Combined Radiotherapy and Chemotherapy of Lymphomas and Other Cancers

[CANCER RESEARCH 31, 1845-1850, November 1971]

Leon Stutzman Department of Health, Roswell Park Memorial Institute, Buffalo, New York Â¡4203

in Stage III patients with Hodgkin's disease is now well Summary accepted (18), and the principle of such total nodal therapy is Although studies of combinations of radiation therapy and now being applied to patients with Stage I and II disease. chemotherapy have shown some indication of usefulness, there Furthermore, techniques of visceral radiation, such as the is little evidence at present supporting their routine utilization inclusion of the entire liver into fields to which is delivered a for any type of localized cancer. dosage high enough to eradicate disease within the port, are However, the long-term control in a portion of patients with being utilized (19). Hodgkin's disease from multiple chemotherapeutic agent The improvement in the techniques of both radiotherapy programs suggests eradication of tumors in these patients, and chemotherapy as they pertain to Hodgkin's disease would indicating a possible alternative to the extension of radiation indicate that an area of competition in curative attempts in therapy to clinically uninvolved areas in the early stage of some categories has developed. It is also apparent that Hodgkin's disease in future therapeutic trials. Hodgkin's disease patients' tolerance to therapy has been This report includes data from a study of combination seriously underrated in the past and that the application of vincristine versus placebo during radiation therapy for combinations including both radiotherapy and chemotherapy lymphoma. Significantly better tumor response was seen at the given electively to patients during their most responsive period end of radiation therapy, with suggestive improvement in of first therapy is entirely appropriate. It is the purpose of this relapse and survival rates in those given the vincristine. report to review the background of such combinations and to Data regarding the tolerance of patients previously treated present some new data from related studies. with extensive radiotherapy during intensive multiple agent chemotherapy indicated little evidence of greater Mechanism of Action of Combination Chemotherapy and hematological toxicity or decreased percentage of scheduled Radiotherapy drug actually delivered as compared to a group of patients not previously irradiated. Response rates to the chemotherapy There would appear to be 3 ways by which combinations program were nearly as high in the previously irradiated group can operate (Table 1). as in those not previously irradiated. Potentiation versus Antagonism

Introduction Although there has been considerable discussion as to whether additive or synergistic activity for various Several years ago, when Burchenal (2) reviewed the combinations of therapeutic agents has been seen in vitro or in utilization of drugs and radiation for various forms of human vivo, any type of potentiation from agents which act cancer, he posed the question as to whether these 2 kinds of somewhat differently one from the other may be of clinical therapeutic modalities were competitors or partners. At that interest. In laboratory models, examples ranging from intense time he felt that there was little competition, since antagonism to mild potentiation have been observed (40). radiotherapy could be curative for certain types of localized When agents are evaluated in animal experiments with disease, whereas chemotherapy is almost never curative in any transplantable tumors, the contribution of transplantation type of cancer. immunity can complicate interpretation of data (26,27). A corollary of this position would note that radiotherapy In a clinical setting, data regarding potentiation or can be of little value in the cure of disseminated cancer with antagonism are of little importance unless a favorable change visceral involvement. in the therapeutic index can be obtained, allowing better However, recent developments in therapy of Hodgkin's destruction of tumor as compared to normal tissues. In this disease has seen considerable change in both of these regard, the experimental animal work of Bruce et al. (1), in therapeutic principles. Data upon the intensive multiple agent which colony-forming cells from both lymphoma and normal chemotherapeutic approach have revealed a sizable proportion hematopoietic tissue are used, may be of much value. Such of long-term, disease-free survivors and would seem to indicate studies allow time-dosage relationship studies of the effects of the probability of cure in some of these patients (6, 29, 35). various drugs and radiation therapy upon the vital stem cell The ability of radiotherapy applied to extended ports both populations of the 2 kinds of tissues, with demonstration of above and below the diaphragm to produce long-term effects possible advantages in therapeutic index. Their work indicates

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Table 1 recruitment of resting cells by the careful timing of the 2 Possible mechanisms of action of combination agents. chemotherapy and radiotherapy While such synchronization may be possible, present data do not allow the formulation of models of dosage and timing \. Simultaneous administration of chemotherapy and radiotherapy which act upon different cell phases or metabolic pathways with of diverse agents upon different normal and tumor tissues at a resultant synergistic antitumor activity. clinical level at this time. 2. Sequential utilization in heavy cytotoxic dosage by which resistant clones which escape the 1st agent could undergo destruction by 2nd Experience With Nonlymphomatous Cancer agent which works by different mechanism. 3. Cell synchronization by sublethal dosage of the 1st agent from which recovery and resultant synchronization would occur which There is a large background of clinical data concerning the would allow a large fraction of tumor cells at their most sensitive utilization of chemotherapeutic agents as adjuvant therapy to phase of cell cycle to be hit at a well-chosen interval with a 2nd the radiation of solid tumors, which are often resistant to agent resulting in marked increase in tumor cell kill. radiation. Although a number of agents devoid of antitumor activity themselves have shown some activity in experimental situations, none except hyperbaric oxygen has reached any that radiotherapy and nitrogen mustard kills at all positions of degree of clinical utilization. the generation cycle. Drugs such as vinblastine, vincristine, and Hydroxyurea has preferential cytotoxic effect in the S cytosine arabinoside kill cells at only 1 portion of the phase of hamster cells, the passage of cells from G! to the S generation cycle but demonstrate excellent therapeutic index period being blocked until removal of the drug, following in favor of tumor kill up to a saturation dosage. which the surviving cells were more sensitive to X-ray (34). Cyclophosphamide, 5-fluorouracil, and actinomycin D showed Others, working with spleen colony formation, showed an no saturation dosage, with a much better tumor cell kill than additive effect of hydroxyurea and X-irradiation, irrespective hematopoietic stem-cell kill. Despite these experimental data, there has been little of whether irradiation was given prior or after drug therapy clinical evidence of examples of interference between drugs (41). and radiation. However, Johnson and Brace (16) suggested the Hydroxyurea is undergoing clinical trials as a radiosensitizer. possibility that previous chemotherapy had altered radiation In a recent report, the drug was compared to a placebo in head response of Hodgkin's disease, based upon the observation of a and neck tumors, in which considerable evidence of 38% incidence of relapse in such patients within radiation potentiation of effect by the drug, particularly in regard to port, whereas a small control group of patients without cervical lymph node metastasis, was noted (32). chemotherapy prior to radiation had no recurrence. Cyclophosphamide started immediately after diagnosis and followed by radiotherapy has shown some promise in small pilot studies in Ewing's sarcoma; the patients remained free of Synchronization disease for longer than expected periods (13, 15). 5-Fluorouracil has been used in a number of trials in Despite the data cited above, there is considerable evidence combination with radiotherapy. Negative (10) or equivocal of a general pattern of radiosensitivity related to the cell cycle (38) results were seen with bronchogenic carcinoma. Some (24). Most cell lines are most sensitive in mitosis, with a evidence of an additive effect has been seen with 5-fluorouracil resistant peak in G! , followed by gain in sensitivity in late GÃŒand radiation upon tumors of the head and neck, especially or early S phase. Another resistant peak occurs late in S or in when given intraarterially (14, 20, 38). Further trials of a early G2. Late in G2, cells may be almost as sensitive as cells in prospective nature for this type of tumor are in progress. mitosis. In rapidly growing neoplasms, such as lymphomas, the Negative results were obtained in carcinoma of the breast, comparatively long-duration S phase may result in a relatively bladder, laryngopharynx, uterine cervix, and glioblastoma large fraction of cells occupying this phase. multiforme (38). In a small group of patients with various Since several agents may act directly (e.g., methotrexate or carcinomas of the gastrointestinal tract, it was not possible to 5-fluorouracil) or indirectly (e.g., cytosine arabinoside or increase the result from adequate radiation, but some hydroxyurea) as DNA-blocking agents resulting in mitotic usefulness may have been present when the full dose of arrest, a higher proportion of cells may be brought into radiation could not be given (12). cell-cycle synchrony which would allow an increased Methotrexate given alone has considerable activity in radiotherapy effect. carcinoma of the head and neck and may be a worthwhile A possible example of clinically useful synchronization in adjuvant to radiotherapy of these relatively radioresistant children with acute leukemia by utilization of 2 drugs has been tumors. Initial studies have indicated a 68% complete response reported by Lampkin et al. (21, 22), who administered a single (20) and a 2-year survival rate of 35% in another (8). The dose of cytosine arabinoside followed in 72 hr by a single dose mucositis reaction to treatment with the combination was of vincristine. Repeated bone marrow aspirates showed a rapid greater than from radiation alone (26). decrease of mitotic figures and uptake of tritiated thymidine, Actinomycin D has a firm investiga tional background as a then recovery to pretreatment levels or above in 72 hr. At this radiation potentiator. It has been variously claimed to produce time vincristine was given, resulting in a high rate of DNA a GI and Gj arrest as well as a partial block in mitosis. It synthesis and a much higher peak of mitotic figures 72 hr after produces an increased skin reaction when used during vincristine than was usual after the drug, which suggested radiotherapy, and other normal tissues (e.g., intestinal

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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1971 American Association for Cancer Research. Combined Radiotherapy and Chemotherapy epithelium) probably have increased sensitivity to damage (3). pressure from obstructive syndromes, Rubin et al. (33) have This drug is used routinely in the early intensive therapy of recently reported good results of spinal cord compression from Wilm's tumor and, along with surgery and radiation, an overall high-increment irradiation alone. survival rate of 80% has been achieved (4). In another series, the survival rate from surgery and irradiation of 34% was Vincristine and Radiation Therapy increased to 61% by the addition of actinomycin D (23). However., no randomized study of prospective nature is In a recently completed study at Roswell Park Memorial available, and the increased survival in Stage III may be the Institute, 50 patients were randomized to receive 3 weekly only group in which the drug makes a useful contribution doses of either vincristine or placebo in a double-blind fashion (25). The drug had no value combined with radiation for lung during a course of radiation therapy for malignant lymphoma. cancer (10). This drug and triethylenemelamine has been used The patients had late-stage disease and large tumors or were with radiation therapy for retinoblastoma in an attempt to considered to have disease at least partially resistant to former keep the necessary dosage of radiation at a lower range (36). therapy. There was no restriction of the radiation dosage, With the use of an experimental group of alkylating agents which averaged about 3000 rad (depth dose) (Table 3). There known as "dual antagonists," some degree of potentiation of were 3 patients with giant follicular lymphoma, 7 patients radiation effect upon bronchogenic carcinoma at the low with lymphosarcoma, 14 patients with Hodgkin's disease, and dosage of 1800 rad was observed; this was thought to be 25 patients with reticulum-cell sarcoma. Vincristine dosage comparable to results in those treated with radiation alone to was either 2 or 3 mg as the 1st weekly dose and 2 mg on the doses of between 3000 and 5000 rad (37). However, succeeding 2 doses given during the 2nd and 3rd week of pulmonary reactions to the therapy were also of equal radiation. severity, suggesting potentiation of damage of the normal The tumor response within the radiation port at the end of tissue. the therapy, was significantly better (p < 0.025) in the Procarbazine, although ineffective alone, was used with vincristine-treated group (Table 4), with 55% complete radiation therapy for 26 patients with mesothelioma, with response as compared with a 19% complete response in the response in 54% while 9 patients treated with radiation alone placebo control group. failed to respond (7). The final maximal response of the irradiated tumor was also better in those receiving vincristine (Table 5); complete Application of Combined Radiotherapy and Chemotherapy to Lymphomas Table 3 In view of the generally satisfactory response of Radiation dosage lymphomatous tumors to radiation therapy alone, there has Patients randomly received 3 weekly doses of either vincristine or 0.9% NaCl solution during the course of local radiation therapy. The been little interest in the routine utilization of combinations radiation dosage was equivalent in the 2 groups. of drugs and radiation to potentiate tumor shrinkage. However, resistant tumors do make up some proportion of No. of patients cases, particularly in the reticulum-cell sarcoma or Hodgkin's sarcoma group, in which techniques of combination therapy Depth dose (rad) Vincristine group Placebo group might be applied to advantage. <10001000-20002000-30003000-4000>40000413111126102 There are a number of situations, some of which were recently reviewed by Gamble et al. (9), in which the combination of drugs and X-ray may be of value in lymphoma therapy (Table 2). Although the fear of radiation edema from intensive Total 29 21 radiotherapy has led to the utilization of drugs for relieving

Table 4 Table 2 Response of study tumor at end of therapy Indications for combination chemotherapy and radiotherapy for lymphoma A significantly better tumor response at the completion of radiation therapy was seen in the group receiving vincristine as compared to the 1. Potentiation of radiation effect for better tumor shrinkage in certain control group. resistant tumors or for those recurring within a former therapy port. 2. To allow lower radiation dosage during therapy of tumors in organs easily damaged by X-rays, e.g., lungs or kidneys. radiotherapyNo. radiotherapyNo. 3. During initial therapy to Stage IV patients with a dominant tumor Type of mass in one area which can be treated locally followed by responseNone of patients1 of patients3 chemotherapy for the smaller disseminated foci. 4. Before radiotherapy to shrink huge tumor masses to allow more reasonable X-ray port size, e.g., mediastinal tumors. Partial 12 4155Placebo- 14 67 5. As "medical decompression" on an emergency basis for obstructive CompleteVincristine- 16%4 4%14 19 syndromes of venae cava, spinal cord, or airways prior to radiation. 6. To control systemic symptoms, e.g., fever, prior to radiation. Total 29 100 21 100

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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1971 American Association for Cancer Research. Leon Stutzman responses were observed in 79% of this group, as compared to regional radiotherapy, apparently due to control of metastatic 57% complete response in those given placebo with radiation, disease. but this was not significantly different. A prospective randomized British study compared the Relapse of the irradiated tumor was observed in only 17% survival of 97 patients with Stage I and II Hodgkin's disease, of the vincristine-treated patients and in 26% of the control one-half of whom were given a single dose of nitrogen group, despite evidence of progressive disease elsewhere in mustard, 0.3 mg/kg, as soon as possible following at least 2500 many of the patients. rad to affected and adjacent node areas (11). Survival data Survival of those receiving the chemotherapy has been have shown a significant difference at the 3-year point, with a better than that of the controls (Table 6). The 50% survival 70% rate survival of the group treated with radiation alone as time for the vincristine-radiotherapy group was 13 months, as compared to an 88% rate in those receiving the combined compared to 5 months in those receiving radiotherapy alone. therapy (31). Eleven of the chemotherapy group are living, while only 3 of Somewhat more vigorous chemotherapy was utilized by the control group survive. Moxley et al. (28) in a trial of 3 cycles of multiple-agent Although inadvertently there were more patients with giant therapy including cyclophosphamide, vincristine, follicular lymphoma and lymphosarcoma in the group methotrexate, and prednisone administered to 14 patients receiving vincristine, better results were seen in all the with Stage I or II disease. Radiation was delivered to involved diagnostic categories when vincristine was given, and 6 of the areas only. A complete remission rate of 86%, with prolonged 11 survivors in the drug-treated group had Hodgkin's disease. duration of remission, was obtained. The authors expressed a Thus, a better local tumor response to the irradiated area preference for chemotherapy first, to be followed by was seen by the addition of vincristine during radiation. Since radiation. the relapse rate was not high in either group, the better These studies indicate a definite field of usefulness of survival seen in those treated with vincristine during radiation combination radiation and chemotherapy for future therapy is probably due to the drug effect on the disease outside the and suggest an attractive alternative or supplement to total radiation area. nodal therapy, especially in the patients with difficult staging situations in which widespread disease is suspected either on Combination Therapy to Achieve Cure of Lymphoma anatomical grounds or by the presence of toxicity. The results of studies now underway will be of considerable importance. In the experimental animal with transplanted lymphoma, The utilization of multiple agents given over a long period marked potentiation of radiation can be achieved by nitrogen would seem as important as sufficient dosage of radiotherapy mustard, cyclophosphamide, vincristine, and vinblastine (30). in the design of future studies. The potentiation upon cure rate is also seen at full doses of

Table 5 Tolerance and Toxicity to Intensive Combinations Maximal response of study tumor Superiority of tumor response of those treated with vincristine A fear that patients would be unable to tolerate needed during radiation therapy, as compared to the control group, was seen at chemotherapy upon relapse after extended radiotherapy has the time of maximal response. proven for the most part groundless. Johnson et al. (16) have reported recovery from most hematological toxicity within 2 radiotherapyNo. radiotherapyNo. to 4 months following completion of extended-field Type of radiotherapy. The marrow granulocytic reserve returns to responseNone of patients1 of patients2 normal 5 months after the completion of such therapy (39). However, Curran and Johnson (4) reported poor tolerance of Partial 5 17 7 33 50% of the heavily irradiated group for approximately 12 CompleteVincristine- 23%4 79Placebo- 12%10 57 months after therapy. The tolerance of patients formerly treated with Total 29 100 29 100 radiotherapy, during a period of intensive 6-month courses of either 4- or 5-drug combination therapy given either in Table 6 combination or sequentially, was analyzed during the course Life table survival of an Acute Leukemia Group B study of therapy of Hodgkin's The survival time following treatment of patients receiving disease activated in 1967. vincristine during a course of regional radiation therapy is better than that of the control group. Of 246 patients, 83 had not received prior radiation therapy. A group of 105 had received radiation to 1 to 3 major survivalVincristine-radiotherapy7259553819Placebo-radiotherapy6738291910lymph node areas; this group would have included those Mo. alter treated with a mantle-type port to all lymph node-bearing treatment36121860% areas above the diaphragm or its equivalent. A 3rd group of 58 patients had received more widespread therapy, usually including areas on both sides of the diaphragm. Hematological toxicity was rated from + to ++++ severity for each course (Table 7). There was little or no evidence of increased toxicity in those most heavily irradiated in the past.

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Table 7 Hematological toxicity during multiple agent chemotherapy according to amount of prior radiotherapy The degree of hematological toxicity of patients treated with intensive 4- or 5-drug multiple-agent routines over a 6-month period revealed no correlation with the number of radiation therapy courses delivered during the earlier stages of disease.

(%)No. degree of toxicity

areasNone1-3>3Maximalof+831055814910161514â€¢H-424731+++172239++++1186 patients 0

The only suggestion of such a relationship was in the +++ B. I., Lynch, J. J.. Holland, J. F., Ross, C., Koons, C. R., Owens, A. group, and this trend is not supported by increased ++++ H., Frei III, E., Brindley, C., Miller, S. P., Brenner, S., Hosley, H. toxicity of this group. F., and Olson, K. B. A Clinical Pharmacologie Study of Furthermore, the formerly irradiated group was able to Chemotherapy and X-ray Therapy in Lung Cancer. Am. J. Med., 43: 186-193, 1967. receive adequate dosage of the drug. Those without former 11. Hancock, P. E. T., and Ledlie, E. M. Treatment of Early Hodgkin's radiation were given 81% of the scheduled drug therapy, while Disease. Lancet, /.â€¢26-27, 1967. those with 1 to 3 areas of radiation tolerated 80% of the 12. Henderson, I. W. D., Lipowska, B., Longheed, S. I., and Longheed, compounds, and those more heavily irradiated were given 76%. M. N. Clinical Evaluation of Combined Radiation and A history of former radiation did not seriously interfere Chemotherapy in Gastrointestinal Malignancies. Am. J. with the response rates obtained with the multiple-drug Roentgenol. Radium Therapy NucÃ.Med.,102: 545-551, 1968. therapy. An overall response rate of 83% in those previously 13. Hustu, H. O., Holton C., James, D., Jr., and Pinkel, D. Treatment given radiation is less than the 95% obtained in those without of Ewing's Sarcoma with Concurrent Radiotherapy and prior therapy, but the rates of complete responses were nearly Chemotherapy. J. Pediat., 73: 249-251, 1968. identical at 56%. 14. Jesse, R. H. Combined Intra-Arterial Infusion and Radiotherapy for Treatment of Advanced Cancer of Head and Neck. Frontiers Radiation Therapy Oncol., 4: 126-131, 1969. References 15. Johnson, R. E. Combined Chemotherapy and Irradiation in Ewing's Sarcoma. Frontiers Radiation Therapy Oncol., 4: 1. Bruce, W. R., Meeker, B. E., and Valeriote, F. A. 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27. Mihich, E. Modification of Tumor Regression by Immunologie 35. Stutzman, L. Simultaneous versus Sequential Multiple Agent Means. Cancer Res., 29: 2345-2350, 1969. Chemotherapy of Hodgkin's Disease. Proc. Am. Assoc. Cancer 28. Moxley, J. H., Ill, DeVita, V. T., Brace, K., and Frei, E., III. Res., Cancer Chemotherapy Rept., 53: 95, 1969. Intensive Combination Chemotherapy and X-irradiation in 36. Topley, N., du V. The Treatment of Bilateral Retinoblastoma with Hodgkin's Disease. Cancer Res., 27. 1258-1263, 1967. Radiation and Chemotherapy in Boniuk Ocular and Adnexal 29. Nicholson, W., Beard, M. E. J., Crowther, D., Stansfeld, A. G., Tumors, pp. 158-170. St. Louis: Mosby, 1964. Vartan, C. P., Malpas, J. S., Fairley, G. H., and Scott, R. B. 37. Velasco, H. A., Ross, C. A., Webster, J. H., Sokal, J. E., Stutzman, Combination Chemotherapy in Generalized Hodgkin's Disease. L., and Ambrus, J. L. Combined Use of AB-132 (Methuredepa) and Brit. Med. i.,3: 7-10, 1970. X-irradiation in the Management of Advanced Bronchogenic 30. Perez, C. A., and Olson, J. Preoperative Irradiation and Carcinoma. Cancer, 17: 841-849, 1964. Chemotherapy in the Cure of a Mouse Lymphosarcoma. 38. Vermund, H., Gollin, F. F., and Ansfield, F. Clinical Studies of Radiology, 92. 136-142, 1969. 5-Fluorouracil as Adjuvant to RT. Frontiers Radiation Therapy 31. Pike, M. C., Hancock, P. E. T., and Ledlie, E. M. Treatment of Oncol.,4: 132-158,1969. Early Hodgkin's Disease (Letter to Editor). Lancet, 2: 1361, 1967. 39. Vogel, J. M., Kimball, H. R., Foley, H. T., Wolf, S. M., and Perry, 32. Richards, G. J., and Chambers, R. G. Hydroxyurea: A S. M. The Effect of Extensive Radiotherapy on the Marrow Radiosensitizer in the Treatment of Neoplasms of the Head and Granulocytic Reserves of Patients with Hodgkin's Disease. Cancer, Neck. Am. J. Roentgenol. Radium Therapy NucÃ.Med., 105: in press. 555-565, 1969. 40. Werkheiser, W. C. Mathematical Simulation in Chemotherapy. N.Y. 33. Rubin, P., Mayer, E., and Poulter, C. Part II: High Daily Dose Acad. Sci., in press. Experience without Laminectomy. Radiology, 93: 1248-1260, 41. Wodinsky, I., Swiniarski, J., and Kensler, C. J. Spleen Colony 1969. Studies of Leukemia L1210. VII. Combined Effects of 34. Sinclair, W. K. The Combined Effect of Hydroxyurea and X-rays Hydroxyurea and -y-Radiations on in Vivo Systems. Frontiers on Chinese Hamster Cells in Vitro. Cancer Res., 28: 198-206, Radiation Therapy Oncol., 4: 79-92, 1969. 1968.

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Leon Stutzman

Cancer Res 1971;31:1845-1850.

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