André Fortin

Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer

PURPOSE The aim of the present study is to investigate whether combined androgen blockade associated with radiation therapy for localized prostate cancer decreases at 12 and 24 months the rate of positive follow-up biopsies and serum PSA compared to radiation therapy alone. This is the report of an interim analysis. METHODS AND MATERIALS One hundred and twenty patients with clinical Stage B1-T2a, B2-T2b/T2c, and C-T3/T4, adenocarcinoma of the prostate were entered in a prospective randomized study. After written informed consent, the subjects were randomly allocated between external beam radiation therapy (EBRT) alone (group 1), 3 months of neoadjuvant combination therapy (LHRH-agonist + Flutamide) prior to EBRT (group 2), and a third group receiving combination therapy 3 months before, during, and 6 months after EBRT. There is no significant difference between the three groups concerning age, stage of disease, grade of tumor, and pretreatment PSA levels. Control transrectal ultrasound (TRUS)-guided needle biopsies (one core was taken from the initial cancer site regardless of the presence or absence of TRUS abnormalities) were done 12 and 24 months after the end of EBRT. Serum PSA measurements were done on schedule visits. RESULTS Ninety-two and 68 patients underwent biopsies at 12 and 24 months, respectively, after the end of radiation therapy. While 62% of control patients at 12 months in Group 1 disclosed residual neoplasm, only 30% and 4% showed residual disease in groups 2 and 3, respectively (p = 0.00005). When looking at 24 months, 65, 28, and 5% showed residual cancer for groups 1, 2, and 3, respectively (p = 0.00001). The PSA measurements indicate also at 12 months a difference between the three groups (p < 0.0001), except at 24 months, the difference between the group 2 and 3 is no longer significant. CONCLUSION The preliminary analysis of this clinical trial indicates that patients treated with radiation therapy alone show a significantly higher rate of positive biopsies at 12 and 24 months after the end of radiation therapy as compared with those treated with total antiandrogen blockade (TAB) and radiation therapy. When analyzing the median PSA serum levels, we found the same advantage at 12 months, but, at the time of the analysis at 24 months, the PSA levels are not different between groups 2 and 3.

Local Failure Is Responsible for the Decrease in Survival for Patients With Breast Cancer Treated With Conservative Surgery and Postoperative Radiotherapy

PURPOSE The aim of the present study was to evaluate the role of local failure (LF) in the survival of patients treated with lumpectomy and postoperative radiotherapy and to investigate whether LF is not only a marker for distant metastasis (DM) but also a cause. METHODS Charts of patients treated with breast conservative surgery between 1969 and 1991 were reviewed retrospectively. There were 2,030 patients available for analysis. The median duration of follow-up was 6 years. A Cox regression multivariate analysis was performed using LF as a time-dependent covariate. RESULTS Local control (LC) was 87% at 10 years. Local failure led to poorer survival at 10 years than local control (55% v 75%, P < .00). In a Cox model, local failure was a powerful predictor of mortality. The relative risk associated with LF was 3.6 for mortality and 5.1 for DM (P < .00). In patients with LF, the rate of DM peaked at 5 to 6 years, whereas it peaked at 2 years for patients with LC. The mean time between surgery and DM was 1,050 days for patients without LF and 1,650 days for patients with LF (P < .00). CONCLUSION Our results show that local failure is associated with an increase in mortality. The difference in the time distribution of distant metastasis for LF and LC could imply distinct mechanisms of dissemination. Local failure should be considered not only as a marker of occult circulating distant metastases but also as a source for new distant metastases and subsequent mortality.

A new approach for the FEM simulation of viscoelastic flows

Abstract We present a finite element method for the simulation of viscoelastic flow. A decoupled approach is employed for the computation of the velocity field and of the components of the extra-stress tensor. The high Weissenberg number problem is addressed by using together two different types of upwinding namely the streamline upwinding technique and the Lesaint-Reviart method. Numerical results are presented for the case of the 4 to 1 plane contraction.

Randomized Phase III Trial to Test Accelerated Versus Standard Fractionation in Combination With Concurrent Cisplatin for Head and Neck Carcinomas in the Radiation Therapy Oncology Group 0129 Trial: Long-Term Report of Efficacy and Toxicity

PURPOSE We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC). PATIENTS AND METHODS Patients had stage III to IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks (SFX) or 72 Gy in 42 fractions over 6 weeks (AFX-C). Cisplatin doses were 100 mg/m(2) once every 3 weeks for two (AFX-C) or three (SFX) cycles. Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. Overall survival (OS) and progression-free survival (PFS) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test. Locoregional failure (LRF) and distant metastasis (DM) rates were estimated by using the cumulative incidence method and Grays test. RESULTS In all, 721 of 743 patients were analyzable (361, SFX; 360, AFX-C). At a median follow-up of 7.9 years (range, 0.3 to 10.1 years) for 355 surviving patients, no differences were observed in OS (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.18; P = .37; 8-year survival, 48% v 48%), PFS (HR, 1.02; 95% CI, 0.84 to 1.24; P = .52; 8-year estimate, 42% v 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; P = .78; 8-year estimate, 37% v 39%), or DM (HR, 0.83; 95% CI, 0.56 to 1.24; P = .16; 8-year estimate, 15% v 13%). For oropharyngeal cancer, p16-positive patients had better OS than p16-negative patients (HR, 0.30; 95% CI, 0.21 to 0.42; P < .001; 8-year survival, 70.9% v 30.2%). There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status. CONCLUSION When combined with cisplatin, AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC. Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification.

Markers of radioresistance in squamous cell carcinomas of the head and neck: a clinicopathologic and immunohistochemical study.

PURPOSE The lack of accurate criteria to predict the response to radiotherapy for individual patients with squamous cell carcinoma of the head and neck (HN-SCC) remains a major problem. The purpose of this study was to investigate the role of several biologic tumor markers to complement clinical prognostic factors in the assessment of response to radiotherapy in SCCs. PATIENTS AND METHODS p53, ki-67, c-erb B-2, heat-shock protein-27 (HSP-27), and glutathione S transferase (GSTpi) were evaluated by immunohistochemistry on biopsies from 101 patients treated for head and neck cancer by radical radiotherapy. Expression of each marker was correlated with local control and survival using Kaplan-Meier curves. A Cox regression multivariate analysis was also performed that included all clinical and immunohistochemical variables. RESULTS Expression of p53 and low cell proliferation allowed identification of patients whose tumors did not respond to radiation. Patients with p53-expressing tumors displayed a relative risk (RR) of 3.78 for not being controlled by radiotherapy compared with patients with p53-negative tumors. For tumors with a high growth fraction (ki-67 > 20%) the RR was 0.25 compared with tumors with a low growth fraction (ki-67 < 20%). When p53 expression and cell proliferation were considered simultaneously in a Cox model, the association with resistance to radiation was significant (P = .000004). The RR for resistance with one (p53 staining or ki-67 < 20%) or two (p53 staining and ki-67 < 20%) unfavorable markers was, respectively, 3.8 and 14.87. CONCLUSION Patients whose tumor expressed p53 with low growth fraction (ki-67 < 20%) had a strong probability not to respond to radiation therapy. Similarly, absence of p53 expression with a high cell proliferation predicted an excellent outcome after radiotherapy even for patients with advanced disease. Prediction of the outcome of radiotherapy would eventually facilitate the early choice of an adequate treatment.

Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial.

PURPOSE To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer. METHODS AND MATERIALS In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received. RESULTS Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed. CONCLUSION In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

The impact of skin washing with water and soap during breast irradiation: a randomized study.

BACKGROUND The effect of washing the irradiated skin during radiotherapy for breast cancer is uncertain. The purpose of this study was to evaluate the impact of washing the breast skin with water and soap during radiotherapy on the intensity of acute skin toxicity. MATERIALS AND METHODS Ninety-nine patients treated for breast cancer were prospectively randomized prior to receiving radiotherapy to the breast into two groups: (1), no washing was allowed during radiotherapy (49 patients); and (2), washing was allowed with water and soap (50 patients). Acute toxicity was recorded according to the Radiation Therapy Oncology Group (RTOG) acute skin toxicity scale for each patient every week during radiotherapy and 1 month after the end of radiotherapy. Symptoms related to skin toxicity were scored by visual analogue scales at the same time intervals. Other data collected included sociodemographic data, characteristics related to the tumor and previous treatments, radiation technique, necessity for a second simulation due to loss of skin marks and treatment interruptions. RESULTS In the non-washing group, the following maximum acute toxicity scores were observed: grade 0, 2%; grade 1, 41%; grade 2, 57%; grades 3 and 4, 0%. For the washing group, the scores were: grade 0, 0%; grade 1, 64%; grade 2, 34%; grade 3, 2%; and grade 4, 0%. Moist desquamation was seen in 33% of non-washing patients, but in only 14% of washing patients. The median scores of pain, itching and burning of the treated skin were higher in the non-washing group, although this was not statistically significant. In a multivariate analysis using logistic regression, acute skin toxicity was associated with the patients weight, concomitant radiochemotherapy and hot spots on dosimetry, and there was a trend toward more acute skin toxicity in the non-washing group. CONCLUSION Washing the irradiated skin during the course of radiotherapy for breast cancer is not associated with increased skin toxicity and should not be discouraged.

Antioxidant vitamins supplementation and mortality: A randomized trial in head and neck cancer patients

There has been concern that long‐term supplementation with high‐dose antioxidant vitamins, especially vitamin E (α‐tocopherol), may increase all‐cause mortality. We conducted a randomized controlled trial with α‐tocopherol (400 IU/day) and β‐carotene (30 mg/day) supplements among 540 head and neck cancer patients treated by radiation therapy. Supplementation with β‐carotene was discontinued during the trial. The supplements were given during radiation therapy and for 3 additional years. During the follow‐up (median 6.5 years), 179 deaths were recorded. All death certificates were obtained. All‐cause and cause‐specific mortality rates were compared between the 2 arms of the trial by Cox regression. All‐cause mortality was significantly increased in the supplement arm: hazard ratio: 1.38, 95% confidence interval 1.03–1.85. Cause‐specific mortality rates tended to be higher in the supplement arm than in the placebo arm. Our results concur with previous reports to suggest that high‐dose vitamin E could be harmful.

p53 and Ki-67 as markers of radioresistance in head and neck carcinoma.

p53 and Ki‐67 are regarded as potential interesting predictors of radioresistance, although their exact influence awaits confirmation on a large cohort of uniformly treated patients.

Effect of treatment delay on outcome of patients with early-stage head-and-neck carcinoma receiving radical radiotherapy

PURPOSE Access to radiotherapy (RT) has been considerably reduced in Quebec since the late 1980s. The aim of the present study was to analyze the impact of delaying treatment on the outcome of patients with early head-and-neck squamous cell carcinomas. MATERIALS AND METHODS This retrospective analysis examined the outcome for all 623 patients with early-stage disease (T1-2, N0-1) who received radical RT between 1988 and 1997 at the Hotel Dieu of Quebec Hospital. Delay was defined as the time from initial evaluation by a radiation oncologist to the beginning of RT. Delay intervals were divided as follows: <30 days, 31-40 days, and >40 days. RESULTS A delay of >40 days was significantly associated with an increased risk of local and neck failure and poorer survival relative to patients treated in <30 days or between 31 and 40 days. The adjusted hazard ratio and (in parentheses) the 95% confidence interval was 2.6 (1.07-6.4), 2.73 (1.38-5.4), and 1.7 (1.1-2.6), respectively, for local failure, neck failure, and survival. In the subgroup of patients with T2N0 disease, delaying RT for >30 days was associated with a poor outcome, as measured by the same end points. CONCLUSION Delaying RT had a deleterious effect on these patients. RT should be started as soon as possible in patients with squamous cell carcinoma of the head and neck, preferably within 20-30 days after evaluation by a radiation oncologist.