphomas and for certain solid tumours can be best tested by the use of autologous bone marrow transplantation following very high intensity regimens. In the study by Karen Fields et al. (1991), an innovative induction regimen (mini ICE) was followed by very high dose therapy with autologous marrow transplantation in those demonstrating an objective response. While longer follow-up is needed, the potential value of this approach in the malignant lymphomas and patients with breast cancer is attested to by the high proportion of individuals progression free following the transplantation programme. Other potential methods for exploiting the dose dependency of resposivenessmalignancies includes peripheral stem cell replacement and the use of hematopoietic growth factors as aids to marrow recovery.
6
G . H. LYMAN A N D A. S. D. SPIERS
Clearly, substantial progress has been made in the treatment of selected malignancies over the past decade. We await yet additional classes of agents with improved antineoplastic activity and safety to complement our enhanced supportive care of patients on more intensive and complex regimens. Nevertheless, we have defined a firm basis upon which to take the next step in our progress against a variety of malignant diseases. REFERENCES Aisner, J. (1991). Current approaches to small cell lung cancer. Hematol. Oncol. Elias, A. D. (1991). Future directions in the management o f soft tissue sarcomas. Hematol. Oncol. Fields, K. K., Elfenbein, G. J., Saleh, R. A., Zorsky, P. E . , Janssen, W. E., Perkins, J. B., Saleh, T. G., Piazza, J . T., Kronish, L. E., Machak, M. C., Lyman, G. H. (1991). Ifosfamide carboplatin, and etoposide in combination for induction and high-dose chemotherapy: Focus on breast cancer and lymphoma. Hematol. Oncol. Holmes, E. C. (1991). Adjuvant therapy of non small cell lung cancer. Hematol. Oncol. MacDonald, J. S. (1991) Gastric cancer: Chemotherapy o f advanced disease. Hematol. Oncol. National Cancer Institute Surveillance Program, Division of Cancer Prevention and Control. Cancer Statistics Review, 1Y73-1987. U.S. Department of Health and Rehabilitative Services, Public Health Service, NIH Publication No. 90-2789. Ozols, R. F. (1991). Advances in the chemotherapy of gynaecologic malignancies. Hematol. Oncol. Ruckdeschel, J. C. (1 99 1). Chemotherapy ofmetastatic non-small cell carcinoma of the lung. Hematol. Oncol. Silverberg, E., Boring, C. C., Squires T. S. (1990). Cancer Statistics, 1990. Ca-A Cancer J . Clin., 40,9-26. Weese, J. L., Nussbaum, M. L. (1991). Gastric cancer-surgical approach. Hematol. Oncol.
