A phase I-B trial of the radiosensitizer: etanidazole (SR-2508) with radiosurgery for the treatment of recurrent previously irradiated primary brain tumors or brain metastases (RTOG Study 95-02).

RTOG 95-02 assessed patient tolerance to hypoxic cell radiosensitizer, etanidazole (SR-2508), combined with radiosurgery. Patients had primary or metastatic brain tumors and previously localized or whole brain irradiation. The toxicity is reported in three groups of patients according to the tumor size. Etanidazole doses of 12g/m2 combined with radiosurgery were well tolerated.

Relationship between the neurotoxicity of the hypoxic cell radiosensitizer SR 2508 and the pharmacokinetic profile.

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.

Phase III randomized trial of amifostine as a radioprotector in head and neck cancer.

PURPOSE: Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients. PATIENTS AND METHODS: Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade > or =2 acute xerostomia, grade > or =3 acute mucositis, and grade > or =2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m(2) intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional control was the primary antitumor efficacy end point. RESULTS: Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade > or =2 acute xerostomia from 78% to 51% (P<.0001) and chronic xerostomia grade > or = 2 from 57% to 34% (P=.002). Median saliva production was greater with amifostine (0.26 g v 0.10 g, P=.04). Amifostine did not reduce mucositis. With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63%, 53% versus 57%, and 71% versus 66%, respectively. CONCLUSION: Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.

Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin's disease.

PURPOSE: The management of early-stage Hodgkin's disease in the United States is controversial. To evaluate whether staging laparotomy could be safely avoided in early-stage Hodgkin's disease and whether chemotherapy should be a part of the treatment of nonlaparotomy staged patients, a phase III intergroup trial was performed. PATIENTS AND METHODS: Three hundred forty-eight patients with clinical stage IA to IIA supradiaphragmatic Hodgkin's disease were randomized without staging laparotomy to treatment with either subtotal lymphoid irradiation (STLI) or combined-modality therapy (CMT) consisting of three cycles of doxorubicin and vinblastine followed by STLI. RESULTS: The study was closed at the second, planned, interim analysis because of a markedly superior failure-free survival (FFS) rate for patients on the CMT arm (94%) compared with the STLI arm (81%). With a median follow-up of 3.3 years, 10 patients have experienced relapse or died on the chemoradiotherapy arm, compared with 34 on the radiotherapy arm (P <.001). Few deaths have occurred on either arm (three deaths on CMT and seven deaths on STLI). Treatment was well tolerated, with only one death on each arm attributed to treatment. CONCLUSION: These results demonstrate that it is possible to obtain a high FFS rate in a large group of stage IA to IIA patients without performing staging laparotomy and that three cycles of chemotherapy plus STLI provide a superior FFS compared with STLI alone. Extended follow-up is necessary to assess freedom from second relapse, overall survival, late toxicities, patterns of treatment failure, and quality of life.

American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants.

PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration-approved agents that have potential chemotherapy- and radiotherapy-protectant activity-dexrazoxane, mesna, and amifostine-and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m(2)/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplantation setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m(2) or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m(2) of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemoth

Radiotherapeutic studies with amifostine (Ethyol).

Radiotherapeutic studies with amifostine (WR-2721; Ethyol, US Bioscience, Inc, West Conshohocken, PA) are reviewed, with evidence that it offers clinical normal tissue protection and no evidence of any tumor protection. Conducting clinical trials with amifostine has been difficult because of the unique (toxicity) endpoints and concerns about tumor protection. The Radiation Therapy Oncology Group has conducted phase I studies and a phase II hemibody study, and is now in the process of conducting phase III amifostine studies. Amifostine remains the most promising compound for testing clinical radioprotection, and as new techniques are developed in radiation therapy to deliver higher doses of radiation, the protection of normal tissues will become even more important. This review will cover both the preclinical and clinical studies involving the use of amifostine with radiation therapy.

Use of a colorimetric microtiter (MTT) assay in determining the radiosensitivity of cells from murine solid tumors.

We assessed the use of a colorimetric assay for determination of radiosensitivity for cells taken directly from murine solid tumors. The assay uses microtier plates and measures the ability of viable cells to reduce a tetrazolium salt (MTT) to an insoluble form, a formazan salt. We established the dependency of the assay on the cell number and time of assay for two murine tumors (EMT-6 and RIF-1). We compared the MTT assay to the standard clonogenic assay and had good agreement of surviving fraction after radiation doses of 2 and 4 Gy. It is possible, therefore, to adapt the MTT assay for use with cell suspensions prepared directly from fresh murine tumors. This may provide a methodology for the determination of the clinical radiosensitivity of tumors including fresh clinical tumor specimens.

Evaluation of the bioavailability of misonidazole (NSC#261037) in capsule and tablet form and pharmacologic effects of daily dosage.

A total of 34 patients were studied in order to evaluate capsule vs. tablet form of misonidazole and intermittent vs. daily administration. These patients were given drug formulation of tablets for one week and capsules for one week on either an intermittent (1, 2, or 3 times per week) or daily schedule. Total doses ranged from 5-15 gm/m2. There was no significant difference seen in mean serum levels or half-lives between capsules and tablets. Daily misonidazole resulted in slight build-up of serum levels in the latter part of the week. There was no difference in toxicities seen with drug daily vs. intermittent administration.

Neuropathy of nitroimidazole radiosensitizers: clinical and pathological description.

The dose limiting toxicity of the nitroimidazole radiosensitizers is peripherial neuropathy. Improved pharmacology of newer drugs has eliminated the encephalopathy. Peripheral neuropathies are predominently mild to moderate paresthesias of both hands and feet. Subjective changes occur with or without minimal objective changes on neurologic exam. All of the neuropathies occurred within 30 days of the last drug dose and are of variable duration. Sural nerve biopsies from patients indicate progressive axonal degeneration affecting both large and small caliber myelinated fibers. Axonal damage appears to be more severe in the distal portion of the nerves. More data are needed for correlation of clinical and pathological changes.

Analysis of prognostic factors in localized gastric lymphoma: the importance of bulk of disease.

PURPOSE: To identify prognostic factors in localized gastric lymphoma patients for optimal therapy selection. METHODS AND MATERIALS: From 1974 to 1990, 77 patients with localized gastric lymphoma (38 Stage IE and 39 Stage IIE) were treated with radiation therapy, chemotherapy, surgery, or a combination. Univariate and multivariate local control and survival analyses were performed on possible prognostic factors, such as patient age, gender, histologic subtype, stage, tumor size, depth of penetration, multicentricity, and treatment modality. RESULTS: At 5 years, the relapse-free survival was 52%; 74% of the relapses occurred at local sites. Smaller tumor size was most strongly associated with local control (p = .001) and relapse-free survival (p < .001). Patients with tumor sizes < or = 5 cm had relapse-free survival of 87%, compared with 41% and 15% for those with tumor sizes of 5.1 cm to 10 cm and > 10 cm, respectively. The 47 patients who received combined-modality therapy had a relapse-free survival of 65%, compared with 24% for the 30 who received single-modality therapy (p < .01). Although patient age, stage, depth of penetration, and resective surgery affected the above endpoints, these factors were not independent predictors of outcome. Analysis of treatment subgroups showed that surgical resection combined with postoperative irradiation was associated with highest local control (p = .002) and the best relapse-free survival (p = .004), when compared with other treatment modalities. In 27 patients with tumor sizes < or = 5 cm, comparison of the 15 patients who had surgery with the 12 who did not failed to reveal a local control benefit from the addition of surgery. CONCLUSION: These data demonstrate that tumor bulk is an important prognostic determinant of local control and relapse-free survival in localized gastric lymphoma patients. Stage IE and IIE lymphoma of the stomach can be selectively treated with primary radiation, but surgical resection may be necessary for large tumors (> 5 cm), followed by adjuvant radiation.

The structure for a radiation oncology protocol. The Committee of Radiation Oncology Group Chairmen.

Multi-institutional Cooperative Group clinical trials involving radiotherapy require unambiguous therapeutic guidelines, so that patients entered from each of the participating institutions will receive essentially uniform treatment. The technical guidelines for a Radiation Oncology Protocol presented in this report represents a consensus of the Radiotherapy Committees in the major NCI funded Cooperative Groups and is derived from over a decade of experience. Although they have been written for external beam therapy, they are applicable to brachytherapy with appropriate technical considerations. It is anticipated that further evolution will occur with the introduction of new technologies such as 3-D treatment planning and delivery, multi-leaf collimation and small field irradiation.

Palliative radiation treatment of cutaneous mycosis fungoides--a dose response.

Between 1966 and 1981, 20 patients (191 lesions) underwent palliative radiation therapy for control of biopsy-proven cutaneous mycosis fungoides. Six patients (47 lesions) and an additional 34 lesions from the remaining 14 patients with complete response to treatment were excluded from the study because of follow-up of less than one year. Included in the remaining 110 lesions were all recurrences and all partial responses. The modalities for treatment included superficial X rays, Cobalt-60 or electron beam irradiation. The total tumor doses employed ranged from 600-4000 cGy. The 110 lesions (14 patients) were retrospectively analyzed to determine the dose required for local control of the lesions. Fifty-three percent of the lesions were classified as plaques, 20% as tumors less than or equal to 3 cm in diameter, and 27% as tumors greater than 3 cm in diameter. Complete response to treatment was observed in 95% of the plaque lesions, 95% of the tumors less than or equal to 3 cm in diameter and 93% of tumor greater than 3 cm in diameter. A complete response to treatment was noted in all lesions receiving greater than 2000 cGy. In the total population of lesions having a complete response, a local infield recurrence rate of 42% was noted in the group receiving less than or equal to 1000 cGy, 32% in those receiving 1001-2000 cGy, 21% in those receiving 2001-3000 cGy, and 0% in the group receiving greater than 3000 cGy. No infield recurrence was seen when the treated lesion received a total tumor dose greater than or equal to TDF of 49. Of those lesions which recurred, the mean time to recurrence for the first three dose ranges above were 5 months, 10 months and 16 months respectively. Eighty-three percent of the 30 recurrences were seen within one year of treatment; 100% of the recurrences occurred within two years of treatment. The data from this study indicate that tumor doses equivalent to at least 3000 cGy at 200 cGy per fraction, five fractions per week (TDF greater than or equal to 49) are needed for adequate local control of cutaneous mycosis fungoides lesions.

Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol.

PURPOSE: This study was prepared to address two objectives: (a) to determine whether progressively higher total doses of hepatic irradiation can prolong survival in a selected population of patients with liver metastases; (b) to refine existing concepts of liver tolerance for fractionated external radiation employing a fraction size which might be appropriate in clinical protocols evaluating elective or adjuvant radiation of the liver. METHODS AND MATERIALS: One hundred seventy-three analyzable patients with computed tomography measurable liver metastases from primary cancers of the gastrointestinal tract were entered on a dose escalating protocol of twice daily hepatic irradiation employing fractions of 1.5 Gy separated by 4 hr or longer. Sequential groups of patients received 27 Gy, 30 Gy, and 33 Gy to the entire liver and were monitored for acute and late toxicities, survival, and cause of death. Dose escalation was implemented following survival of 10 patients at each dose level for a period of 6 months or longer without clinical or biochemical evidence of radiation hepatitis. RESULTS: The use of progressively larger total doses of radiation did not prolong median survival or decrease the frequency with which liver metastases were the cause of death. None of 122 patients entered at the 27 Gy and 30 Gy dose levels revealed clinical or biochemical evidence of radiation induced liver injury. Five of 51 patients entered at the 33 Gy level revealed clinical or biochemical evidence of late liver injury with an actuarial risk of severe (Grade 3) radiation hepatitis of 10.0% (+/- 7.3% S.E.) at 6 months, resulting in closure of the study to patient entry. CONCLUSION: The study design could not credibly establish a safe dose for hepatic irradiation, however, it did succeed in determining that 33 Gy in fractions of 1.5 Gy is unsafe, carrying a substantial risk of delayed radiation injury. The absence of apparent late liver injury at the 27 Gy and 30 Gy dose levels suggests that a prior clinical trial of adjuvant hepatic irradiation in patients with resected colon cancer may have employed an insufficient radiation dose (21 Gy) to fully test the question.

Additivity of radiosensitization by the combination of SR 2508 (etanidazole) and Ro 03-8799 (pimonidazole) in a murine tumor system.

The nitroimidazole radiosensitizers SR 2508 and Ro 03-8799 have different dose-limiting toxicities in man and hence can be used in combination. Such therapy will be beneficial only if their radiosensitizing properties are additive, which this study sought to determine using clinically relevant radiosensitizer concentrations in the EMT6 tumor in the flanks of BALB/c mice. 240 mg/kg of each drug gave tumor concentrations (+/- 2 se) 55 min after i.v. administration of the combination of 50.4 +/- 10.6 micrograms/g (236 +/- 50 nmol/g) for SR 2508 and 39.7 +/- 9.0 micrograms/g (137 +/- 31 nmol/g) for Ro 03-8799. The radiosensitization by both agents administered both singly and in combination at 240 mg/kg and singly at 480 mg/kg was measured, giving sensitizers 30 min before 20 Gy of 250 kV X rays. Tumor response was assayed by clonogenic cell survival. SER values (with 95% confidence limits) were 1.28 (1.20-1.37) for 240 mg/kg SR 2508, 1.20 (1.10-1.30) for 240 mg/kg Ro 03-8799, 1.46 (1.33-1.59) for 240 mg/kg of both drugs in combination, 1.46 (1.38-1.55) for 480 mg/kg SR 2508 and 1.46 (1.31-1.62) for 480 mg/kg Ro 03-8799. These data confirm the additivity of radiosensitization by the two drugs administered in combination.

Clinical trials with hypoxic cell sensitizers: time to retrench or time to push forward?

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.

Phase I trial of the hypoxic cell radiosensitizer SR-2508: the results of the five to six week drug schedule.

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.

Logistics in designing clinical trials for etanidazole (SR 2508): an RTOG experience.

In a Phase II study of etanidazole (SR 2508), the dose of 17 x 2 g/m2 (total drug dose: 34 g/m2) was tested in 33 patients and the toxicity was deemed acceptable. A Phase III trial is now in progress comparing conventional radiotherapy with conventional radiotherapy plus etandizole (2 g/m2 i.v. 30 to 60 min before radiotherapy each Monday, Wednesday, and Friday to 34 g/m2 in 17 doses) in patients with unresectable head and neck carcinomas. A recent analysis showed only 14.7% grade 1 and 3.9% Grade 2 peripheral neuropathy. In the initial study design, 133 evaluable patients per treatment arm could achieve an 80% level of power of detecting a 15% difference in local-regional control rates between the radiotherapy arm (25% local-regional control at 2 years) and the radiotherapy plus etanidazole arm (assuming a 40% rate). Allowing for 20 ineligible cases in each arm, a total number of 306 was required. An interim analysis showed that 27% of the patients assigned to radiotherapy plus etanidazole are receiving less than 14 doses of the drug. It is assumed that less than 14 drug doses will not produce any therapeutic gain, therefore, a true 40% local-regional control rate in the radiotherapy plus etanidazole arm will be observed as a 36% rate when analyzed by assigned treatment. Using this information, the study was modified to have an 80% level of power in detecting a difference between a 25% local-regional control rate in the radiotherapy group and a 36% rate in the radiotherapy plus etanidazole group. Allowing for a 10% patient ineligibility rate, 518 patients are required. With 12 patients entered per month, it is estimated that patient accrual to this study will continue through October 1991.

Cost accounting in radiation oncology: a computer-based model for reimbursement.

PURPOSE: The skyrocketing cost of medical care in the United States has resulted in multiple efforts in cost containment. The present work offers a rational computer-based cost accounting approach to determine the actual use of resources in providing a specific service in a radiation oncology center. METHODS AND MATERIALS: A procedure-level cost accounting system was developed by using recorded information on actual time and effort spent by individual staff members performing various radiation oncology procedures, and analyzing direct and indirect costs related to staffing (labor), facilities and equipment, supplies, etc. Expenditures were classified as direct or indirect and fixed or variable. A relative value unit was generated to allocate specific cost factors to each procedure. RESULTS: Different costs per procedure were identified according to complexity. Whereas there was no significant difference in the treatment time between low-energy (4 and 6 MV) or high-energy (18 MV) accelerators, there were significantly higher costs identified in the operation of a high-energy linear accelerator, a reflection of initial equipment investment, quality assurance and calibration procedures, maintenance costs, service contract, and replacement parts. Utilization of resources was related to the complexity of the procedures performed and whether the treatments were delivered to inpatients or outpatients. In analyzing time motion for physicians and other staff, it was apparent that a greater effort must be made to train the staff to accurately record all times involved in a given procedure, and it is strongly recommended that each institution perform its own time motion studies to more accurately determine operating costs. Sixty-six percent of our facility's global costs were for labor, 20% for other operating expenses, 10% for space, and 4% for equipment. Significant differences were noted in the cost allocation for professional or technical functions, as labor, space, and equipment costs are higher in the latter. External beam treatment-related procedures accounted for more than 50% of all technical and professional revenues, simulation for 8% to 10%, and other physics/dosimetry procedures for 11% to 14% of revenues. Some discrepancies were identified between the actual cost and level of reimbursement of various procedures. Details are described in the manuscript. CONCLUSION: It is imperative to develop an equitable reimbursement system for radiation oncology services, based on cost accounting and other measures that may enhance productivity and reduce the cost per procedure unit, while at the same time preserving the highest quality of service provided to patients.

Radiation therapy alone or combined with misonidazole in the treatment of locally advanced non-oat cell lung cancer: report of an RTOG prospective randomized trial.

From September 1979 to February 1983, 268 patients with unresectable, locally advanced (RTOG Stage III), non-small cell lung cancer were randomized to receive radiation therapy alone (RT) (50 Gy large field and 10 Gy boost), or combined with misonidazole (400 mg/m2 2-4 hr prior to RT daily for 5-6 weeks to a maximum dose of 12 g/m2 or until tumor progression). One hundred twenty-three patients who received irradiation alone and 116 given RT + misonidazole were evaluable for toxicity, time to tumor progression, and survival as of April 1987. The distribution of patient characteristics was similar in both treatment groups; 59% of the patients had a Karnofsky score of 90 or better, 53% had adenocarcinoma or large cell tumors, and 47% had Stage T3 tumors. Complete tumor regression was reported for 33 (27%) patients treated with radiation therapy alone and 24 (21%) who received misonidazole + RT. Median survival was 8 months with RT alone and 7.4 months with misonidazole + RT. Ninety-five percent of the patients have died. Seventy percent of the patients treated with radiation alone and 77% of those treated with misonidazole + RT died of progressive disease. Three patients treated with radiation alone and two with RT + misonidazole died subsequent to radiotherapy-related pneumonitis or pulmonary fibrosis. There was no significant improvement in response rates, local control, or survival for patients who received daily misonidazole along with irradiation compared with patients treated by irradiation alone.

Large fraction irradiation with or without misonidazole in advanced non-oat cell carcinoma of the lung: a phase III randomized trial of the RTOG. Radiation Therapy Oncology Group.

The Radiation Therapy Oncology Group (RTOG) investigated the use of misonidazole as an hypoxic cell sensitizer in a Phase III prospective randomized trial employing radiotherapy, 600 cGy twice weekly to a total of 3600 cGy with and without misonidazole in the treatment of locally advanced non-metastatic squamous cell, adeno, or large cell carcinoma of the lung. Between January 1980 and July 1983, 117 patients from 21 institutions were enrolled. One-hundred eight patients were evaluable; 53 in the combined treatment arm and 55 in the radiation alone arm. Grade 3 or worse complications associated with radiation occurred in 17% of patients. Esophageal toxicity accounted for the majority of complications. Two (4%) patients in the radiotherapy plus misonidazole group experienced grade 3 peripheral neurotoxicity. Complete or partial responses were produced in 58% of the patients with radiotherapy alone and 36% of those treated with radiotherapy plus misonidazole (p = 0.08). At the time of first progression, over 50% of the patients had persistent local disease. Median survival was 7 months regardless of treatment. Misonidazole in the dose and schedule employed did not enhance the effect of radiotherapy on either local tumor control or overall survival in patients with advanced lung cancer.