Synergistic cytotoxic and antitumor effects of irradiation and taxol on human HeLa cervix carcinoma and mouse B16 melanoma cells.

Several articles have appeared in the scientific literature which report that taxol has the ability to block and/or prolong cells in the G2/Mp phase of the cell cycle by inducing extremely stable microtubules. The G2/M phase is known to be the most radiosensitive phase of the cell cycle. It is the purpose of this study to evaluate the effect of combination taxol and ionizing radiation on tumor cell lines which have not been previously reported in the literature. Decrease in viability and inhibition of proliferation of HeLa and B16 cells induced by irradiation were dose-dependent and significantly enhanced by pretreatment the cells with taxol. Similar antitumor effects of irradiation and taxol were demonstrated by flow cytometric analysis of chromatic fragment formation induced in these cells. The exact mechanism by which taxol enhanced the tumoricidal effect of irradiation is not known. Cell cycle analysis showed that taxol was effective in blocking HeLa and B16 cells at the G2/M stage, at which the tumor cells are believed to be most sensitive to irradiation. This study is in agreement with others who have found that taxol is a powerful radiation sensitizer. Clinical research protocols have been developed and are under way to determine if taxol produces similar synergistic effects in patients undergoing radiation therapy.

Influence of elevated temperature on natural killer cell activity, lymphokine-activated killer cell activity and lectin-dependent cytotoxicity of human umbilical cord blood and adult blood cells.

PURPOSE: To determine whether hyperthermia is to the benefit or detriment of host immune function, the effect of hyperthermia was evaluated on various functions of T-lymphocytes from human umbilical cord blood and compared to that of adult blood. METHODS AND MATERIALS: Nonadherent mononuclear cells from cord blood or adult blood were used as the effector cells. To generate lymphokine activated killer (LAK) cells, effector cells were kept in culture for 5 days in complete medium containing recombinant human interleukin-2. To activate effector cells to become cytotoxic, cells were kept in culture in complete medium containing Con A. Cytotoxicity was determined in a standard 4-h chromium release assay using K-562 human erythroleukemic cells (in the natural killer cell activity assay) or Daudi cells (in the LAK cell activity or Lectin dependent cytotoxicity assay) as targets. For heat effects, cells in complete medium were heated at the desired temperature in a water bath for 1 h. RESULTS: Lymphokine-activated killer cell activity, lectin-dependent cytotoxicity and T-cell proliferative capacity were not deficient in human cord blood. Cytotoxic activities of T-cells from adult blood as well as from cord blood can be enhanced at febrile range (< or = 40 degrees C), and were significantly decreased by exposure to 1 h at 42 degrees C. CONCLUSION: The febrile responses (< or = 40 degrees C) to infection, in the course of malignant disease and with biological response modifiers treatment, may all be related to host defense mechanisms. Based on these observations, whole body hyperthermia (< or = 40 degrees C), in combination with the appropriate cytokines, may have therapeutic potential in the treatment of neonatal infections and malignancies under certain circumstances. Hyperthermia in febrile range may, therefore, confer an important immunoregulatory advantage to the host. In contrast, tumor killing therapeutic temperature (> 42 degrees C) which inhibits host immunocompetence should probably be used only for local hyperthermia.

Complications associated with intraperitoneal 32P.

The charts of all patients having received intraperitoneal 32P in the Indiana University Department of Radiation Oncology were retrospectively reviewed for complications and potentially related factors. Ninety-five patients had received this therapy, with a mean follow-up of 43.6 months. The majority of patients (81) had ovarian cancer. Complications were defined as mild if no intervention was required, moderate if medical intervention was required, and severe if the event was life-threatening or required surgical correction. Twenty patients (21%) had acute side effects recorded, with 15 of them (16%) being mild. The moderate complications (five patients) consisted of three cases of bowel obstruction, and two cases of abdominal pain requiring narcotics. There were no severe acute side effects. Chronic complications were found in 15 patients (20% actuarial 5-year incidence). Seven cases were mild (12% 5-year incidence), one was moderate (1%), and seven cases were classified as severe (7.4% 5-year incidence). All moderate and severe cases were bowel obstructions. Acute side effects were found to be related only to the volume of instillate (P = 0.049). Chronic complications were found to be related only to adjunctive pelvic/abdominal radiotherapy, with a 44% 5-year rate in patients receiving the combination having complications vs 17% (P = 0.04) (or 4.7% if mild complaints are excluded, P = 0.002) of those with 32P only. Comparison is made to other reports in the literature.

Evaluation of 45 degrees C hyperthermia and irradiation. II. A phase I clinical trial in humans by the Radiation Therapy Oncology Group.

This report describes the experience in 40 evaluable patients entered into a Radiation Therapy Oncology Group (RTOG) study to evaluate the feasibility of administering 45 degrees C for 15 minutes for superficial malignant lesions: 18 patients (45%) tolerated only 1 heat session at 45 degrees C; 7 (17.5%), 2 sessions; 4 (10%), 3 sessions; and 3 (7.5%) tolerated > or = 4 sessions. The overriding reason for discontinuing at 45 degrees C treatment was pain. Of the 40 evaluable patients, 22 (55%) had complete tumor regression, and 8 (20%) had partial regression. Tumors < or = 3 cm in diameter had significantly better complete tumor response than lesions > 3 cm (85% vs 41%) (p = .02). We conclude that 45 degrees C heating is difficult to use in patients chiefly because of pain; this may be due in part to inadequacy of currently available external hyperthermia equipment. Caution must be exercised in the application of thermal isoeffect heat dose concepts in clinical practice until further trials have been performed and a better understanding of the time-temperature relationship is established.

Clinical experience with hyperthermia in conjunction with radiation therapy.

The authors have reviewed the medical records of 421 sessions of hyperthermia treatments in 73 patients treated between 1987 and 1992 at the University Heights Cancer Center and the Indiana University Medical Center in Indianapolis, Ind. Temperatures attained during the course of therapy on each patient have been averaged and the results were evaluated for complete, partial, or no response. All patients had previously failed conventional radiation therapy, chemotherapy and surgery. Responses were defined as: (1) Complete response-lesions that completely disappeared during treatment and the response was sustained for a minimum of 6 months. (2) Partial response-lesions that underwent a reduction in size of greater than 50%. (3) No response-less than 50% reduction in tumor size during the course of treatment. Response varied somewhat according to histology and anatomical site of treatment; however, complete response was achieved in 45%, partial response in 48% (for an overall response of 93%), and no response in 7% of the patients. The response achieved varied with temperature attained and a minimum temperature of 40 degrees C for 40 min produced the greatest number of responses. Response to hyperthermia was directly related to the temperature achieved and the length of time the temperature was applied.

Recurrent squamous carcinoma of the vulva.

OBJECTIVE: This study reviews experience at Indiana University with recurrent squamous carcinoma of the vulva over an 18-year period from 1971 to 1989. The pattern of recurrence, time interval to recurrence, and efficacy of salvage therapy are evaluated in the context of the primary tumor. STUDY DESIGN: This is a retrospective study of 40 patients, 21 of whom underwent primary therapy for invasive squamous carcinoma of the vulva at Indiana University. RESULTS: Vulvar recurrences were observed in 17 patients (43%), the groin was involved in 12 (30%), whereas pelvic and distant recurrences were observed in 2 (5%) and 9 (22.5%) patients, respectively. Salvage surgery and/or radiotherapy were successful in 25 patients (62.5%) alive from 1 to 144 months (median 8 months) from secondary therapy. Survival after retreatment varied significantly by site of recurrence (p = 0.002), tumor grade (p = 0.009), and interval to recurrence (p < 0.001). Best outcomes were in patients with initial stage I or II disease (International Federation of Gynecology and Obstetrics), grade 1 tumors, local failure, and interval to relapse of > 16 months' duration. Two of 12 patients with groin recurrences were salvaged with surgery and radiotherapy. CONCLUSION: Long-term follow-up of patients with vulvar cancer and careful restaging at the time of recurrence are mandatory. Although local and nodal recurrences may be controlled with surgery and/or radiotherapy, regional recurrences are usually fatal.

A reliable method for quantitating chromatin fragments by flow cytometry to predict the effect of total body irradiation and hyperthermia on mice.

The frequencies of chromatin fragments, including micronuclei, in murine thymus cells, spleen cells and bone marrow cells have been used as a quantitative indicator of gamma-ray induced chromosome damage and could be used to screen potential radioprotective agents as well. The yield of chromatin fragments induced in mice receiving different dosage levels of total body irradiation alone and in mice also given whole body hyperthermia as a potent radioprotector were assessed by flow cytometric analysis. Our results demonstrated that chromatin fragments induced by irradiation in vivo was clearly dose-dependent and that chromatin fragments could potentially serve as a biological indicator of radiation damage. One hour of whole body hyperthermia at 40 degrees C (+/- 0.2 degree C) given 20 hours before a lethal dosage (900 cGy) of total body irradiation protects 100% of DBA/2 mice from an LD 100/16 irradiation dose (dose of irradiation that killed 100% of the mice in 16 days). This is in good agreement with the percent of chromatin fragments formed in the cells of the protected animals, which showed no significant difference from those observed in the normal mice. The results indicate that whole body hyperthermia protected the thymus and bone marrow from irradiation damage. This study provides further evidence which supports that whole body hyperthermia can act as a potent radioprotector in vivo. Measurement of the frequencies of chromatin fragments by flow cytometry is simple and reliable. The method can be applied to screen radioprotective agents.

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.

Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group.

A total of 307 patients with superficial measurable tumors were registered on a Radiation Therapy Oncology Group (RTOG) protocol involving fractionated radiation therapy, either alone or followed immediately by hyperthermia (42.5 degrees C, 45-60 min). Overall complete response (CR) was observed in 30% of the lesions treated with radiotherapy (RT) and 32% of those receiving RT and heat. Response was found to be significantly related to both maximum tumor diameter (less than 3 or greater than or equal to 3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In tumors less than 3 cm in diameter in the breast, trunk, and extremities, a better CR rate was noted with irradiation and heat (62 and 67%) than with irradiation alone (40 and 0%). However, in the head and neck there was only minimal difference in CR with irradiation alone or combined with hyperthermia (50 vs 38%). In lesions less than 3 cm treated with irradiation and heat, there was improved local control. In lesions greater than 3 cm, there was no difference in local control between the two treatment arms. The higher response rate in patients with smaller lesions (less than 3 cm) may be explained by the fact that these tumors are easier to heat. Problems in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to map the temperature distribution in a tumor. Acute and late toxicities in both treatment arms were comparable, except for an overall 30% incidence of thermal blisters in the heated tumors.

Whole body hyperthermia: a potent radioprotector in vivo.

Interleukin-1 has been reported to be an effective radioprotective agent in mice subjected to lethal doses of irradiation. Production of Interleukin-1 can be increased by whole body hyperthermia. Therefore, whole body hyperthermia was assessed for its efficacy in protecting the lethal effects of ionizing radiation in DBA/2 mice. One hour of 40 degrees C +/- 0.2 whole body hyperthermia given 20 hr before 900 cGy total body irradiation protected 100% of DBA/2 mice from an LD 100/16 radiation dose (dose of irradiation that killed 100% of the mice in 16 days). Lethal doses of total body irradiation produced profound monocytopenia, decreased cellularity of thymus, spleen, and bone marrow, and suppressed Interleukin-1 production. Interleukin-1 production was determined using the thymocyte proliferation assay. Whole body hyperthermia accelerated recovery of blood leukocytes by up to 5 days post-total body irradiation in DBA/2 mice. Thymocytes, spleen, and bone marrow cells were activated by whole body hyperthermia, as assessed by the cell's response to Concanavalin A. This was accompanied by accelerated Interleukin-1 generation. Our results provide the first evidence that whole body hyperthermia acts as a potent radioprotector in vivo, effects that may be mediated by Interleukin-1.

Prophylactic irradiation of the para-aortic lymph node chain in stage IIB and bulky stage IB carcinoma of the cervix, initial treatment results of RTOG 7920.

From November 1979 to October 1986, 367 patients were entered onto RTOG 7920 and randomized to receive either pelvic irradiation alone or pelvic plus para-aortic radiation. Patients with Stage IIB cervical carcinoma who had not undergone curative surgery and patients with Stages IB and IIA cervical carcinoma who were determined by digital exam to have primary tumors measuring 4 cm or greater in lateral dimension were eligible for this study. Clinically apparent or surgically involved para-aortic nodes were reason for exclusion from the study. Pelvic irradiation consisted of 1.6-1.8 Gy per day for 5 days per week to a total of 40-50 Gy. Para-aortic irradiation delivered 44 to 45 Gy in 1.6-1.8 Gy per day, 5 days per week. Pelvic irradiation was to be completed in 4 1/2 to 6 1/2 weeks and para-aortic irradiation in 4 1/2 to 5 1/2 weeks. Intracavitary brachytherapy delivered a total of 4000-5000 mg hr of radium-equivalents or 30-40 Gy to point A. Patients were stratified prior to random treatment assignment by histology, para-aortic nodal status (negative vs. unevaluated), and FIGO stage. As of June 1, 1989, 30 cases were excluded, including five patients who were inevaluable. Two patients who refused the assigned treatment were also excluded. Therefore, a total of 330 cases were analyzable. At 5 years the estimates of survival, the primary endpoint, for the pelvic only and pelvic plus para-aortic irradiation arms are 55% and 65%, respectively (p = 0.043). Several secondary endpoints were also analyzed. Estimates for loco-regional control at 5 years are, for pelvic irradiation only, 66%, and for pelvic plus para-aortic irradiation, 75% (p = 0.21). Distant metastases are estimated in 32% of pelvic irradiation only patients and 25% of pelvic plus para-aortic irradiation patients at 5 years (p = 0.17). When the first disease failure patterns are examined, more patients fail distally when treated only with pelvic radiation than when using pelvic plus para-aortic fields (p = .04). In analysis of patients with grade 3 (severe), grade 4 (life-threatening), and grade 5 (fatal complications), 8% of the patients in both groups had grade 3 severe complications. In the pelvic plus para-aortic group, 11 patients had grade 4 and 2 had grade 5 complications, whereas 6 had grade 4 and none had grade 5 in the pelvic only treatment group.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of interleukin 2 treatment combined with local hyperthermia in mice inoculated with Lewis lung carcinoma cells.

Recombinant human (rhu) interleukin 2 (IL-2) was evaluated alone and in combination with local hyperthermia (LH) in mice inoculated s.c. with 5 x 10(5) Lewis lung carcinoma cells. Four treatment regimens were begun 6 days postinoculation at a time when the tumor had grown to approximately 8.0 mm in diameter. Treatments were: group 1, saline injected as control; group 2, LH; group 3, rhuIL-2; or group 4, LH combined with rhuIL-2. LH utilized hot water circulation by a Brann Thermomix 1420. The intratumor temperature was maintained at 43 +/- 0.2 degrees C for 30 min each on days 6 and 10 and rhuIL-2 was given s.c. at 5 x 10(4) units twice a day for 5 days. Thirty mice in each group were sacrificed 28 days after tumor inoculation. An additional 20 mice in each group were observed for survival time. The size of primary tumor and the number of lung metastases were reduced and the survival time was prolonged in mice treated by either LH or IL-2. However, a greater antitumor effect in Lewis lung carcinoma tumor-bearing mice was observed using IL-2 therapy combined with LH. Tumor growth was associated with increased splenic granulocyte-macrophage progenitor cells and an abnormal L3T4+/Lyt-2+ lymphocyte subset ratio (less than 1.0). Splenic granulocyte-macrophage progenitor cell numbers and the L3T4+/Lyt-2+ ratio returned to normal in the group treated with combination therapy, the best responder group. The L3T4+/Lyt-2+ ratio did not change in the groups treated with single therapy. These results suggest the efficacy and possible clinical relevance of combined therapy with rhuIL-2 and LH for certain metastatic tumors.

Doxorubicin as an adjuvant following surgery and radiation therapy in patients with high-risk endometrial carcinoma, stage I and occult stage II: a Gynecologic Oncology Group Study.

The Gynecologic Oncology Group studied the use of adjuvant doxorubicin after surgery and radiation therapy for endometrial carcinoma in a randomized, prospective manner. The study population consisted of patients clinically stage I or II (occult) who, after surgical-pathologic evaluation, had one or more risk factors for recurrence: greater than 50% myometrial invasion, pelvic or aortic node metastasis, cervical involvement, or adnexal metastases. All patients without aortic node metastasis received 5000 rads to the whole pelvis at 160-180 rads per day. If aortic node metastasis was documented, aortic field radiation to the top of T12 was offered. The aortic target dose was 4500 rads at 150 rads per day. After completion of radiation therapy, the patients were randomized to receive doxorubicin bolus therapy (60 mg/m2 starting dose) to a maximum cumulative dose of 500 mg/m2. Between November 1977 and July 1986, 92 patients were entered into the doxorubicin (DOX) treatment arm, and 89 patients entered the no-DOX arm. There was no statistically significant difference in survival or progression-free interval of the two arms. The 5-year survival rates for patients with deep myometrial invasion, cervical involvement, and pelvic node metastases were similar (63-70%), whereas the rate for patients with aortic node metastases was 26%. There was no significant difference in the recurrence pattern between the two treatment arms. There were no cases of grade 3 or 4 cardiac toxicity. Twelve patients (6.9%) developed small bowel obstruction after radiation therapy. There were three treatment-related deaths in the DOX arm and two in the radiation therapy-only arm. We conclude that, because of protocol violations, small sample size, and the number of patients lost to follow-up, this study was unable to determine what effect use of doxorubicin as adjuvant therapy had on recurrence, progression, and survival of the endometrial cancer study population. The combination of surgical staging and postoperative radiation as used in this study appears to increase the risk of bowel complications.

An overview of the role of radiation therapy and hyperthermia in treatment of malignant melanoma.

From January, 1970 until December, 1987, a total of 188 malignant melanoma lesions in 92 patients were treated at the Department of Radiation Oncology, Indiana University Medical Center, Indianapolis, Indiana. Response was evaluated in 181 evaluable lesions treated by radiation alone and radiation plus hyperthermia to assess differences in response to a total dose, dose per fraction and overall time of treatment, as well as effects of adjunctive hyperthermia treatment. Different fractions of radiation, ranging from 100 cGy to 1000 cGy, were used. Local hyperthermia was administered for one hour following radiation treatment using microwave with different frequencies. The tumor temperature was also monitored during treatment. With a radiation dose of less than 400 cGy per fraction, and complete response rate (CR) was 34% (16/47) and the objective response rate (OR) was 62% (29/47). When hyperthermia was added, the complete response rate rose from 34% to 70%. With a dose of more than 400 cGy per fraction, the CR was 63% (48/77), and OR was 95% (73/77). When hyperthermia was added, the complete response rate rose from 63% to 77%.

The effect of whole body hyperthermia on the immune cell activity of cancer patients.

The effect of moderate whole body hyperthermia (WBH) on the immunological responses of cancer patients was studied by monitoring their peripheral blood mononuclear cells (PBMC) in vitro. WBH of 2 degrees C above normal body temperature was induced in patients by utilizing a 433 MHz microwave system with a series of 6-9 external antennae. A total of three treatments were given with a frequency of one per week. Blood samples were drawn before treatment, when the target temperature was attained, and one hour after heating was discontinued. Changes in the number of PBMC, the mitogenic response, natural killer cell activity, and the production of Interleukin-1, Interleukin-2, and Interferon (IL-1, IL-2, IF) were measured in vitro. Mitogenic responses were increased 2-3 fold when the temperature was raised. Although there was an increase in the number of PBMC, during the course of heating, repeated treatment resulted in a selective and transient reduction in the number of PBMC. Nevertheless, the PBMC were capable of producing a higher level of cytokines and attained an enhanced ability to destroy target cells in vitro. The results indicate that, by inducing a fever-like condition, the immunological responses are enhanced in vitro.

Micronuclei assay--a predictive variable for tumor response to treatment.

Our preliminary data indicate that the formation of micronuclei (MN) in treated tumor cells is a predictive variable for tumor response to treatment. In a pilot study involving four patients who received both radiation therapy and hyperthermia, fine needle aspirate (FNA) samples were taken and analyzed before therapy, and after each 1000 centigray (cGy) up to 3000 cGy. The results indicate a correlation between increasing formation of micronuclei and decreasing tumor volume. All of the patients in this Study have had their tumors under control for at least one year. Our preliminary data demonstrated that a high level of micronuclei in tumor cells correlates with favorable response of the tumor to treatment with radiation and heat. The assay is easy to perform and FNA biopsy could be done in the clinic with minimal discomfort to the patient.

Historical aspects of hyperthermia in cancer therapy.

The use of hyperthermia in cancer therapy had its origin in antiquity. Recently, some have hailed hyperthermia as the new fourth method of cancer therapy, and others have branded the treatment as "quackery" surrounded by mysticism, ignorance, and confusion. The American Cancer Society has been ambivalent, first placing it on its infamous unproven cancer therapy methods list, along with Laetril, Hoxey's cancer pills, hot water enemas, snake root oil, and other various and sundry "cancer cures." A few years ago the Society removed it from its list after deciding that hyperthermia may indeed have a place in future cancer therapy. This brief historical review highlights some of the most important early clinical discoveries and basic laboratory studies, which should help convince even the most avid skeptics of hyperthermia of the necessity of continuing the study of this most controversial form of cancer therapy.

Skin cancer in patients with chronic radiation dermatitis.

The cases of 76 patients with chronic radiation dermatitis resulting from low-dose ionizing radiation for benign disease were reviewed retrospectively for risk factors leading to the development of neoplasia. The patients were studied with respect to original hair color, eye color, sun reactive skin type, benign disease treated, area treated, age at treatment, and age at development of first skin cancer. Analysis of data showed 37% of patients had sun-reactive skin type I, 27% had type II, and 36% had type III. Types IV through VI were not represented. There appeared to be an overrepresentation of types I and II. Increased melanin pigmentation may therefore be either directly or indirectly protective against the development of skin cancers in patients who have received low-dose superficial ionizing radiation for benign disease. The sun-reactive skin type of patients with chronic radiation dermatitis may be used as a predictor of skin cancer risk when the total dose of ionizing radiation is not known.

Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a Report by the Radiation Therapy Oncology Group.

Since February 1981, 300 patients with superficial measurable tumors were randomized on an RTOG protocol (81-04) involving fractionated radiation therapy (4.00 Gy twice weekly for a total of 32.00 Gy), either alone or followed immediately by hyperthermia (42.5 degrees C, 60 min). This is a report of 218 eligible patients with single lesions: 107 treated with radiotherapy alone (RT), 111 with radiotherapy plus hyperthermia (RT + HT). Only 56% of the 24 tumors less than 3 cm and 36% of the 53 lesions larger than 3 cm received what was felt to be "adequate" therapy (greater than or equal to 29 Gy and 8 heating sessions). Overall complete response (CR) was observed in 28% of the patients treated with RT, and 32% of the patients receiving RT and heat. Response has been found in previous analyses of this and other RTOG studies to be significantly related to both maximum tumor diameter (less than 3 or greater than or equal to 3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In the head and neck tumors less than 3 cm in diameter there was no difference in CR with irradiation alone or combined with hyperthermia (46% vs 43%). However, in the breast, and trunk and extremities a better CR rate was noted with irradiation and heat (55% and 67%) than with irradiation alone (33% and 0). In lesions less than 3 cm treated with irradiation and heat the probability of remaining in response was 80% compared with 15% with irradiation alone. In lesions larger than 3 cm no difference in CR was observed in either treatment group. It has been hypothesized that the response rate is higher in patients with smaller lesions (less than 3 cm) and in breast/chest wall, trunk/extremity lesions because these tumors and anatomical sites are easier to heat adequately. Problems encountered in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to accurately represent the temperature distribution in a tumor. Furthermore, differences in equipment and treatment practices among institutions add to the variability in heat administration data collected. In addition, tumor response may be difficult to judge because of short survival of some patients and occasionally rapid tumor regression that may cause necrosis which may be misinterpreted as persistent tumor.(ABSTRACT TRUNCATED AT 400 WORDS)