D. Gonzalez

Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma

The value of hyperthermia as an adjuvant to radiotherapy in patients with malignant melanoma was studied in a European multicentre trial. 134 metastatic or recurrent lesions of malignant melanoma in 70 patients were randomly assigned to receive radiotherapy (three fractions of 8 Gy or 9 Gy in 8 days) alone or followed by hyperthermia (43 degrees C for 60 min). Overall, the 2-year actuarial local tumour control was 37 (SE 5)%. Univariate analysis showed a beneficial effect of hyperthermia (radiation alone 28% vs combined treatment 46%, p = 0.008) and radiation dose (24 Gy 25% vs 27 Gy 56%, p = 0.02), but no effect of tumour size (< or = 4 cm 42% vs > 4 cm 29%, p = 0.21). Cox multivariate regression analysis showed the most important prognostic variables to be hyperthermia (odds ratio for 2-year local control 1.73 [95% CI 1.07-2.78], p = 0.023), tumour size (0.91 [0.85-0.99], p = 0.05), and radiation dose (1.17 [1.01-1.36], p = 0.05). Addition of heat did not significantly increase acute or late radiation reactions. Heating was well tolerated, but because of difficulties with equipment only 14% of treatments achieved the protocol objective. The overall 5-year survival rate was 19%, but 38% of the patients for whom all known disease was controlled survived 5 years. Adjuvant hyperthermia significantly improved local tumour control when applied in association with radiation in treatment of malignant melanoma. Successful local treatment of patients with a single or a few metastatic malignant melanoma lesions has significant curative potential.

Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology.

The ESHO protocol 3-85 is a multicentre randomized trial investigating the value of hyperthermia as an adjuvant to radiotherapy in treatment of malignant melanoma. A total of 134 metastatic of recurrent malignant melanoma lesions in 70 patients were randomized to receive radiotherapy alone (3 fractions in 8 days) or each fraction followed by hyperthermia (aimed for 43°C for 60 min). Radiation was given with high voltage photons or electrons. Tumours were stratified according to institution and size (above or below 4 cm) and randomly assigned to a total radiation dose of either 24 or 27 Gy to be given with or without hyperthermia. The endpoint was persistent complete response in the treated area. A number of 128 tumours in 68 patients were evaluable, with an observation time between 3 and 72 months. Sixty-five tumours were randomized to radiation alone and 63 to radiation + heat. Sixty received 24 Gy and 68 tumours received 27 Gy, respectively. Size was ≤4 cm in 81 and >4 cm in 47 tumours. Overall the 2-year actuarial local tumour control was 37%. Univariate analysis showed prognostic influence of hyperthermia (rad alone 28% vs. rad + heat 46%, p = 0.008) and radiation dose (24 Gy 25% vs. 27 Gy 56%, p = 0.02), but not of tumour size (small 42% vs. large 29%, p = 0.21). A Cox multivariate regression analysis showed the most important prognostic parameters to be: hyperthermia (odds ratio: 1.73 (1.07-2.78), p = 0.02), tumour size (odds ratio: 0.91 (0.85-0.99), p = 0.05) and radiation dose (odds ratio: 1.17 (1.01—1.36), p = 0.05). Analysis of the heating quality showed a significant relationship between the extent of heating and local tumour response. Addition of heat did not significantly increase the acute or late radiation reactions. The overall 5-year survival rate of the patients was 19%, but 38% in patients if all known disease was controlled, compared to 8% in the patients with persistent active disease.

The Dutch Deep Hyperthermia Trial: results in cervical cancer

Background : Radiotherapy plus hyperthermia was compared to radiotherapy alone in the Dutch Deep Hyperthermia Trial, in patients with advanced bladder, cervical, and rectal tumours. The overall results, published elsewhere, demonstrate that addition of hyperthermia to radiotherapy improves both pelvic control and overall survival rates. The therapeutic gain appeared especially worthwhile in locally advanced cervical tumours. Here, the results in patients with cervical cancer are summarized and discussed, and further details provided. Methods : From 1990-1996, 114 patients with cervical cancer were entered into this prospective randomized trial. RT was applied to a median total dose of 68 Gy. HT was given once weekly. The median follow-up time was 43 months. All randomized patients were included in the statistical analysis, which was done by intention to treat . The primary end points of the trial were complete response (CR) and duration of pelvic control (PC), secondary end points were overall survival (OS) and toxicity. Besides, an economic evaluation was performed. Results : CR rates were 57% following RT and 83% following RT + HT( p = 0.003). The difference in PC was maintained during follow-up, with 3-year LC rates of 41% following RT and 61% following RT + HT. The 3-year OS rates were 27% and 51% following RT and RT + HT, respectively ( p = 0.009). When the patients were divided into two subgroups by whether or not the planned RT was completed, a beneficial effect of hyperthermia was observed in both subgroups. Radiation toxicity was not enhanced by HT. Additional hyperthermia proved to be cost-effective, with maximum discounted cost-per-life-year gained of about Euro 4000. Conclusion : Hyperthermia in addition to standard radiotherapy of locally advanced cervical tumours results in therapeutic gain and is cost-effective.

Primary non-Hodgkin's lymphoma of the central nervous system. Results of radiotherapy in 15 cases.

Primary non‐Hodgkins lymphoma (NHL) of the central nervous system is a rare disease. The number of cases reported in the literature does not exceed 200. The current series comprises 15 cases of primary NHL of the CNS. In 12 cases material for pathology was obtained at surgery. In the other three cases the diagnosis was established by cytologic examination of the cerebrospinal fluid (CSF). The type of lymphoma was predominantly the diffuse lymphocytic type. All the patients received irradiation on the whole brain by means of two opposite lateral fields. The administered total doses were 40 Gy in four weeks in ten cases, 50 to 60 Gy in 5 to 6 weeks in four cases and 30 Gy in three weeks in one case. All but three patients are dead although initially a good tumor response was obtained as confirmed in most of the cases by CT scan. The mean survival of the dead patients was 14.5 months. No relationship was found between the administered dose and the relapse‐free time. In six cases (40%) evidence of seeding was observed. Because of the poor results obtained with irradiation either of only the tumor bearing area or whole brain and because of the high risk of seeding through the CSF, the irradiation of the entire CNS is recommended in patients with primary NHL of the brain.

Results of radiotherapy in patients with stage I orbital non-Hodgkin's lymphoma

This paper describes the results of radiotherapy in early stage orbital non-Hodgkins lymphoma. From 1970 to 1985, 33 orbital localizations in 30 patients were treated. The total dose applied ranged from 21 to 57 Gy (2 Gy per fraction), two-thirds of all patients received a dose of 40 Gy. The complete-response rate was 94% and the 10 years actuarial survival was 90%; no significant difference in survival was observed between patients with low grade or intermediate grade lymphoma. No local recurrence was detected during follow up and 20% of the patients developed generalized disease. Two optic nerve neuropathies and three retinopathies were observed in five patients, four of these occurred at a dose level of less than 43 Gy. Keratitis occurred in 58% of the patients treated, a sicca syndrome in 30% and cataract of different grades in 58% of the patients treated. Although local control was excellent, severe complications were observed in 13% of the patients who received a dose of less than 43 Gy.

Combined treatment with radiation and hyperthermia inmetastatic malignant melanoma

In 24 patients with metastatic malignant melanoma, combined treatment with radiation and hyperthermia was administered to 38 localizations, radiation alone to 8 comparative localizations and hyperthermia alone to 3 localizations. Hyperthermia was administered during one hour by using a 433 MHz microwave generator. The heat treatment was given within 30 min following irradiation. Although an intratumoral temperature of 43 degrees C was aimed, considerable variations occurred during one session and from session-to-session. Radiation schedules consisted in either one large fraction (6-8 Gy) once a week in 14-21 days or two fractions (4-5 Gy) twice a week in 21 days. In the group of patients receiving irradiation once a week, three heat treatments were administered. In the twice-a-week radiation schedule, six heat sessions were given. The overall complete response (CR) rate in patients receiving combined treatment was 50%. In the group of patients treated with hyperthermia and irradiation schedules of 8 Gy per fraction, the CR rate was 83%. Irradiation alone achieved 38% CR rate but some of these CR relapsed during follow-up whereas the comparative area treated with radiation and heat remained under control at this time. The lesions treated with heat alone did not show any response to treatment. Enhancement of the acute skin reactions was generally observed. However, because the total doses were relatively low, this enhancement did not constitute a clinical problem. CR appears to occur more frequently in small tumor sizes. The highest and lowest temperature ever registered during any session of hyperthermia did not seem to correlate with the tumor response.

Toxicity of high-dose radiotherapy combined with daily cisplatin in non-small cell lung cancer: results of the EORTC 08912 phase I/II study

The purpose of this work was to study the feasibility of concurrent chemoradiation in patients with inoperable non-small cell lung cancer (NSCLC). 40 patients with inoperable NSCLC were treated with escalating doses of radiotherapy and cisplatin (cDDP). The radiation dose was increased step by step from 60.5 to 66 Gy in daily fractions of 2.75 Gy. Chemotherapy was also increased step by step from 20 to 24 daily doses of cDDP 6 mg/m(2) and given concurrently with radiotherapy. A dose of 40 Gy/2 Gy/20 fractions (fx) was given to the EPTV (elective planning target volume) which included the gross tumour volume with a margin of 2 cm and part of or the entire mediastinum. During each session a boost dose of 0.75 Gy was given simultaneously to the BPTV (boost planning target volume), which encompassed the GTV (gross tumour volume) with a margin of 1 cm, for the first 20 fx, so the total dose to the tumour was 55 Gy. Cisplatin 6 mg/m(2) was given 1 h prior to radiotherapy at each fraction. From then on the dose of radiation to the BPTV and the dose of cDDP were increased step by step. In group I the BPTV was irradiated with two extra fractions of 2.75 Gy to a total dose of 60. 5 Gy without cDDP. In group II the same total dose of 60.5 Gy was given but the last two fractions were combined with cDDP. In group III four extra fractions of 2.75 Gy were given to the BPTV to a total dose of 66 Gy, only two of these fractions combined with cDDP. Finally, in group IV a total dose of 66 Gy was given in 24 fractions, all fractions combined with cDDP. All patients were planned by means of a CT-based conformal treatment planning. The maximal length of the oesophagus receiving >/=60.5 Gy was 11 cm. 40 patients were evaluable for acute and late toxicity and for survival. Acute toxicity grade >/=3 (common toxicity criteria, CTC) was rarely observed; nausea/vomiting in 3 patients (8%), leucopenia in 2 patients (5%), thrombocytopenia in 2 patients (5%), whilst 2 patients (5%) suffered from severe weight loss. Late side-effects (European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group, EORTC/RTOG) were: oesophageal toxicity >/=grade 3 in 2 patients (5%) and radiation pneumonitis grades 1 (3%) and 2 (3%) in 1 patient each. Overall actuarial 1- and 2-year survival was 53% and 40%, respectively. The 1- and 2-year local disease-free interval was 65% and 58% respectively. Radiotherapy at a dose of 66 Gy/2.75 Gy/24 fx combined with daily cDDP 6 mg/m(2) given over 5 weeks is feasible and results in a good local disease-free interval and a good survival rate. This treatment schedule is at present being tested as one of the two treatment arms of EORTC phase III study protocol 08972/22973.

Phase II trial of weekly locoregional hyperthermia and cisplatin in patients with a previously irradiated recurrent carcinoma of the uterine cervix

The biologic rationale for combining cisplatin with locoregional hyperthermia (HT) relates to the potentiating effect of HT on cisplatin cytotoxicity.

Chestwall recurrences of breast cancer: results of combined treatment with radiation and hyperthermia.

In 35 patients with chestwall recurrences of breast carcinoma, 45 lesions were treated with combined radiation and hyperthermia. The majority of the lesions received 6 fractions of 4 Gy, twice a week during 3 weeks. Hyperthermia was administered within 30 min after irradiation, aiming a tumor temperature of 43 degrees C during one hour. The percentage of complete response (CR) was 57%. In small lesions, the percentage of CR was 80%. The mean duration of the response was 7 months. Response rate increased with increasing temperature. Particularly, mean temperature and isoeffect thermal dose correlated very well with response rate. In nine cases, comparative lesions were treated with either radiation alone or radiation combined with hyperthermia. The response rates were 3/9 and 7/9, respectively. Acute skin reactions were enhanced by the combined treatment. However, late skin reactions were not increased. Although the prognosis of patients with chestwall recurrences is determined by the presence of distant metastases, local control remains an important objective. Combined treatment with radiation and hyperthermia offers the possibility of obtaining a high local control rate particularly in relatively small lesions.

Accelerated radiotherapy in glioblastoma multiforme: a dose searching prospective study

The EORTC Radiotherapy Cooperative Group performed a prospective phase II study in glioblastoma multiforme using accelerated radiotherapy in escalating doses. The aims of the study were to investigate acute and late toxicity as well as tumor response and survival. Only the CT-enhanced tumor zone plus a margin of 2-3 cm were treated (mean volume, 1034 +/- 477 cm3). Radiotherapy was administered with 5-18 MV photons. The radiation schedule consisted of 3 fractions of 2 Gy/day, separated with at least 4 h. The first group of patients was scheduled to receive a total dose of 42 Gy, 21 fractions in 9 days. The total dose was then escalated up to 48 Gy (24 fractions in 10 days), 54 Gy (27 fractions in 11 days) and 60 Gy (30 fractions in 12 days). The numbers of patients entered in each dose-level group were 15, 17, 18 and 16, respectively. Acute toxicity was mild, nausea/vomiting was absent in 91% of the patients. In 80% of the patients the neurological condition improved or remained stable compared with the start of radiotherapy but in 58% of the patients steroids were necessary, either increased in dose or initiated. Acute toxicity did not increase with increasing radiation doses although patients treated with 60 Gy more often required steroids than the other groups. Late toxicity was strongly suspected in 2 patients receiving 52 Gy and 56 Gy, respectively. Within the whole group of 66 patients only one recurrence outside the primary site was found.(ABSTRACT TRUNCATED AT 250 WORDS)