Raul C. Urtasun

Abbreviated Course of Radiation Therapy in Older Patients With Glioblastoma Multiforme: A Prospective Randomized Clinical Trial

PURPOSE To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM). PATIENTS AND METHODS One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). RESULTS All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02). CONCLUSION There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.

A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916)

From 1979 through July 1983, 859 patients were enrolled in a Phase III RTOG Protocol (7916) evaluating the role of Misonidazole combined with radiation in the treatment of brain metastasis. Patients were randomized to one of four treatment arms (3.0 Gy x 10 fractions with or without 1 g/m2 of Misonidazole [total 10 g/m2] versus 5.0 Gy x 6 fractions with or without 2 g/m2 of Misonidazole) [total 12 g/m2]. Among the 779 analyzable cases, 63% had a lung primary and 12% had breast. Of the histologic types, 43% were adenocarcinoma and 24% were squamous cell. Seventy-eight percent had a Karnofsky of greater than 70. Of the 779 cases, 773 are dead (99%). Median survival is 3.9 months, with 60% alive at 3 months, 35% at 6 months, and 15% at 1 year. Survival was evaluated by treatment arm, Misonidazole status, and fractionation scheme; none showed any statistical significance. Favorable prognostic factors were assessed (age less than 60, Karnofsky of 70-100, controlled primary and brain metastasis only) in each treatment arm and no difference was found. Brain metastasis was cause of death in 1/3, and 19-33% of patients were retreated. Because up to 1/3 of the patients in this study died secondary to uncontrolled brain metastasis, improvement in local control remains an important goal. Until proven otherwise, the treatment of choice for the majority of patients still remains a conventional palliative course of 3.0 Gy x 10 fractions.

A report of RTOG 8206: A phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic osseous metastases

Hemibody irradiation (HBI) in a single exposure is an effective and safe technique for palliation of symptoms due to widespread bony metastases (RTOG 78-10). The present study (82-06) sought to explore the possibility that HBI added to local-field irradiation might delay the onset of metastases in the hemibody effected, as assessed by bone scans and X rays, and decrease the frequency of further treatment. The results of this clinical trial establish that 800 cGy of HBI is indeed causes micro-metastases to regress, perhaps completely. A total of 499 patients were randomized to receive either HBI or no further treatment following completion of standard palliative local field irradiation (300 cGy x 10) to the symptomatic site. Improvement was seen in time-to-disease progression at one year, 35% for local + HBI versus 46% on the local-only control arm. Time-to-new disease in the targeted hemibody was also improved. At one year, 50% of patients on the local + HBI arm showed new disease compared to 68% on the local-only arm. Furthermore, the median time-to-new disease within the targeted HBI area was 12.6 months for the local + HBI arm versus 6.3 months for patients in the local-only arm. Time-to-new treatment within the hemibody segment was also delayed. At one year, 76% of the local only group had been retreated versus 60% in the local + HBI arm. There were no fatalities and no radiation pneumonitis was seen in the local + HBI arm. Overall, the incidence of toxicities was low (5-15%). The occurrence of severe hematopoetic toxicities were significantly different in the local + HBI arm, but they were transitory. One life-threatening thrombocytopenia occurred, for a limited time, indicating excellent tolerance to HBI. This clinical trial demonstrates that HBI has the potential to be used to treat systemic and occult metastases, particularly if both halves of the body can be treated.

Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma

SummaryBecause the percentage of dividing cells in malignant glioma is small, cell cycle specific drugs such as VP16 are most effective if given continuously over prolonged periods. In this study, we chose a dose of 50 mg/day to minimize therapy interruptions for myelosuppresion. VP16 was given until the neutrophil count dropped to < 1.0 × 109/L or the platelets fell to < 75 × 109/L and resumed when the counts rose to normal levels. We treated 46 patients with supratentorial malignant glioma (15 anaplastic astrocytoma, 21 glioblastoma multiforme, 9 anaplastic oligodendroglioma, l undifferentiated primary malignant brain tumor) at the time of tumor progression. All had KPS ≥ 70 at study entry. All patients had prior RT,13 with adjuvant nitrosourea. Twenty-four had prior nitrosourea chemotherapy for tumor progression, 7 had no prior chemotherapy. We treated 20 patients with VP16 at first progression and 26 at second or later progression. All patients had CT or MR scans and clinical evaluation every 8 weeks. Median time to tumor progression (TTP) was 8.8 weeks for all evaluable patients, 8.6 weeks for those treated at first progression and 8.4 weeks for those treated at second progression, 9.1 weeks for anaplastic astrocytoma, 7.5 weeks for glioblastoma multiforme and 17.1 weeks for anaplastic oligodendroglioma. There were 8 responses and 11 patients with stable disease for at least 8 weeks (R + SD = 42%). Prolonged low-dose oral VP15 is well tolerated, with minimal myelosuppression. Prolonged low-dose oral VP16 is modestly effective treatment for patients with recurrent malignant glioma and is more effective for anaplastic astrocytoma and anaplastic oligodendroglioma than glioblastoma multiforme.

Clinical phase I study of the hypoxic cell radiosensitizer RO-07-0582, a 2-nitroimidazole derivative.

RO-07-0582 toxicity studies were performed in 12 patients for a total of 16 assays. Single and multifraction dose schedules were used, and drug concentrations in solid tumor tissue, cerebrospinal fluid, and blood (at 14 to 24 hr.) were established. A severe peripheral neuropathy occurred in 1 patient on the multifraction regimen when the total dosage reached 24 g. Drug absorption and concentration in the blood do not significantly differ from that of metronidazole. Maximum blood levels were reached at from 2 to 4 hr., and several days subsequent to administration had stabilized to levels only slightly above control levels.

Radiobiological characterization of the inactivating events produced in mammalian cells by helium and heavy ions.

Abstract Homogeneous populations of stationary phase and G 1-phase Chinese hamster cells were irradiated in stirred suspensions placed in the plateau regions and the extended Bragg peaks of particle beams from the 184 in. cyclotron and Bevalac at Berkeley. Cell inactivation data were best-fitted to the linear quadratic expression. SSo=exp (− αD − βD2). The increase in RBE observed with increasing LET up to 100–150 keV/μ resulted predominantly from an increase in the single-hit mechanism (a). The double-hit mechanism (√β) increased by ∼ 10% over the same range of LET for these energetic particle beams. The ratio, RBE (spread peak)/RBE (plateau), is an important factor to maximize for therapeutic considerations. The ratio is greater than 1.0 and increases with particle Z -value up to carbon for beams whose Bragg peaks had been spread to 4 cm. Its value decreases for Ne and becomes less than 1.0 for Ar. Chemical radiosensitizers have been studied in combination with He and beavy-lon beams. OERs were measured for hamster cells irradiated in the plateaus and spread peaks and found to decrease with increasing LET. The sensitizers, metronidazole, Ro 7-0582, and Ro 7-0741, at 5 mM concentration were effective in reducing the OERs of the beams studied by ∼ 55%, ∼ 75% and ∼ 85%, respectively. Such drugs appear to have a potential benefit in radiotherapy planned with heavy ions.

Misonidazole combined with hyperfractionation in the management of malignant glioma

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.

Initial report of the phase I trial of the hypoxic cell radiosensitizer SR-2508

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 patients 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.

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 patients 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.

The impact of regional nodal radiotherapy (dose/volume) on regional progression and survival in unresectable non-small cell lung cancer: an analysis of RTOG data

PURPOSE To evaluate in-field progression and survival of patients with unresectable non-small cell lung cancer (NSCLC) in relation to adequacy of coverage of thoracic regional nodal areas in the radiotherapy volume. MATERIALS AND METHODS A total of 1705 patients from four large RTOG trials (78-11, 79-17, 83-11 and 84-07) were analyzed for this purpose. For each of these trials, the dose delivered to nodal regions was recorded and an assessment of adequacy of field borders was made. Each nodal site was assessed for progression, defined as in-field or out-of-field. In patients who had adequate borders on nodal regions, the results were analyzed according to the dose delivered. RESULTS The majority (74%) of patients were between the age of 55-75. Forty-six percent of the patients had KPS of 60-80 and 52% had KPS of 90-100. Sixty percent of patients had a weight loss of less than 5% in the 6 months prior to diagnosis. Deviations from the protocol in field borders (borders not per protocol) were most frequent for the contralateral hilum (25.2%) and least frequent in the ipsilateral hilum (6.3%). The adequacy of ipsilateral hilar coverage was important for preventing the in-field progression (11.6 vs. 22% for adequately vs. inadequately covered ipsilateral hilum, respectively, P=0.01), however, did not influence the 2-year-survival (35 vs. 37%) or median survival (1.3 vs. 1.1 year). Neither the in-field progression nor the 2-year-survival were affected by adequacy of nodal coverage in the mediastinum, ipsilateral supraclavicular area and contralateral hilum, even when different doses were analyzed. CONCLUSION These data suggest that elective irradiation of mediastinal, contralateral hilar and supraclavicular lymph nodes may not be necessary in the treatment of unresectable NSCLC.