Radiation therapy,cisplatin and hyperthermia in combination in management of patients with recurrent carcinomas of the head and neck with metastatic cervical lymph nodes

Twenty-one patients with recurrent carcinomas of the head and neck with metastatic cervical lymph nodes were treated with radiation therapy, cisplatin and hyperthermia in combination, in an attempt to investigate any potential contribution in terms of safety, response, duration of palliation and quality of life. Patients not initially treated with radiation therapy were treated with a median dose of 70Gy and patients initially treated with radiation therapy with a median dose of 30Gy. The median number of weekly cisplatin courses was five and the median number of twice weekly local external ultrasound hyperthermia sessions was five. Average T₉₀, Average T₅₀ and Average T₁₀ were 39.9±1.2°C, 42.4±1.3°C and 44.5±0.8°C, respectively, and Average CEM 43°C T₉₀, Average CEM 43°C T₅₀ and Average CEM 43°C T₁₀ were 7.8±9.6min, 22.6*plusmn;18.8 min and 39.3±25.1 min, respectively. Mean follow-up was 1 year. Nodal complete response was achieved in eight patients and palliation of presenting symptoms in 19. Overall survival was 39% at 1 year. Grade 3 acute skin toxicity was observed in one patient and Grade 3 acute haematological toxicity in one. Radiation therapy, cisplatin and hyperthermia in combination appear to be safe and might improve response, prolong duration of palliation and reinstate quality of life in patients with recurrent carcinomas of the head and neck with metastatic cervical lymph nodes.     

The interaction of cisplatin plus etoposide with radiation +/- hyperthermia

The addition of concurrent etoposide and cisplatin to radiation +/- hyperthermia was evaluated in the murine FSaIIC fibrosarcoma tumor system. Tumor growth delay (TGD) demonstrated that when the drugs were tested with radiation (3 Gy daily X 5) plus (43 degrees X 30 min) local hyperthermia, cisplatin/hyperthermia/radiation (TGD approximately 25 days) was significantly more effective than etoposide/hyperthermia/radiation (TGD approximately 14 days). The addition of etoposide to cisplatin/hyperthermia/radiation, however, yielded a significantly longer growth delay (approximately 34 days). Tumor cell survival studies demonstrated that hyperthermia (43 degrees C, 30 minutes) was dose modifying for etoposide cytotoxicity (dose modifying factor approximately 2.0 as determined by comparisons of the slopes of the curves). The addition of etoposide to cisplatin modified cisplatin killing only slightly at 37 degrees C or 43 degrees C. Considerable additional cell kill was observed over a range of radiation doses with cisplatin, hyperthermia, and etoposide added singly or in combination, especially at the lowest radiation dose tested (5 Gy), but essentially no dose modification was observed. Evaluation of Hoechst 33342 dye-selected tumor subpopulations demonstrated that cisplatin, etoposide, radiation (10 Gy), etoposide plus radiation, and cisplatin plus radiation killed significantly fewer dim (presumably hypoxic) cells than bright (presumably normally oxygenated) cells. Hyperthermia killed more dim than bright cells. The combination of hyperthermia with cisplatin and radiation, however, resulted in approximately 5-fold lesser kill in dim cells, and the addition of etoposide increased this differential to 6.4-fold. These results indicate that etoposide adds small but measurable antitumor effects when used with cisplatin alone or with cisplatin in combination with radiation +/- hyperthermia (especially at lower radiation fraction sizes).     

Feasibility and patient tolerance of a novel transrectal ultrasound hyperthermia system for treatment of prostate cancer.

This report describes patient tolerance and toxicity of a transrectal ultrasound hyperthermia system used with external beam radiation therapy in treatment of locally advanced prostate cancer. Nine patients with clinical T2B-T3B (4th edition AJCC criteria) disease received external beam radiation therapy, with two hyperthermia treatments scheduled at least 1 week apart during the first 4 weeks of radiation. Five patients also received hormonal therapy. Interstitial and anterior rectal wall thermometry were performed. Median temperature for each treatment (T50) was 40.8 degrees C and mean CEM T90 = 43 degrees C was 3.4 min. Rectal wall temperature was maintained at < or = 40 degrees C. Treatment duration was limited in three of 17 sessions due to positional discomfort which was alleviated with light IV sedation and use of a 'New Life' mattress (Comfortex, Inc. Winoba, MN, USA). Acute toxicity was limited to NCI common toxicity criteria grade 1 and no excess toxicity was noted with full course radiation therapy +/- hormonal therapy. These findings are consistent with those reported in a previous phase I trial assessing this device. Given the favourable toxicity profile demonstrated to date, modification of treatment parameters for this ongoing phase II study have been instituted that should further the efficacy of transrectal ultrasound hyperthermia for treatment of prostate cancer.     

Effect of 41 degrees C and 43 degrees C on cisplatin radiosensitization in two human carcinoma cell lines with different sensitivities for cisplatin

The effect of trimodality treatment consisting of hyperthermia, cisplatin and radiation was investigated in two cell lines with different sensitivities to cisplatin. Hyperthermia treatment was performed for 1 h at 41 degrees C and 43 degrees C in order to compare the effects of the two temperatures. Clonogenic assays were performed with cisplatin-sensitive SiHa human cervical carcinoma and cisplatin-resistant SW-1573 human lung carcinoma cell lines. Cells were treated with various combinations of hyperthermia, cisplatin and radiation. Radiation was performed after 1 h of simultaneous hyperthermia and cisplatin treatment. Cisplatin exposure was for 1 h or continuous without refreshment of the cisplatin-containing medium. SiHa cells were more sensitive to cisplatin than SW-1573 cells. Hyperthermia at 41 degrees C decreased survival in SW-1573 cells but was not cytotoxic in SiHa cells. Hyperthermia at 43 degrees C decreased survival dramatically in both cell lines with SiHa being the most sensitive. The addition of hyperthermia at 41 degrees C and 43 degrees C to cisplatin treatment led to enhanced cell kill in both cell lines compared with cisplatin alone. Radiosensitization was observed after continuous but not after 1 h of cisplatin treatment. Hyperthermia at 43 degrees C increased radiosensitivity whereas hyperthermia at 41 degrees C did not. A combination of 41 degrees C hyperthermia with continuous cisplatin treatment had an additive effect on SW-1573 cells but enhanced cisplatin radiosensitivity of SiHa cells. In SW-1573 cells trimodality treatment using 43 degrees C hyperthermia enhances cisplatin radiosensitivity. We conclude that hyperthermia at 43 degrees C enhances cisplatin-induced radiosensitization in both cisplatin-sensitive and -resistant cell lines. Hyperthermia at 41 degrees C was also able to increase cisplatin-induced radiosensitivity but only in the cisplatin-sensitive SiHa cell line.     

Radiation therapy, cisplatin and hyperthermia in combination in management of patients with carcinomas of the head and neck with N2 or N3 metastatic cervical lymph nodes.

Fifty-three patients with carcinomas of the head and neck with N2 or N3 metastatic cervical lymph nodes were treated with radiation therapy (median, 70 Gy), cisplatin (median, 6 weekly courses) and hyperthermia (median, 6 twice weekly sessions). Local complete response was achieved in 82% and nodal complete response in 85% of patients. Overall survival was 51% and disease-free survival was 54% at 2 years. Toxicity was acceptable. Radiation therapy, cisplatin and hyperthermia in combination prove to be effective and safe in management of these patients.     

Interaction of SR-4233 with hyperthermia and radiation in the FSaIIC murine fibrosarcoma tumor system in vitro and in vivo

The effects of SR-4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), a hypoxic cell cytotoxic agent, were assayed against the FSaIIC murine fibrosarcoma in vitro and in vivo alone and in conjunction with hyperthermia and radiation. In vitro, a concentration of 500 microM of SR-4233 upon exposure of the cells for 1 h decreased the survival of hypoxic cells by about 1 log more than euoxic cells at 37 degrees C and pH 7.40. At the same concentration at pH 6.45, this difference in cytotoxicity increased to about 3 logs. In conjunction with 42 or 43 degrees C hyperthermia at pH 7.40, the killing of both euoxic and hypoxic cells was markedly increased (hypoxic greater than oxic), and the effect of hyperthermia on SR-4233 cytotoxicity was further increased at pH 6.45. SR-4233 proved to be an effective radiosensitizer of hypoxic cells in vitro, producing an enhancement ratio of 2.6 +/- 0.2 at pH 7.40 and 2.7 +/- 0.2 at pH 6.45. In vivo, however, SR-4233 (50 mg/kg) used with single dose radiation (10, 20, or 30 Gy) did not alter the slope of the radiation dose-dependent tumor growth delay curve but did produce a significant additive increase in tumor growth delay. Local hyperthermia (43 degrees C, 30 min) plus SR-4233 (30 mg/kg) produced a tumor growth delay of 9.1 +/- 2.2 days, whereas SR-4233 alone caused a tumor growth delay of only 1.7 +/- 0.9 days and the hyperthermia, only 1.4 +/- 0.7 days. The tumor growth delay increased to 28.2 +/- 4.4 days with the addition of daily radiation (3 Gy for 5 days) to SR-4233 and hyperthermia given on treatment day 1 only. Hoechst 33342 dye-selected tumor subpopulation analysis at 24 h following treatment demonstrated that SR-4233 (30 mg/kg) was more toxic to dim (presumably hypoxic) cells by about 1.8-fold. The addition of hyperthermia to treatment with SR-4233 increased the killing of dim cells by about 5-fold but of bright cells by only 2-fold. Trimodality treatment with SR-4233, hyperthermia, and radiation increased the killing of bright cells by about 6.5-fold and of dim cells by about 16.5-fold as compared with radiation alone. These results indicate that SR-4233 might be used quite effectively with radiation and/or hyperthermia to treat tumors with significant hypoxic subpopulations.     

Using units of CEM 43 degrees C T90, local hyperthermia thermal dose can be delivered as prescribed.

A randomized study was designed in dogs with spontaneous soft tissue sarcomas to gain information about the relationship between hyperthermia dose and outcome. The study compared two levels of thermal dose applied to dogs with heatable tumours, so it was necessary to deliver either a low (2-5 CEM 43 degrees C T90) or high (20-50 CEM 43 degrees C T90) thermal dose as precisely as possible. It was also desirable to have similar numbers of hyperthermia treatments in each thermal dose group. Identification of heatable tumours and randomization to high or low heat dose group was done during the first hyperthermia treatment. This was readily accomplished using mapping of temperatures in thermometry catheters, manual recording of thermal data, and visual inspection of raw thermal data with subsequent adjustment of the duration of the hyperthermia treatment. An analysis of precision of thermal dose delivery was conducted after approximately 50% of projected accrual had been met in a randomized phase III assessment of thermal dose effect. Fifty-four dogs were eligible for randomization; in 48 dogs the tumour was deemed heatable according to predetermined temperature criteria applied during the first heat treatment. Twenty-four dogs were randomized to the high heat dose group, and 24 to the low heat dose group. Median (range) total thermal dose for dogs in the high dose group was 43.5 CEM 43 degrees C T90 (16.4-66.6) compared to 3.2 CEM 43 degrees C T90 (2.1-4.6) for dogs in the low dose group. There was no overlap of thermal doses between groups. Thus, thermal dose could be delivered accurately, being within the predetermined range in 47 of the 48 dogs. Thermal dose quantified as CEM 43 degrees C T50, however, did overlap between groups and the clinical significance of this finding will not be known until outcome data are analysed. Most dogs in both groups received five hyperthermia treatments. Median (range) treatment duration for dogs in the high dose group was 300 min (147-692) compared to III min (51-381) for dogs in the low dose group. Relatively simple but accurate methods of delivering prescribed thermal dose as described herein will aid the translation of clinical hyperthermia from the research setting into more general practice once the characteristics of the relationship between hyperthermia dose and outcome are understood.     

A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy.

We prospectively evaluated whether delivering a thermal dose of > 10 cumulative equivalent minutes at 43 degrees C to >90% of the tumour sites monitored (CEM43 degrees T90) would produce a pathologic complete response (pCR) in > 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients > or = 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0 Gy, five times a week, to a median total dose of 50 Gy and an initial hyperthermia treatment (HT) of I h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140 MHz. Further HT was given for patients with CEM43 degrees T90 > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43 degrees T90 > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of > or = 75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43 degrees T90 > or = 10, 14 (56%) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10%) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43 degrees T90 failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed.     

Trimodality therapy (drug/hyperthermia/radiation) with BCNU or mitomycin C

To develop multimodality treatment combinations with high curative potential in advanced local disease, BCNU (N,N'-bis(2-chloroethyl)-N-nitro-sourea) and mitomycin C were tested with hyperthermia and radiation in the FSaIIC fibrosarcoma system. Growth delay experiments demonstrated that, while neither BCNU nor mitomycin C produced dose modification of the radiation response, and hyperthermia (43 degrees C, 30 min) produced only a moderate dose modification (1.4 +/- 0.2), the combination of BCNU plus hyperthermia resulted in a radiation dose modifying factor (DMF) of 1.9 +/- 0.3, and mitomycin C plus hyperthermia a dose modifying factor of 2.1 +/- 0.4. Tumor cell survival over a range of BCNU doses administered i.p. immediately before hyperthermia resulted in a dose modifying factor of 1.8 +/- 0.2 versus drug alone. With mitomycin C however, giving the drug immediately prior to heating produced a dose modifying factor due to hyperthermia of only 1.2 +/- 0.10. Hoechst 33342 diffusion was used to separate tumor cells into predominately oxic and hypoxic subpopulations. Administration of the single, double and trimodality therapies showed that BCNU was 3.1-fold more toxic to the oxic versus the hypoxic cells whereas mitomycin C was 3.5-fold more toxic to the hypoxic compared to the oxic cells. Hyperthermia was 1.4-fold more toxic to the hypoxic versus the oxic cells whereas 10 Gy of radiation was 2.0-fold more toxic to the oxic compared to the hypoxic cells. The combination of hyperthermia plus radiation increased killing in both Hoechst dye defined subpopulations but relatively more in the hypoxic cells in which killing was 1.8-fold greater than in the oxic cells. When heat was delivered immediately after i.p. administration of the anticancer drugs, hyperthermia increased BCNU killing in the oxic cells by 17.2-fold versus 4.4-fold in the hypoxic cells and increased mitomycin-killing by 2.6-fold in the oxic cells versus 17-fold in the hypoxic cells. Use of the full trimodality treatment, given in the sequence drug (BCNU, 50 mg/kg or mitomycin-C 5 mg/kg)----heat (43 degrees C, 30 min)----radiation (10 Gy) produced a 3 log kill in the oxic cells versus a 2 log kill in the hypoxic cells with BCNU and a 2 log kill in the oxic cells versus a 3 log kill in the hypoxic cells with mitomycin C. These results indicate that the use of selected anticancer drugs with hyperthermia and radiation can produce highly cytotoxic interactions which markedly modify the effect of radiation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Radiation therapy and concurrent cisplatin in management of locoregionally advanced nasopharyngeal carcinomas

Radiation therapy in combination with chemotherapy in the management of locoregionally advanced nasopharyngeal carcinomas is evaluated in an attempt to improve locoregional response, reduce locoregional failure and reduce systemic failure. The current study was designed to investigate radiation therapy and concurrent cisplatin in this context. From 1992 through 1997, 70 patients with locoregionally advanced nasopharyngeal carcinomas were treated with radiation therapy and concurrent cisplatin. External beam radiation dose was 60 Gy for T1, T2 and T3 tumors, 70 Gy for T4 tumors and 70 Gy for metastatic cervical lymph nodes. An intracavitary brachytherapy boost (10 Gy) was applied for T1, T2 and T3 tumors. Cisplatin (30 mg/m2) was administered weekly during external beam radiation therapy. Locoregional complete response was achieved in 63 patients, locoregional failure was observed in 4 patients and systemic failure was observed in 15. N-stage predicted systemic failure. Overall survival, locoregional failure-free survival and systemic failure-free survival were 63%, 79% and 75%, respectively, at three years. Grade 3 acute skin toxicity was observed in 2 patients, Grade 3 acute mucous membrane toxicity was observed in 6 and Grade 3 acute hematological toxicity was observed in 2 patients. Despite improved locoregional response, reduced locoregional failure and improved survival with radiation therapy and concurrent cisplatin, systemic failure remains prevalent for locoregionally advanced nasopharyngeal carcinomas.     

Addition of 2-nitroimidazole radiosensitizers to cis-diamminedichloroplatinum(II) with radiation and with or without hyperthermia in the murine FSaIIC fibrosarcoma

We have examined the ability of misonidazole (MISO) or etanidazole (ETA) to improve the antitumor efficacy of cisplatin (CDDP), hyperthermia, and radiation in the FSaIIC murine fibrosarcoma. A growth delay of about 25 days was produced with CDDP (5 mg/kg) and hyperthermia (43 degrees C, 30 min) prior to radiation (3 Gy daily for 5 days) on day 1. The addition of MISO (1 g/kg) on day 1 resulted in a tumor growth delay of about 28 days. The addition of ETA at 0.5 g/kg or 1 g/kg resulted in tumor growth delays of about 33 and 43 days, respectively. Tumor cell survival assay showed that MISO was additive with CDDP either at 37 degrees C or with hyperthermia (43 degrees C, 30 min). In contrast, ETA at both 0.5 g/kg and 1 g/kg was dose modifying over the CDDP dosage range at 37 degrees C or 43 degrees C. Analysis of tumor cell killing in Hoechst 33342 selected bright (presumably oxic) and dim (presumably hypoxic) tumor cell subpopulations demonstrated that the addition of MISO to the CDDP trimodality regimen increased killing in the dim cell subpopulation, while the addition of ETA increased tumor cell killing in both subpopulations, although the greater effect was in the dim cell subpopulation. These results indicate that ETA may add to the efficacy of the CDDP trimodality in the clinic and may be of value as a chemosensitizer with CDDP.     

Effect of pH, oxygenation, and temperature on the cytotoxicity and radiosensitization by etanidazole.

The effect of etanidazole was examined in vitro and in vivo in the FSaIIC tumor system. At pH 7.40 and 37 degrees C, etanidazole at 5-500 microM for 1 hr was minimally cytotoxic. At 42 degrees C and 43 degrees C, however, the cytotoxicity of etanidazole increased. Etanidazole was more cytotoxic at pH 6.45 and 37 degrees than at pH 7.40 by about 1 log. Increasing the temperature to 42 degrees C or 43 degrees C at pH 6.45 during drug exposure, however, caused little increase in drug killing above the lethality of hyperthermia. When the radiosensitizing abilities of etanidazole were tested in vitro, there was a radiation dose modifying factor of 2.40 at pH 7.40, but only 1.70 at pH 6.45. In vivo, etanidazole (1 g/kg) produced a radiation dose modifying factor of 1.47, whereas 43 degrees C for 30 min produced a radiation dose modifying factor of 1.38. The combination resulted in a radiation dose modifying factor of 2.29. When the cytotoxicities of hyperthermia (43 degrees C x 30 min), etanidazole (500 mg/kg or 1 mg/kg), and radiation (10 Gy) combinations were assayed by Hoechst 33342 dye selected tumor subpopulations, 43 degrees C x 30 min increased the killing of irradiated dim cells by approximately 9.2-fold but by only 2.9-fold in bright cells. Etanidazole (1 g/kg) increased radiation killing of bright cells by about 3-fold and dim cells by about 4.3-fold. The combination of hyperthermia and etanidazole increased the killing of both dim and bright cells exposed to radiation by approximately 10-fold versus 10 Gy alone.     

Association of rectal toxicity with thermal dose parameters in treatment of locally advanced prostate cancer with radiation and hyperthermia

PURPOSE: Although hyperthermia has been used for more than two decades in the treatment of pelvic tumors, little is known about the potential impact of heat on rectal toxicity when combined with other treatment modalities. Because rectal toxicity is a concern with radiation and may be exacerbated by hyperthermia, definition of the association of thermal dose parameters with rectal toxicity is important. In this report, we correlate rectal toxicity with thermal dose parameters for patients treated with hyperthermia and radiation for prostate cancer. METHODS AND MATERIALS: Thirty patients with T2b-T3b disease (1992 American Joint Committee On Cancer criteria) enrolled in a Phase II study of external beam radiation +/- androgen-suppressive therapy with two transrectal ultrasound hyperthermia treatments were assessed for rectal toxicity. Prostatic and anterior rectal wall temperatures were monitored for all treatments. Rectal wall temperatures were limited to 40 degrees C in 19 patients, 41 degrees C in 3 patients, and 42 degrees C in 8 patients. Logistic regression was used to estimate the log hazard of developing National Cancer Institute Common Toxicity Criteria Grade 2 toxicity based on temperature parameters. The following were calculated: hazard ratios, 95% confidence intervals, p values for statistical significance of each parameter, and proportion of variability explained for each parameter. RESULTS: Gastrointestinal toxicity was limited to Grade 2. The rate of acute Grade 2 proctitis was greater for patients with an allowable rectal wall temperature of >40 degrees C. In this group, 7 of 11 patients experienced acute Grade 2 proctitis, as opposed to 3 of 19 patients in the group with rectal wall temperatures limited to 40 degrees C (p = 0.004). Preliminary assessment of long-term toxicity revealed no differences in toxicity. Hazard ratios for acute Grade 2 proctitis for allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax were 9.33 (p = 0.01), 3.66 (p = 0.03), and 2.29 (p = 0.08), respectively. A model combining these three parameters explained 48.6% of the variability among groups. CONCLUSION: Rectal toxicity correlates with maximum allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax for patients undergoing transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer. Further definition of this association of thermal dose parameters with rectal toxicity in treatment of pelvic malignancies with hyperthermia should advance the goal of delivering thermal therapy in an effective yet safe manner.     

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.     

A phase I-II trial of cisplatin, hyperthermia and radiation in patients with locally advanced malignancies

A Phase I-II trial testing the addition of systemic cisplatin (CDDP) to local hyperthermia and radiation was conducted to determine the dose of cisplatin that is tolerable once weekly for 6 weeks and to estimate the therapeutic potential of this trimodality combination in patients with locally advanced malignancies. Cisplatin at 20 mg/m2 (4 patients), 30 mg/m2 (8 patients), and 40 mg/m2 (12 patients) was given rapidly (over 5-10 min) i.v. after prehydration with 1 liter of normal saline. After approximately two-thirds of the cisplatin dose had been delivered, microwave hyperthermia was begun and continued for 60 min; the target minimum tumor temperature was 43 degrees C. Following hyperthermia, a 400 cGy fraction of radiation was delivered to the tumor. On other days during the treatment weeks, additional 200 cGy fractions were given to total doses of 6,000-6600 cGy in patients with full radiation tolerance or 2400-3600 cGy in patients with limited radiation tolerance. The 24 patients in this trial had a median age of 57 years and the predominant sites/tumor types were head and neck/squamous cell carcinoma (9) and chest wall/breast adenocarcinoma (9). Seventeen of the 24 treated tumors (70%) had previously been irradiated. Eighteen patients (75%) had received prior chemotherapy and nine patients (38%) had previously been treated with cisplatin. Bone marrow suppression was dose limiting in patients heavily pretreated with chemotherapy and chest wall radiation. No significant toxicities were observed at the 20 and 30 mg/m2 dose levels, but 5 of the 12 patients (42%) treated at 40 mg/m2 required modification of the cisplatin dose because of blood count suppression in four patients and mild renal dysfunction in one patient. Each of the patients with bone marrow suppression, however, had been heavily pretreated except for one patient with thrombocytopenia due to hypersplenism. Nausea and vomiting were mild with use of a standard, multiagent antiemetic regimen. Twelve patients (50%) attained a complete regression (CR) and 12 patients (50%) a partial regression (PR). Complete regression appeared to correlate with small tumor volumes (115 cc for CR versus 199 cc for PR patients) and higher tumor temperatures (4.6 average minimum equivalent minutes at 43 degrees C in CR versus 2.0 min in PR patients). Local toxicities included second degree burns in 12 patients (50%) and third degree burns in 6 (25%), but all burns healed in 4-12 weeks without surgical intervention.(ABSTRACT TRUNCATED AT 400 WORDS)     

Simultaneous therapy with high-dose cisplatin and radiation for unresectable squamous cell cancer of the head and neck: a phase I-II study

Studies using simultaneous radiation therapy and conventional doses of cisplatin have suggested improvement in local control and patient survival. This study was undertaken to determine toxicity and patient tolerance to concomitant high-dose cisplatin (40 mg/m2 per day X 5) and radiation (60 Gy in 6 wk +/- 10-Gy boost to residual tumor). Seventeen patients with advanced, inoperable squamous cell cancer primary tumor in the head and neck were treated (15 males and 2 females; median age, 57 yr). Cisplatin was started on day 1 of radiation therapy and repeated every 28 days for three cycles. Normal saline infusion (250 ml/hr) was started 12 hours prior to the first dose and continued 12 hours after the fifth dose. The daily dose of cisplatin was dissolved in 250 ml of 3% NaCl and given over 30 minutes. The cisplatin dose for subsequent cycles was reduced 10 mg/m2 per day only for a nadir granulocyte count less than 500/mm3 or fever greater than 101 degrees F during leukopenia. Of the 17 patients who started therapy, 15 have completed therapy; 1 patient died after one cycle, and 1 died after two cycles. Eleven patients received three cycles of cisplatin, and 10 patients required one dose reduction (6 at course 2 and 4 at course 3). Seven possible infections were successfully treated. Grade 2 neuropathy occurred in 3 patients, and renal toxicity greater than grade 1 occurred in 1 patient. Additional toxic effects were median WBC count nadir of 1.8 X 10(3)/mm3, platelet count nadir of 128 X 10(3)/mm3, hemoglobin nadir of 9.8 g/dl, and median weight loss of 5%.(ABSTRACT TRUNCATED AT 250 WORDS)     

A single institution experience with concurrent capecitabine and radiation therapy in weak and/or elderly patients with urothelial cancer

PURPOSE: To describe a single institution experience in delivering concurrent capecitabine and radiation in elderly patients with urothelial cancer. METHODS AND MATERIALS: The records of patients with urothelial carcinoma treated with capecitabine and radiation at Wayne State University were reviewed. Capecitabine was administered at a median dose of 1600 mg/m2/day (range, 1200-1800 mg/m2). Concurrent radiation therapy (RT) of 40-45 Gy was delivered to a small pelvic field with a four-field technique, with additional boost to tumor area (total, 54-68.4 Gy). RESULTS: Fourteen patients who were not candidates for cystectomy or cisplatin-based therapy were treated with capecitabine and concurrent radiation therapy. Median age was 80 years (range, 46-88 years). Five patients had a performance status of 3. Nine patients had localized disease, and 5 patients had advanced disease. The most common overall toxicities were fatigue (43%), diarrhea (Grade 2, 14% and Grade 3, 29%), and dehydration (43%), with no Grade 4 or 5 toxicities. Of 14 patients, 3 (20%) required hospitalization for management of toxicities. Seven patients required dose modification, and the therapy was relatively well tolerated. Clinical complete response was seen in 11 of 13 evaluable patients (77%). At a median follow-up of 10.5 months, only 3 of 11 responders had relapsed. CONCLUSION: Concurrent capecitabine and radiation therapy is well-tolerated and demonstrates promising efficacy in urothelial carcinoma, thus offering a tolerable therapeutic option in elderly patients or those with impaired performance status.     

Combination radiotherapy of urinary bladder carcinoma with chemohyperthermia.

The combination therapy of urinary bladder cancer with radiation and hyperthermia with bleomycin was investigated. Immediately following daily external irradiation (40 Gy/4 weeks), patients were irrigated with a solution of warmed saline (intravesical temperature, 42-43 degrees C) containing 30 micrograms/ml bleomycin. Of a total of 56 patients, complete responses were observed in 25, and partial responses in 21. Among T2-T3 cases, an 84% response rate was noted in combination therapy, whereas a 56% response rate was observed after radiation alone (50-70 Gy). The side-effects of the combination therapy were limited to reversible bladder irritation, and bladder capacity could be maintained within normal limits. These results suggest that combination therapy represents an effective conservative therapy for the management of bladder cancer.     

Intraoperative interstitial hyperthermia in conjunction with intraoperative radiation therapy in a radiation-resistant carcinoma of the abdomen: report on the feasibility of a new technique

The application of a new technique of intraoperative interstitial hyperthermia (IOHT) and intraoperative radiation therapy (IORT) was investigated for unresectable abdominal carcinoma. A 43-year-old white male presented with severe back pain due to metastatic adenocarcinoma in the left paravertebral area, producing erosion of the body of T12. The disease had not responded to external beam radiation therapy. The tumor was approached through a thoraco-abdominal incision and IOHT was delivered via interstitial electrodes. Temperature was monitored at 16 locations within the tumor. An LCF hyperthermia unit was utilized to deliver RF power and produced a treatment temperature of 43 degrees C for 60 minutes uniformly throughout the treatment volume. Immediately following hyperthermia treatment, the lesion was treated with 15 meV electrons via IORT to a tumor dose of 25Gy. The patient recovered without complication and had complete relief from pain. Posttreatment CT scans have demonstrated control of disease over a 5-month follow-up period. A clinical pilot study has been established to further investigate the application of this combination therapy.