- Email: [email protected]
Drug summary: Nitrosoureas
Int. J. Radiation Oncology Biol. Phys., Vol. 5, pp. 1592-1595 c Pergamon Fkess Ltd., 1979. Printed in the U.S.A.
??Nitrosourea
DRUG SUMMARY: NITROSOUREAS CHARLES G. MOERTEL, M.D. MayoClinic, Rochester,MN 55901
Streptozotocin, forming Chlorozotocin, nausea and vomiting are greatly reduced and become essentially no clinical problems at all. Nephrotoxicity and hepatotoxicity are observed with BCNU, CCNU and methyl-CCNU, but they are rare-less than 2% of patients. Streptozotocin, on the other hand, produces frequent and occasionally lethal nephrotoxicity. This is really the dose-limiting toxic effect. Streptozotocin also produces frequent alterations of liver function. Again, a pleasant surprise, with Chlorozotocin, both nephrotoxicity and hepatotoxicity essentially disappear. Dose-limiting toxicity for BCNU, CCNU and methyl-CCNU is hematologic and of a unique pattern. If you follow counts closely in these patients, you find they will develop a mild nadir of leukopenia from which they will quickly recover 10 days later. They then develop a delayed nadir of thrombocytopenia at three to four weeks and a remarkably delayed second nadir of leukopenia at five to six weeks. I have never had this phenomenon of greatly delayed hematologic toxicity adequately explained and I think it would be interesting to find out why this occurs. In addition, with repeated treatment, cumulative bone marrow toxicity will develop, frequently making it impossible to continue treatment with these agents or any other drug toxic to the bone marrow. Streptozotocin has hardly any bone marrow toxicity. On the other hand, when the chloroethyl group is added to form Chlorozotocin, the typical nitrosourea bone marrow toxicity appears again. In humans, BCNU, CCNU, and methyl-CCNU have similar spectrums of therapeutic activity. All have produced some responses in lymphomas, gliomas, small cell lung cancers, melanomas, gastric cancers, colorectal cancers and scattered other tumors. For many of these, such as melanoma and gastrointestinal carcinoma, responses have been partial and transient and of no substantive value to the patient. BCNU treatment of glioma and the addition of CCNU to combination chemotherapy of lymphoma have both produced significant survival in-
Since this session has been dominated by laboratory research, it seems appropriate to lay some clinical background. The nitrosoureas have been in clinical use for more than a decade, and two of them, BCNU and CCNU, have been approved for marketing. As a class they have had a broad spectrum of activity in animal model screens and a correspondingly broad activity in human neoplasia. The basic structure of the nitrosourea moiety is very simple and the addition of two chloroethyl groups yields BCNU. BCNU has a high degree of alkylating activity, as well as carbamylating activity. If one adds a chloroethyl group and a cyclohexyl group to the nitrosourea moiety, the result is CCNU-adding a methyl group to that yields methyl-CCNU. Both of these also have high alkylating and carbamylating activity. If a sugar moiety is added to the nirosourea core, you have Streptozotocin, and if both a sugar moiety and a chloroethyl group are added you have Chlorozototin. Both of these agents have markedly reduced carbamylating activity. These different additions to the nitrosourea core produce some striking changes in the effects of these agents on both animal and human models. In the Lewis lung tumor for example, methyl-CCNU shows a striking superiority in therapeutic effect to both BCNU and CCNU. On the other hand, for subcutaneously implanted L-1210, methyl-CCNU is inferior to both BCNU and CCNU. In humans, changes in structure of the nitrosoureas produce some interesting changes in toxicity. BCNU, CCNU and methyl-CCNU all produce considerable nausea and vomiting. Normally these effects do not begin until about four or five hours after drug administration. They then persist for about three to four hours, and then rapidly disappear. Streptozotocin is the most toxic of all the nitrosoureas in this respect, producing very severe nausea, vomiting and anorexia that frequently persists long after treatment stops and occasionally makes therapy completely intolerable. Surprisingly, when the chloroethyl group is added to 1593
1594
Radiation Oncology 0 Biology 0 Physics
creases and this was the basis of their approval for marketing. Streptozotocin has a narrow range of activity confined to the APUD tumors-islet cell carcinomas and carcinoids. Chlorozotocin has really just entered into Phase II trials but responses have been observed in a few tumor types of the same variety that are also known to respond to either BCNU, CCNU or methyl-CCNU. Dr. Philip Schein and his group have raised the possibility, based on animal model data, that the optimum therapeutic effect with Chlorozotocin may be obtainable at doses which produce no toxicity or minimal toxicity. We are currently addressing this question in a randomized controlled study conducted jointly with Georgetown University. The question of the role of nitrosoureas in combined modality radiation therapy, chemotherapy trials is presently difficult to assess. The main interest in this arena has centered around the treatment of gliomas. In their first controlled trial, the Brain Tumor Study Group compared no treatment, with BCNU alone, with radiation therapy alone, and with BCNU plus irradiation. They found some survival advantage with the nitrosourea alone, a significantly greater advantage with irradiation alone, but they found no difference of consequence between irradiation alone and radiation plus BCNU. In the second study, they compared irradiation alone to methylCCNU alone to irradiation plus BCNU to irradiation plus methyl-CCNU. It is already apparent that methyl-CCNU alone is the inferior arm and that the combination of methyl-CCNU and irradiation holds no advantage over radiation alone. On the other hand, in contrast to their first study, the combination of BCNU and radiation now produces a significant survival advantage over radiation therapy alone (personal communication with Dr. Michael Walker). We find the same apparent conflict in studies of CCNU. Our Mayo Clinic studies showed no advantage for treatment with combined CCNU and irradiation compared to irradiation alone. On the other hand, the EORTC Brain Tumor Group found that CCNU did prolong survival of glioma patients but only when given on relapse after radiation therapy. They did not feel that concomitant administration of CCNU and radiation produced any improvement in survival or symptom-free interval. In this session, it is apparent that our colleagues in the laboratory are trying to help us out of this quandry by guiding us toward more effective combined radiation-nitrosourea therapy and particularly by directing us toward more effective timing in the administration of these two modalities. Deen et al. studied both BCNU and CCNU combined with radiation using in vitro 9L brain tumor cells. They found the dose enhancement ratio was minimally im-
September
1979, Volume 5, Number 9
proved with CCNU but was more definitely improved with BCNU. This was most impressive when BCNU was applied 15 to 23 hours before radiation. Bateman et al. used human xenographs of pancreatic carcinoma. They found that methyl-CCNU potentiated radiation effect and the most ideal timing for nitrosourea administration in this system was three hours before radiation. Lelieveld et al. used implanted EMT6, KHT, and RIF-1 tumors and tested BCNU given at intervals from 24 hours before radiation to 24 hours after radiation. They found no consistent patterns indicating radiation enhancement by BCNU. In one experiment of 23, however, there did seem to be such an effect. This was the KHT tumor with BCNU given two hours before radiation. Wheeler ef al. used intracerebral 9L tumors and administered BCNU 2, 6, or 16 hours before radiation in a fractionated schedule. Combination therapy produced a significant increase in life span compared to irradiation alone and administration of BCNU 16 hours before radiation therapy was significantly superior to either two hours or six hours. Barker et al. also used the 9L brain tumor and gave BCNU six hours before, immediately preceding, and six hours after radiation. They found both survival and cures to be improved by the combinations, but they got the best results with BCNU given six hours after radiation. Begg et al. used subcutaneous EMT6 tumors in mice and administered BCNU at a wide range of intervals from 64 hours before radiation to 64 hours after radiation. They found enhancement of radiation effect which was greatest when the drug was given one to eight hours after radiation. Lelieveld et a/. used two mouse strains to test enhancement of normal tissue reaction by the addition of BCNU to radiation. They found no enhancement of radiation myelitis. In BALB mice who were not anesthetized they found no enhancement of radiation skin reaction, but in anesthetized C3H mice they did find enhancement. This was greatest when BCNU was given just before radiation. Goldstein et al. used LAF-1 mice to assay the effects of combined BCNU and radiation on the intestinal crypts. They found BCNU did enhance radiation cell kill with progressively greater BCNU effect from 18 hours before radiation to two hours before radiation. The effect was reduced if BCNU was given after radiation. It is of interest that the addition of BCNU did not appear to inhibit repair of radiation damage. With regard to the two clinical studies reported, there seems to be a conflict as to whether or not hydroxyurea really potentiates the antitumor radiation effects in malignant glioma. Levin et al. claim
Drug Summary: Nitrosoureas
that it does, but Costanza et al. claim that it does not. Perhaps the answer to the apparent conflict can be found in differences in data handling and means of data analysis as well as in the fact that one group used a rather subjective endpoint, whereas the second group used the very hard endpoint of patient survival. As a clinician reviewing all of this information, I am a bit perplexed as to just what pearls I should take home to guide me in designing my clinical trials. It would appear that the radiation sensitizing effect of the nitrosoureas is far more easy to demonstrate in rodent systems than it is in the human model. Unfortunately, this is an oft-repeated problem in chemotherapy of human malignant disease. If we
0 C. G.
MOERTEL,
M.D.
1595
assume that the combination of nitrosoureas and irradiation holds a potential of significant clinical value, then we must address the question of the most ideal way to combine these two modalities. Here I am afraid the radiation biologist has left us very confused. Based on the results of various individual studies, I could conclude that it is most ideal to administer the nitrosourea 15 hours before irradiation, two hours before irradiation, simultaneously with irradiation, or six hours after irradiation. While we will continue to cheer our radiation biology colleagues on from the sidelines, I am afraid we are not yet at the stage where we can comfortably incorporate their results into our clinical practice.
??Nitrosourea
DRUG SUMMARY: NITROSOUREAS CHARLES G. MOERTEL, M.D. MayoClinic, Rochester,MN 55901
Streptozotocin, forming Chlorozotocin, nausea and vomiting are greatly reduced and become essentially no clinical problems at all. Nephrotoxicity and hepatotoxicity are observed with BCNU, CCNU and methyl-CCNU, but they are rare-less than 2% of patients. Streptozotocin, on the other hand, produces frequent and occasionally lethal nephrotoxicity. This is really the dose-limiting toxic effect. Streptozotocin also produces frequent alterations of liver function. Again, a pleasant surprise, with Chlorozotocin, both nephrotoxicity and hepatotoxicity essentially disappear. Dose-limiting toxicity for BCNU, CCNU and methyl-CCNU is hematologic and of a unique pattern. If you follow counts closely in these patients, you find they will develop a mild nadir of leukopenia from which they will quickly recover 10 days later. They then develop a delayed nadir of thrombocytopenia at three to four weeks and a remarkably delayed second nadir of leukopenia at five to six weeks. I have never had this phenomenon of greatly delayed hematologic toxicity adequately explained and I think it would be interesting to find out why this occurs. In addition, with repeated treatment, cumulative bone marrow toxicity will develop, frequently making it impossible to continue treatment with these agents or any other drug toxic to the bone marrow. Streptozotocin has hardly any bone marrow toxicity. On the other hand, when the chloroethyl group is added to form Chlorozotocin, the typical nitrosourea bone marrow toxicity appears again. In humans, BCNU, CCNU, and methyl-CCNU have similar spectrums of therapeutic activity. All have produced some responses in lymphomas, gliomas, small cell lung cancers, melanomas, gastric cancers, colorectal cancers and scattered other tumors. For many of these, such as melanoma and gastrointestinal carcinoma, responses have been partial and transient and of no substantive value to the patient. BCNU treatment of glioma and the addition of CCNU to combination chemotherapy of lymphoma have both produced significant survival in-
Since this session has been dominated by laboratory research, it seems appropriate to lay some clinical background. The nitrosoureas have been in clinical use for more than a decade, and two of them, BCNU and CCNU, have been approved for marketing. As a class they have had a broad spectrum of activity in animal model screens and a correspondingly broad activity in human neoplasia. The basic structure of the nitrosourea moiety is very simple and the addition of two chloroethyl groups yields BCNU. BCNU has a high degree of alkylating activity, as well as carbamylating activity. If one adds a chloroethyl group and a cyclohexyl group to the nitrosourea moiety, the result is CCNU-adding a methyl group to that yields methyl-CCNU. Both of these also have high alkylating and carbamylating activity. If a sugar moiety is added to the nirosourea core, you have Streptozotocin, and if both a sugar moiety and a chloroethyl group are added you have Chlorozototin. Both of these agents have markedly reduced carbamylating activity. These different additions to the nitrosourea core produce some striking changes in the effects of these agents on both animal and human models. In the Lewis lung tumor for example, methyl-CCNU shows a striking superiority in therapeutic effect to both BCNU and CCNU. On the other hand, for subcutaneously implanted L-1210, methyl-CCNU is inferior to both BCNU and CCNU. In humans, changes in structure of the nitrosoureas produce some interesting changes in toxicity. BCNU, CCNU and methyl-CCNU all produce considerable nausea and vomiting. Normally these effects do not begin until about four or five hours after drug administration. They then persist for about three to four hours, and then rapidly disappear. Streptozotocin is the most toxic of all the nitrosoureas in this respect, producing very severe nausea, vomiting and anorexia that frequently persists long after treatment stops and occasionally makes therapy completely intolerable. Surprisingly, when the chloroethyl group is added to 1593
1594
Radiation Oncology 0 Biology 0 Physics
creases and this was the basis of their approval for marketing. Streptozotocin has a narrow range of activity confined to the APUD tumors-islet cell carcinomas and carcinoids. Chlorozotocin has really just entered into Phase II trials but responses have been observed in a few tumor types of the same variety that are also known to respond to either BCNU, CCNU or methyl-CCNU. Dr. Philip Schein and his group have raised the possibility, based on animal model data, that the optimum therapeutic effect with Chlorozotocin may be obtainable at doses which produce no toxicity or minimal toxicity. We are currently addressing this question in a randomized controlled study conducted jointly with Georgetown University. The question of the role of nitrosoureas in combined modality radiation therapy, chemotherapy trials is presently difficult to assess. The main interest in this arena has centered around the treatment of gliomas. In their first controlled trial, the Brain Tumor Study Group compared no treatment, with BCNU alone, with radiation therapy alone, and with BCNU plus irradiation. They found some survival advantage with the nitrosourea alone, a significantly greater advantage with irradiation alone, but they found no difference of consequence between irradiation alone and radiation plus BCNU. In the second study, they compared irradiation alone to methylCCNU alone to irradiation plus BCNU to irradiation plus methyl-CCNU. It is already apparent that methyl-CCNU alone is the inferior arm and that the combination of methyl-CCNU and irradiation holds no advantage over radiation alone. On the other hand, in contrast to their first study, the combination of BCNU and radiation now produces a significant survival advantage over radiation therapy alone (personal communication with Dr. Michael Walker). We find the same apparent conflict in studies of CCNU. Our Mayo Clinic studies showed no advantage for treatment with combined CCNU and irradiation compared to irradiation alone. On the other hand, the EORTC Brain Tumor Group found that CCNU did prolong survival of glioma patients but only when given on relapse after radiation therapy. They did not feel that concomitant administration of CCNU and radiation produced any improvement in survival or symptom-free interval. In this session, it is apparent that our colleagues in the laboratory are trying to help us out of this quandry by guiding us toward more effective combined radiation-nitrosourea therapy and particularly by directing us toward more effective timing in the administration of these two modalities. Deen et al. studied both BCNU and CCNU combined with radiation using in vitro 9L brain tumor cells. They found the dose enhancement ratio was minimally im-
September
1979, Volume 5, Number 9
proved with CCNU but was more definitely improved with BCNU. This was most impressive when BCNU was applied 15 to 23 hours before radiation. Bateman et al. used human xenographs of pancreatic carcinoma. They found that methyl-CCNU potentiated radiation effect and the most ideal timing for nitrosourea administration in this system was three hours before radiation. Lelieveld et al. used implanted EMT6, KHT, and RIF-1 tumors and tested BCNU given at intervals from 24 hours before radiation to 24 hours after radiation. They found no consistent patterns indicating radiation enhancement by BCNU. In one experiment of 23, however, there did seem to be such an effect. This was the KHT tumor with BCNU given two hours before radiation. Wheeler ef al. used intracerebral 9L tumors and administered BCNU 2, 6, or 16 hours before radiation in a fractionated schedule. Combination therapy produced a significant increase in life span compared to irradiation alone and administration of BCNU 16 hours before radiation therapy was significantly superior to either two hours or six hours. Barker et al. also used the 9L brain tumor and gave BCNU six hours before, immediately preceding, and six hours after radiation. They found both survival and cures to be improved by the combinations, but they got the best results with BCNU given six hours after radiation. Begg et al. used subcutaneous EMT6 tumors in mice and administered BCNU at a wide range of intervals from 64 hours before radiation to 64 hours after radiation. They found enhancement of radiation effect which was greatest when the drug was given one to eight hours after radiation. Lelieveld et a/. used two mouse strains to test enhancement of normal tissue reaction by the addition of BCNU to radiation. They found no enhancement of radiation myelitis. In BALB mice who were not anesthetized they found no enhancement of radiation skin reaction, but in anesthetized C3H mice they did find enhancement. This was greatest when BCNU was given just before radiation. Goldstein et al. used LAF-1 mice to assay the effects of combined BCNU and radiation on the intestinal crypts. They found BCNU did enhance radiation cell kill with progressively greater BCNU effect from 18 hours before radiation to two hours before radiation. The effect was reduced if BCNU was given after radiation. It is of interest that the addition of BCNU did not appear to inhibit repair of radiation damage. With regard to the two clinical studies reported, there seems to be a conflict as to whether or not hydroxyurea really potentiates the antitumor radiation effects in malignant glioma. Levin et al. claim
Drug Summary: Nitrosoureas
that it does, but Costanza et al. claim that it does not. Perhaps the answer to the apparent conflict can be found in differences in data handling and means of data analysis as well as in the fact that one group used a rather subjective endpoint, whereas the second group used the very hard endpoint of patient survival. As a clinician reviewing all of this information, I am a bit perplexed as to just what pearls I should take home to guide me in designing my clinical trials. It would appear that the radiation sensitizing effect of the nitrosoureas is far more easy to demonstrate in rodent systems than it is in the human model. Unfortunately, this is an oft-repeated problem in chemotherapy of human malignant disease. If we
0 C. G.
MOERTEL,
M.D.
1595
assume that the combination of nitrosoureas and irradiation holds a potential of significant clinical value, then we must address the question of the most ideal way to combine these two modalities. Here I am afraid the radiation biologist has left us very confused. Based on the results of various individual studies, I could conclude that it is most ideal to administer the nitrosourea 15 hours before irradiation, two hours before irradiation, simultaneously with irradiation, or six hours after irradiation. While we will continue to cheer our radiation biology colleagues on from the sidelines, I am afraid we are not yet at the stage where we can comfortably incorporate their results into our clinical practice.