Pascal Pommier

Is There a Role for Pelvic Irradiation in Localized Prostate Adenocarcinoma? Preliminary Results of GETUG-01

PURPOSE To assess the benefit and toxicity and quality-of-life (QOL) outcomes of pelvic nodes irradiation in nonmetastatic prostate carcinoma patients. PATIENTS AND METHODS Between December 1998 and June 2004, 444 patients with T1b-T3, N0 pNx, M0 prostate carcinoma were randomly assigned to either pelvic and prostate radiotherapy or prostate radiotherapy only. Patients were stratified according to the prognostic factor of lymph node involvement (LNI). Short-term 6-month neoadjuvant and concomitant hormonal therapy was allowed only for patients in the high-risk group. The pelvic dose was 46 Gy. The total dose recommended to the prostate was changed during the course of the study from 66 Gy to 70 Gy. Criteria for progression-free survival (PFS) included biologic prostate-specific antigen recurrences or a local or metastatic evolution. Acute and late toxicities were recorded according to the Radiation Therapy Oncology Group and Late Effects in Normal Tissues Subjective, Objective, Management, and Analytic scales, respectively. The QOL outcome was recorded with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, the International Prostatic Symptom Score, and the Sexual Function Index scales. RESULTS With a 42.1-month median follow-up time, the 5-year PFS and overall survival were similar in the two treatment arms for the whole series and for each stratified group. On multivariate analysis, low LNI risk and hormonal therapy were statistically associated with increased PFS. However, subgroup analyses based on these factors did not show any benefit for pelvic irradiation. There were no significant differences in acute and late digestive toxicities and in QOL outcomes. CONCLUSION Pelvic node irradiation was well tolerated but did not improve PFS.

Phase III Randomized Trial of Calendula Officinalis Compared With Trolamine for the Prevention of Acute Dermatitis During Irradiation for Breast Cancer

PURPOSE The effectiveness of nonsteroid topical agents for the prevention of acute dermatitis during adjuvant radiotherapy for breast carcinoma has not been demonstrated. The goal of this study was to compare the effectiveness of calendula (Pommade au Calendula par Digestion; Boiron Ltd, Levallois-Perret, France) with that of trolamine (Biafine; Genmedix Ltd, France), which is considered in many institutions to be the reference topical agent. PATIENTS AND METHODS Between July 1999 and June 2001, 254 patients who had been operated on for breast cancer and who were to receive postoperative radiation therapy were randomly allocated to application of either trolamine (128 patients) or calendula (126 patients) on the irradiated fields after each session. The primary end point was the occurrence of acute dermatitis of grade 2 or higher. Prognostic factors, including treatment modalities and patient characteristics, were also investigated. Secondary end points were the occurrence of pain, the quantity of topical agent used, and patient satisfaction. RESULTS The occurrence of acute dermatitis of grade 2 or higher was significantly lower (41% v 63%; P <.001) with the use of calendula than with trolamine. Moreover, patients receiving calendula had less frequent interruption of radiotherapy and significantly reduced radiation-induced pain. Calendula was considered to be more difficult to apply, but self-assessed satisfaction was greater. Body mass index and adjuvant chemotherapy before radiotherapy after lumpectomy were significant prognostic factors for acute dermatitis. CONCLUSION Calendula is highly effective for the prevention of acute dermatitis of grade 2 or higher and should be proposed for patients undergoing postoperative irradiation for breast cancer.

Intensity-modulated radiotherapy in head and neck cancer: Results of the prospective study GORTEC 2004–03

BACKGROUND AND PURPOSE In 2003, the French Authority for Health (HAS) recommended the use of intensity modulated radiotherapy (IMRT) in prospective trial before its routine use. The Oncology and Radiotherapy Group for Head and Neck Cancer (GORTEC) proposed to evaluate prospectively acute and late toxicities, locoregional control and overall survival for patients treated for head and neck cancer (HNC) with IMRT and bilateral neck irradiation. MATERIALS AND METHODS Between 2002 and 2008, 208 patients with HNC were treated with IMRT in 8 centres. There were 38 nasopharynx, 117 oropharynx, 25 pharyngo-larynx, 24 oral cavity and 4 unknown primary (28.5% stage I-II and 71% Stage III-IV). Ninety-three patients (46%) had postoperative IMRT and 78 patients (37.5%) received concurrent chemotherapy. The doses were 70 Gy to the gross tumour, 66 Gy to the high-risk postoperative sites and 50 Gy to the subclinical disease. Toxicities were graded according to the RTOG-EORTC scales. RESULTS The median follow-up was 25.3 months (range: 0.4-72 months). There were 29 local-regional failures: 24 were in-field, three were marginal and one was out-field. The two-year loco-regional control and overall survival were 86% and 86.7%, respectively. At 18 months, grade ≥ 2 xerostomia was 16.1%. A mean dose to the spared parotid below 28 Gy led to significantly less grade ≥ 2 xerostomia (8.5% vs 24%) with a relative risk of 1.2 [95% CI: 1.02-1.41, p = 0.03]. Grade ≥ 2 xerostomia increased by approximately 3% per Gy of mean parotid dose up to 28, Gy then 7% per Gy above 33 Gy. CONCLUSIONS IMRT for HN cancer seems to reduce late toxicities without jeopardising local control and overall survival.

Dose escalation with 3D-CRT in prostate cancer: French study of dose escalation with conformal 3D radiotherapy in prostate cancer—preliminary results

PURPOSE To evaluate the feasibility of dose escalation in a multi-institutional study in prostate cancer patients. METHODS AND MATERIALS Between October 1995 and October 1998, 164 patients with localized adenocarcinoma of the prostate were treated with 3-dimensional conformal radiotherapy at one of five French institutions. The dose of radiation was escalated from 66 to 80 Gy (ICRU point). The maximum dose to the rectal wall was limited to 75 Gy. RESULTS Results were compared in two groups, one (group 1) receiving the standard dose (n = 46 patients; 66 to 70 Gy) and the other (group 2) receiving the escalated dose (n = 118 patients; 74 to 80 Gy). There was no difference in the characteristics of patients between the two groups. The mean follow-up time was 32 months in group 1 and 17.5 months in group 2. No statistical difference between the two groups was observed in the incidence of late gastrointestinal and urinary toxicities. The probability of achieving a posttreatment prostate-specific antigen nadir of </=1 ng/mL in the 120 patients who did not receive neoadjuvant androgen-deprivation therapy was significantly higher in the dose-escalation group and was directly related to the dose of radiation given. CONCLUSION This multi-institutional study demonstrated the feasibility of escalating the dose of radiation to 80 Gy in prostate cancer patients.

Impact of target volumes and radiation technique on loco-regional control and survival for patients with unilateral cervical lymph node metastases from an unknown primary

PURPOSE To compare the impact of an unilateral post-operative irradiation or a bilateral irradiation in terms of loco-regional control and survival in patients with cervical lymph node of squamous cell carcinoma from an unknown primary (CUP). METHODS AND MATERIALS Ninety five patients with epidermoid carcinoma involving unilateral cervical lymph nodes from an unknown primary were treated in two institutions from 1990 to 2007. Post-operative radiation therapy was delivered to one side of the neck in 59 cases, to both sides of the neck in 36 cases. There were 11 women and 84 men ranging in age from 38 to 80 years (median 59 years). Neck dissection was performed in 79 patients while 16 patients underwent single lymph node sampling only. RESULTS After a median follow-up of 3.3 years, the nodal relapse rate was 34% after unilateral neck irradiation and 25% after bilateral radiotherapy (p=0.21). Six contralateral lymph node relapses occurred after unilateral irradiation (10%). The 5-year overall survival rate of the entire group was 24%. The 5-year OS rates were 22% after unilateral irradiation and 23%, after bilateral radiotherapy (p=0.944). The occult primary occurred in 12% after unilateral irradiation and 6% after bilateral radiotherapy. The radiation technique (3D-CRT or IMRT vs. 2D: p=0.026) was prognostic on loco-regional control. Independent prognostic determinants on overall survival were the WHO status (p=0.013) and the radiation technique (2D vs.3D-CRT or IMRT; p=0.029). There was no difference in loco-regional control (p=0.639) and no difference in survival (p=0.493) when chemotherapy was associated. CONCLUSIONS Retrospective comparisons between bilateral and unilateral neck radiotherapies did not show differences in terms of loco-regional control and survival. However, patients local regional control and survival are significantly improved after 3D-CRT or IMRT.

Prospective evaluation of early lung toxicity following three-dimensional conformal radiation therapy in non-small-cell lung cancer: preliminary results.

PURPOSE Radiation pneumonitis is the restricting complication following lung cancer irradiation. The correlation between dose-volume histograms (DVHs) and pneumonitis, with a clinical, radiological, and respiratory function evaluation was assessed. Special endpoint was the evaluation of respiratory function after three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS Fifty-four patients with non metastatic non-small-cell lung cancer (NSCLC) were treated with a curative intent with 3D-CRT (66 Gy). Thirty-one patients were treated postoperatively (pneumonectomy in 9 patients) for residual tumor or massive nodal involvement (N2 or N3); 23 patients were treated with exclusive radiotherapy. Clinical evaluation, CT scan, and pulmonary functional tests were performed before and 6 weeks after irradiation. The DVHs were calculated applying lung density heterogeneity. RESULTS Twenty patients had radiation pneumonitis. Irradiation significantly decreased total lung capacity. Volume of the PTV2 (more than 200 cm(3)) was a significant prognostic factor for lung complication. CONCLUSION DVHs combined with initial pulmonary functional tests can predict pulmonary toxicity and could allow us to adjust volume that received total highest dose with acceptable toxicity.

Cost-effectiveness of particle therapy: Current evidence and future needs

PURPOSE Questions are being raised regarding the cost of particle therapy (PT), and with them criticism that PT is too expensive to allow the expected gain in effectiveness. This paper aims to get more insight in the cost and cost-effectiveness of particle therapy and to discuss a future strategy that allows for critical assessment of this health technology. MATERIAL AND METHODS A systematic literature review based on an earlier published comprehensive review was performed and updated until June 1st 2008. Besides, current business plans of PT projects were examined. Additionally, results retrieved from a cost-simulation tool developed under auspice of the ENLIGHT were discussed. RESULTS The current literature on cost-effectiveness of PT is scarce, non-comparable, and largely not performed according to standard health technology assessment criteria. Besides, different perspectives for cost evaluations have been used, making it difficult to compare and to determine the relative impact in terms of costs for this new treatment modality. CONCLUSIONS Evidence on the cost-effectiveness of PT is scarce. Adequate reimbursement is necessary to support such innovative yet costly treatments. For now, model-based economic evaluations performed at least from a health care perspective may help us to gain evidence-based insight into cost-effectiveness.

Radiochemotherapy of locally advanced anal canal carcinoma: prospective assessment of early impact on the quality of life (randomized trial ACCORD 03).

BACKGROUND AND PURPOSE The aim of this study was to prospectively assess the quality of life (QOL) of patients treated by concomitant chemo radiation for locally advanced anal canal carcinoma. MATERIALS AND METHODS We report on a subgroup of 119 patients enrolled in a 306-patient therapeutic intensification prospective trial (ACCORD 03). This trial evaluated the impact on colostomy-free survival of induction chemotherapy and/or high dose radiotherapy (factorial design 2 *2 treatment arms). QOL was assessed both before and 2 months after treatment using the EORTC QLQ-C30 questionnaire as well as a questionnaire relating to anal sphincter conservative treatment (AS-CT). RESULTS Compared to pre-treatment scores, patients reported significant improvement in their emotional function (+8.4 points p=0.002), global health status (+5.9 points p=0.0007), as well as a decrease in insomnia (-13.8 points p<0.0001), constipation (-12.0 points p<0.0001), appetite loss (-10.3 points p<0.0001) and pain (-9.6 points p=0.0002). The AS-CT degree of satisfaction with intestinal functions score was increased (+11.2 points p<0.0001). CONCLUSION This is the first prospective study comparing QOL of patients with advanced anal canal carcinoma, before and 2 months after conservative treatment. Two months after treatment, QOL was improved. Induction chemotherapy and/or high dose radiotherapy did not provide a negative impact on QOL.

Conformal radiotherapy for paranasal sinus and nasal cavity tumors: three-dimensional treatment planning and preliminary results in 40 patients

PURPOSE To assess the possibility to deliver a high and homogeneous irradiation with respect to maximal tolerated dose to the visual pathways for paranasal sinus and nasal cavity tumors. METHODS AND MATERIALS Forty patients with advanced stage malignant tumors were treated with postoperative (30) or primary (10 patients) conformal radiotherapy (CRT). Five patients were previously irradiated. Six to 15 individually shaped isocentric noncoplanar field arrangements, using a multileaf collimator were designed. Dose-volume histograms (DVH) for the planning target volumes (PTV) and the optic pathways were analyzed in 31 cases. RESULTS Median and maximal delivered doses to the PTV were 60 (+/-3) and 66 (+/-4) Gy. Dose distributions for critical organs are detailed. Median follow-up was 19 months (3 to 48). Local, nodal, and metastatic recurrences occurred in 8, 2, and 7 cases, respectively. Major prognostic factor for local recurrences was central nervous system (CNS) involvement. One patient died of meningitis. Two patients developed cataract, and 1 patient ipsilateral blindness due to vascular glaucoma. CONCLUSION CRT for locally advanced paranasal sinus and nasal cavity tumors enables the delivery of high homogeneous doses to the PTV with respect to critical organs, with a low toxicity and a high local control.

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity

PURPOSE Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).