Dionisio Gonzalez

Improved Survival in Patients with Locally Advanced Prostate Cancer Treated with Radiotherapy and Goserelin

BACKGROUND We conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer. METHODS From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin. RESULTS Data were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P=0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001). CONCLUSIONS Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer.

Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group.

OBJECTIVE The survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers. SUMMARY BACKGROUND DATA A previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastrointestinal Tract Cancer Cooperative Group of EORTC has been followed by other studies with conflicting results. METHODS Eligible patients with T1-2N0-1aM0 pancreatic head or T1-3N0-1aM0 periampullary cancer and histologically proven adenocarcinoma were randomized after resection. RESULTS Between 1987 and 1995, 218 patients were randomized (108 patients in the observation group, 110 patients in the treatment group). Eleven patients were ineligible (five in the observation group and six in the treatment group). Baseline characteristics were comparable between the two groups. One hundred fourteen patients (55%) had pancreatic cancer (54 in the observation group and 60 in the treatment group). In the treatment arm, 21 patients (20%) received no treatment because of postoperative complications or patient refusal. In the treatment group, only minor toxicity was observed. The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group (log-rank, p = 0.208). The 2-year survival estimates were 41% and 51 %, respectively. The results when stratifying for tumor location showed a 2-year survival rate of 26% in the observation group and 34% in the treatment group (log-rank, p = 0.099) in pancreatic head cancer; in periampullary cancer, the 2-year survival rate was 63% in the observation group and 67% in the treatment group (log-rank, p = 0.737). No reduction of locoregional recurrence rates was apparent in the groups. CONCLUSIONS Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well tolerated. However, the benefit in this study was small; routine use of adjuvant chemoradiotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region.

Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.

PURPOSE To investigate the potential gain of the concomitant use of radiotherapy and chemotherapy in improving local control and reducing the need for colostomy, a randomized phase III trial was performed in patients with locally advanced anal cancer. MATERIALS AND METHODS From 1987 to 1994, 110 patients were randomized between radiotherapy alone and a combination of radiotherapy and chemotherapy. The patients had T3-4NO-3 or T1-2N1-3 anal cancer. Radiotherapy consisted of 45 Gy given in 5 weeks, with a daily dose of 1.8 Gy. After a rest period of 6 weeks, a boost of 20 or 15 Gy was given in case of partial or complete response, respectively. Surgical resection as part of the primary treatment was performed if possible in patients who had not responded 6 weeks after 45 Gy or with residual palpable disease after the completion of treatment. Chemotherapy was given during radiotherapy: 750 mg/m2 daily fluorouracil as a continuous infusion on days 1 to 5 and 29 to 33, and a single dose of mitomycin 15 mg/m2 administered on day 1. RESULTS The addition of chemotherapy to radiotherapy resulted in a significant increase in the complete remission rate from 54% for radiotherapy alone to 80% for radiotherapy and chemotherapy, and from 85% to 96%, respectively, if results are considered after surgical resections. This led to a significant improvement of locoregional control and colostomy-free interval (P = .02 and P = .002, respectively), both in favor of the combined modality treatment. The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate at that time increased by 32% by the addition of chemotherapy to radiotherapy. No significant difference was found when severe side effects were considered, although anal ulcers were more frequently observed in the combined-treatment arm. The survival rate remained similar in both treatment arms. Skin ulceration, nodal involvement, and sex were the most important prognostic factors for both local control and survival. These remained significant after multivariate analysis. The improvement seen in local control by adding chemotherapy to radiotherapy also remained significant after adjusting for prognostic factors in the multivariate analysis. Event-free survival, defined as free of locoregional progression, no colostomy, and no severe side effects or death, showed significant improvement (P = .03) in favor of the combined-treatment modality. The 5-year survival rate was 56% for the whole patient group. CONCLUSION The concomitant use of radiotherapy and chemotherapy resulted in a significantly improved locoregional control rate and a reduction of the need for colostomy in patients with locally advanced anal cancer without a significant increase in late side effects.

Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial

Summary Background Local-control rates after radiotherapy for locally advanced tumours of the bladder, cervix, and rectum are disappointing. We investigated the effect of adding hyperthermia to standard radiotherapy. Methods The study was a prospective, randomised, multicentre trial. 358 patients were enrolled from 1990 to 1996, in cancer centres in the Netherlands, who had bladder cancer stages T2, T3, or T4, N0, M0, cervical cancer stages IIB, IIIB, or IV, or rectal cancer stage M0–1 were assessed. Patients were randomly assigned radiotherapy (median total dose 65 Gy) alone (n=176) or radiotherapy plus hyperthermia (n=182). Our primary endpoints were complete response and duration of local control. We did the analysis by intention to treat. Findings Complete-response rates were 39% after radiotherapy and 55% after radiotherapy plus hyperthermia (p Interpretation Hyperthermia in addition to standard radiotherapy may be especially useful in locally advanced cervical tumours. Studies of larger numbers of patients are needed for other pelvic tumour sites before practical recommendations can be made.

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials

PURPOSE Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Results of postoperative radiotherapy for resectable hilar cholangiocarcinoma.

The aim of this study was to assess the value of radiotherapy, and especially intraluminal brachytherapy, after resection of hilar cholangiocarcinoma by analyzing long-term complications and survival. Between 1983 and 1998, 112 patients underwent resection of a hilar cholangiocarcinoma. Of the 91 patients who survived the postoperative period, 20 patients had no additional radiotherapy, 30 patients had only external radiotherapy (46 ± 11 Gy), and 41 patients had a combination of external (42 ± 5 Gy) and intraluminal brachytherapy (10 ± 2 Gy). Overall, 88% of the patients had late complications, with a significantly higher rate of complications occurring among patients receiving external beam irradiation and brachytherapy. Second to abdominal pain (56%), cholangitis (49%) was the most frequent complication and occurred significantly more often in patients who had received brachytherapy. Retrograde bile leakage after closure of the temporary jejunostomy was a troublesome complication in 24% of patients treated with brachytherapy. Overall median survival after treatment with adjuvant radiotherapy was longer than after resection without additional radiation (24 months versus 8 months, respectively). There was, however, no significant benefit from the use of intraluminal brachytherapy. In conclusion, additional radiotherapy after resection of hilar cholangiocarcinoma significantly improved survival and is recommended by giving external beam irradiation but not intraluminal brachytherapy.

Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: Data from a phase III trial

PURPOSE The objective of this study was to determine whether the thermal dose delivered during hyperthermia treatments and other thermal factors correlate with outcome after combined radiation and hyperthermia of breast carcinoma recurrences. Data were from the combined hyperthermia and radiation treatment arms of four Phase III trials, which when pooled together, demonstrated a positive effect of hyperthermia. METHODS AND MATERIALS Four Phase III trials addressing the question of whether hyperthermia could improve the local response of superficial recurrent breast cancer to radiation therapy were combined into a single analysis. Thermal dosimetry data were collected from 120 of the 148 breast cancer recurrence patients who received hyperthermia. The data were analyzed for correlations between thermal parameters as well as important clinical parameters and outcome (complete response rate, local disease free survival, time to local failure, and overall survival). RESULTS Five thermal parameters were tested, all associated with the low regions of the measured temperature distributions. Max(TDmin) and Sum(TDmin) were associated with complete response where TDmin is the minimum thermal dose measured by any of the tumor temperature sensors during a treatment: Max(TDmin) is the maximum of TDmin over a series of treatments. Using a categorical relationship with a cutoff of 10 min for Sum(TDmin), the complete response rate was 77% for Sum(TDmin) > 10 min and 43% for Sum(TDmin) < or = 10 min (p = 0.022, adjusted for study center and significant clinical factors). The overall complete response rate for hyperthermia and radiation was 61% compared to 41% for radiation alone. Either Max(TDmin) or Sum(TDmin) were also associated with local disease free survival, time to local failure and overall survival. CONCLUSIONS An earlier report of this trial demonstrated a significant benefit when hyperthermia was added to radiation in the treatment of breast cancer recurrences. The analysis of thermal factors demonstrates that parameters representative of the low end of the measured temperature distributions are associated with initial complete response rate, local disease-free survival, time to local failure and overall survival.

Feasibility and efficacy of high dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma.

The feasibility and efficacy of high dose conformal radiotherapy were examined in the treatment of patients with locally advanced, unresectable pancreatic carcinoma.

INFLUENCE OF BLADDER AND RECTAL VOLUME ON SPATIAL VARIABILITY OF A BLADDER TUMOR DURING RADICAL RADIOTHERAPY

PURPOSE To assess the spatial variability of a bladder tumor relative to the planning target volume boundaries during radical radiotherapy, and furthermore to develop strategies to reduce spatial variability. METHODS AND MATERIALS Seventeen patients with solitary T2-T4N0M0 bladder cancer were treated with a technique delivering 40 Gy/2 Gy in 20 fractions to the whole bladder with a concomitant boost to the bladder tumor of 20 Gy in 1 Gy fractions in an overall time of 4 weeks. CT scans were made weekly, immediately after treatment, and matched with the planning CT scan. Spatial variability of the tumor, as well as bladder volume and rectal diameter, were scored for each patient each week. RESULTS In 65% of patients, a part of the tumor appeared outside the planning target volume boundaries at least one time during the course of radiotherapy. No consistent relation of this variability with time was found. Bladder volumes and rectal diameters showed marked variability during the course of treatment. A large initial bladder volume and rectal diameter predicted a large volume variation and a large tumor spatial variability. CONCLUSION In this study, a margin of 1.5 to 2 cm seemed to be inadequate in 65% of the patients with respect to spatial variability. Bladder volume and rectal diameter were found to be predictive for spatial variability of a bladder tumor during concomitant boost radiotherapy.

Early results of the EORTC randomized clinical trial on multiple fractions per day (MFD) and misonidazole in advanced head and neck cancer.

From Feb. 1981 to Oct. 1984, a randomized clinical trial was carried out in the EORTC Radiotherapy Group, comparing classical radiotherapy 70 Gy/7 weeks to MFD (3 X 1.6 Gy/day for 10 days, 3 weeks rest, followed by a boost to 67.2 or 72 Gy), with or without Misonidazole (1 g/m2 every irradiation day, total 12 to 14 g/m2) in advanced head and neck cancer (all T3 and T4, all N2, N3 and N1 greater than 3 cm). A total of 523 patients were entered in the study. At the time of analysis (4/85), the median follow-up time was 64 weeks. No significant differences in survival or locoregional control could be demonstrated between the three treatment arms at this time. Whereas early mucosal reactions were heavier in the MFD-arms, no differences in late effects (fibrosis, edema, xerostomy) were found between the three treatment arms. Five patients (all MFD + Misonidazole) died with local complications (edema, necrosis). All five had cancer of the laryngopharynx and 3 of them died from a hemorrhage. Factors affecting prognosis were tumor site, tumor stage, nodal status, and histological differentiation.