Didier Cowen

LATE RECTAL TOXICITY AFTER CONFORMAL RADIOTHERAPY OF PROSTATE CANCER (I): MULTIVARIATE ANALYSIS AND DOSE-RESPONSE

PURPOSE The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis. METHODS AND MATERIALS Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy-13 patients, 75. 6 Gy-36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy-39 patients, 75.6 Gy-83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables. RESULTS A dose response for >/= Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with >/= Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p < 0.02), and 2) smaller anatomically defined rectal wall volume (p < 0.05). After 75.6 Gy, the following factors were significant: 1) smaller anatomically defined rectal wall volume (p < 0.01), 2) higher rectal D(max) (p < 0.01), 3) enclosure of rectal contour by Iso50 (p < 0.01), 4) patient age (p = 0.02), and 5) history of diabetes mellitus (p = 0.04). In addition to these five factors, acute rectal toxicity was also significantly correlated (p = 0.05) with late rectal bleeding when patients from both dose groups were combined in multivariate analysis. CONCLUSION A multivariate logistic regression model is presented which describes the probability of developing late rectal bleeding after conformal irradiation of prostate cancer. Late rectal bleeding correlated with factors which may indicate that a greater fractional volume of rectal wall was exposed to high dose, such as smaller rectal wall volume, inclusion of the rectum within the 50% isodose on the isocenter slice, and higher rectal D(max).

Low energy Helium-Neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: Results of a double blind randomized trial

PURPOSE To evaluate the efficiency of Helium-Neon (He-Ne) laser in the prevention of oral mucositis induced by high dose chemoradiotherapy before autologous bone marrow transplantation (BMT). METHODS AND MATERIALS Between 1993 and 1995, 30 consecutive patients receiving an autologous peripheral stem-cell or bone marrow transplant (BMT) after high dose chemoradiotherapy were randomized to possibly receive prophylactic laser to the oral mucosa after giving informed consent. Chemotherapy consisted of cyclophosphamide, 60 mg/kg intravenously (I.V.) on day (d)-5 and d-4 in 27 cases, or melphalan 140 mg/kg I.V. on d-4 in three cases. Total body irradiation (TBI) consisted of 12 Gy midplane dose in six fractions (4 Gy/day for three days). He-Ne laser (632.8 nm wavelength, power 60 mW) applications were performed daily from d-5 to d-1 on five anatomic sites of the oral mucosa. Oral examination was performed daily from d0 to d + 20. Mucositis was scored according to an oral exam guide with a 16 item scale of which four were assessed by the patients themselves. Mean daily self assessment scores for oral pain, ability to swallow and oral dryness were measured. A daily mucositis index (DMI) and a cumulative oral mucositis score (COMS) were established. Requirement for narcotics and parenteral nutrition was recorded. RESULTS The COMS was significantly reduced among laser treated (L+) patients (p = 0.04). The improvement of DMI in L+ patients was also statistically significant (p < 0.05) from d + 2 to d + 7. Occurrence and duration of grade III oral mucositis were reduced in L+ patients (p = 0.01). Laser applications reduced oral pain as assessed by patients (p = 0.05) and L+ patients required less morphine (p = 0.05). Xerostomia and ability to swallow were improved among the L+ patients (p = 0.005 and p = 0.01, respectively). Requirement for parenteral nutrition was not reduced (p = NS). CONCLUSION Helium-Neon laser treatment was well tolerated, feasible in all cases, and reduced high dose chemoradiotherapy-induced oral mucositis. Optimal laser treatment schedules still needs to be defined.

RADIOTHERAPY AND IMMEDIATE TWO-STAGE BREAST RECONSTRUCTION WITH A TISSUE EXPANDER AND IMPLANT: COMPLICATIONS AND ESTHETIC RESULTS

PURPOSE To report complications, failure rate, and esthetic results in patients undergoing immediate breast reconstruction with a tissue expander and implant, with or without adjuvant treatment. METHODS AND MATERIALS We reviewed the records of the 77 patients who underwent immediate breast reconstruction with an expander/implant between January 1999 and December 2000. Complications were assessed using the Common Toxicity Criteria, version 2, scale. Esthetic results were assessed by the physician using five criteria. RESULTS Of the 77 patients, 55 had received adjuvant radiotherapy. The median follow-up was 25 months. Complications appeared to correlate with radiotherapy (14% for nonirradiated patients; 51% for irradiated patients; p = 0.006) and adjuvant chemotherapy (54% with chemotherapy [CHT] vs. 25% without CHT; p = 0.02). Breast reconstruction failed in 21% of patients (9% of nonirradiated patients and 24% of irradiated patients; p = 0.1), and chemotherapy was associated with a worse rate of failure (34% with CHT vs. 6% without CHT, p = 0.005). Adjuvant tamoxifen, however, correlated neither with complications (45% with tamoxifen vs. 39% without; p = 0.15) nor with failure (21% with tamoxifen and 23% without, p = 0.79). Esthetic results were acceptable in 60% of cases. CONCLUSION Immediate breast reconstruction with an expander/implant can be considered even for patients requiring adjuvant treatment. However, the complication and failure rates are three times higher after postexpander radiotherapy.

Local and distant failures after limited surgery with positive margins and radiotherapy for node-negative breast cancer.

PURPOSE To determine the outcome of patients with positive margins after lumpectomy for breast cancer and to address the issue of the relationship between local recurrences and distant metastasis in the absence of chemotherapy. METHODS AND MATERIALS Among 3697 patients with primary breast cancer, we retrospectively analyzed 152 patients who had undergone conservative surgery with axillary dissection, had infiltrating carcinomas with positive margins, were node-negative, and received radiotherapy without chemotherapy. One-third received hormonal therapy. Endpoints were local failure and distant metastasis. Median follow-up was 72 months. RESULTS Five- and 10-year recurrence-free survival were 0.80 and 0.71 respectively for local recurrences, and 0.85 and 0.73 respectively for metastasis. Infiltrating carcinoma on the margins was associated with early local relapse as opposed to intraductal carcinoma. Local and distant recurrences had similar patterns of yearly-event probabilities. Hazard of relapsing from metastasis was 2.5 times higher after a local recurrence. In the multivariate analysis, negative estrogen receptors (ER-)(p = 0.0012), histologic multifocality (p = 0.0028), and no hormonal therapy (p = 0.017) predicted local relapses, while ER- (p = 0.004) and pathologic grade (p = 0.009) predicted metastasis. Hormonal therapy did not prevent early local recurrences. CONCLUSION In this population, reexcision is advisable for local purposes and because the data support the hypothesis that local and distant recurrences are tightly connected.

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.

A RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED MULTICENTER STUDY OF MESALAZINE FOR THE PREVENTION OF ACUTE RADIATION ENTERITIS

BACKGROUND AND PURPOSE Symptoms of acute radiation enteritis (ARE), dominated by diarrhea, occur in more than 70% of patients receiving pelvic irradiation. Eicosanoids and free radicals release have been implicated in the pathogenesis. Mesalazine (5-ASA) is a potent inhibitor of their synthesis in the mucosa and could therefore be of some interest in preventing ARE. PATIENTS AND METHODS The study was performed in six radiotherapy units in France who agreed on standardized irradiation procedures. One hundred and fifty-three patients planned for external beam radiotherapy to the pelvis > or = 45 Gy for prostate (n = 97) or uterus (n = 54) cancer were randomized on a double blind basis to receive prophylactic 5-ASA (4 g/day Pentasa) or placebo. Patients with concomitant chemotherapy were excluded. Prostate and uterus cancers were chosen since these centropelvic tumors require a similar radiotherapy protocol during the first step of treatment and involve a comparable volume of small intestine. The symptoms of ARE and their severity were assessed every week during irradiation, and 1 and 3 months after its end. All patients followed a low fiber and low lactose diet. End points were diarrhea, use of antidiarrheal agents, abdominal pain, and body weight. Effficacy was evaluated using intention to treat. RESULTS (means +/- SD) Groups did not differ for age (mean 64 +/- 9 years), sex, tumor site, or irradiation procedure. During irradiation, diarrhea occurred in 69% and 66% of the 5-ASA and placebo groups, respectively (chi2, P = 0.22). Curves of survival without diarrhea did not differ between groups (logrank P = 0.09). Severity of diarrhea did not differ between groups except at d15 where it was significantly more severe in the 5-ASA group (ANOVA P = 0.006). Duration of diarrhea did not differ (22 +/- 15 days in both groups, P = 0.88). Abdominal pain was less frequently reported in the 5-ASA group at d28 (34% vs. 51%, P = 0.048). Use of antidiarrheal agents and body weight did not differ between groups. CONCLUSION Mesalazine 4 g/day did not decrease the symptoms of ARE.

Results of the GYNECO 02 Study, an FNCLCC Phase III Trial Comparing Hysterectomy with No Hysterectomy in Patients with a (Clinical and Radiological) Complete Response After Chemoradiation Therapy for Stage IB2 or II Cervical Cancer

BACKGROUND Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery. METHODS A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6-8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003-2006) and are reported on here. RESULTS Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively. CONCLUSIONS Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power).

Thallium-201 perfusion scintigraphy in the evaluation of late myocardial damage in left-side breast cancer treated with adjuvant radiotherapy

PURPOSE To evaluate late myocardial damage after adjuvant radiotherapy using a mixed-beam (photons plus electrons) technique to treat the internal mammary lymph nodes in left-side breast cancer. METHODS AND MATERIALS A bicycle ergometer stress test coupled with thallium-201 perfusion scintigraphy and analysis by single-photon computed tomography (CT) was performed on 19 patients treated with left-side breast/chest wall and internal mammary radiation for breast cancer between 1987 and 1993. To be sure that we would evaluate late toxicity caused by the irradiation, patients had to fulfill the following eligibility criteria: left-side breast cancer, treatment between 1987 and 1993 and no recurrence during follow-up, age < or = 75 years, no known risk for coronary artery disease, no previous chemotherapy, internal mammary field treated with an association of photons and electrons, and CT scan-based treatment planning. RESULTS Median age at scintigraphy was 59 years. Two patients did not reach optimal exercise level and were not evaluable. Among the 17 evaluable patients representing 91.6 patient years of follow-up, there were no perfusion defects by visual or quantitative analysis. CONCLUSION The mixed-beam technique seemed to spare the heart from harmful irradiation and to protect the myocardium. Results need to be confirmed on the long-term use of this technique.

Combined brachytherapy and surgery for early carcinoma of the uterine cervix: analysis of extent of surgery on outcome.

PURPOSE The aim of this retrospective study was to evaluate the survival data and rates and patterns of complications and recurrences for patients who had early uterine cervix carcinoma and underwent brachytherapy and subsequent surgery. METHODS AND MATERIALS Between January 1990 and December 1997, 192 women with cervical carcinoma (Stages IA2 with vascular invasion [n = 28], IB1 [n = 144], and IIA [n = 20]) underwent brachytherapy, delivering 60 Gy and then hysterectomy with external iliac lymphadenectomy. Piver class I, II, and III hysterectomies were performed on 136, 38, and 18 patients, respectively. Adjuvant chemoradiotherapy was delivered to patients with positive lymph nodes. RESULTS The median follow-up time was 61 months. After brachytherapy, a pathologically complete response (CR) was observed in 137 (71.3%) of 192 women. The distribution of CRs according to tumor stage was as follows: Stage IA2, 24 (85.7%) of 28; Stage IB1, 105 (72.9%) of 144; and Stage IIA, 8 (40%) of 20. Patients with Stage IB1 cancer had 13 lymph node metastases (9%), as did 6 with Stage IIA disease (30%). Pelvic recurrences occurred in 9 (4.6%) of the 192 patients; in 3, local relapses were associated with relapses at distant sites. Ten patients had systemic relapses (5.2%). Recurrences at distant sites were more frequent (p < 0.02) in partial responders, and other recurrences were more frequent in patients with lymph node metastases (p < 0.04). The overall 5-year disease-free survival rate was 91.2% (96.2% for Stage IA2, 91% for Stage IB1, and 84.4% for Stage IIA cancers). The class of hysterectomy did not influence the outcome. Late complications occurred in 28 patients (Grade 1, 24 [12.5%]; Grade 2, 4 [2%]; and Grade 3, 1 [0.5%] of 192 patients). CONCLUSIONS Combined treatments resulted in high local control and low morbidity rates in patients with early-stage cervical carcinoma. Limited surgery seemed to be adequate after intracavitary therapy.

High-Dose Split-Course Radiation Therapy for Anal Cancer: Outcome Analysis Regarding the Boost Strategy (CORS-03 Study)

PURPOSE To retrospectively assess the clinical outcome in anal cancer patients treated with split-course radiation therapy and boosted through external-beam radiation therapy (EBRT) or brachytherapy (BCT). METHODS AND MATERIALS From January 2000 to December 2004, a selected group (162 patients) with invasive nonmetastatic anal squamous cell carcinoma was studied. Tumor staging reported was T1 = 31 patients (19%), T2 = 77 patients (48%), T3 = 42 patients (26%), and T4= 12 patients (7%). Lymph node status was N0-1 (86%) and N2-3 (14%). Patients underwent a first course of EBRT: mean dose 45.1 Gy (range, 39.5-50) followed by a boost: mean dose 17.9 Gy (range, 8-25) using EBRT (76 patients, 47%) or BCT (86 patients, 53%). All characteristics of patients and tumors were well balanced between the BCT and EBRT groups. RESULTS The mean overall treatment time (OTT) was 82 days (range, 45-143) and 67 days (range, 37-128) for the EBRT and BCT groups, respectively (p < 0.001). The median follow-up was 62 months (range, 2-108). The 5-year cumulative rate of local recurrence (CRLR) was 21%. In the univariate analysis, the prognostic factors for CRLR were as follows: T stage (T1-2 = 15% vs. T3-4 = 36%, p = 0.03), boost technique (BCT = 12% vs. EBRT = 33%, p = 0.002) and OTT (OTT <80 days = 14%, OTT ≥80 days = 34%, p = 0.005). In the multivariate analysis, BCT boost was the unique prognostic factor (hazard ratio = 0.62 (0.41-0.92). In the subgroup of patients with OTT <80 days, the 5-year CRLR was significantly increased with the BCT boost (BC = 9% vs. EBRT = 28%, p = 0.03). In the case of OTT ≥80 days, the 5-year CRLR was not affected by the boost technique (BCT = 29% vs. EBRT = 38%, p = 0.21). CONCLUSION In anal cancer, when OTT is <80 days, BCT boost is superior to EBRT boost for CRLR. These results suggest investigating the benefit of BCT boost in prospective trials.