G. Calais

Randomized Trial of Radiation Therapy Versus Concomitant Chemotherapy and Radiation Therapy for Advanced-Stage Oropharynx Carcinoma

Background: We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). Methods: A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m 2 per day) and 5-fluorouracil (600 mg/m 2 per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. Results: Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P = .02 and .04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). Conclusion: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.

Preoperative radiotherapy (RT) for rectal cancer: Predictive factors of tumor downstaging and residual tumor cell density (RTCD): Prognostic implications

PURPOSEnTo determine predictive factors and prognostic value of tumor downstaging and tumor sterilization after preoperative RT for rectal cancer.nnnMETHODS AND MATERIALSnBetween 1977 and 1994, 167 patients with a histologically proven adenocarcinoma (70 T2, 65 T3, 29 T4, and 3 local recurrences) underwent preoperative RT. Median dose was 44 Gy (5-73 Gy). Surgery was performed in a mean time of 5 weeks after RT. Pathologic specimens have been reviewed by the same pathologist in order to specify the modified Astler Coller classification (MAC), and to quantify the residual tumor cell density (RTCD).nnnRESULTSnAccording to the MAC, there was 9 stage 0 (5%), 10 stage A (6%), 103 stage B1-B3 (62%), and 45 stage C1-C3 (27%) tumors. Seventeen percent and 56% of the patients who received a dose > or = 44 Gy had respectively a 0-A and a B tumor, compared to 4 and 69% in those who received a dose < 44 Gy (p = 0.04). Tumor differentiation and a longer interval before surgery were significantly associated with a more frequent downstaging, and preoperative staging correlated well to the postoperative pathological findings. According to the RTCD, 62 tumors (37%) showed no or only rare foci of residual tumor cells (Group 1); 62 (37%) showed an intermediate RTCD (Group 2); and 43 (26%) a high RTCD (Group 3). No predictive factor of RTCD was statistically significant. In univariate analysis, postoperative staging was a significant prognostic factor, with corresponding 5-year overall survival rates in 0-A, B, and C stages of 92, 67, and 26% (p < 0.01). RTCD was not a prognostic factor. However, overall and disease-free survival rates for patients with complete pathologic response of 83% at 2 and 5 years suggested a better outcome in this subgroup of patients.nnnCONCLUSIONnThe favorable influence of higher doses of preoperative RT on pathologic stage has been observed. Tumor differentiation, preoperative classification and time before surgery were the other predictive factors of tumor downstaging. However, there was no predictive factor of complete pathologic response. Even after preoperative RT, postoperative staging remained a prognostic factor.

Conservative treatment feasibility with induction chemotherapy, surgery, and radiotherapy for patients with breast carcinoma larger than 3 cm

Background. The traditional surgical treatment for operable breast carcinoma larger than 3 cm is mastectomy. To avoid mutilating surgery, the authors administered primary chemotherapy to 158 patients with operable nonmetastatic large breast carcinoma with a TNM classification of T2 greater than 3 cm and T3 with a lymph node status of NO‐N1. Conservative treatment was proposed for patients responding to the chemotherapy and whose tumor was reduced to 3 cm or less. The purpose of the study was to evaluate the feasibility and treatment results of this strategy.

Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study.

BACKGROUND AND PURPOSEnThe aim of the study was: (1) to confirm the action of pilocarpine hydrochloride (Salagen) against xerostomia: (2) to correlate the response to dose/volume radiotherapy parameters.nnnMATERIALS AND METHODSnFrom June 1995 to February 1996, 156 patients with severe radiation induced xerostomia received pilocarpine hydrochloride orally. IS mg per day with a 5 mg optional increase at S weeks up to a daily dose of 25 mg beyond 9 weeks.nnnRESULTSnOne hundred and forty five patients are fully evaluable. Treatment compliance was 75%. Thirty eight patients (26%) stopped treatment before week 12 for acute intolerance (sweating, nausea, vomiting) or no response. No severe complication occurred. Ninety ses en patients (67%) reported a significant relief of symptoms of xerostomia at 12 weeks. Within 12 weeks, the size of the subgroup ith normal food intake almost doubled (13-24 patients) while the size of the subgroup with (nearly) impossible solid food ingestion decreased by 38% (47 vs. 29 patients). The impact on quality of life was considered important or very important by 77% of the responders.nnnCONCLUSIONSnNo difference was found according to dose/volume radiotherapy parameters suggesting that oral pilocarpine hydrochloride: (1) acts primarily by stimulating minor salivary glands: (2) can be of benefit to patients suffering of severe xerostomia regardless of radiotherapy dose/volume parameters: (3) all responders are identified at 12 weeks.

Radiotherapy with high dose rate brachytherapy boost and concomitant chemotherapy for stages IIB and III esophageal carcinoma: Results of a pilot study

PURPOSEnRadiotherapy (RT) and concomitant chemotherapy (CT) is the standard treatment for non resectable esophageal cancer. Usual total radiation dose is 50 Gy. In order to enhance local control rate a Phase II study was initiated to evaluate the feasibility of a combined treatment with an external radiation dose of 60 Gy and three cycles of concomitant CT, using the three main active drugs (CDDP, 5 FU and MMC), followed by a high dose rate (HDR) brachytherapy delivering 10 Gy.nnnMETHODS AND MATERIALSnFifty-three patients, 48 men and 5 women, were entered in this study. Stages were evaluated with CT scan and with endoscopic sonography. Fifteen were Stage IIB, 38 Stage III. Treatment consisted of conventional fractionated RT to a total dose of 60 Gy delivered with 2 Gy per fraction, one fraction per day and five fractions per week. The CT regimen was a combination of Cisplatinum (CDDP) 20 mg/m2 and 5 Fluorouracil (5FU) 600 mg/m2 continuous infusion, from days 1-4 Mitomycin C (MMC) was given at 6 mg/m2 on day 1. Three cycles were administered on days 1, 22, and 43. Brachytherapy was delivered one week after the end of external radiation therapy.nnnRESULTSnFull radiation therapy dose was delivered for 94% of the patients. CT compliance, evaluated on the mean relative dose-intensity was 85% for CDDP, 81% for 5FU and 51% for MMC. Overall grade 3 and 4 WHO toxicity rates were 23% and 7%, respectively. Haematologic toxicity was the most limiting factor. One patient died from treatment toxicity. Local control rate at one year was 74%. Three-year actuarial survival rate was 27%. Distant metastasis was the main cause of treatment failure. Swallowing score was good for 75% of the patients. Stage, performance status and weight loss were prognostic factors.nnnCONCLUSIONnThis regimen with high dose RT, HDR brachytherapy and concomitant CT is feasible; however, a high level of haematologic toxicity was observed with the CDDP, 5FU and MMC regimen. Despite a poor compliance with CT, treatment results are very encouraging for patients with locally advanced disease.

Primary chemotherapy and radiosurgical breast-conserving treatment for patients with locally advanced operable breast cancers

PURPOSEnThe traditional surgical treatment for operable breast cancer larger than 3 cm is mastectomy. In order to avoid mutilating surgery, we administered primary chemotherapy to 80 patients with operable non metastatic large breast cancer T2 > 3 cm and T3, N0-N1. The purpose of the study was to evaluate the breast-conserving rate induced by this treatment strategy and determine if it is a safe alternative for women with locally advanced breast carcinomas that are responders to an induction chemotherapy.nnnMETHODS AND MATERIALSnThe mean age was 50.1 years. Forty-three patients were T2 > 3 cm, 37 were T3. Twenty-six were N0 and 54 were N1. Mean tumor size was 5.4 cm. Patients were treated with three courses of the MVCF regimen (Mitoxantrone, Vindesin, Cyclophosphamide, and 5 Fluorouracil) every 4 weeks and then with a radiosurgical combination.nnnRESULTSnThe overall response rate to induction chemotherapy was 51% with 17.5% complete tumor regression. Twenty-one percent of the patients developed grade 3 or 4 chemotherapy toxic effects, all acceptable and reversible. Breast-conserving treatment was feasible in 42.5% (34/80). Twenty patients (25%) were treated with a radiosurgical combination (tumorectomy+radiation therapy), 14 (17.5%) with radiotherapy alone (external irradiation and brachytherapy). Age, tumor stage, histology, hormonal status, hormonal receptors rate had no influence on the frequency of the observed regressions. Isolated recurrences occurred in five patients, two conservatively treated and three treated with mastectomy. Metastatic relapses were observed in 20 patients (12% in the responders and 38.5% in the non responders to chemotherapy) (p < 0.02). Five-year actuarial survival was 73% and was significantly better for responders to the induction treatment.nnnCONCLUSIONnThese results suggest that primary chemotherapy and radiosurgical breast conserving treatment is a safe alternative to mastectomy for patients with locally advanced operable breast cancer. The long-term benefit of this strategy must be evaluated in well designed controlled trials.

In situ tumour radio sensitization induced by clofibrate administration: single dose and fractionated studies

It is generally accepted that hypoxia is a common occurrence in many experimental and human tumours and that it is a major cause of local failure after radiotherapy. Many attempts have been made over the last years to eliminate this problem. One of the manoeuvres to improve tumour oxygenation is to manipulate the binding affinity of oxygen (O2) and haemoglobin (Hb). Previous studies have shown that some antilipidaemic drugs (clofibrate and its analogues) can reduce the Hb/O2 binding affinity and sensitize various animal tumours to radiation. The present study evaluated the ability of clofibrate to sensitize in situ a mouse carcinoma (CaNT) to radiation. Clofibrate at 1.5 mmol/kg increased the tumour radiosensitivity, when it was administered per os 2-6 h before a single radiation dose or 2 to 4 h before each of 10 fractions in 5 days. In both the single dose and fractionated regimens, the radiosensitizing effect was drug dose-dependent, but was only statistically significant at doses from 1.0 to 2.0 mmol/kg. These results suggest that clofibrate may be an effective radiosensitizer at radiation doses that are clinically relevant. Further experiments need to be carried out to evaluate clofibrate analogues for their radiosensitizing properties. Clofibrate tolerable doses in man have to be determined first in order to know if clofibrate and analogues could play a role in the clinical management of tumours where hypoxia may limit the outcome of radiotherapy.

Disappearance of the in situ component: a criterion predictive of metastasis in breast cancer after local relapse*

Local recurrence after conservative treatment of breast cancer is associated with a significant risk for metastasis. In order to identify criteria predictive of metastasis in this subset of women, we analyzed a series of 35 patients with local relapse among 512 consecutive patients treated with tumorectomy and radiotherapy. When relapse occurred within 2 years of initial treatment, overall 2-year survival from the time of local relapse was 39.5%. When local relapse occurred more than 2 years from initial therapy, 2-year survival was 80.5% (p < 0.001). Pathological slides of both initial and recurrent tumors were reviewed and compared. In 17 patients, local relapse and initial tumor had the same morphological features, with an in-situ component either absent or present in the same proportion. Metastasis occurred in two of these patients. In contrast, 9 of 12 patients in whom the proportion of non-invasive carcinoma had decreased at the time of local recurrence developed metastasis. Overall 2-year survival from the time of relapse was significantly better in the former group of patients (93.3% versus 52.5%, p < 0.05). We concluded that early relapses have a poor prognostic significance and that disappearance of the in-situ component or increase of the invasive component at the time of relapse is a feature predictive of tumor-related death and that more intensive therapy might benefit to this subset of women.

Abdomino pelvic irradiation after second-look laparotomy for stage III ovarian carcinoma

OBJECTIVEnThe purpose of this retrospective analysis of 34 patients with stage III ovarian carcinoma was to review results and morbidity of whole abdominal irradiation after surgery and chemotherapy.nnnMETHODS AND MATERIALSnAll of the 34 patients had reached a complete clinical remission after first cytoreductive surgery and chemotherapy. After second-look laparotomy each patient underwent whole abdominal irradiation. Except for two patients with chronic myelosuppression, the dose administered was of 22.5 Gy to the abdominal cavity with a boost of 22.5 Gy added to the pelvis.nnnRESULTSnThree and 5-year overall survival rates were 62% and 43%, respectively. Three and 5-year disease-free survival rates were 53% and 38%. Twenty-three patients (68%) developed local relapse or local disease progression. Metastasis occurred in five cases and were always associated with an abdominal cavity recurrence. Residual disease after first cytoreductive surgery appeared as a prognostic factor in univariate analysis. Patients with unresected residuum had a 5-year survival probability of 35% versus 83% for patients without residual disease. We observed 12% grade-3 intestinal toxicities and one fatal case of radiation enteritis.nnnCONCLUSIONnDespite its curative potential, the long term benefit of whole abdominal irradiation in the multimodality treatment of advanced ovarian carcinoma must be evaluated in well designed controlled trials.