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From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m 2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1-3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.

Purpose: This phase II study tested the efficacy and safety of tirapazamine (Sanofi Synthelabo Research, Malvern, PA), a bioreductive agent, in glioblastoma multiforme (GBM) patients. The patients were staged according to a model constructed by a recursive partitioning analysis (RPA) of glioma patients in prior Radiation Therapy Oncology Group (RTOG) trials and compared with a matched standard population, as predicted by the model., Patients and Methods: A total of 124 patients diagnosed with a GBM were treated with radiation therapy and intravenous tirapazamine between January 27,1995, and April 25,1997. All patients received 60 Gy in 2-Gy fractions. Tirapazamine was delivered three times a week for 12 treatments during radiotherapy. Fifty-five patients received tirapazamine at 159 mg/m(2). A second dose level, 260 mg/m(2), was opened, and 69 patients were entered., Results: There was no significant survival advantage to the drug in any RPA class at either dose level. The median survival time was 10.8 months for the patient population treated with the 159-mg/m(2) dose of tirapazamine and 9.5 months for the group treated with the 260-mg/m (2) dose of tirapazamine. Survival times by RPA class for patients receiving tirapazamine at 159 mg/m(2) were 27.4 months (class III), 10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). Survival times by RPA class for patients receiving tirapazamine at 260 mg/m(2) were 16.2 months (class III), 10.3 months (class IV), 5. 1 months (class V), and 1.3 months (class VI). Patients in RPA class III treated in the 159 mg/m(2) dose arm had a notably longer survival than patients in the RTOG database RPA class III, but the difference did not reach statistical significance. There were no fatal toxicities. Grade 3/4 toxicities were more frequent at the higher dose level., Conclusion: Survival in the population treated with radiation and tirapazamine was equivalent to the control population. Patients in RPA class III treated with radiation and tirapazamine at the 159-mg/m(2) dose had a longer survival when compared with the historical controls. The improvement in survival did not reach statistical significance. Toxicity was acceptable in both treatment arms, but grade 3/4 toxicities were more frequent in the higher dose regimen.

Purpose: We report the toxicity, patterns of failure and survival of a cohort of patients with limited disease (LD) small-cell lung cancer (SCLC) treated with combined radiation and chemotherapy. During the course of thoracic irradiation, we added intravenous (i.v.) etanidazole (SR-2508, a third-generation 2-nitroimidazole) as a hypoxic cell sensitizer in an attempt to reduce the primary local failure rate and improve survival., Methods and Materials: Between July 1988 and August 1990, 30 consecutive patients with limited disease SCLC were enrolled and treated on a Phase II protocol receiving a standard combination chemotherapy regimen utilizing i.v. cisplatin 25 mg/m2/day x 3 days, i.v. etoposide 100 mg/m2/day x 3 days alternating with intravenous cyclophosphamide 1000 mg/m2/day, intravenous doxorubicin 15 mg/m2, and intravenous vincristine 2 mg (CAV) to a total of six cycles every 3 weeks. Radiotherapy and etanidazole were started after the first cycle of chemotherapy. Etanidazole was administered intravenously at a dose of 2 g/m2 three times per week for a total of 30 g/m2 during the course of thoracic radiation that delivered 50.00 Gy tumor dose in 25 fractions in an overall time of 6 weeks., Results: The overall response rate of the primary lesion in the thorax was 96% (CR + PR), with 64% complete responses. The median time to treatment failure was 18 months. Of the patients that have relapsed, only 18% failed in the thorax (alone or concomitant with other sites). This is a marked improvement compared to the 40-50% rate reported in the literature. The 2-year crude survival was 46%. The 3- and 5-year crude survival rate with no evidence of disease was 33 and 30%, respectively. We have observed a 10% increase in the incidence of transient etanidazole related peripheral neuropathies compared to previous etanidazole studies not utilizing systemic chemotherapy. There was no increased incidence of radiation esophagitis, pulmonary toxicity, or nephro- or myelotoxicity over and above what has been routinely observed with this radio/chemotherapy regimen. There were no treatment related deaths., Conclusion: The moderate increase in etanidazole-related transient peripheral neuropathies could have been related to the concomitant use of etanidazole with vincristine and cisplatin. Although the almost 50% improvement in the incidence of tumor failure rate in the thorax in this small group of patients did not correlate with an equal marked improvement in their survival, the 5-year survival outcome in our series is at least equal or better than the best reports in the literature of larger clinical trials. We believe there is sufficient data from this study, particularly the improvement of local tumor control, to warrant a large randomized controlled clinical trial, using the most current systemic chemotherapy with concomitant thoracic irradiation with or without the most effective available hypoxic cell cytotoxic/sensitizer.

A hyperfractionated radiation therapy (HFX RT) trial (1.2 Gy twice daily, b.i.d.) (HFX) for non-small cell lung cancer (NSCLC) showed that 69.6 Gy resulted in better survival than did lower total doses (Radiation Therapy Oncology Group, RTOG 83-11) and that cisplatin concurrent with irradiation improved local control and survival over RT alone (Radiation Therapy Oncology Group, RTOG 91-06). Concurrent combination chemotherapy and HFX could improve both local and systemic control. In a phase II trial (RTOG 91-06) for inoperable NSCLC, two cycles of PE were used [cisplatin 50 mg/m2 intravenously (i.v.) days 1 and 8, etoposide 50 mg orally (p.o.) b.i.d., 75 mg/day if body surface area (BSA) < 1.7 m2, days 1-14] starting on day 1 of HFX (69.6 Gy) and repeated on day 29. HFX/PE was compared with HFX (69.6 Gy) from an earlier phase II trial (RTOG 83-11). Seventy-six patients treated with HFX/PE and 203 patients who received HFX alone were compared for toxicity, response, survival, and patterns of failure. The rates of grade 4 nonhematologic toxicity were similar (3.0% for HFX/PE, 3.0% for HFX), but grade 4 hematologic toxicity occurred only with HFX/PE 56.6%. Three (3.9%) HFX/PE patients had fatal toxicity (2 pulmonary, 1 renal); 1 HFX patient had fatal esophageal toxicity. Response and metastasis rates were similar for the two treatments, but infield (p = 0.054) and overall (p = 0.04) progression-free survival rates were better with HFX/PE. Median survivals were 18.9 months with HFX/PE and 10.6 months with HFX. Two-year survival rates were 36% for HFX/PE and 22% for HFX (p = 0.014). The differences in survival between HFX/PE and HFX remained borderline statistically significant (p = 0.0593) in the multivariate model, which included weight loss, Karnofsky performance status (KPS), sex, and stage. HFX/PE is an effective regimen in patients with inoperable NSCLC, although it is considerably more toxic, and is undergoing a comparison in a three-arm randomized phase III study against induction cisplatin/vinblastine plus standard once-daily RT and against cisplatin/vinblastine concurrent with standard RT.

Purpose: This study evaluated the toxicity and tumor efficacy of the halopyrimidine IUdR as a chemical modifier of radiation response in patients with malignant glioma. The preliminary results published in 1993 demonstrated no real advantage in the group of patients with glioblastoma. However, a benefit appeared to be evolving in the group of patients with Anaplastic Astrocytoma (AA). We are now presenting the results on the long-term follow-up of patients with AA., Methods and Materials: Between August 1987 and October 1991, 79 patients were entered in a prospective study with newly diagnosed malignant glioma. Twenty-one of 79 were AA. The study was designed to have a fixed dose of radiation consisting of 60.16 Gy in 32 fractions in 6.5 weeks but varying the dose schedule of IUdR, delivered in a continuous intravenous infusion of long (96 h) or short (48 and 24 h) duration, every week for the 6.5 weeks of radiation treatment., Results: The last AA patient was entered in March 1991. Ninety-five percent of the AA patients were under 59 years of age and 86% had a Karnofsky score 80. Thirty-eight percent had a tumor diameter of less than 5 cm and 52% had a tumor diameter between 5-10 cm. Seventy-six percent had partial or total tumor resection. The toxicity of this treatment was acceptable and has already been published elsewhere. At the time of this report, 14 out of 21 patients with AA are dead. The median survival, calculated from the Kaplan-Meier, is 3.2 years. Thirty-three percent of the patients have survived 5 years. These results compare favorably with the best results reported in the literature with postoperative external radiation plus chemotherapy, median survival time (MST) of 3 years, and previous Radiation Therapy Oncology Group (RTOG) experience with radiation alone, MST of 2 years., Conclusions: Our findings in patients with AA corroborate the improved therapeutic results published recently when combining external radiation with "long" infusion of i.v. BUdR and indicate the need to proceed with randomized Phase III studies utilizing halogenated pyrimidines and radiation. One such study has already been activated, RTOG # 94-04.

Tumour oxygenation status in individual patients may be assessed using the bioreduction and linkage of 2-nitroimidazole markers to viable hypoxic cells in vivo with subsequent detection by conventional nuclear medicine techniques. Iodoazomycin arabinoside (IAZA) was radiolabelled with Iodine-123 and administered i.v. to 51 patients with newly diagnosed malignancies whose tumours were subsequently imaged by planar and single-photon emission computed tomographic (SPECT) procedures. Quantitative analyses of radiotracer avidity were performed at 24 h post-injection and tumour-normal tissue ratios of greater than 1.10 were deemed positive for tumour hypoxia. By this criterion, the frequencies of hypoxia in small-cell lung cancer, squamous cell carcinomas of head and neck and malignant gliomas were 60% (9/15), 40% (6/15) and 0% (0/11) respectively. The correlation of positive IAZA scans with tumour control and survival in patients with lung cancer and head and neck tumours is currently under study. Preliminary observations in neck metastases from squamous cell carcinoma of head and neck tumours indicates decreased local control at 3 months post-treatment in tumours with IAZA avidity. This study concludes that: (1) 123I-IAZA can be administered safely and repeatedly as an outpatient routine imaging procedure in cancer patients during initial work-up and follow-up; (2) that retained drug can be detected by conventional nuclear medicine procedures in inaccessible deep-seated tumours; and (3) that this technique could prove useful for identifying those patients for whom hypoxia-directed therapy is indicated.

Purpose: To evaluate the toxicity and tumor efficacy of the halopyrimidine IUdR (NSC #39661, IND 22475) as a chemical modifier of radiation response when used in a high dose short time infusion versus the acceptable 4 day infusion., Methods and Materials: In August 1987 we initiated a prospective study in patients with newly diagnosed anaplastic astrocytoma and glioblastoma. The study was designed to have a fixed dose of radiation (60.16 Gy = 1.88 Gy in 32 fractions in 6.5 weeks) but varying the dose schedule of IUdR, keeping the total dose between 21 and 24 g/m2. IUdR was delivered in a 96, 48, or 24 hr continuous intravenous infusion per week for 6.5 weeks during radiation treatment., Results: The study was closed for patient accrual on October 1, 1991. Twenty-two patients were treated on the 96 hrs, 32 on the 48 hr and 25 on the 24 hr schedules. The incidence of glioblastoma ranged between 68 and 75% in the three arms. Seventy percent of the patients had a Karnofsky of 80-90% at the onset of treatment. Over 50% of the patient population were under age 55. Drug tolerance was related to the duration of the IUdR infusion. Toxicities were most pronounced in the 96 hr IUdR infusion schedule where 27.4% of the patients reported a grade 3 drug toxicity. No fatal or grade 4 toxicities were observed. More patients on the 24 and 48 hr schedule received at least 80% of the IUdR dose specified per protocol. We did not observe a trend in acute normal tissue radiation reactions in any of the three arms. The median survivals calculated from the Kaplan-Meier plot are 13.4, 10.5, and 11 months, respectively, for the 96, 48, and 24 hr infusions. The Cox Proportional Hazards model showed that any difference in survival can be attributed to histological grade, type of previous surgery and, to some extent, age of the patient. Dose schedule was not a significant predictor of survival, although statistically nonsignificant trend toward longer survival is seen in those patients with glioblastoma treated in the "long" 4 day schedule., Conclusion: Overall, our treatment combination, particularly for patients with glioblastoma, has not shown convincing evidence of an improvement in survival. Of interest, however, it is the 2 year survival rate of 68% for patients with anaplastic astrocytoma. In our experience, the administration of IUdR is laborious, time consuming and with bothersome acute gastrointestinal and hematological toxicities.

Tumor perfusion and oxygenation status have been suggested as factors which may influence treatment outcome in cancer patients. Nuclear medicine assays of tumor perfusion [99mTc-hexamethylpropylenamine oxime (HMPAO)] and tumor hypoxia [123I-iodoazomycin arabinoside (IAZA)] have recently been developed and described. We report on measurements of perfusion and oxygenation status of 27 tumors in 22 patients using these probes. An inverse correlation between tumor uptake of HMPAO and IAZA was measured (p < 0.05), with severe perfusion deficit usually associated with an increased uptake of the hypoxic marker. This trend was observed for limited stage small-cell lung carcinoma, squamous-cell carcinoma of the head and neck, soft-tissue sarcoma, brain metastases from small-cell lung carcinoma and adenocarcinoma of the prostate as a group, but not for glioblastoma multiforme. Whereas each imaging agent can yield information about the physiological status of tumor and normal tissue, the information resulting from their combined use could be important in cancer therapy.

In a prospective study, proton (1H) and phosphorus (31P) nuclear magnetic resonance spectroscopy were used to search for effects of brain tumor radiotherapy on normal human central nervous system. Phosphorus spectroscopy data at 1.5 T seems to suggest that any radiation induced damage that may occur as a result of therapeutic brain irradiation, does not alter the relative concentrations of phosphorus metabolites or the intracellular pH beyond the limits of normal variation (approximately +/- 20%). Proton spectroscopy, on the other hand, detects post radiation changes in the ratios of certain nuclear magnetic resonance visible metabolites following radiotherapy, particularly choline/N-acetylaspartate, and especially in regions of brain receiving high doses of radiation. Such changes may be indicative of the release of membrane bound choline during radiation induced demyelination of brain. Of interest, we have found elevated metabolite ratios of 31P in normal central nervous system prior to radiotherapy, which persisted throughout the time span of the study in both the ipsilateral and contralateral cerebral hemispheres.

Background: Many studies have reported differences in cancer incidence and survival between populations of Blacks and Whites. A 45% higher death rate from lung cancer for Black men and a survival duration for Black patients with lung cancer that is generally shorter than that for White patients have also been reported., Purpose: The purpose of this study was to evaluate whether race affects known prognostic factors for non-small-cell lung cancer in Black versus White patients. This analysis attempts to determine which prognostic factors may contribute to the reported differences in disease outcome., Methods: We used data from 1565 patients with non-small-cell lung cancer treated in four randomized prospective trials conducted by the Radiation Therapy Oncology Group (RTOG). The data were pooled for a retrospective analysis of survival and prognostic factors by race., Results: Univariate analysis showed significant differences between Blacks and Whites with regard to sex, weight loss, histology, and RTOG T stage (P < .05), but the only clinically significant difference (P < or = .01) was weight loss. Despite these findings, overall survival for Blacks and Whites did not differ significantly (P = .67). Median survival for Blacks and Whites with a Karnofsky performance status (KPS) of 90 or more was 12.1 and 11.3 months, respectively (P = .45). Survival for Blacks and Whites with a KPS of less than 90 was 7.8 and 6.8 months, respectively. Cause of death did not differ between the two races. For both races, KPS, age, sex, weight loss, and RTOG T and N stages were significant prognostic factors for survival (P < .01), but race was not a significant prognostic factor., Conclusion: Further studies of the differential in cancer survival for Blacks and Whites may be indicated, but greater impact may be achieved by addressing socioeconomic factors, lifestyle and occupational risk factors, health education, and access to adequate health care.

We attempted to show a dose effect relationship for radiation therapy by treating patients harbouring malignant glioma with increasing doses of radiation in a step-wise fashion. We postulated that no increase in delayed toxicity would be seen because we used hyperfractionation technique. Between January 1981 and December 1988 we treated 280 patients three times daily at 4 hour intervals. 100 patients received a total dose of 6141 cGy, 73 patients received 7120 cGy, and 107 patients received 8000 cGy. CCNU was given at the time of tumor progression following radiotherapy. Median time to tumor progression was 28 weeks for patients who received 6141 cGy, 27 weeks for patients who received 7120 cGy and 36 weeks for patients who received 8000 cGy. Median survival was 46 weeks for patients who received 6141 cGy, 38 weeks for patients who received 7120 cGy and 45 weeks for patients who received 8000 cGy. There was no statistically significant difference in either time to tumor progression or survival among the three treatment arms and no dose response effect was seen. There was no increase in delayed radiation toxicity when the total radiation dose was increased up to 8000 cGy.

Experience with the use of external beam conventional radiation over a period of several decades has shown that in every instance where there has been a major advance in the physical delivery of radiation to the tumor (beam energy and characteristics and precise tumor dose delivery) there has been a corresponding major improvement in the treatment results. The advent of megavoltage sources following the invention and use of Cobalt 60 and medical linear accelerator units during the late 1940's and early 1950's and their major impact on tumor control and patient survival in solid tumors such as carcinoma of the prostate, Hodgkin's Disease, head and neck tumors and cancer of the cervix are being discussed. Most recently, the use of computerized tomography and computer systems for treatment planning is likely to show a further improvement in the therapeutic results.

Two tumor cell lines were established from each of three human malignant glioma biopsy specimens (M059, M067, M071) and sensitivity to treatment with radiation or chemotherapeutic agents (BCNU, nitrogen mustard) was determined. The effects of recombinant human interferon-alpha (rIFN) on the radiation response and of buthionine sulfoximine (BSO) on the drug response were investigated as well. For tumor M059, two cell lines that differed significantly in radiosensitivity were isolated (surviving fractions at 2 Gy = 0.02 and 0.64). The chemosensitivity and response to chemical modification differed as well. Cell lines established from tumor M071 differed in their response to rIFN only and were not sensitized by BSO. M067 cell lines showed little difference and were not sensitized by either agent. These results suggest that differences may exist both within and among human malignant gliomas with regard to their sensitivity to drugs, radiation, and the ability of chemical agents to modify treatment responses.

The inherent radiosensitivity of early passage cells derived from 22 patients with tumors of glial origin has been determined using a clonogenic assay system. The mean (+/- SD) surviving fraction at 2 Gy was 0.37 +/- 0.22 (range = 0.02-0.87). No correlation between inherent radiosensitivity and tumor cell plating efficiency or intracellular glutathione was observed. Tumor cells that were both resistant to nitrosoureas and expressed the Mer+ phenotype did not differ significantly in their radiosensitivity as compared to cells that were repair deficient (Mer-) and sensitive to nitrosoureas. Initial clinical follow-up suggests that factors in addition to inherent tumor cell radiosensitivity, such as performance status and age, continue to be the most important determinants of the response of patients with primary brain tumors to radiotherapy.

Biopsy samples and cultured cells derived from them were obtained from 39 patients with malignant glioma and were analyzed for 1) glutathione (GSH) content; 2) sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or nitrogen mustard (HN2) treatment and 3) the effect of buthionine sulfoximine (BSO) treatment on BCNU and/or HN2 cytotoxicity. The average GSH concentration of biopsy specimens was lower than those of cultured cells (2.36 +/- 0.44 vs. 11.42 +/- 2.32 nmol/10(6) cells). While some of the tumor specimens were sensitive to either BCNU or HN2, the majority were resistant to both. However, 8 of 23 tumors tested showed enhanced sensitivity to BCNU following treatment with BSO. Five of 17 tumors were similarly sensitized to HN2 by BSO. These results suggest that BSO chemosensitization may be of value for certain patients and that screening assays may help identify treatment-sensitive individuals.

In a Phase I trial SR 2508 was administered by rapid intravenous infusion to 102 patients receiving radiation therapy. The dose-limiting toxicity was peripheral sensory neuropathy (PN) which was related to the cumulative dose administered. The highest single daily dose, 3.7 g/m2, was tolerated without toxicity. The lowest cumulative toxic dose was 21.6 g/m2, and the highest non-toxic dose was 40.8 g/m2. Grade 1 neuropathies were mild and self-limited; grade 2 neuropathies were long-lasting and debilitating. In a retrospective analysis, the risk of developing neurotoxicity was related to the cumulative drug exposure calculated by the area-under-the-curve (AUC) of plasma concentration versus time. There was an increased incidence of neuropathy in patients with a cumulative AUC of greater than or equal to 36 mM-hr. At a total dose of 34 g/m2 over 6 weeks, the incidence of Grade 1 neuropathy was approximately 30%; no grade 2 neuropathy occurred at this dose and schedule. Additional toxicities observed included nausea and vomiting (6%), skin rash (4%), and transient arthralgias (3%). One patient had transient abnormalities in liver function tests of unknown etiology. (In a more recent Phase II trial neutropenia has been observed which may be related to SR2508). Approximately three times more SR 2508 is tolerable compared to misonidazole, and it appears that severe neuropathy can be avoided by monitoring individual patient pharmacokinetic parameters. Evaluation of the efficacy of this hypoxic cell sensitizer is in progress.

As an extension of studies on the clinical use of nitroimidazoles as radiosensitizers, single-dose pharmacokinetic studies of iv metronidazole (500 mg/100-ml vials) were performed in eight consenting patients. Single doses of 0.5, 1.0, 1.5, and 2.0 g (0.29-1.21 g/m2) were administered iv by a zero-order infusion pump. Serial timed blood and urine samples were assayed for metronidazole and its two metabolites (acetic acid and ethoxy compounds) using a high-pressure liquid chromatographic assay. Open two-compartment kinetic characteristics of metronidazole were computed from simultaneous plasma infusion and urine excretion-rate equations using a nonlinear least-squares regression analysis program (NONLIN). Means of the four kinetic parameters were (h-1): k12, 1.18; k21, 0.86; k10, 0.22; and k'e, 0.46 x 10(-4). Means of the apparent volumes of distribution were (liters/kg): Vc, 0.41; VB, 1.02; and Vss, 0.75. The mean (+/- SD) for alpha-half-life was 1.2 +/- 1.3 hours, and that for beta-half-life was 9.8 +/- 5.9 hours. Seven of the eight patients received a second identical dose orally 1 week later, and the absolute bioavailability was estimated to approximate 100%. Unless the oral route is not feasible and if immediate high peak blood levels are not necessary, oral metronidazole is the preferred route of administration of metronidazole for its radiosensitizing effects.

In a previously published paper, the results of a preliminary clinical trial comparing systemic radiation (upper and lower hemibody technique) versus systemic chemotherapy in the management of all stages of small cell lung cancer (SCLC), suggested that hemibody radiation (HBI) was as efficient as systemic chemotherapy, particularly for patients with early disease. We are now presenting the final results of the above trial. The two year survival has shown that as many patients in the HBI as in the chemotherapy arm have reached this endpoint. However, there is a difference in favor of chemotherapy on both the median and one year survival for those patients with advanced stages. Therefore, as of June 1981, we have initiated a study incorporating HBI as a consolidating-maintenance agent for patients with all stages of the disease who have received a 3 1/2 months induction systemic chemotherapy plus local chest irradiation. Up to date, 65 patients have been entered and our median survival for those who received the complete treatment is 62.5 weeks.

Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, we reported a preliminary study suggestive that Dexamethasone (DEXA) does have a protective effect against peripheral neuropathies (PN) resulting from toxicity of misonidazole. Furthermore, in that study we have observed that DEXA did not alter the plasma pharmacokinetics of misonidazole. We are presently investigating the use of DEXA (2 mg t.i.d. during treatment), with escalating doses of MISO in an attempt to modify its neurotoxicity. To date, 16 patients have been registered to receive total doses of MISO ranging from 13.5 to 17.5 gm/M2 given in 9 equally divided doses over 3 weeks. DEXA, 2 mg t.i.d. is given 3 days prior to the first dose and continues for the duration of therapy. All patients receive palliative radiation. No toxicity was seen at the total dose of 13.5 gm/M2. One grade I PN occurred in the first four patients receiving 15.5 gm/M2. Six additional patients were entered at this dose level and no further incidence of PN was observed. Patients are being entered at the next step of 17.5 gm/M2.

Although considerable laboratory in vitro and in vivo evidence is now available suggesting that misonidazole (MISO) enhances chemotherapy tumor responses, experience with human tumors is limited. Further, the mechanism of this enhancement is not definitely known. One possible mechanism is that MISO alters the pharmacokinetics of the chemotherapeutic agent, vice versa or both. We studied a group of patients with recurrent malignant gliomas, following radiotherapy. After proven recurrence, they were treated with i.v. BCNU in combination with oral MISO in an 8 week cycle. Our aims were: 1. To obtain a second remission; 2. To assess the toxicity of this combination; 3. To assess the plasma pharmacokinetics of each drug alone and in combination. Six patients entered the protocol. Four of six patients obtained either a partial or subpartial response. Prolonged moderate myelosuppression was observed in 2/6 patients after 3 cycles; 2/6 patients experienced seizures after the first cycle of chemotherapy for the first time in the course of their disease. The plasma pharmacokinetic data indicates no evidence of a MISO-BCNU drug interaction.

This study is part of a clinical program to assess the use of nitroimidazoles as radiosensitizers of hypoxic tumor cells. A total of 37 patients with malignant tumors have been entered into the study to receive oral high-dose metronidazole in conjunction with radiation. Twenty-eight patients with malignant brain tumors received 6 gm/m2 three times a week for 3 weeks (a mean total dose of 5.3 gm/m2). Maximum mean plasma drug concentration of 1 mM was obtained at 4 hours after drug ingestion with a mean half-life of 13 hours. Tissue and cerebrospinal fluid levels of 80% to 90% of the plasma levels were obtained at 4 to 6 hours. A linear relationship between increased drug dose and increased plasma concentration was observed at doses of 2.5 gm/m2 up to 6 gm/m2. Acute gastrointestinal and central nervous system toxicity was the dose-limiting factor (50% and 25%, respectively, at total doses of 5.3 gm/m2). Pharmacokinetic studies of intravenous metronidazole were performed in eight consenting patients. Single doses of 0.5, 1, 1.5, and 2 gm were administered intravenously by zero-order infusion pump. Seven of the eight patients received a second identical dose orally 1 week later and the results were compared. Open two-compartment kinetic characteristics of metronidazole were computed from simultaneous plasma infusion and urine excretion rate equations, by use of a nonlinear least-squares regression analysis program (NONLIN). The mean (+/- SD) for alpha half-life was 1.2 +/- 1.3 hours, and that for the beta half-life was 9.8 +/- 5.9 hours. The absolute oral bioavailability was estimated to approximate 100%.

Some electron-affinic drugs, developed as hypoxic cell radiosensitizers, become selectively bound to the molecules of hypoxic cells by metabolism. This technique has been used to identify zones of chronically hypoxic cells in multicellular spheroids and animal tumours. Tritiated-misonidazole was administered to a patient with advanced melanoma 22 h prior to the surgical resection of a large metastatic s.c. lesion growing on the face. Autoradiographic analysis of histological sections revealed zones of intense labelling by the radioactive drug, indicative of tumour cells which were chronically hypoxic. This technique appears to provide an indirect measurement of tissue pO2 at the cellular level from which estimates of the tumour hypoxic fraction can be made. These data are encouraging as regards the development of 'sensitizer-adduct' procedures for the invasive and non-invasive measurement of hypoxia in both tumours and normal tissues.

Stationary-phase populations of Chinese hamster V-79 cells were irradiated with 250 kV X-rays and the Bragg peaks (spread to a width of 4 cm) of energetic He-, C-, Ne-, and A-ion beams produced at the 184-inch cyclotron and BEVALAC at Lawrence Berkeley Laboratory. Survival curves were generated with each radiation for cells suspended in air-saturated and nitrogen-saturated medium with and without sensitizer present. The oxygen enhancement ratios (OERs) measured for X-rays with 1mM metronidazole and 0.5 mM misonidazole were 2.0 and 1.6 respectively. The OERs without sensitizer for He-, C-, Ne-, and A-ion Bragg peaks were 2.4, 1.7, 1.6 and 1.4 respectively. For each type of radiation tested the presence of hypoxic-cell sensitizers resulted in an additional reduction in the measured OERs, indicating that these drugs should be of benefit in the radiotherapy planned with these and other high LET radiations.

The therapeutic value of sequential hemi-body irradiation (HBI) as a primary treatment for small-cell lung cancer (SCLC) was compared to 3-drug cyclic chemotherapy (CC) in a group of 64 patients with early and advanced disease. Thirty patients were randomized to receive sequential HBI and 34 to receive CC. All patients received a local radiation boost to the primary lesion. An overall response rate of 87% was obtained in patients treated with sequential HBI and 88% in patients treated with CC. In patients with early disease, the estimated median survival was 43 weeks when treated with HBI and 42 weeks when treated with CC, but in advanced disease the estimated median survival was 15 weeks and 44 weeks respectively. Of the patients with an initial complete response, the estimated median survival was 51 weeks for HBI and 62 weeks for CC. From these observations we suggest that sequential HBI treatment technique with local radiation boost is an efficient method of tumour control in patients with early small-cell lung cancer.

Sarcoma - lymphocyte-mediated cytotoxicity and serum blocking of this activity was studied by the in vitro microcytotoxicity test in three patients with osteogenic sarcoma who received preoperative irradiation. All three patients had complete histologic disappearance of the tumor between three to five months after irradiation. Lymphocyte cytotoxicity was present before and after treatment in two patients and post-treatment in one. No serum blocking activity was detected in any of these three patients. They are all alive over four years post-therapy without evidence of active disease.

With a view to modifying misonidazole (MISO) neurotoxicity, we initiated a randomized clinical study to assess a possible drug interaction and toxicity protection when dexamethasone (DXM) is administered concomittantly with MISO. The ongoing study consists of: 1. Pharmacokinetic evaluation; 2. Assessment of toxicity. Fourteen patients undergoing radiation therapy for different types of malignant neoplasia (excluding brain tumors) have been randomized to receive either MISO alone, or DXM one week prior and during treatment with MISO. Five of seven patients receiving MISO alone developed peripheral neuropathies while only one out of 7 patients that received MISO with DXM coverage developed a transient and mild neuropathy. Pharmacokinetic evaluation of MISO in plasma and urine of those patients receiving DXM has shown no evidence of drug interaction. It is postulated that the mechanism of action of DXM is at the nerve cell membrane level, restoring and stabilizing cell surface properties. In future studies we will investigate the use of DXM with increasing doses of MISO above the recommended maximum dose of 12 gm/m2, hoping to achieve a higher tumor tissue level of MISO while avoiding unacceptable toxicity. The effect of Allopurinol on the plasma kinetics of MISO was studied in four additional patients, observing also no evidence of drug interaction.

From March 15, through August 31, 1983, 37 patients have been entered on the RTOG Phase I trial of SR-2508. The drug was given intravenously three times weekly for three weeks. The starting total dose was 11.7 g/m2 and the highest total dose given was 32 g/m2. The lower lipophilicity of SR-2508 has produced the expected decrease in terminal half-life (5.4 hrs) of drug excretion and increase in total drug excreted unchanged in the urine (71%) compared to misonidazole or desmethylmisonidazole. The maximum single dose (3.7 g/m2) administered was well tolerated. With multiple doses peripheral neuropathy is the dose-limiting toxicity. The lowest cumulative dose producing toxicity was 21.6 g/m2, the highest non-toxic dose was 29.7 g/m2. The use of an individual patient's drug exposure as measured by the area under the curve of drug concentration vs time may be an excellent predictor of toxicity. This may eventually permit individualization of dose and prevention of serious toxicity. A single dose of 2 g/m2 will produce a tumor concentration of drug (approx. 100 micrograms/ml) that will yield a sensitizer enhancement ratio of 1.5 to 1.7. Using a starting dose of 2 g/m2 three times weekly, patients are now being studied on a five week drug schedule to further evaluate predictability of drug toxicity in preparation for clinical trials of drug efficacy.

The human tolerance to multiple dosages of misonidazole (Ro-07-0582) was studied in 28 patients with different types of malignant neoplasias. The mean total dose for this group of patients was 16.2 g. The main toxicity was peripheral neuropathy with an overall incidence of 35%. This neuropathy occurred more frequently and with greater severity when the drug was administered 3 times a week and when patients received total doses of over 18 g. The best tolerated schedule appears to be once or twice a week up to total dosages of 18 g or less (approximately 11 g/m2). Electron microscopy of a sural nerve biopsy from an affected patient revealed residual of previous distal axonal degeneration, with some segmental demyelination and remyelination, which affected both large and small myelinated nerve fibres.

Since January 1981, 52 patients have entered the Radiation Therapy Oncology Group Phase I trial with intravenous (i.v.) desmethylmisonidazole (DMM). DMM is less lipophilic than misonidazole (MISO) and theoretically will be less neurotoxic due to lower penetration into neural tissue and more rapid elimination. The drug is administered intravenously to achieve the maximum drug concentration in tumor for a given dose. The protocol slowly escalates the total dose of drug administered. At this time the planned dose on the three week schedule is 1g/m2 five times per week to a total of 15g/m2, and on the seven week schedule is 1.25g/m2 twice weekly to a total dose of 17.5g/m2. The preliminary plasma pharmacokinetic data demonstrates high peak plasma levels within five minutes of the end of the drug infusion. Compared to MISO the percent of DMM excreted in the urine is increased, 63% vs 10%, and the elimination half-life is decreased: DMM, i.v. 5.3h; MISO, i.v. 9.3h; MISO, oral 10 to 13h. Neurotoxicity has been observed in approximately 30% of patients given a cumulative dose of greater than 11g/m2. This is in comparison to a 50% incidence in the RTOG Phase I study with oral MISO at doses of 12g/m2. There is not sufficient data to evaluate the relationship between neurotoxicity and drug exposure. Further patient accrual on this study is required to better define the properties of DMM.

Various attempts have been made to improve the effectiveness of radiation in the treatment of cerebral malignant astrocytomas. A trend favoring multiple daily fractionated (MDF) radiation therapy over conventional single daily fractionated (CF) radiation therapy was identified in our previous study. In order to assess the effect of MDF with and without misonidazole, a province-wide prospective randomized trial was initiated in January 1981. By March 1984, 124 patients with histologically verified grade III and IV astrocytomas were randomized to CF (5800 cGy/6 weeks/30 fractions), MDF (6141 cGy/4.5 weeks/69 fractions at 89 cGy every 3-4 hours, three times a day) and MDF in combination with misonidazole (1.25 g/m2 three times weekly for the first 3 weeks). Thirty-eight patients were randomized to CF, 43 patients to MDF, and 43 patients to MDF and misonidazole. At the preliminary assessment in July 1984, the median survival time was 27 weeks for the CF group, 39 weeks for the MDF group and 49 weeks for MDF and misonidazole group. The 1-year actuarial survival rate from surgery was 20% for CF group, 41% for MDF group, and 45% for MDF and misonidazole group. There is a statistically significant difference (P less than 0.001) between the CF and MDF group. However, the addition of misonidazole does not significantly alter survival.

Misonidazole is a 2-nitroimidazole compound currently being assessed as a radiosensitizing agent. The effects of misonidazole on human bone marrow hematopoiesis were assayed by culture of committed granulocyte-macrophage progenitor cells (CFU-C). Three groups of patients with nonhematologic malignancies were selected for study. The first group of patients received a single, large dose of misonidazole; the second group received smaller, multiple doses of misonidazole; and the third group who did not receive any misonidazole served as irradiation controls. In 14 of 16 patients who received single or multiple doses of misonidazole, there was a significant decrease in the number of CFU-C present in the bone marrow after misonidazole therapy. In five patients who received irradiation only, there was no difference in the number of pre- and post-treatment bone marrow CFU-C. In misonidazole treated patients, extensive washing of post-treatment bone marrow samples failed to return CFU-C growth to control values. Suppression of CFU-C growth persisted for 3 weeks and returned to control values by 8 weeks. This reduction in the proliferative capacity of human bone marrow progenitor cells suggests that misonidazole may add to the myelotoxicity already associated with radiotherapy, systemic chemotherapy, or as combination of the two.

As part of a phase II study with the hypoxic cell radiosensitizer, misonidazole, we have encountered two cases of dermatitis. When all drugs were withdrawn and the patients were challenged with a small single dose of misonidazole, identical adverse reactions reappeared demonstrating a drug-related skin hypersensitivity.

Metronidazole was administered orally to 25 patients and its maximum concentration in blood and tumor tissues, its ability to cross the blood/brain barrier and concentrate in the cerebrospinal fluid and brain tumor tissue, its immediate and long-term toxicity, and its enhancement of irradiation in normal tissue were studied. Maximum blood concentrations of 700-1,200 muM (120-220 mug/ml) were obtained at four hours with doses of 6 g/m2. Moderate and transient nausea and vomiting were the only immediate signs of toxicity. No long-term toxicity was found up to 18 months after administration of the drug. These data indicate that metronidazole can feasibly be adminstered in clinical trials of fractionated radiotherapy using dosages ranging from 9.5 to 11 g three times a week for three to four weeks.

Treatment-resistant, chronically hypoxic tumor cells have been assumed to exist in some solid human tumors, limiting their curability. To date, six patients with different types of tumors have been studied using radioactive labelled electron affinic compounds that bind to hypoxic cells. Although the gross clinical appearance of the tumors in all six patients was of a large and fixed mass which might on clinical grounds be expected to contain hypoxic cells, we have observed drug binding to hypoxic regions in only two, a rapidly growing small cell lung cancer (SCLC) and a malignant melanoma. The hypoxic fraction of the malignant melanoma was found to be 6% and the SCLC tumor approximately 10%. We have observed that areas of maximum adduct formation can be found in tumor cells immediately adjacent to blood vessels, suggesting that blood flow over the labelling interval was restricted. These preliminary studies suggest that sensitizer adduct formation in human tumor tissue may be a useful measure of tissue pO2 at the cellular level and that tumor hypoxia might be more related to the rate of tumor growth and histological grading than to tumor size.

Complete pharmacological data from 71 patients treated on the phase I trial of SR 2508 were analyzed to see if the dose-limiting toxicity of peripheral neuropathy is related to the individual patient's pharmacokinetic profile. In a retrospective analysis, the risk of toxicity was best predicted by using the bivariate model of total drug exposure and the time over which the treatment course was given. Drug exposure [area under the curve (AUC)] for a single treatment was calculated by the integral over time of the serum concentration of SR 2508. Since the AUC was constant during the course of a patient's treatment, the total drug exposure (total-AUC) was estimated by the product of the AUC times the number of drug administrations. While the clinical efficacy of hypoxic cell sensitizers remains to be proven, SR 2508 is better tolerated than its predecessors, misonidazole and desmethylmisonidazole, as three times the amount of SR 2508 can be given. If this model is confirmed in the current phase II and III trials, the probability of developing neuropathy would be predictable for an individual patient from measurements made at the time of the first drug dose, allowing for the adjustment of drug schedule to avoid all but minor toxicity.

Previously, investigators at this institute have studied the use of upper hemibody irradiation as a consolidation agent following combination chemotherapy for small cell lung cancer. There was no improvement in survival compared to that in the group treated with chemotherapy alone. In our present pilot study, we are investigating the toxicity and efficacy of using hemibody irradiation (HBI) as a non-cross-resistant agent early in a program of alternating chemotherapy consisting of six treatment cycles. Toxicity due to the combined effects of chemotherapy (cisplatin and etoposide plus cyclophosphamide, doxorubicin, and vincristine) plus HBI is reported. The HBI was given at a dose of 1,000 cGy in four fractions for limited disease or as a single 800-cGy dose for extensive disease. Bone marrow suppression following HBI necessitated a subsequent delay in the chemotherapy cycle or dose reduction in 55% of the 33 patients. Six patients developed diffuse interstitial pneumonitis following chemotherapy and HBI; 3 have died, and in 2 of these, the etiology was opportunistic infection. In our previous studies utilizing HBI either alone or as consolidation therapy after induction chemotherapy, a low incidence of lung toxicity occurred. This increased incidence suggests a possible drug-radiation interaction when HBI is used as an alternating agent with doxorubicin and cisplatin.

Nineteen patients with various solid tumors were treated with Corynebacterium parvum for 10 consecutive days at doses ranging from 0.5 to 6 mg/m2. Major toxic effects included rigors and cyanosis, hypertension, headache, nausea, and vomiting. Toxicity was maximal during the first 3 days of treatment and decreased or even disappeared when, on subsequent days, increasing doses of the vaccine were given. Objective tumor regressions were observed in four patients.

Sixty-five patients were entered on the long schedule of the Phase I trial of SR-2508. The planned total doses ranged from 30 to 40.8 g/m2 using various treatment schema including daily, split course, and every-other-day schedules. The individual dose size was 2 g/m2 for 56 patients and 1.7 g/m2 for nine. In contrast to misonidazole and desmethylmisonidazole, more SR-2508 can be administered as the duration of therapy is lengthened. All six patients on the 30 g/m2 step tolerated the drug without toxicity. This total dose was not achievable in the three week schedule. Additionally, a number of patients did not develop neuropathy at a cumulative dose of 40.8 g/m2. Although the analysis is not yet complete, a given patient's drug exposure as measured by their total AUC (mMxhr), defined as the area-under-the-curve of serum concentration of SR-2508 vs. time for a single dose times the number of doses given, is useful in predicting toxicity for that patient. The recommended starting schedule for the Phase II and III trials is 34 g/m2 over a 6 week period (2 g/m2 every other day). A total AUC of approximately 39 mMxhr should be tolerable. The drug regimen must be altered for patients who have a high AUC. Therefore, it is mandatory to have an accurate and rapid pharmacokinetic analysis for each patient. The clinical efficacy of the hypoxic cell sensitizers remains to be proven. However, using the guidelines derived from the Phase I trial, SR-2508 should be a relatively safe drug, producing minor or no toxicity.

Multiple daily fractionated radiation therapy (MDF) may be more effective than conventionally fractionated radiation therapy (CF) in the treatment of malignant glioma. The hypoxic cell sensitizer misonidazole (MISO) could be more effective when employed with small fractions of radiation every 4 hours to take advantage of the long half-life of the drug. To evaluate MDF and MDF in combination with MISO, a randomized prospective trial was initiated. Between January 1981, and December 1982, patients with histologically verified astrocytoma with anaplastic foci or glioblastoma multiforme were randomized to CF (5800 cGy, 30 fractions, 6 weeks), MDF (6141 cGy, 69 fractions, 4 1/2 weeks, at 89 cGy every 4 hours 3 times daily) and MDF in combination with MISO (1.25 gm/M2 three times weekly for the first 3 weeks). In January 1983, the CF arm was dropped and a high dose MDF arm added (7120 cGy, 80 fractions, 5 1/2 weeks, at 89 cGy per fraction every 4 hours 3 times daily). CCNU chemotherapy was given at the time of tumor progression. One hundred and twenty-eight patients were evaluated (38 CF, 42 MDF, 37 MDF plus MISO, and 11 high dose MDF). Median survival was 29 weeks for CF, 45 weeks for MDF and 50 weeks for MDF plus MISO. Survival was significantly improved for patients treated with MDF compared to patients treated with CF (p less than .002). The addition of MISO to MDF did not result in further improvement in survival. Acute toxicity was acceptable. No clinically apparent delayed toxicity was observed.

Results of world-wide clinical trials with misonidazole are discussed. An attempt is made to assess the reasons for the lack of positive results and the cost-benefit analysis is critically reviewed. The data on the clinical investigations of the second generation misonidazole analogues SR-2508 and RO-03-8799 are presented. Emphasis is placed on future work such as tumor selection for clinical trials, reduction of drug toxicity and methods to increase the drug radiosensitizing properties. Because of the large amount of knowledge, experience, productivity and good scientific clinical data accummulated with nitroimidazoles over the past five years, it is recommended that this is the time to push forward with the work on the newest, more efficient compounds.

This is the final report of the Phase I Protocol for the initial clinical study of Multiple Dose WR-2721 with radiotherapy (RTOG 80-02). The essential object of the study was to determine the highest dose of WR-2721 that could be given daily for the greatest number of weeks 15 to 30 minutes before conventional radiation treatment schedules. Eighty-four patients were entered into various dose levels. The major and dose-limiting toxicities were emesis, hypotension and malaise. The latter symptom was characterized by increasing weakness, fatigability, and ill-feeling. The maximum tolerated dose (MTD) established by this study is 340 mg/m2 given 4 days a week (excepting Wednesday) for 5 weeks. The drug is delivered intravenously in 7 minutes. There were no long-term blood chemistry changes. There were no deaths due to the administration of the radioprotector.