Clinical calculator predictive of chemotherapy benefit in stage 1A uterine papillary serous cancers.

OBJECTIVE: Determine the utility of a clinical calculator to predict the benefit of chemotherapy in stage IA uterine papillary serous cancer (UPSC). PATIENTS AND METHODS: Data were collected from NCDB from years 2010-2014. Based on demographic and surgical characteristics, a clinical score was developed using the random survival forest machine learning algorithm. RESULTS: Of 1,751 patients with stage IA UPSC, 1,012 (58%) received chemotherapy and 739 (42%) did not. Older age (HR 1.06), comorbidities (HR 1.31), larger tumor size (HR 1.27), lymphovascular invasion (HR 1.86), positive peritoneal cytology (HR 2.62), no pelvic lymph node dissection (HR 1.51), and no chemotherapy (HR 2.16) were associated with poorer prognosis. Compared to no chemotherapy, patients who underwent chemotherapy had a 5-year overall survival of 80% vs. 67%. To better delineate those who may derive more benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low, moderate, and high-risk groups with associated 5-year OS of 86%, 73%, and 53%, respectively. Using the calculator to assess the relative benefit of chemotherapy in each risk group, chemotherapy improved the 5-year OS in the high (42% to 64%; p < 0.001) and moderate risk group (66% to 79%; p < 0.001) but did not benefit the low risk group (84% to 87%; p = 0.29). CONCLUSION: Our results suggest a clinical calculator is useful for counseling and personalizing chemotherapy for stage IA UPSC.

Prognostic discrimination of subgrouping node-positive endometrioid uterine cancer: location vs nodal extent.

BACKGROUND: The 2009 International Federation of Gynecologists and Obstetricians elected to substage patients with positive retroperitoneal lymph nodes as IIIC 1 (pelvic lymph node metastasis only) and IIIC 2 (paraaortic node metastasis with or with positive pelvic lymph nodes). We have investigated the discriminatory ability of subgrouping patients with retroperitoneal nodal involvement based on location, number, and ratio of positive nodes. METHODS: For 1075 patients with stage IIIC endometrioid corpus cancer abstracted from the Surveillance, Epidemiology, and End Results databases for 2003-2007, Kaplan-Meier analyses, Cox proportional hazard models, and other quantitative measures were used to compare the prognostic discrimination for disease-specific survival (DSS) of nodal subgroupings. RESULTS: In univariate analysis, the 3-year DSS were significantly different for subgroupings by location (IIIC 1 vs IIIC 2; 80.5% vs 67.0%, respectively, P=0.001), lymph node ratio (≤ 23.2% vs >23.2%; 80.8% vs 67.6%; P<0.001), and number of positive lymph nodes (1, 2-5, >5; 79.5, 75.4, 62.9%, P=0.016). The ratio of positive nodes showed superior discriminatory substaging in Cox models. CONCLUSION: Subgrouping of stage IIIC patients by the ratio of positive nodes, either as a dichotomized or continuous parameter, shows the strongest ability to discriminate the survival, controlling for other confounding factors.

Endometrial stromal sarcoma: a population-based analysis.

To determine independent prognostic factors for the survival of patients with endometrial stromal sarcoma (ESS), data were abstracted from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute from 1988 to 2003. Kaplan-Meier and Cox proportional hazards models were used for analyses. Of 831 women diagnosed with ESS, the median age was 52 years (range: 17-96 years). In total, 59.9% had stage I, 5.1% stage II, 14.9% stage III, and 20.1% had stage IV disease. Overall, 13.0, 36.1, and 34.7% presented with grades 1, 2, and 3, respectively. Patients with stage I-II vs III-IV disease had 5 years DSS of 89.3% vs 50.3% (P<0.001) and those with grades 1, 2, and 3 cancers had survivals of 91.4, 95.4, and 42.1% (P<0.001). In multivariate analysis, older patients, black race, advanced stage, higher grade, lack of primary surgery, and nodal metastasis were independent prognostic factors for poorer survival. In younger women (<50 years) with stage I-II disease, ovarian-sparing procedures did not adversely impact survival (91.9 vs 96.2%; P=0.1). Age, race, primary surgery, stage, and grade are important prognostic factors for ESS. Excellent survival in patients with grade 1 and 2 disease of all stages supports the concept that these tumors are significantly different from grade 3 tumors. Ovarian-sparing surgeries may be considered in younger patients with early-stage disease.

Thermosensitization by sulfhydryl compounds of exponentially growing Chinese hamster cells.

The effect of various sulfhydryl compounds on the survival of exponentially growing monolayer cultures of Chinese hamster cells (HA1) heated to temperatures of 37-43 degrees was examined. Concentrations of cysteamine which were nontoxic or minimally toxic at room temperature or 37 degrees became increasingly toxic at elevated temperatures, greatly potentiating the killing produced by heat alone in the absence of cysteamine. This enhancement of hyperthermia-induced cell killing increased with increasing cysteamine concentration, increasing duration of cysteamine exposure, and increasing temperature. Studies with synchronized Chinese hamster cells heated at 43 degrees for 1 hr in the presence of 16 mM cysteamine demonstrated that the potentiation of heat killing occurred in all phases of the cell cycle. Similarly, enhancement of hyperthermia-induced cell killing was seen for asynchronous cells exposed to 2-amino-ethylisothiourium bromides and cysteine, but the magnitude of the effect differed for the various sulfhydryl compounds.

Development and decay of systemic thermotolerance in rats.

The development and decay of thermotolerance to the lethal effect of systemic hyperthermia were investigated in Sprague-Dawley rats. Systemic hyperthermia was induced by partial submersion of gas-anesthetized rats in a controlled-temperature water bath. Survival was determined for rats challenged for periods of 10 to 90 min at 42.5 degrees at intervals of 24 to 144 hr after a sublethal conditioning exposure of 41.8 degrees for 1 hr. Survival curves and times of exposure at 42.5 degrees lethal to 50% of the animals (LD50) were determined for the conditioned animals and compared with those obtained for simultaneously treated control (unconditioned) rats. The thermotolerance ratios (LD50 for conditioned animals at various times after sublethal conditioning exposure divided by the LD50 for the control animals) were calculated and compared with the ratios reported in the literature for cells heated in vitro or for tissues heated locally in vivo. Pretreatment of rats at 41.8 degrees for 1 hr resulted in an increase in the LD50 for rats challenged 24 to 96 hr later, with a maximum increase noted at 48 hr (56.5 min compared with 25 min for control; thermotolerance ratio, 2.3). The animals remained relatively resistant to the second heat treatment at 96 hr and returned to control levels of heat sensitivity by 120 hr. The development and kinetics of thermotolerance to lethality induced by wholebody hyperthermia need to be considered in the design of multiple-fraction treatment plans.

Anatomical site-specific modalities for hyperthermia.

The clinical application of hyperthermia in the treatment of deep-seated tumors remains an empirical science. The pleomorphic nature of the neoplasms and the great diversity in the anatomy and physiology of the individual tumor locations make the treatment of nearly every neoplasm a unique challenge. A wide variety of devices is required, both for the administration of hyperthermia and for the measurement of the temperatures achieved. At Stanford University, these include the BSD Medical Corp. annular phased array system, an isospherical ultrasound device, and interstitial radiofrequency for deep heating. Ultrasound transducers and a variety of microwave applicators are used for superficial hyperthermia. Six illustrative case studies, selected from the 91 patients treated in our program since October 1981, are presented, with discussion and comparison of treatment devices. Difficulties in deep heating were encountered in several instances, believed secondary to the thickness of the s.c. fat, the relatively high heat-induced tumor blood flow, and the presence of adjacent bone. It is suggested that ultimate improvement in clinical results will be possible once a better understanding is achieved of such anatomical and physiological factors.

Radiotherapy with curative intent: an option in selected patients relapsing after chemotherapy for advanced Hodgkin's disease.

Thirteen patients who had relapsed or failed to obtain a complete remission after combination chemotherapy for the treatment of advanced Hodgkin's disease were treated with subtotal or total lymphoid irradiation with curative intent. Twelve of the 13 patients achieved a complete response (CR). Five of the 12 CRs subsequently relapsed at 3, 9, 9, 12, and 19 months. One patient died of leukemia 11 months following radiotherapy. The actuarial relapse-free survival at 1 year was 60%, and six patients (50%) remain disease-free with a median follow-up of 34 months (range, 10 to 115 months) following the completion of radiotherapy. Patients who failed to obtain a CR to their initial chemotherapy, whose chemotherapy CR was of short duration, or who relapsed initially in extranodal sites, tended to have a worse outcome with radiotherapy. Patients who had long disease-free intervals after initial chemotherapy or relapsed only in nodal sites tended to do relatively well. Radiation therapy was well tolerated with no major toxicity. Potentially curative radiation therapy should be considered an option in the management of selected patients who relapse following combination chemotherapy for advanced Hodgkin's disease.

Second neoplasms in patients with Hodgkin's disease following combined modality therapy--the Yale experience.

From 1969 to 1982, 183 patients with previously untreated stages IIIB and IV Hodgkin's disease and relapsing Hodgkin's disease after radiation therapy were treated with combination chemotherapy plus low-dose irradiation (CRT). One hundred fifty patients who achieved a complete response (CR) were analyzed for risk of developing a second neoplasm. Median follow-up has been 8.3 years. Actuarial survival of all patients is 74% at 10 years with a relapse-free survival of 68%. An additional 24 patients with stage IIIA disease were also treated with CRT. There were 22 CRs at risk who were analyzed. Median follow-up has been 3+ years with an actuarial survival of 90% at five years and a relapse-free survival of 83%. Second neoplasms have developed in 14 of 172 patients at risk: acute nonlymphocytic leukemia (ANLL; five patients); aggressive histology non-Hodgkin's lymphoma (NHL; three patients); and a variety of solid neoplasms (six patients). Time to second neoplasm diagnosis after initial treatment ranged from 12 to 141 months. Five patients were older than 40 years. At the time of diagnosis of the second malignancy, 11 patients were free of Hodgkin's disease (for 36 to 141 months) and three were receiving therapy for recurrent Hodgkin's disease. The 10-year actuarial risk (%) of developing ANLL was 5.9 +/- 2.8; for NHL, the risk was 3.5 +/- 2.4, and for solid neoplasms, 5.8 +/- 3.0. Our results suggest that combination chemotherapy plus low-dose irradiation does not appear to significantly increase the risk of developing second neoplasms above that already reported for combination chemotherapy when administered as either initial or salvage treatment of Hodgkin's disease.

Combined modality therapy for advanced Hodgkin's disease: 15-year follow-up data.

From 1969 through 1982, 184 patients with advanced Hodgkin's disease (HD) were treated with combined modality therapy (CMT) at Yale University. The data were reanalyzed in November 1986, with a mean follow-up of 10 years. The patient population consisted of 102 newly diagnosed stages IIIB and IV patients, and 82 patients who had relapsed after initial radical radiotherapy. From 1969 through 1978, the treatment program was induction chemotherapy with nitrogen mustard, vincristine, vinblastine, procarbazine, and prednisone (MVVPP) for three cycles (6 months) followed by low-dose radiation (1,500 to 2,500 cGy) for patients who had achieved complete remission (CR), to all disease sites present before the onset of chemotherapy. From 1978 to 1982, selected "poor-risk" advanced-stage patients received nitrogen mustard, vincristine, procarbazine, prednisone plus Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (MOPP-ABVD) induction chemotherapy, while the remaining patients were randomized between MVVPP and MOPP. One hundred fifty-one patients have achieved CR (82%); 23 (15%) of these 151 have relapsed, with the remaining 128 patients in continuous CR. A total of 62 patients have died, 45 due to HD, and 17 due to other causes. Twelve of these 17 patients died of second malignancies. The 15-year actuarial survival of all patients is 54%. It is 71% if deaths due only to HD are considered. Within the overall group of advanced HD patients, age and multiple extranodal sites of involvement continue to constitute adverse risk factors. The three drug programs used were all equivalent. No improvement resulted from the use of MOPP-ABVD in the poor-risk patients. These results compare favorably with those recently published by the National Cancer Institute (NCI). CMT resulted in an approximate 20% improvement in survival with no increase in second malignancies when compared with chemotherapy alone.

New directions for radiation biology research in cancer of the uterine cervix.

A simplified model for tumorigenesis, locoregional growth, and metastases is proposed for carcinoma of the cervix. With the use of this model, four potential areas for future directions for radiobiologic-clinical research are identified. The first area concerns the influence of human papillomavirus infection and p53 mutations on tumor biology, with particular reference to radiosensitivity and metastatic potential. Research in this area should be most fruitful. The second area focuses on the influence of hypoxia on clinical outcome in carcinoma of the cervix. The use of selective hypoxic cell toxins (e.g., tirapazamine) for phase II testing in hypoxic tumors is recommended. The third area concerns the development and clinical confirmation of assays for the prediction of intrinsic tumor radiosensitivity (e.g., surviving fraction after 2 Gy) and normal tissue radiosensitivity. The need exists for more rapid assays so that their results can be available prior to institution of therapy. The influence of the intrinsic radiosensitivity of normal tissues (especially in patients who are heterozygotes for ataxia-telangiectasia and patients with autoimmune disease) may permit identification of those at increased risk for complications so that alternative, less toxic treatment can be allocated. The fourth area for additional study concerns the influence of both intrinsic (c-myc amplification, matrix metalloproteinase levels) and extrinsic factors (fever, immunosuppression) on the development of distant metastases. Such investigations will permit identification of patients at high risk of developing distant metastases so that adjuvant treatments (e.g., chemotherapy or metalloproteinase inhibitors) can be explored. It is believed that future clarification of our proposed model will lead to other worthwhile areas for therapeutic intervention.

Axillary-subclavian vein thrombosis following combination chemotherapy and radiation therapy in lymphoma.

Four patients with deep venous thrombosis of the upper extremity (DVTUE) following combined modality therapy (mantle radiotherapy and chemotherapy) for either Hodgkin's disease or non-Hodgkin's lymphoma were seen at Stanford University Medical Center between March 1980 and April 1984. A total of 235 patients had received similar combined modality therapy during this time period. Three patients presented with acute onset of DVTUE and were anticoagulated. One patient who was referred with a several month history of DVTUE was observed closely after diagnostic evaluation revealed no evidence of recurrent Hodgkin's disease. All patients remained without evidence of their original lymphoma and had developed adequate venous collateralization. These cases of DVTUE were felt to be treatment related, a previously unreported late complication of combined irradiation and chemotherapy. Methods of diagnosis and therapeutic options are discussed.

Thermal treatment parameters are most predictive of outcome in patients with single tumor nodules per treatment field in recurrent adenocarcinoma of the breast.

PURPOSE: In previously reported studies using radiation therapy (XRT) and hyperthermia (HT) for treatment of superficial metastases from adenocarcinoma of the breast, we have identified several pretreatment and treatment parameters that correlated with rate of initial complete response (ICR) recorded at 3 weeks and duration of local control (DLC). These parameters include minimal intratumoral temperature, Tmin, and the temperature exceeded by 90% of the measured intratumoral temperatures, T90. Recently, others have shown that thermal dose defined as the cumulative time of isoeffective treatments with T90 = 43 degrees C (CUM EQ MIN T90 43) was predictive of complete response in superficial tumors. We have assessed the prognostic value of several formulations of this parameter for both ICR and DLC in a relatively uniform patient population treated with XRT-HT. METHODS AND MATERIALS: The corresponding EQ MIN T90 43 were calculated for 332 HT treatments in 111 HT fields in 83 patients who started treatment between October 1982 and May 1992. Each field contained only one measurable superficially located nodular tumor recurrence or metastasis from adenocarcinoma of the breast that was treated with XRT-HT, had mapped or multiple point temperatures recorded, and had at least one posttreatment follow-up evaluation. The thermal doses from all treatments delivered to a field were added to obtain the total thermal dose, SUM EQ MIN T90 43. Logistic and life-table multivariate analyses were performed to determine which pretreatment parameters (including initial T-stage, prior XRT, and tumor volume at the time of HT) and treatment parameters (including XRT dose, Tmin, T90, thermal dose, and hormonal therapy) best correlated with ICR and DLC. RESULTS: Of the treatment parameters tested, SUM EQ MIN T90 43 had the strongest correlation with both ICR (p = 0.0002) and DLC (p = 0.0014). Also, SUM EQ MIN T90 43 contributed to the best multivariate models predictive of ICR and DLC. CONCLUSION: For this relatively uniform patient population, we have confirmed that SUM EQ MIN T90 43 is the treatment parameter most strongly correlated with not only response following XRT-HT, but also duration of local control. This formulation of thermal dose should permit prescriptions to be written for HT treatments. Prospective trials designed to confirm this thermal dose relationship are to be encouraged.

Reduction of pain and local complications when buffered lidocaine solution is used as a local anesthetic in conjunction with hyperthermia treatments: results of a randomized trial.

Unbuffered lidocaine (pH = 6.5) is commonly employed as a local anesthetic prior to transcutaneous placement of catheters for use in temperature monitoring during hyperthermia treatments. The most frequent complaint associated with this procedure is stinging or burning pain at the injection site. Tender firm subcutaneous nodules at sites of lidocaine infiltration for catheter placement have also been noted in fields treated with radiation and hyperthermia. A reduction in the pain associated with lidocaine infiltration has been reported by the use of alkalinized (buffered) local anesthetic solutions. To confirm this finding in patients treated with hyperthermia for superficially-located tumors, a randomized prospective double blind trial comparing unbuffered (pH 6.5) and buffered (pH 7.3) 2% lidocaine (without epinephrine) was undertaken. Between March and October 1990, a total of 54 hyperthermia treatment fields were each randomized to buffered or unbuffered lidocaine to be used at the time of all catheter placements (146 placements). Patients were scored both for the pain noted during the infiltration of lidocaine and the pain noted with subsequent catheter placement. In addition, the development of subcutaneous nodules at the sites of catheter placement was monitored at the time of 3-week follow-up. Follow-up was available for all but two fields. Treatment fields that received the buffered anesthetic had a statistically significant reduction in the pain associated with infiltration of lidocaine (p less than 0.05) without any compromise in its therapeutic efficacy as observed on a linear Visual Analog Scale. Furthermore, the incidence of subcutaneous nodules was lower in the fields treated with the buffered solution (1/23 vs 7/29, p = 0.05 for buffered and unbuffered solutions, respectively). The results of this trial support the use of buffered lidocaine prior to catheter placement for hyperthermia treatments as a method of reducing pain at infiltration and the subsequent development of subcutaneous nodules.

Thermal tolerance to whole body hyperthermia.

Thermal tolerance, that is, a reduced sensitivity to a succeeding heat treatment, has been noted in vitro and following local hyperthermia in normal tissues and malignant tumors. However, information is sparse concerning thermal tolerance following systemic hyperthermia, thereby limiting our ability to design optimally fractionated systemic hyperthermia treatment protocols. A technique for reproducibly inducing systemic hyperthermia in the rat is described, and the survival curve for rats exposed at 42.5 degrees C for periods of up to 75 minutes is presented. Using this system, increased survival of rats to systemic hyperthermia at 42.5 degrees C was demonstrated 30 hours after an initial sublethal conditioning exposure (41.8 degrees C for 1 hour). The LD50 (the time of exposure lethal to 50% of the rats) at 42.5 degrees C was increased by a factor of approximately 2 in the animals exposed to the sublethal conditioning. This increase in LD50 demonstrates the development of thermal tolerance to killing by whole body hyperthermia.

Temperature elevation during brachytherapy for carcinoma of the uterine cervix: adverse effect on survival and enhancement of distant metastasis.

Possible effects of fever during intracavitary radiation therapy on patient survival, local-regional control or metastatic spread of disease were analyzed in a group of 398 patients with previously untreated, invasive carcinoma of the uterine cervix, managed with a combination of external beam irradiation and intracavitary radium (ICR) applications at Yale-New Haven Medical Center and affiliated hospitals from January 1953 through December 1977. Cox step-wise proportional hazard models were used to test for the influence of elevated temperatures during ICR placements, controlling for the influence of other pretreatment patient parameters, including FIGO stage, age, blood count, prior supracervical hysterectomy and number of prior pregnancies. Increasing maximum temperatures noted during ICR placements were associated with: decreased patient survival (p = 0.014) and increased frequency with time of distant metastasis as the initial sites of treatment failure (p = 0.038). When patients were dichotomized on the basis of maximum temperature during ICR, distant metastasis as the initial site(s) of treatment failure was noted twice as frequently in patients with maximum temperatures greater than or equal to 101.0 degrees F (12.5%; 10/80 patients) than in those with maximum temperatures less than 101.0 degrees F during ICR placement (6.3%; 20/318 patients). No statistically significant differences were noted between the two groups in their distributions by stage, age, histology, year of diagnosis, or pretreatment hemoglobin, and the sites of distant metastasis and time course for clinical detection were similar in both groups. These results are in agreement with prior clinical studies in cancer of the uterine cervix which noted a poor prognosis in patients with cancer of cervix who developed fever during treatment. In addition, the finding of an association between an increased frequency of distant metastasis and temperature elevation during the ICR provides, for the first time, clinical data supporting the reports of an alteration or enhancement of distant metastasis following the application of whole body hyperthermia in murine, rabbit and canine tumors.

Local hyperthermia and radiation therapy in the retreatment of superficially located recurrences in Hodgkin's disease.

Five patients with Hodgkin's disease, nodular sclerosing subtype, who had multiple failures after chemotherapy and radiation therapy were treated for palliation with low-dose radiation therapy and hyperthermia to seven superficially located sites of recurrence. Six of the seven areas were in previously irradiated fields and one was at the margin of the prior radiation therapy field. Local control was obtained for all lesions and was maintained for the duration of the patients survival (5 to 27 months). Four of the five patients expired with no relapse in the area of treatment. One patient remains alive and free of recurrence in his treatment fields. Temperatures were monitored using thermistors, fluoroptic systems or thermocouples manually mapped through closed-end catheters inserted into the tumor and thermal parameters and temperature distributions were calculated. Excellent heating was obtained with 46.4% of monitored intratumoral temperatures greater than or equal to 43 degrees C. The average of the monitored intratumoral temperatures for all treatments (Tave) was 43.2 degrees C; the average of the monitored intratumoral minimal temperatures for all treatments (T min) was 40.1 degrees C, and the average of all monitored intratumoral maximum temperatures (T max) was 46.7 degrees C. In comparison with temperatures obtained in 277 superficially located tumors of other histologies, Tmax was significantly higher in Hodgkin's disease lesions (p = 0.007). The difference in Tave approached significance (p = 0.058). These initial results support the role of radiation therapy and hyperthermia for palliation of isolated superficial recurrences in patients with Hodgkin's disease who have failed conventional therapies. In addition, this approach may aid in cytoreduction prior to bone marrow transplant in patients with superficially located bulky recurrent disease. Hyperthermia may also be considered in combination with chemotherapeutic agents for palliative treatment of recurrences.

Secondary external-beam radiotherapy and hyperthermia for local recurrence after 125-iodine implantation in adenocarcinoma of the prostate.

At Stanford, six patients underwent a course of external radiotherapy after local recurrence following 125-iodine implantation. Four of the six patients also received concomitant hyperthermia. Four patients were initially managed with hormonal manipulation at time of local relapse and subsequently received external beam radiotherapy with or without hyperthermia. The hyperthermia was non-invasively induced using an annular phased array radiative electromagnetic system. Treatment was well tolerated, and none of the patients experienced severe rectal or bladder complications. Three patients are free from disease; one patient experience local-regional recurrence based on biopsy; one recurred in the bladder, was treated with cystoprostatectomy and subsequently succumbed to metastatic disease; and one patient died of presumed metastatic disease. External-beam irradiation with concurrent hyperthermia can be safely delivered to treat locally recurrent prostatic carcinoma after 125-iodine implantation.

Important prognostic factors influencing outcome of combined radiation and hyperthermia.

Clinical experience with combined local-regional hyperthermia and radiation therapy has been rapidly accumulating over the past few decades. Its superior efficacy to the use of radiation alone has been demonstrated in several retrospective and prospective reports in the literature. It is evident now that there are several important factors that will influence the final outcome of the treated patients. The parameters that will be discussed in this paper include: I. Pretreatments factors: 1. tumor dimension 2. tumor histology 3. tumor site. II. Treatment factors: 1. radiation therapy dose 2. hyperthermia parameters: (a) thermal variables (b) number of heat treatments (c) sequence of hyperthermia and radiation treatments (d) hyperthermic device. Finally, evaluation of response and complications will also be discussed. The importance of abiding by an accepted reporting system will be emphasized, and clarification of times at which response assessments were made will also be discussed. With the availability of longer term follow-up, use of an actuarial method of reporting becomes more important. The future of hyperthermia and radiation remains very promising but a lot of questions still need to be answered by well-conducted and reported clinical trials.

Glioblastoma multiforme: treatment by large dose fraction irradiation and metronidazole.

In an attempt to overcome the possible radioresistance of glioblastoma multiforme related to the large shoulder on the in vitro survival curves and to sensitize hypoxic tumor cells, a treatment protocol was instituted at Yale University Medical Center and affiliated hospitals, using large dose fraction irradiation therapy in conjunction with the hypoxic cell sensitizer metronidazole. Nineteen patients with biopsy-confirmed, previously untreated, cerebral grade IV glioblastoma multiforme were, following surgery, irradiated once a week at 600 rad per fraction, 3.5 to 4 hours after ingestion of metronidazole, 6 gm/m2. A total of 7 treatments were employed, with all patients maintained on antiseizure medications and corticosteroids. Metronidazole levels were determined prior to each treatment and patients were followed closely clinically and with serial computerized tomography (CT) scans. The treatment was well tolerated, in general, with no untoward side effects related to the high dose fraction irradiation. The majority of the patients experienced varying degrees of gastrointestinal upset lasting up to several hours following metronidazole administration. Three patients died of pulmonary emboli. One patient experienced moderately severe ototoxicity. A median survival of 9.4 months was obtained for all 19 patients, suggestive of a prolongation of survival compared to historical controls treated with conventionally fractionated radiation or with unconventional radiation fractionation schemes and metronidazole or misonidazole.