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.

Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy.

Forty-two evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4'-epimer of doxorubicin in cumulative doses ranging from 147 mg/m2 to 888 mg/m2. In this study of the Northern California Oncology Group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. However, when these biopsies were compared to 119 biopsies obtained from 98 patients treated with doxorubicin, milligram for milligram, epirubicin caused less endomyocardial injury than doxorubicin (P = 0.0013). Age, sex, type of primary malignancy, prior cardiac disease, and hypertension did not influence the degree of histologically demonstrated anthracycline injury induced by epirubicin.

Postoperative radiation therapy for epithelial ovarian cancer: the curative role based on a 24-year experience.

We updated 152 cases of epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stages I through III, treated at the Stanford Medical Center (Stanford, Calif) with irradiation as the only postoperative therapy. In 133 patients, radiation was directed only to those regions of known disease, while it was delivered to the whole abdomen and pelvis by the Martinez technique in 19 patients. Mean follow-up time was 6.8 years. The results were analyzed as freedom from relapse (FFR) at 15 years; overall, FFR constituted 44% of the patients. Statistically significant differences of FFR appeared between stages II (60%) and III (16%); among the histopathologic variants endometrioid (64%), serous papillary (45%), and undifferentiated (7%); between pathologic grades 2 (68%) and 3 (20%); between amounts of postoperative residual disease less than 2 cm (48%) and greater than 2 cm (16%); and between ages less than 40 (80%) and greater than or equal to 40 (38%). Considering all stages and grades together, FFR in the 54 cases with unfavorable residuum (greater than 2 cm) was 14%. Among the 98 with favorable residuum (none, or less than 2 cm) FFR was 62%; and 14 (39%) of the 36 relapses were in the untreated upper abdomen. Results in the favorable group support effectiveness of irradiation as postoperative therapy. These patterns of relapse suggest that whole-abdominopelvic irradiation would further increase FFR. We believe that, for favorable disease as defined such radiotherapy should be the standard for comparison.

Advanced epithelial ovarian cancer: salvage whole abdominal irradiation for patients with recurrent or persistent disease after combination chemotherapy.

Between 1979 and 1984, 53 patients received whole abdominal irradiation in a curative salvage effort for residual (32 patients) or recurrent (21 patients) epithelial ovarian cancer after combination chemotherapy (cisplatin-based in 48 patients). Residual cancer less than or equal to 2 cm in diameter was confirmed at operation in all patients before irradiation consisting of 2,550 to 3,000 rad to the whole abdomen with partial liver/kidney shielding and boosting of the dose to the diaphragmatic/paraaortic nodal regions and pelvis to approximately 4,000 and 5,000 rad, respectively. Twelve patients (23%) did not complete therapy as a result of hematologic intolerance. Actuarial overall and disease-free survival at 3 years are 35% and 30%, respectively, with follow-up for disease-free patients ranging from 30 to 79 months (median, 43 months). Twenty-seven of 36 relapses (75%) occurred within the irradiated abdomen alone. At 3 years, 70% of patients with well- or moderately-differentiated tumors were disease-free v 10% of those with poorly differentiated tumors (P less than .001). Among prognostic factors evaluated, including grade, initial residual disease before chemotherapy, residual disease at time of irradiation, age, chemotherapy response v progression, and completion of irradiation, only grade and initial residual disease before chemotherapy were statistically significant in multivariate analysis (both P less than .01). Patients with the combination of high-grade tumor, initial residual disease greater than 2 cm before chemotherapy, and macroscopic disease after "second-look" laparotomy do not benefit from irradiation. Eleven patients (21%) developed an apparent treatment-related bowel obstruction after completion of irradiation. Selected subsets of patients do well; however, the role of irradiation in this setting can be confirmed only with randomized clinical study.

Toxicity of open-field whole abdominal irradiation as primary postoperative treatment in gynecologic malignancy.

Between June 1979 and March 1985, 77 patients received whole abdominal radiation as the sole postoperative treatment for gynecologic malignancy. With an open-field technique of irradiation, a median of 3,000 cGy was delivered to the entire abdominal contents with partial liver and kidney shielding; the total dose to the pelvis after boosts was 5,100 cGy, and that to the sub-diaphragmatic and para-aortic nodal regions was 4,200 cGy. The primary sites of malignancy were the endometrium in 41 patients, ovary in 25, uterus in 5, fallopian tube in 4, and cervix in 2. Seven patients (9%), all older than 60 years, experienced acute gastrointestinal toxicity that interrupted treatment, only one of whom failed to complete the prescribed course as a result. Hematologic toxicity was sufficient to interrupt therapy in 21 patients (27%), 1 of whom failed to complete therapy as a result. Hematologic toxicity was not increased in elderly patients. All patients were followed up for a minimum of 30 months (median, 43 months) or until death. Six patients experienced a treatment-related bowel obstruction (two of whom had concomitant progressive intra-abdominal disease); the 3-year actuarial risk for a treatment-related bowel obstruction was 9%. This risk was significantly increased by high-dose boosting for residual disease. Only one instance of clinical radiation pneumonitis occurred, and no cases of clinical hepatitis were noted; however, subclinical evidence of pulmonary and hepatic radiation effect was frequent. Whole abdominal irradiation as described has modest toxicity for patients with gynecologic cancer who are at high risk for intra-abdominal failure.

The effect of glutathione (GSH) depletion in vivo by buthionine sulfoximine (BSO) on the radiosensitization of SR 2508.

The effect of glutathione depletion (GSH) on the efficacy of SR 2508 was evaluated in two murine tumor models with single large doses of radiation or with low doses administered in an accelerated fractionated schedule. To deplete tumor GSH, buthionine sulfoximine (BSO) was administered in the animals drinking water (10 mM) following two i.p. injections of 450 mg/kg. This treatment decreased RIF and MCA tumor GSH concentrations by 95% and 80%, respectively. Mice (C3H/Sed) received BSO for 48-72 hr before the first dose of radiation, and were maintained on BSO drinking water for the duration of the fractionated course of therapy. SR 2508 (200-1000 mg/kg) was injected 45 min prior to each fraction of radiation. Radiation was administered as a single dose of 15 Gy or 20 Gy, for RIF and MCA tumors, respectively. Alternatively, animals received a fractionated course of radiotherapy which consisted of 2.5 Gy/fraction for the RIF, and 3 Gy/fraction for the MCA tumors, b.i.d. for five days (total of 10 fractions). Tumor response with and without BSO, and with and without SR 2508, was determined by regrowth delay. BSO pretreatment increased the efficacy of SR 2508 with single dose radiation in the MCA but not RIF tumor. SR 2508 administered with fractionated radiation produced lower enhancement ratios (SER) than with a single radiation dose. However, BSO significantly enhanced the efficacy of SR 2508 with fractionated radiation. BSO increased the maximum SER for SR 2508 (3 mM/fraction) from 1.2 to 1.4 in the RIF tumor, and from 1.4 to 1.8 in the MCA tumor. BSO also increased the toxicity of SR 2508 by a factor of 2. However, the ability of BSO to increase the efficacy of low doses of sensitizer at clinically relevant doses of radiation suggests that this combined modifier treatment may be of clinical benefit.

Initial results of a phase I trial of continuous infusion SR 2508 (etanidazole): a radiation therapy oncology group study.

To exploit both the oxygen-mimetic and "pre-incubation" or continuous exposure effects of the 2-nitroimidazole radiosensitizers, we are conducting a Phase I trial of continuous infusion SR 2508 for patients receiving brachytherapy. Following the administration of a loading dose of 2 g/m2, SR 2508 is administered by continuous infusion for 48 hr. Twenty-one patients have completed treatment. The initial total dose was 8 g/m2 with patients currently receiving 15 g/m2. No toxicity has been observed. At the higher doses the steady-state plasma concentrations have been between 50 and 70 micrograms/ml. It is not yet known whether or not hypoxic sensitizers will be of benefit clinically, and if so, when during a course of treatment is the optimal time to use them. Given the lack of toxicity and plasma concentrations achievable with continuous infusion, future studies will be conducted using SR 2508 during both the external beam and brachytherapy aspects of treatment.

Combination of external beam irradiation and multiple-site perineal applicator (MUPIT) for treatment of locally advanced or recurrent prostatic, anorectal, and gynecologic malignancies.

We have devised a single after-loading applicator, the Martinez Universal Perineal Interstitial Template (MUPIT), which has been used in combination with external beam irradiation to treat 104 patients with either locally advanced or recurrent malignancies of the cervix, vagina, female urethra, prostate, or anorectal region. Twenty-six patients treated for prostate cancer are excluded because of their short follow-up. Local failure developed in 13 of the 78 remaining patients (16.6%)--major complications developed in 4 patients (5.1%). Follow-up has been 1 year to 7 1/2 years; 60/78 patients have been followed for more than 2 years. All local recurrences and complications occurred before 18 months. The device consists of two acrylic cylinders, an acrylic template with an array of holes that serve as guides for trocars, and a cover plate. In use, the cylinders are placed in the vagina and/or rectum or both and then fastened to the template so that a fixed geometric relationship among the tumor volume, normal structures, and source placement is preserved throughout the course of the implantation. Appropriate computer programs have been developed to calculate the dose from these implants. The advantages of the system are (a) greater control of the placement of sources relative to the tumor volume and critical structures, as a result of the fixed geometry provided by the template and cylinders, and (b) improved dose-rate distributions obtained by means of computerized optimization of the source placement and strength during the planning phase. We conclude that the local control rate (83.4%) with low morbidity (5.1%) achieved with the combination of external beam irradiation and MUPIT applicator in these patients with locally advanced malignancies represents an improvement over previous published results with other applicators.

Final report of the phase I trial of continuous infusion etanidazole (SR 2508): a Radiation Therapy Oncology Group study.

Seventy-eight patients have been treated on a Phase I trial using continuous infusion etanidazole while undergoing brachytherapy for locally advanced tumors. There were two sequential schemata, the first treated 63 patients with doses ranging from 8-23 g/m2 over 48 hr and the second treated 15 patients with doses ranging from 20-23 g/m2 over 96 hr. The tumor sites were: brain (n = 42), cervix (n = 22), and breast (n = 14). Patients received a loading dose of etanidazole of 2 g/m2 followed by a continuous infusion for a total of 48 or 96 hr while radioactive implants were in place. Of the 63 patients in the 48-hr study, 52 were entered at doses of less than or equal to 21 g/m2 and there were no definite neuropathies but two patients with the cramping/arthralgia syndrome. Of the 11 patients entered at 22-23 g/m2, 1 patient had symptoms of peripheral neuropathy (Grade II) and 6 had the cramping/arthralgia syndrome. This is a new syndrome, distinct from the peripheral neuropathy, characterized by transient alterations in sensations consisting of cramping, arthralgias, or tingling that resolved completely at intervals varying from a few hours to about 1 week post-treatment. The cramping/arthralgia syndrome limited dose escalation; therefore, the maximum tolerated dose over 48 hr was determined to be 20-21 g/m2. The 96-hr infusion was limited to patients with recurrent gliomas undergoing stereotactic implantation. To date, 15 patients have been treated with doses of 20-23 g/m2. No toxicity was encountered at doses less than or equal to 22 g/m2. At 23 g/m2, one patient developed Grade III neuropathy and three patients had mild cramping/arthralgia syndrome, for whom the drug was discontinued. Therefore, it appears the maximum tolerated dose at 96 hr will be approximately 23 g/m2, which is 10-15% higher than for the 48-hr infusion.

Historical vignette: The radium bomb: Harvey Cushing and the interstitial irradiation of gliomas.

Harvey Cushing performed over 2000 operations on patients with brain tumors, including 832 for gliomas. He implanted radioactive radium needles, known as a "radium bomb," in a small number of these patients. He was not impressed with the results and did not pursue this method of treatment in a serious way. The authors present here Cushing's little-known experience with brachytherapy and discuss the reasons for his lack of interest in this technique, despite his advocacy of radiotherapy for certain lesions. An interesting perspective is offered for contemporary neurosurgeons involved in the treatment of brain tumors with cranial irradiation.