Inf. J. Rodiotion Oncdogy Bio/. Phys.. Vol. 18. pp. 981-992 Printed in the U.S.A. All rights reserved.

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0360-3016/90 $3.00 + .W 0 1990 Pergamon Pres

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??ASTRO Special Feature

PRESIDENTIAL ADDRESS: SYSTEMIC RADIOTHERAPY-THE STANLEY E. ORDER, The Johns Hopkins Oncology Center, Department

NEW FRONTIER

M.D., Sc.D., F.A.C.R.

of Radiation Oncology, 600 North Wolfe Street, Baltimore, MD 2 1205

The present day use of systemically administered isotopes and conjugated isotopie combinations are reviewed. Administration of 13’Iodine in thyroid cancer led to a 97% local control and 50% complete remission of pulmonary metastases. Specificity directed isotopie therapy (metabolic, hormonal, and antibody) is discus& and iacludes factors such as tumor physiology and isotopie linkage. The clinical results and new knowledge being gained in Hodgkin’s disease, non-Hodgkin’s, colorectal, hepatoma, intrahepatic biliary and gliomatous cancers are reviewed. The dose response relationship to tumor remission is demonstrated in Hodgkln’s treated with 1311antiferritin (40% partlal remlssion) and more recently qttrium antlfenitin (50% complete response). Varied routes of administration, the problem of anti-antibody and bone marrow transplantation are discus&. Finally, the challenge to radiobiologists, physicists, chemists, immunologists, nuclear radiologists, and radiation oncologists is emphasized by definition of the new laboratory and clinical approaches being developed in systemic radiation therapy. Isotopes, Antibody, Systemic treatment.

for cancer, a retention of 5% or greater of the infused 13’1 at the thyroid remnant, indicates that an increased failure rate wil1 occur (5). This is due to competition for subsequent 13’1and reduced tumor uptake. Mazzafeni et al. found that surgery followed by hormonal therapy reduced local regional recurrence from 32% to 1 l%, while “‘1 ablation of the normal thyroid with thyroid hormone reduced local recurrence to 2.7% (p < 0.001) (49). Using more elegant techniques of physics and dosimetry, Maxon et al. demonstrated that with 1311concentrations relatively equal, the differente between successful thyroid ablation and failure was related to a prolonged effective half life resulting in doses 4.4 times greater leading to successful remission p < 0.05 (48). Brown et al. fiom the Royal Marsden achieved disease-free survival in patients with lung metastasis for thyroid cancer, in contrast to survival rates for bony metastasis (p -C0.005) ( 12). Finally, Beierwaltes, who had extensive experience with 13’1when he was at Michigan, and associates have reported 20-year or greater survival from 13’1systemic administration in patients with thyroid cancer and pulmonary metastasis (4). 13’1treatment regimens have demonstrated the principles of systemic radiotherapy, that is, high tumor uptake and prolonged effective half life in the tumor leads to prolonged survival and even cure of metastatic disease. In spite of these dramatic results, the failure to identify other tumor sites with selective isotopie uptake led to a long period of quiescence without further developments in systemic radiation therapy.

INTRODUCI’ION

The success of radiation oncology has been built on local regional control and cure for carcinoma of the cervix (24), head and neck cancers (53), Hodgkin’s disease (33), prostate cancer (2), and other malignancies. More recently, conservative surgery and organ preservation have been integrated with radiation and/or chemotherapy to treat breast cancer (29) and bladder cancer (71) as well. Radiation oncologists in the United States, however, have not participated in the care of systemic metastases other than for palliation of involved organ sites (58), even though our specialty has a tradition of systemic treatment with radioactive isotopes. Therapy based on the use of radioactive isotopes has proved successful not only in local and systemic treatment, but recently has opened a new frontier in cancer therapy that challenges our training programs to modernize, challenges our radiobiologists to understand the mechanisms of the cytotoxic effects of continuous variable low dose rate radiation, and challenges our physicists with new problems in dosimetry as wel1 as new methods of analysis. METHODS “‘Iodine:

AND MATERIALS

a classic in systemic radiation therapy

Normal thyroid tissue metabolizes iodine. Thyroidectomy for papillary and follicular cancer larger than 1.5 cm3 presents a risk of local regional and distant failure (4). Beierwaltes et af. reported that after thyroidectomy

Accepted for publication

16 November 1989. 981

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Rebirth of isotope therapy 89Strontium, a pure beta emitter Eb = 0.583, Tf = 50 days, is selectively taken up by bony metastasis (66). Administration has varied from 2 mCi to 20 mCi, producing in 60%-70% of patients palliative relief of bone pain, dependent on dose administered, and patient selection ( 13, 66). Hematologie toxicity has not been reported for 89Strontium at most doses used. Personal experience indicates, particularly in previously treated patients, that such toxicity occurs. In a randomized progressive study, which remains controversial, Correns et al. reported less pain relief with 89Sr than for placebo (not statistically different) however with longer survival for the group treated with 89Sr (13). Stable response to hormone therapy was said to favor the placebo group, as welk providing more relief of pain (13). Despite this disparity, increased survival from 12 months for placebo to 27 months in the 89Sr treated patients indicated a possible therapeutic advantage for isotopie therapy. A trans-Canadian trial comparing placebo to 89Sr is currently underway, although the data are not yet available. Among the fundamental questions remaining regarding the use of 89Sr is its potential adjuvant efficacy in patients with poor prognosis, a normal bone scan, and with early metastases. To presume that 89Srwil1 not be beneficial in micrometastatic disease cannot be based on the fact that scanning fails to demonstrate the lesion, since such nuclear stans require background-foreground differences and are not sensitive to the minima1 calcium exchange to which 89Sris sensitive. In addition, how wil1 hormone treatment, local regional irradiation, and hemi-body irradiation compare to, and be additive to, a 89Srprogram? Wil1 there be new therapeutic opportunities in breast cancer metastatic to bone, as wel1 as in prostatic cancer? 89Srproffers a new approach to bone metastases that avoids the integration in hematopoietic cells evident with the use of 32P and the consequent leve1 of hematopoietic toxicity (1). Specificity directed isotope therapy Beginning with a clinical application in 195 1, Beierwaltes achieved a 9-year complete remission of a metastatic melanoblastoma with 27 mCi of 13’1iodinated rabbit immunoglobulin (3). Later Pressman et al. and Spar et al. carried out laboratory and clinical studies with 13’1 antifibrin (64,74). Clinical interest, however, waned until a renaissance occurred in the diagnostic applications of 13’1antiCEA and 13’1antiferritin (26, 44, 55). The discovery .of monoclonal antibody production made by Kohler et al. led to a burst of activity, since a reagent pure monospecific antibody could be derived for any tumor desired (37). Most monoclonal antibodies were generated against tumor associated antigens and were neither unique nor tumor specific with one exception, the idiotype antibody generated by B-cel1 lymphoma (52). In this latter instance, the tumor generated immunoglobulin was to be the antigenic target for monoclonal antibody, that is, anti-idiotypic antibody (52). Al1 other antigenic

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specificities in other tumors were to show cross reactivities with other malignancies, and, in some instances, with normal tissues. How then was specific localization to be achieved? To answer this, we must consider the area of innate tumor physiology and become familiar with discoveries made in the development of radiolabeled antibodies. As oncologists may not have a general appreciation of this, a brief introduction of the subject wil1 be followed by the clinical history of radiolabeled antibodies to the present day. Tumor physiology Tumor physiology has proved important in understanding the underlying mechanisms of radiolabeled antibody tumor targeting. Jain observed that innate tumor biology both resists and complements radiolabeled antibody targeting of tumors (31, 32). Increased interstitial pressure and lack of lymphatic pathways, as wel1 as reduced centra1 vasculature, inhibit radiolabeled antibody tumor deposition, whereas increased neovascular permeability and hydraulic conductivity aid in tumor targeting. Rostock et al. in more pragmatic terms, described by basic laboratory studies the clinical observation concerning neovascular amplification of radiolabeled antibody tumor targeting (67-69). In a series of rodent hepatomas he found that given equal antigenic content and equal tumor size, the neovasculature determined the extent of radiolabeled antibody targeting. As larger tumors had reduced antigenic production (ferritin), radiolabeled antibody deposited peripherally better than centrally in such tumors. The clinical observation (4 1) that external radiation would increase neovascular permeability was demonstrated in the laboratory to be effective only in tumors with abundant vascular structure as shown by Msirikale et al. (54). Finally, Delaloye et al. has reported that the beta blocker, Esmolol, aids in increasing radiolabeled antibody tumor targeting (Table 1) (14). Further research concerning modification of vascular permeability is needed. Isotope linkage (chemistry) At fust review, it would seem that 13rI would be the ideal isotope for radiolabeled antibody treatment, having an average beta energy of 0.183 Mev and physical half life of 8 days for cytotoxic purposes, and emitting gamma rays for tumor visualization and quantitation. Certainly, from the viewpoint of ease of antibody labeling, “‘1 proved ideal. There are several techniques for radiolabeling (10, 46, 5 1, 64), al1 widely used and successful. Additionally, the minima1 systemic toxicity of the isotope (hypothyroidism) and the extensive clinical experience were, and are, favorable for its use. However, to date dose rates of 5 rad/hr and continuous variable rate low dose radiation have been the outcome of clinically applied 1311iodinated radiolabeled antibodies (38-40).

Systemic radiotherapy 0 S. E. ORDER Table 1. Isotopes

Isotope 13’1(Beta & gamma)

Physical $ life

Mean energy

8 days

0.183 Mev

50 days

0.583 Mev

(ft?)

2.7 days

0.937 Mev

rste;i

3.8 days

0.781 Mev

(K) ZI?Bi

6 1.8 hours 60 minutes

(2X?) (afpha) -1

7.2 hour

0.142 6.09 6.05 5.87

89Sr

60 days

for therapeutic

Mev Mev (10%) Mev (25%) Mev

Auger electrons 0.008-0.226 Mev

The use of 9oYttrium has a clinical tradition in therapy, particularly in more recent times in Europe, in the treatment of arthritis as a colloidal preparation (77). 9“Yttrium has a pure beta emission of 0.937 Mev and a physical half life of 2.7 days. To obtain pretreatment evaluation of 9oYttrium labeled antibodies, the same chelation procedure and linkage must be made with the antibody and the isotope “‘Indium, a gamma emitter used for dosimetry. This apparent disadvantage has in reality proved advantageous, allowing for any inappropriate deposition of radiolabeled antibody to be determined before the therapeutic application of the 9oYttrium labeled antibody. In clinical experience approximately four times the radiation dose has been achievable using 9oY as the isotope conjugated to the antibody rather than 13’1(41, 6 1). The chelation chemistry of yttrium has been complex in that if not tightly chelated, unbound 9oYttrium would result in bone toxicity (30). Complexities of chelation and chelate linkage are not restricted only to antibodies and immunoconjugates, but also to other biologie carriers. Interest in this new area of research has led Claude Meares to introduce a new journal, Bioconjugate Chemistry, to explore the issues, techniques and basic mechanisms of bioconjugation. Not only must the chelate for metallic isotopes linked to antibodies be tightly bound, but the isotope must not become free of the chelate during the biodegradation of the complex if undue hematologie toxicity from free 9oY is to be avoided. Our first experiences with a DPTA 9oY chelate and linkage in hepatocellular cancer demonstrated nonspecific binding to the normal liver due to reticuloendothelial attraction. This nonspecific dose reduced the therapeutic ratio of specific tumor binding to nonspecific binding. A newer linkage that would reduce nonspecific binding and allow excretion of the chelated isotope is being evaluated. lE6Rhenium has fostered considerable interest due to the similarity of its chemical binding properties to those

983

consideration

Features Scan and treat. Free isotope not dangerous. Easy to label Often dehalogenates from monoclonal antibody NO integration with marrow cells. Good exchange with bony metastasis Chelation chemistry complex. Increased cytotoxicity over 13’1. “’ In needed for scan & dosimetry 99Tc chemistry. More energetic than “‘1 Photon-like x-ray for detection NO oxygen dependence. NO dose rate dependency. range NO oxygen dependence. NO dose rate dependency. range Auger electron intemalized

Short Short

of 9YTechnetium (25). It has an average beta energy of 0.78 1 and a physical half life of 3.8 days. It also emits an x-ray r 137 Kev for imaging and quantitation (25). 67Copper has generated some interest as wel1 due to its unusual decay, emitting an x-ray like photon for detection and quantitation. The beta energy is 0.142 and the physical half life 2.4 days. There have been no reports of clinical trials with this isotope to date. In addition to beta emitting isotopes. alpha emission from “‘Bismuth, and “‘Astatine have demonstrated efficacy in laboratory studies (6, 7, 45). Protocols for intracavitary treatment, and for exogenous treatment of involved bone marrow in marrow transplantation programs have been proposed with alpha emitting isotopes linked to antibody, but no clinical studies have as yet been reported. The lack of oxygen effect and the minima1 distance of irradiation have been cited as features of interest in this form of irradiation. Furthermore, there is no doserate dependence for alpha particles. Finally. ‘*‘Iodine, whose Auger electrons once internalized within the tumor cel1 are cytotoxic led to the possibility of high dose application without significant hematologic toxicity (11).

Antibod_v, the carrier qf specifcity (immunology) A discussion of antibody specificity could be directed toward differences in polyclonal and monoclonal antibodies, and distinctions between whole IgG, IgG subclasses, and antibody fragments, as wel1 as antibody chimerism, for example, murine-human, etc. Rather than elucidate the various features of antibodies and fragments, however, exploring data from the clinical trials and reviewing the new knowledge they provide wil1 serve the discussion. Further, approaching radiolabeled antibodies from the classic dose-response of tumor to external radiation probably offers more of an appreciation of the lack of parallelism between these two forms of ra-

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May 1990, Volume 18, Numher 5

CT scan demonstrating pulmonary nodules in a Hodgkin’s patient failing two major Fig. 1. (a) The pretreatment courses of chemotherapy. (b) “‘Indium polyclonal antifenitin scan demonstrating tumor targeting prior to yttrium antiferritin treatment. “‘Indium and WYttrium are similarly chelated and distributed similarly with the antiferritin antibody. (c) The post treatment CT scan following yttrium antiferritin with complete remission of the malignancy.

diation in the present state of the art (3). Extemal radiation being high dose rate interrupted (24 hr) and fractionated, and radiolabeled antibody, low dose rate, variable and continuous. We have observed that extemal radiation for active Hodgkin’s disease requires 4000 cGy/4 weeks and seems to be equivalent in our preliminary experience to

2000 cGy of variable low dose rate irradiation from 9oY antiferritin (78, 79).

ling

Hodgkin s disease

Ferritin was purified, crystallized, and prepan :d asi an immunogen (20, 34) from Hodgkin? splenic in filtra Res.

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985

Fig. 1. (Con&)

It was demonstrated to be synthesized and secreted by Tlymphocytes of Hodgkin’s infiltrates (57, 65). When 13’1 was conjugated to antifenitin, fundamental biologie and clinical data could be obtained. The clinical discovery that intravenous administration of radiolabeled antibody resulted in selective tumor targeting without deposition in normal ferritin bearing tissues led to laboratory investigation (56, 57, 60, 67-69). Laboratory studies showed no differente in uptake in normal tissues between 13’1 antiferritin and 1311normal immunoglobulin (67-69). Thus, specific binding of antiferritin did not occur in the normal spleen, marrow, etc (67-69). By contrast, syngeneic ferritin bearing tumors implanted in experimental animals produced selective tumor targeting by 13’1antiferritin (67-69). The selectivity of radiolabeled antibody for tumor deposition resulted from ferritin synthesis and secretion by the tumor and from the permeable nature of tumor neovasculature. This phenomenon was described as the biologie window (56, 57, 60). We began the Hodgkin’s studies in patients who had failed MOPP, ABVD or other major chemotherapy programs. This study (RTOG 83-09) demonstrated that the technology was transferable, being used in California, at the University of California at San Francisco, and in a private hospita1 environment at Albert Einstein in Philadelphia (Table 1) (42). Using 1311antiferritin, 40%, partial remission was seen in 37 patients (42). The polyclonal antibodies were derived from immunization of intact animals with the crystallized ferritin (20, 34, 42). Toxicity to the treatment was hematologie, delaying additional treatments (42). To avoid sensitization and anti-antibody reaction, patients were treated in cycles, each cycle using antibody obtained from a different species, rabbi& pig, etc. Due to the malignant disorder, however, there was

natura1 immunosuppression and anti-antibody was not a problem (36). The next major step was to evaluate whether dose escalation would lead to an increased response. The linkage and chelation of 9 to antifetitin was to provide this opportunity. It required laboratory reassurance that free 9oY did not occur after intravenous administration of 9oY antiferritin. Normal animal and tumor bearing animal studies prior to clinical trials were reassuring. To avoid treatment delays related to hematopoietic toxicity, autologous marrow was removed and re-infused 16 days later when there was no significant residual radiation. To date 10 patients treated in a Phase 1-11dose escalation study have shown a 50% complete remission rate, while optimal dose seeking data are being obtained (Fig. 1). In these preliminary studies, we have noted that continuous radiation in a range from 1,000 cGy to 2 100 cGy has been associated with remission (78, 79). Vriesendorp et al. have pioneered studies in canines to determine the limits of hematologie toxicity, and calculate the upper limits even with autologous marrow infusion in man to be 240 mCi (79). Experimental studies with the present chelated 9oY antiferritin, have provided preliminary evidente that the liver with radiation induced hepatitis may be the second limiting organ once hematopoietic toxicity is resolved by marrow transplantation. Vriesendorp has also compared clinical tumor targeting with monoclonal antiferritin administration for Hodgkin’s disease with polyclonal antiferritin. The polyclonal antiferritin has been superior. Yet in laboratory animals bearing ferritin positive tumors, the monoclonal antiferritin is superior. In the clinical studies, 0 out of 4 patients showed tumor targeting with monoclonal antiferritin whereas 12 out of 13 targeted with polyclonal antiferritin.

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Many questions remain to be answered. How much cold antibody must be added to the radioactive antibody for infusion? How many antigen binding sites does polyclonal antibody bind compared to monoclonal antibody? Does mouse versus rabbit immunoglobulin, due to the individual protein structure of the immunoglobulins, pose a significant differente in regard to catabolism, tumor targeting and tumor effective half life? Other areas that must also be pursued to perfect radioimmunoglobulins include fractionation of radiolabeled antibody, tumor saturation dose, new chelate linkage to techniques for better biodistribution, integration with chemotherapy, substitution for TB1 in comparative marrow transplantation trials in Hodgkin’s disease, development of human-murine chimeric antibody, and blended monoclonal antibodies for broader specific ferritin binding. The 20-50% remission variation in the conventional forms of treatment of advanced Hodgkin’s disease failing chemotherapy are due in part to patient selection. There remains considerable room for improvement, and 9oY antiferritin has real promise as this radiolabeled antibody is further refined for clinical use. Clearly, dose-response has been demonstrated for the radiolabeled antibody that is, 40% partial remission with 13’1antiferritin, to 50% complete remission with 9oY antiferritin (42, 78, 79). In addition, the use of autologous bone marrow to prevent potentially fata1 marrow toxicity, and to allow earlier cyclic treatment has been accomplished (78, 79). Future studies wil1 involve determination of the maxima1 safe dose for effectiveness, fractionation, comparison to TB1 and combination with chemotherapy. Non-Hodgkin ‘s lymphoma

The B cel1 non-Hodgkin’s lymphomas offer a favorable dose-response, that is, 3000 cGy/3 weeks external radiation. One of the early reports of response to antibody treatment involved non-labeled anti-ID antibody, although a complete remission of 6 years in the first patient was not duplicated in other patients (52). Even more fascinating was the recurrence of the monoclonal idiotypic lymphoma following leg trauma in this patient, and the subsequent complete remission following external radiation to the Iesion. Was the original response an immune modulated one? Following this initial response, replication of such remissions remain unique. Parker et al., using anti-idiotype antibodies and the same 9oYttrium chelate as our group at very modest doses, has made two important observations in the first two patients (62). If the idiotypic antibody is circulating in sufficient titer, it wil1 inhibit the anti-idiotypic localization in the tumor and thus inhibit any therapeutic response. Without a circulating idiotypic antibody titer tumor, targeting and remission occurred even during this dose escalation study. To date in the two patients treated, there has been no significant toxicity. Another approach to non-Hodgkin’s lymphoma has been the 13’1anti-Lym-1 antibody. DeNardo et al. re-

May 1990, Volume 18. Number 5

ported over 90% remission using fractionated courses for the treatment of 28 patients with both B cel1 lymphoma and chronic lymphatic leukemia (15, 16). Future therapeutic plans cal1 for 9’? radiolabeled antibody. Press and the group at Seattle have taken an even more aggressive approach using 13’1anti-MDI, which recognizes B cel1 lymphoma, substituting the radiolabeled antibody in place of total body irradiation (63). Single dose escalation up to 600 mCi with the patients in isolation has led to complete remission in 4 out of 4 patients (63). Patients with splenomegaly and large tumor burdens did not demonstrate uniform tumor targeting and were not treated. Patients with modest tumor burdens and no splenomegaly were chosen for the treatment. These patients’ tumors al1 targeted with radiolabeled antibody and were remitted.

DISCUSSION Solid tumors Colorectal cancer metastatic to the liver. Perhaps the most intensely studied disorder and the one least associated with therapeutic response has been colorectal metastasis treated with 13’1antiCEA IgG and Fabz. The metastatic lesions are relatively hypovascular compared to primary liver malignancies and as such do not offer the access to whole IgG antiCEA. When the CEA antibody is modified to Fabz the reduced molecular weight allows for vascular penetration and excellent imaging is obtained (27, 44). However, the reduced tumor effective half life results in a reduced tumor dose and does not compensate for the somewhat increased concentration of radiolabeled antibody. Worldwide there are multiple programs attempting to solve this fundamental problem. Remission rates are so poor as to indicate they are rare and not worthy of report. In quantitative assessments of radiolabeled antibodies in tumors the maximum dose achieved to date has been in the 2000 cGy range; more than 5000 cGy is most probably needed for colorectal metastasis. The problem of effective therapy of colorectal metastasis must take into account the requirements for remission (higher tumor doses), features which oppose one another (the need for penetration with reduced vascularity, thus, Fab2 which in effect penetrates better but reduces tumor dose). Additionally, chelated Fabz with a metallic isotope 9”Yor lg6Re must clear the kidney more rapidly or nephrotoxicity could be a problem. Hepatocellular cancer (nonresectable). Using 13’1antiferritin in a multimodality program (RTOG 78-28; 830 1) a dose escalation from 30 mCi to 150 mCi was carried out (60). The only toxicity recorded was a lowering of WBC and platelets 4-6 weeks after infusion but with subsequent recovery (2 1, 60). The dosimetry as determined by Leichner et al. revealed 30 mCi of 13’1antiferritin at 8- 10 mCi/mg IgG saturated hepatocellular cancers (3840). The tumor effective half life was 3.9-5.4 (mean 4.6

Systemic radiotherapy 0 S. E. ORDER

days) days, and therefore a second dose of 20 mCi was given 5 days later to resaturate the tumor. In addition, it was found that for tumors smaller than 1000 cm3 or gram& 20 mCi saturated the tumor, and that 10 mCi 5 days later would resaturate the tumor. Tumor doses averaged 1 lOO- 1200 cGy. A trial with antiAFP (alpha fetoprotein) could only achieve 300 cGy and the trial was discontinued (38). Cyclic treatment was developed next, in which the species of derivation from which the immunoglobulin was derived was altered. The final sequence was rabbit, pig, baboon and horse, since the immunoglobulins from these species had tumor effective half lives of at least 3 days (60). Integration of chemotherapy using high doses of doxorubicin and 5FU led to too long a treatment delay following a single course of treatment as a result of hematologie toxicity. However, modest doses, 15 mg doxorubicin and 500 mg 5FU, resulted in an acceptable hematologie nadir at 4-6 weeks with recovery of the patient for the next treatment by the eighth week (60). Median survivals from this Phase 1-11 trial were 5 months for AFP+ and 104 months for AFP-. As the cellular division rate of AFP+ hepatoma was 30 days or less, progression and lessened response of these patients was inevitable considering that radiolabeled antibody was given every 8 weeks (60). RTOG 83- 19 was a natura1 follow-up study, being randomized, prospective and comparing after an induction treatment, full dose chemotherapy, 60 mg/m* doxorubicin and 500 mg/m* 5FU every 3 weeks to 13’1antiferritin and 15 mg doxorubicin, and 15 mg 5FU every 8 weeks (59). During the course of determining tumor dose from radiolabeled antibody, tumor volumetrics became an active part of the program (22, 57, 59, 60, 81). It soon became apparent that tumor volumetrics which could determine from patient’s CT or MRI examinations the extent of cancer, would more accurately define and quantitate tumor remission and progression than the physical examination (8 1). ECOG had chosen as one criteria of remission in hepatocellular cancer that the physical sum of al1 palpable liver below the Costa1 margins must be reduced by 30% (23). We converted these criteria into volume. Non-resectable hepatomas average 1500 cm3, and a T3 cancer of the head and neck is greater than 125 cm3, so hepatocellular cancer being 8-10 times larger made it seem rational in adopting 30% reduction for remission analysis. Thus, a 1500 cm3 hepatoma required a 500 cm3 reduction, this remission volume is 3 times the size of a T3 cancer of the head and neck. This system of tumor volumetrics has since been disseminated through RTOG and other institutions, and is of value in at least 95% of patients seen (Fig. 2). Along with tumor volumetrics, clinical examination, liver chemistries, and AFP titers were used to evaluate the patients in the randomized prospective study. The study allowed crossover to the other form of treatment if there was tumor progression (59). Recently. the randomized prospective trial has been completed (59). The trial demonstrated equivalent sur-

987

Fig. 2. The tumor volumetrics of a patient treated with 13 cycles of radiolabeled antiferritin demonstrating minima1 change in normal liver and significant tumor reduction with remission of 3 years.

viva1 for chemotherapy or radiolabeled antibody, except that al1 long-term AFP-survivors had antibody treatment. The two unique findings of the trial were that in AFP negative patients crossover to radiolabeled antibody therapy had a higher remission rate than primary randomization to radiolabeled antibody, and that non-resectable hepatocellular cancer could be converted to resectability by radiolabeled antibody (59, 72. 73). In the laboratory Dillehay and Williams were to demonstrate that the continuous variable low dose rate irradiation of a hepatocellular cancer in tissue culture caused the cells to enter G2 and M phases, where the radiation at low dose rate led to tumor cel1 kil1 (80). Thus, patients who were AFP- and who had failed chemotherapy were highly sensitive to subsequent radiolabeled antibody. In fact, of the 5 patients in RTOG 83-19 who became resectable, 3 were AFP- and crossed over to antibody therapy to gain remission necessary for resection. Our total experience documents 11 patients who have had conversion of non-resectable to resectable hepatocellular cancer by the use of radiolabeled antibodies. Of the 11 patients 80% presently have a greater than 3-year survival. Another study which was initiated in patients with metastatic hepatocellular cancer, was the use of 9oY antiferritin to achieve higher doses of radiation (6 1). In this instance 20 mCi was demonstrated not to cause significant hematologie toxicity, whereas 30 mCi did (61). The unexpected finding that the chelate antibody was overly attracted to the normal liver was termed “chelate domination.” This normal liver attraction did not allow for effective primary tumor treatment although metastatic lesions were resolved. These findings also led to development of a new chelate-linker-antibody immunocon-

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jugate, which is presently being tested in patients with primary and metastatic hepatoma. Another development has been a chemically modified antibody which is being evaluated clinically for its nonimmunogenicity. Theoretically, this antibody would allow continuous cyclic treatment without anti-antibody production (RTOG 88-23). While these developments in antibody technology are ongoing, a new multimodality clinical trial was completed using external radiation of 2100 cGy and 50 mg/m2 cisplatin, I.V., followed by monthly intra-arterial cisplatin of 50 mg/m2. Of 21 AFP+ patients, the median survival is 16 months, in contrast to 5 months with doxorubicin and 5FU ( 19). There was no significant hematologie toxicity (19). This program wil1 be used in conjunction with radiolabeled antibodies in new trials. Intrahepatic biliary cancer. In direct contrast to the experience with 13’1antiCEA in colorectal cancer metastatic to the liver, the same antibody in intrahepatic biliary cancer that is primary and within the liver yields affirmative results (76). In this primary malignancy, neovasculature is present in sufficient quantity to allow for significant radiolabeled antibody targeting. Stillwagon et al. reported 37 patients with non-resectable intrahepatic cholangiocarcinomas, 57% of whom were previously treated or who had metastatic disease (76). Using radiation plus chemotherapy induction followed by cyclic 13’1antiCEA, and tumor volumetrics for analysis, there was a 33% remission rate with a median survival of 6.5 months, and for remitters, the median survival was 15.2 months. The longest partial remission was 4 years (76). Gliomas Brady et al. have utilized 1251labeled anti-epidermal growth factor antibody in the treatment of 14 patients (11). One complete remission and one partial remission have been reported. The internalization of the 1251leads to auger electron irradiation which is cytotoxic. Imaging is accomplished with 13’1and treatment with 1251. Varied routes of administration. Intraperitoneal with whole therapy antiserum in experimental ovarian cancer demonstrated the advantage of direct antibody binding of tumor cells. This was soon translated into more elegant studies by Epenetos and co-workers, using antibodies to milk fat globulin, AUA and placental alkaline phosphatase labeled with 1311and administered intraperitoneally in ovarian cancer (17, 18). More recently, studies with 9oY labeled antibodies demonstrated in their system that the 9oY became free of the chelate and led the investigators to propose EDTA to be given intravenously to chelate the free 9v and reduce hematopoietic toxicity. Overall responses remain limited and micrometastatic disease responds more favorably than macrometastatic disease. Epenetos has also explored intrapleural treatment using the same premise of immediate contact of antibody and tumor cells.

May 1990, Volume 18, Number 5

Intrathecal radiolabeled antibody has also been used in neuroectodermal with an exceptional but not reproducible response (35). However, the lack of significant toxicity holds promise for this technique if other problems such as increased tumor dose and cyclic treatment are solved. These innovative approaches require further investigation but are technically feasible and have been associated with a very limited number of remissions to date. Anti-antibody. Klein et al. reported as high as 60% antiantibody production by patients with hepatocellular cancer treated with polyclonal antibody, in contrast to the absente of such response in Hodgkin’s patients similarly treated (36). DeNardo et al. took advantage also of the low incidence of anti-antibody due to natura1 immunosuppression in Non-Hodgkin’s lymphoma ( 15, 16). However, anti-antibody production remains a major problem in the treatment of solid tumors where the patients immune system may be aroused by the foreign protein of heterologously derived antibody, murine, in the case of monoclonal, and rabbi& etc. in polyclonal applications. We are presently evaluating a chemically modified antibody in solving the immunogenicity problem. Other important approaches include the chimeric (murine and human) antibodies that are being generated (28, 43, 70). These antibodies have different isotopes for conjugation and cytotoxicity. The Fab2 fragments of these antibodies may have lives of sufficient length to allow for greater ease of tumor penetration, while sustaining a tumor half life with newer isotope linkages that causes significant tumor cytotoxicity. Metabolic and hormonally related compounds. Perhaps the most recent innovative approach to radiolabeled compounds has been the administration of 1311meta-iodobenzylguanidine or MIBG in pheochromocytoma, neuroblastoma and other endocrine malignancies. MIBG is an analogue of norepinephrine, and as such, approximately one half of the tumor cells wil1 show uptake (47). Although the estimates of tumor dose remain questionable, there have been tumor responses reported in as many as 50% of the patients (47). Isolated to laboratory research in tissue culture, i3’I labeled tamoxifen demonstrated tumor cel1 cytotoxicity (9). When studied in our laboratory, tumor bearing animals due to uptake in other sites, did not show preferential tumor uptake and remission because of reduced radiation tumor dose. More recently, “‘IVME2, an estradiol that would radiate by auger electrons has also been studied (8). The translation of preclinical studies to clinical protocols has not yet occurred. The opportunities for such compounds are vast. Radiobiology Continuous variable low dose rate irradiation has demonstrated not only tumor cel1 cytotoxicity, but also significant shifts in the tumor cel1 cycle (80). A more basic understanding of tumor cel1 response, repair, toxicity and interaction with this form of radiation is necessary to guide

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radioactive immunoglobulin protocols to more idealized fractionation schemes. Drug integration, which has barely been studied, may provide increased tumor cytotoxicity and hormonal interaction might amplify or inhibit the potential tumoricidal effects of radiolabeled antibodies. Timing of agents, duration of exposure and combination therapy could be elucidated by intensive laboratory studies to eventually aid in guiding clinical trials. Physics Clearly, the dosimetry is challenging when internal disseminated metastatic tumor is targeted. New methods are, and wil1 continue to evolve. Leichner’s contribution has been not only to determine tumor dose, but to create a system of tumor volumetrics for remission and progression analysis that has proved to be invaluable in liver malignancies, both primary and metastatic (2 1, 38-41. 81). As more is learned about the dose-response in this form of radiation, the precision of individual patient dosimetric determinations becomes more valuable. Bone marrow transplantation Autologous bone marrow transplantation has allowed dose escalation of both 13’Iodine and 9oYttrium. Hematologic toxicity was the major limiting factor in most present protocols (Hodgkin% non-Hodgkin’s), and the ability to use marrow and increase tumor dose is of significance. Wil1 radiolabeled antibodies replace TBI? Can the combination of high dose radiolabeled antibodies and chemotherapy remit advanced malignancies? The need for autologous marrow studies with the new agents is of paramount importante to achieve greater potential from present day and future radiolabeled compounds. Future perspectives The use of 89Strontium for metastatic prostatic cancer needs to be studied in dose escalation and fractionation studies, in combination with hormones, and, most importantly, in adjuvant randomized prospective studies. Radiolabeled antibodies wil1 be studied in terms of chemical modification, human-murine chimerism, and tissue culture derivation of human antibodies (28,43, 50,

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70). Al1 of these studies are directed toward allowing cyclic treatment by developing a non-immunogenic immunoglobulin either chemically or genetically. Another important area of development is the need to have radiolabeled antibodies, or antibody fragments, that deliver higher tumor doses. In this regard, the bifunctional approach of Stickney et al. where one Fab end recognizes the tumor antigen, and the other a chelate is followed 24 hr later by a chelate infusion heavily bound by isotope (75). This approach allows for clearing of the immunoglobulin in the normal tissue with optimization of normal tumor to tissue ratios. In addition, the chelate may be bound with more isotope for a higher tumor dose once the antibody fixed to the tumor binds the chelate as well. Preliminary clinical studies with this approach have been accomplished and a forma1 therapeutic trial is anticipated. The challenge Systemic radiation therapy offers a wide variety of new approaches in the treatment of malignancy. The agents used in systemic radiation therapy require an understanding of the biology, physics and chemistry and mechanisms underlying the response to treatment. The evaluation of systemic radiation therapy allows radiation oncologists to enter into the treatment of disseminated malignancies and to participate in future adjuvant protocols. Although these agents deliver radiation, we wil1 not be able to carry out such treatments if we are not sufficiently knowledgeable and if we do not offer appropriate leadership. The scientific disciplines of our speciality, radiobiology and physics in combination with clinical radiation oncology, now have the opportunity to expand activity in this field while systemic radiation therapy is stil1 in its early development. The academie departments of radiation oncology must identify this discipline, and respond to it by developing training, research, and clinical protocols to foster its advancement. In combination with our present expertise in local regional external irradiation, it can only amplify our knowledge and enhance our speciality, and, more importantly, lead to progress in cancer therapy.

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