Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: two cooperative phase II studies of the AIO/ARO/ACO.

BACKGROUND: The current two studies evaluate the feasibility, toxicity and efficacy of an adjuvant combined modality treatment strategy containing a three to four-drug chemotherapy regimen plus 5-fluorouracil (FU)-based radiochemotherapy. PATIENTS AND METHODS: Between December 2000 and October 2003, a total of 86 patients were included in both studies. Patients with completely resected gastric adenocarcinoma including a D1 or D2 lymph node dissection (LND) were eligible. Treatment consisted of two cycles of folinic acid 500 mg/m2, 5-FU 2000 mg/m2 continuous infusion over 24 h once weekly for 6 consecutive weeks, paclitaxel 175 mg/m2 in weeks 1 and 4 and cisplatin 50 mg/m2 in weeks 2 and 5 (FLPP; n=41) or two cycles of the same 5-FU/folinic acid schedule but with cisplatin 50 mg/m2 only in weeks 1, 3 and 5 (FLP; n=45). Radiation with 45 Gy plus concomitantly applied 5-FU 225 mg/m2/24 h was scheduled in between the two cycles. RESULTS: Patients characteristics were: D1/D2 LND FLP group 53%/42%; FLPP group 27%/68%; stage distribution: UICC stages III/IV(M0) FLP group 63% and FLPP group 66%. Median follow-up was 10 months (3-25) for FLP and 18 months (2-51) for FLPP patients. CTC grade 3/4 toxicities during the first cycle/chemoradiation/second cycle of FLP: granulocytopenia 3%/0/27%, anorexia 6%/10%/8%; diarrhea 8%/0/4%, nausea 3%/0/4%; FLPP: granulocytopenia 0/0/37%, anorexia 5%/11%/6%; diarrhea 5%/0/3, nausea 3%/8%/0%; early death in one patient due to Pneumocystis carinii pneumonia. Projected 2-year progression-free survival was 64% (95% CI 56% to 68%) for the FLP and 61% (95% CI 42% to 78%) for the FLPP group. CONCLUSIONS: Both chemoradiation regimens appear feasible with an acceptable toxicity profile indicating that cisplatin can be added to 5-FU/FA and that even a four-drug regimen can be investigated further in prospective clinical trials in completely resected gastric cancer patients. Treatment should be given in experienced centres in order to avoid unnecessary toxicity.

Thermoradiotherapy of the chest wall in locally advanced or recurrent breast cancer with marginal resection.

BACKGROUND AND PURPOSE: Evaluation of the efficacy of combined hyperthermia and radiotherapy (TRT) in high-risk breast cancer patients with microscopic involved margins (R1) after mastectomy or with resected locoregional, early recurrence with close margins or R1-resection. Main endpoint was local tumour control (LC); secondary endpoints were overall survival (OS), disease free survival (DFS) and acute toxicity. MATERIAL AND METHODS: Between 1997-2001, 50 patients were treated with TRT. Thirteen patients (group 1) received a post-operative TRT in a high-risk situation (free margin <1 cm or R1, N+), 37 patients (group 2) received TRT after close/R1 resection of a locoregional recurrence. Thirteen out of 37 patients in group 2 already had had two-to-seven recurrences prior to TRT. Median radiation dose was 60 Gy (range: 44-66.4 Gy), the additional local hyperthermia (>41 degrees C, 60 min) was given twice a week. Median follow-up for patients at risk was 28 months. All statistical tests were done using Statistica software. RESULTS: Actuarial OS for all patients at 3 years accounted for 89%, DFS for 68% and LC for 80%. Actuarial OS was 90% for group 1 and 89% for group 2, with four patients having died so far. DFS at 3 years was 64% in group 1 and 69% in group 2, actuarial 3 year LC was 75% and 81%, respectively. For patients with recurrent chest wall disease, there was no difference concerning local control between patients who underwent TRT with or without prior radiation. No prognostic factors could be detected due to the small number of patients investigated. The combined modality treatment was well tolerated. Grade IV toxicity, according to the Common Toxicity Criteria, did not occur. CONCLUSION: The results concerning local tumour control and overall survival in these high-risk patients are promising, especially for TRT for the treatment of local recurrences. A longer follow-up is needed to estimate late toxicity.

Current and potential role of thermoradiotherapy for solid tumours.

The disappointing results for inoperable, locally advanced or recurrent solid tumours of the uterine cervix, rectum, chest wall, liver and deep seated, high-risk sarcomas after conventional radiotherapy alone necessitate the search for improved treatments. A benefit from simultaneous radiochemotherapy with regard to local tumour control and survival has been shown for a rising number of tumour entities. Radiofrequency hyperthermia is established in only a few centres, and represents another option to intensify the effect of radio- and chemotherapy. Altogether 11 randomised phase III trials with more than 1,000 patients proved the combination of hyperthermia (40-42 degrees C for at least 1 h) and radiation therapy in reference to local tumour control. Two of these trials could demonstrate a survival benefit; e.g. in locally advanced cervical cancer, stage FIGO IIB-IVa, the 3-year survival was improved from 27 to 51% with the addition of hyperthermia. Frequently trial design (main endpoint local tumour control), a low number of patients or a short follow- up period are the reasons why most trials of thermoradiotherapy failed to demonstrate a survival benefit. Disadvantageous effects of hyperthermia like an increased rate of distant metastases as a result of hyperthermia-induced elevated perfusion can be largely ruled out. While at the moment the equivalence of thermoradiotherapy and radiochemotherapy is still under evaluation, future studies have to investigate the question whether hyperthermia can add benefits when used in combination with simultaneous radiochemotherapy. An ongoing investigation of hyperthermia in multimodal treatment strategies for locally advanced solid tumours is warranted. These trials will help to improve temperature monitoring and temperature distribution and define particular groups of patients who will profit from the addition of hyperthermia. The 'Interdisziplinäre Arbeitsgruppe Hyperthermie', a working group of the German Cancer Society, introduces clinical protocols, treatment devices, and provides information for patients at www.hyperthermie.org.

Thermoradiotherapy for locally recurrent breast cancer with skin involvement.

PURPOSE: This retrospective analysis investigated the effectiveness and side-effects of combined hyperthermia and radiation therapy in locally recurrent breast cancer after primary modified radical mastectomy. The aim of the thermoradiotherapy was to reduce the substantial risk of symptomatic chest wall disease. MATERIALS AND METHODS: Between May 1995-August 1998, 39 extensively pre-treated women with progressive locoregional chest wall tumours were treated with local radiofrequency hyperthermia, given twice a week immediately before radiotherapy. Sixty-two per cent of the patients had received previous radiotherapy, with a median dose of 50 Gy, 64% had received chemotherapy, 36% hormonal therapy, and 13% local therapy with miltefosin, respectively. Nine patients were treated for microscopic residual disease after local tumour excision (R1-resection) and 30 patients for gross macroscopic nodular recurrences. Twenty-seven patients had two adjacent hyperthermia fields at the ipsilateral chest wall to cover the whole irradiation area. Each field received a median of seven local hyperthermia sessions (range 2-12, average 5.6 sessions) just before radiation therapy, with a median dose of 60 Gy (range 30-68 Gy). The monitored maximum(average) and average(average) epicutaneous temperatures were 42.1 degrees C and 41.0 degrees C, respectively. Maximum(average) and average(average) intratumoural temperatures of 43.0 degrees C and 41.1 degrees C, respectively, were achieved in nine chest wall recurrences with intratumoural temperature probes. Concurrent hormonal therapy was administered in 48%, and concurrent chemotherapy in 10% of patients. RESULTS: Median overall survival time was 28 months (Kaplan Meier), with 71% and 54% of patients living 1 and 2 years after thermoradiotherapy. The median time to local failure has not been reached, local tumour control after 2 years being 53%. Actuarial 1 and 2 year local tumour controls for microscopic residual disease were 89%, and for macroscopic nodular recurrences 71% and 46%, respectively (p = 0.09). Actuarial 1 and 2 year local tumour controls after treatment with a total dose of less than 60 Gy were 51% and 38%, respectively, and, after a total dose greater than 60 Gy, 84% and 60% (p = 0.01), respectively. Actuarial 1 year local tumour control was 92% after complete tumour remission, versus 57% after partial remission (p = 0.002). Three of the 39 patients died of cancer en cuirasse, 13 patients due to distant metastases. Acute thermoradiotherapy related erythema, dry desquamation and moist desquamation were seen in 28.2%, 30.7%, and 30.7% of patients, respectively. Soft tissue necrosis occurred in two patients with previous post-operative delayed wound healing, and in one patient above a silicon implant. CONCLUSION: This study showed that, in extensively pre-treated patients with locally recurrent breast cancer, local tumour control after thermoradiotherapy depended on tumour resectability, response of macroscopic tumour to thermoradiotherapy, and total irradiation dose.

An on-line phase measurement system for quality assurance of the BSD 2000. Part I: technical description of the measurement system.

The hyperthermia system BSD 2000 with the ring applicator Sigma 60 utilizes the principle of a phase controlled group radiation source. The accuracy of the phase relationship between the four receiving HF signals is crucial for the position of the electric field inside the applicator. Therefore, essential significance falls to the phase control of the system. An automatic phase measuring technique has been developed to register immediately the phase position of the four channels of the BSD 2000 with respect to a reference signal. The system improves the insurance of the technical safeguarding. In the first part of this work, the technical realization of the measurement system is described and first measurements with the system are given. In the second part, results with respect to the quality assurance of the BSD 2000 system are presented.

An on-line phase measurement system for quality assurance of the BSD 2000. Part II: results of the phase measurement system.

Phase constancy and accuracy are significant for regional hyperthermia with phased array radiofrequency hyperthermia systems. They are both necessary for a precise target steering in therapy. For the BSD 2000 system (BSD Medical Corp. Salt Lake City, Utah, USA), the phase values of all channels are checked with a self-developed automatic on-line phase measurement system. On different days the phases are measured under identical conditions, where the output paths are cut off with 50 ohm dummy loads to suppress the influence of the radiation conditions of the antennae on the measurement values. The results show how the phase values of the four channels change in the first 30 min and from day to day. During this time interval after the start the phases drop down by up to 15 degrees. For the time later changes are very slight and the differences from day to day are negligible. The phase shift that occurs in the first 30 min is as high as a change of the target point by 1 cm. Earlier switching on of the amplifiers prevents this shift occurring during the treatment. The measurement system provides a good tool for determination of phase accuracy and is easy to realize.

Cystosarcoma phyllodes malignum: a case report of a successive triple modality treatment.

This paper reports on a woman with a rapidly growing recurrent cystosarcoma phyllodes malignum after two major attempts of surgery. In this situation, neoadjuvant hyperfractionated radiotherapy, superficial hyperthermia and ifosfamide were administered. Toxicity was mild. Resection of the tumour bed revealed a pathologically complete response with an actual disease free follow-up of 48 months.

Appendicitis during locoregional thermoradiotherapy of advanced or recurrent rectal and cervical cancer, a report of two cases.

INTRODUCTION: Local tumour control after irradiation alone for advanced, inoperable carcinomas of the bladder and rectum or inoperable recurrent cervical carcinoma is usually disappointing. Both preclinical and clinical studies reported improvements by adding hyperthermia to radiotherapy. Reports for phase II/III trials do not indicate any enhanced side effects. However, two cases of acute suppurating appendicitis were observed in a series of patients treated with deep regional hyperthermia. MATERIALS, METHODS AND RESULTS: Eighty patients with advanced, inoperable, or recurrent rectal or recurrent cervical tumours were treated with deep regional hyperthermia (313 sessions) in addition to radiotherapy between September 1995 and October 1998. The treatment for two of these patients (2.5%) had to be discontinued after the fourth/second hyperthermia treatments at 19.8/10.8 Gy total dose, respectively, for symptoms of pain in the right pelvis and elevated rectal temperature. Both patients underwent laparotomy and were found to have suppurative appendicitis. In addition to the retrocoecal location in both patients, evidence of preexisting chronic appendicitis, and appendiceal faecalith were observed in each patient. CONCLUSION: The development of acute appendicitis in 2.5% of patients during a course of deep regional thermoradiotherapy for pelvic tumour is much higher than the expected incidence of appendicitis in the general population (< 1/1000) (Korner et al. 1997). An enhanced risk of suppurative appendicitis in patients undergoing pelvic thermoradiotherapy cannot be excluded, especially in retrocoecal located appendices with obstructed appendix lumen from preexisting chronic appendicitis or faecalith.

[Role of sodium selenite as an adjuvant in radiotherapy of rectal carcinoma]. / Zur Rolle von Natriumselenit als Adjuvans in der Strahlentherapie des Rektumkarzinoms.

BACKGROUND: In various epidemiologic studies an association of low selenium blood levels and reduced glutathione peroxidase with an increased risk of cancer incidence was described. The antitumoral therapy and a suboptimal nutrition could intensify this deficiency. Every reduction of disease related and therapeutic caused symptoms may improve life quality. APPLICATION: We report our preliminary experiences in the adjuvant radiochemotherapy of advanced rectal cancer (UICC II/III) corresponding to the NCl recommendation. An oral selenium supplementation was carried out with 2000 micrograms Na2SeO3 after every course of fluorouracil chemotherapy and daily 400 micrograms Na2SeO3 after irradiation of tumor region and lymph nodes. A weekly life quality assessment was explored with special interest in diarrhea, dysurie, pain, appetite, nausea and emesis. CONCLUSION: Damages to normal tissue specially to DNA enzymes and membranes caused by free radicals is one mechanism in tumorgenesis, tumor progression and therapeutic consequence. A radioprotective effect of selenium is verified by in vitro and in vivo data. Our data show that oral selenium intake in rectal cancer patients is easily tolerated with no side effects. Improving life quality and secondary cancer prevention with supplementation of selenium has to be proven in prospective randomized studies.