Evaluation and impact of residual disease in locally advanced cervical cancer after concurrent chemoradiation therapy: results of a multicenter study.

BACKGROUND: The aim of this study was to evaluate the diagnosis and impact of residual disease (RD) after concurrent chemoradiation therapy (CRT) in locally advanced cervical cancer (FIGO IB2-IVA). METHODS: This retrospective multicenter study included 159 patients who were treated with completion surgery after CRT between 2006 and 2012. Magnetic resonance imaging (MRI) was performed 4-6 weeks after CRT and compared to pathological evidence of residual disease. Kaplan-Meier survival curves were plotted and univariate/multivariate analyses were performed to assess the association between RD and the outcome. RESULTS: Residual disease was present in 45.3% of the patients and detected by MRI in 57.1%. The MRI had a 29.2% false positive rate and an 11.1% false negative rate. The overall survival (OS) rates at 3 and 5 years were 78.6% (CI 95% [71%-86.9%]) and 76.5% (CI 95% [68.2%-85.7%]), respectively. The disease free survival (DFS) rates at 3 and 5 years were 73.4% (CI 95% [65.6%-82%]) and 71.1% (CI 95% [62.7%-80.1%]), respectively. RD greater than 10 mm decreased DFS (HR = 4.84, p = 0.03), whereas RD between 1 and 10 mm (HR = 0.31, p = 0.58) and less than 1 mm (HR = 0.37, p = 0.54) had no impact on DFS. The OS was not changed by RD. DISCUSSION: The MRI accuracy value is not sufficient to select patients who might benefit from completion surgery. Residual disease over 10 mm decreased DFS but did not impact OS.

[Prophylactic cranial irradiation in non-small cell lung cancer]. / Irradiation prophylactique cérébrale dans les cancers bronchopulmonaires non à petites cellules.

Prophylactic cranial irradiation (PCI) has become part of the standard treatment in patients with small cell lung cancer (SCLC) in complete remission. Not only does it decrease the risk of brain recurrence by almost 50%, it has a significant positive effect on survival (5.4 percent increase at 3 years). As the prognosis of patients with locally advanced non-small cell lung cancer (NSCLC) has improved with combined modality treatment, brain metastases have also become an important cause of failure (10 to 30%, approaching 50% in certain studies as in SCLC). Survival after treatment of brain metastases is poor and impact on quality of life of patients is important. As in SCLC, 4 randomised evaluating PCI in NSCLC have been carried out in the seventies and early eighties. If 3 out of 4 trials have shown a significant decrease of brain metastases, none of them demonstrated any impact on survival. Thus PCI cannot be recommended as standard treatment in NSCLC, however new trials would be needed.

[The role of radiotherapy in the management of patients with small cell lung cancer]. / Place de la radiothérapie dans la prise en charge des carcinomes bronchiques à petites cellules localisés.

Small cell lung carcinomas are aggressive on account of their high and early risk of dissemination. They represent less than 20% of all lung cancers and only a third of these present with limited stage disease at diagnosis. Currently, treatment is based on synchronous thoracic irradiation and chemotherapy combining platinum salts and etoposide with or without other drugs. Because of the high risk of brain metastases, prophylactic cranial irradiation (PCI) is indicated in patients with a complete response and should be part of the standard management of these patients on the basis of a meta-analysis showing a 5% increase in survival at three years. In limited stage disease 5 year survival rates can reach 25% but the majority of patients will relapse. This progress is the consequence of a better combination of thoracic and cerebral irradiation and polychemotherapy. Even in extensive disease PCI reduces the risk of brain metastases and significantly improves overall survival. Many issues are subject to further clinical research concerning modalities of combination radio-chemotherapy, radiotherapy target volumes, optimum dosage, and the use of drugs in association with irradiation.

[Lung cancer: is there a place for elective nodal irradiation?]. / Cancers bronchiques : la radiothérapie prophylactique des aires ganglionnaires a-t-elle encore une place ?

The use of conformal radiotherapy in lung cancer has considerably evolved with the advent of improved staging technologies and methods of radiation delivery. Patients with limited disease, inoperable for medical reasons, may be treated with conformal radiotherapy alone; patients with more advanced disease are treated with combined chemo-radiotherapy. If local control may be improved by radiotherapy dose escalation according to several studies, toxicity and more particularly pulmonary toxicity seems to be related to radiation volume. Thus the use of elective nodal irradiation is being questioned. Data for early stage (stage I) non-small-cell lung cancer treated with conformal radiotherapy or stereotactic hypofractionated radiotherapy strongly supports the use of smaller fields that do not incorporate elective nodal regions; local control and survival rates approach those of surgical series. In locally advanced non-small cell lung cancer, eliminating elective nodal irradiation allows to maximize tumor dose and minimize normal tissue toxicity in combined modality treatments; results are encouraging. The use of staging modalities such as positron emission tomography and eventually oesophageal ultrasonography is increasing, allowing to encompass the tumor volume with more accuracy. Several studies have confirmed that involved-field irradiation results into a regional nodal rate of less than 10%. Further larger-scale studies would be needed to definitely establish "no elective nodal irradiation" as a standard in non-small cell lung cancer. There are very few data concerning small cell lung cancer.

[Small cell lung cancer (CPC). Management of patients presenting with limited stage small cell carcinoma of the lung]. / Les cancers à petites cellules. Modalités actuelles de la prise en charge des patients présentant un carcinome bronchique à petites cellules localisé.

Small cell carcinomas represent less than 20% of all lung cancer. Only a third of these patients present with limited stage disease. Treatment is based on a combination of chemotherapy and radiotherapy including a platinum salt with or without another drug. Conformational thoracic radiotherapy is administered either classically fractionated or in an accelerated form. Prophylactic cranial irradiation is indicated in patients with a good response. An improvement in outcomes has been obtained with this regimen. Even in limited stage disease 5 year survival remains about 25% in the best series. The majority of patients will relapse and the risk of cerebral metastases is particularly high, reaching nearly 50% at 2 years even in patients with a complete response. Prophylactic cranial irradiation should be part of the standard management of patients with a complete response on the basis of a meta analysis showing a 5% increase in survival at three years. Even though combination treatments have improved survival, a number of questions remain that should stimulate further clinical trials to establish the optimum regimes of chemotherapy and radiotherapy and the optimum strategies for combining the two. In addition the potential role of targeted therapy in selected patients must be examined.

[Thymic tumors]. / Tumeurs épithéliales thymiques.

Thymomas and thymic carcinomas are rare and slow-growing tumors, which develop within the anterior mediastinum. Thymomas are often associated with autoimmune disorders and most particularly myasthenia gravis. The treatment of choice remains a complete surgical resection. Postoperative radiotherapy is often combined in case of invasive thymoma invading into adjacent organs. Postoperative radiotherapy in stage II with invasion into capsule has been more controversial lately. In inoperable locally advanced, or metastatic thymic tumors, neoadjuvant cisplatin-based followed by surgery and radiotherapy has given interesting results in the past years.

[Modalities of radiotherapy in small cell lung cancer: thoracic radiotherapy and prophylactic cerebral irradiation]. / Modalités de la radiothérapie dans les carcinomes bronchiques à petites cellules: radiothérapie thoracique et irradiation prophylactique cérébrale.

Small cell lung cancers (SCC) represent 20% of all lung cancers. After the initial control of the extension, only one third of the patients with SCC will finally have limited disease. The treatment of limited SCC currently relies on chemo-radiotherapeutic combinations that have improved overall survival and survival without metastases over the last few years. Nevertheless, even in limited forms, survival at 5 years varies from 10 to 15% and rarely exceeds 25% in the best series. The risk of relapse is high: although around 70% of patients with a limited form will have complete response, only 15 to 20% of them will exhibit prolonged survival. Indeed, most patients relapse, and the risk of cerebral dissemination for example is particularly high, reaching 50% at 2 years even in complete responders. After the results of a meta-analysis evaluating prophylactic cranial irradiation (PCI) among SCC complete responders, demonstrating 5% enhancement of survival at 3 years, PCI is part of the standard management of SCC in complete response. Despite the improvement in overall survival with the combined treatments, the mediocre results observed in terms of long-term survival warrant further clinical trials in order to define the optimal polychemotherapeutic and radiotherapeutic modalities, the best means of combining these two therapies and the place for new therapies.

Response to neo-adjuvant intraperitoneal and intravenous immunochemotherapy followed by interval secondary cytoreduction in stage IIIc ovarian cancer.

DESIGN: The aim of this study was to determine the effect of intraperitoneal (i.p.) neo-adjuvant immunochemotherapy, followed by secondary interval cytoreduction in bulky ovarian carcinoma, considered inoperable at first exploratory laparotomy. PATIENTS AND METHODS: From 1980 to 1996, 13 naive patients with stage IIIc ovarian cancer underwent an initial laparotomy. Cytoreduction was judged too dangerous in these patients due to the large bulk of the tumor and the extent of peritoneal carcinomatosis. Simple biopsies were performed. The patients received an intraperitoneal cisplatin-based protocol monthly plus immunotherapy (DGZ). The interval secondary cytoreduction was started either when the patients seemed to be in complete remission or after a minimum of 4 courses of chemotherapy if the patients' results were stagnant or deteriorated. Immunochemotherapy was then resumed for a total of up to 10 courses. RESULTS: At secondary cytoreduction, six patients were in complete remission as demonstrated histologically and cytologically. Seven patients were in incomplete remission. In six, debulking was completed without visceral resection. The seventh patient still had nodules more than 2 cm in diameter. Median overall survival was 57 months (range: 6-165). CONCLUSION: Intraperitoneal immunochemotherapy was effective in bulky tumors, making optimal secondary cytoreduction possible in almost all cases.

Alternating radiotherapy and chemotherapy in limited disease small cell lung cancer.

In a pilot study of 29 patients treated for localized small cell lung cancer, three new approaches were introduced, i.e. an increased initial drug dose, an early alternation of chemotherapy and thoracic radiotherapy and initial accelerated and hyperfractionated irradiation. The results were interesting. However, a high rate of fatal toxicity (21%) was observed.

[New therapeutic strategies and current research in inoperable locally advanced non small-cell lung cancers (stage IIIB)]. / Stratégies thérapeutiques récentes et voies de recherche actuelles dans les cancers du poumon inopérables (stade IIIB) non à petites cellules.

Treatment of patients with inoperable locally advanced non small-cell lung cancer (NSCLC) remains disappointing with less of 5% of patients alive at 5 years. Both initial local control and circumvention of concomitant undetectable metastatic chemoresistant cells are the critical targets for the oncologists in charge of this disease. Results of a recent meta-analysis including 22 randomized studies comparing standard treatment (i.e. radiotherapy) to sequential chemoradiotherapy have undoubtabely well defined the role of cisplatine-containing chemotherapy in stage IIIB NSCLC, even if the 5 year survival benefit remains modest. However, high complete response rates and prolonged overall survival were observed with combinations of new promising chemotherapy regimens and new fractionated radiation schedules in several phase II studies. These results have to be corroborated by prospective randomized trials. Integration of more aggressive and more toxic strategies such as radical surgery in these initial inoperable locally advanced NSCLC are evaluating. Around these conventional therapies, the stage IIIB NSCLC represent a favoured target to elaborate innovative therapeutic approaches based on emergence of biotherapies as recombinant cytokines, antitumoral vaccine and gene therapy programs. The contribution of these new therapeutic options opens new directions in the therapeutic strategy and leads to hope a new promising era in the management and outcome of patients with these tumors.

[Optimization of combined radiotherapy and chemotherapy in treatment of non-small cell lung carcinoma]. / Optimisation de l'association radiothérapie et chimiothérapie dans les carcinomes bronchiques non à petites cellules.

PURPOSE: To report the results of CEBI 140 and 142 trials. These trials were aimed at improving the local control in stage III non-small cell carcinoma with concomitant chemotherapy and radiotherapy in the CEBI 140 trial, and with concomitant chemotherapy and radiotherapy followed by local excision in the CEBI 142 trial. MATERIAL AND METHODS: Thirty-four patients presenting with stage III non-small cell lung carcinoma were included into the CEBI 140 trial from December 1989 to December 1992. Patients were treated with a combination of daily cisplatin (6 mg/m2 per day, 144 mg/m2 in total), vindesine once a week (2.5 mg/m2, 15 mg/m2 in total) and bifractionated radiotherapy (60 Gy/48 fractions/6 weeks) followed by two cycles of cisplatin 120 mg/m2 (at d18 and d45 after completion of radiochemotherapy) and three cycles of vindesine (6 mg/m2 at d24, d31, and d38 after completion of radiochemotherapy). Twenty-eight patients presenting with stage IIIB non-small cell carcinoma-were included into the CEBI 142 trial since January 1993. Patients received a combination of cisplatin (100 mg/m2 at d1 and d24, 200 mg/m2 in total), vinblastine (4 mg/m2 at d1 and d24, 8 mg/m2 in total), 5-fluorouracil in continuous infusion (1,000 mg/m2 from d1 to d3, and from d24 to 26, 6,000 mg/m2 in total) and bifractionated radiotherapy (two series of 21 Gy/14 fractions/9 days, 11 days apart) followed by a new evaluation and surgical excision. RESULTS: In the CEBI 140 trial, all patients received a complete course of radiotherapy, but the dose of cisplatin was decreased in 27% of the cases, and the dose of vindesine in 88%. There were two toxicity-related deaths. Three months after completion of the protocol, there were 50% of complete responders. The overall survival rates at 1, 2 and 3 years were 53, 33, and 11%, respectively, and disease-free survival rates 21 11, and 11%, respectively. In the CEBI 142 trial the immediate tolerance was good. Twenty-one patients (75%) underwent surgical resection. Four tumors could not be resected. Resection was histologically incomplete in one case, and complete in the 16 remaining cases. With a median follow-up of 14 months, ten patients were alive and disease-free. CONCLUSION: Preliminary results of the CEBI 142 trial are encouraging. More patients and longer follow-up are needed for definitive conclusion. It would be of interest to implement a randomized trial comparing the CEBI 142 scheme and classical radiation therapy.

Concurrent cisplatin-vindesine and hyperfractionated thoracic radiotherapy in locally advanced nonsmall cell lung cancer.

PURPOSE: Local failure is a major problem in locally advanced nonsmall cell lung cancer. The main objective of this Phase II trial was to test the feasibility of a combined concurrent radiotherapy and chemotherapy approach in an attempt to improve local control. METHODS AND MATERIALS: From December 1989 to December 1992, 34 patients were included. The treatment schedule consisted of hyperfractionated radiotherapy (60 Gy in 48 fractions and 6 weeks with two daily sessions of 1.25 Gy), cisplatin (6 mg/m2 every day of radiotherapy), and vindesine (2.5 mg/m2 once weekly). After a 3-week rest period, two full cycles of cisplatin (120 mg/m2 on weeks 10 and 14) and vindesine (2.5 mg/m2 on weeks 11, 12, and 13) were given. Treatment evaluation with thoracic computed scan, bronchoscopy, and bronchial biopsies was performed 3 months after completion of radiation therapy. Failure rates were estimated using a competing risk approach. RESULTS: The complete response rate was 50%. Local failure rates at 1 and 3 years were 53 and 56%, respectively. Distant metastases rates at 1 and 3 years were 26.5 and 29%. Overall survival rates at 1, 2, and 3 years were respectively 53, 33, and 12%. Severe esophagitis was observed in three patients (9%). Lethal toxicity was observed in two patients. CONCLUSION: This Phase II trial confirms the feasibility of this type of approach with specific dose reduction and suggests that it may improve local control compared to conventional approaches.

Local relapse and contralateral tumor rates in patients with breast cancer treated with conservative surgery and radiotherapy (Institut Gustave Roussy 1970-1982). IGR Breast Cancer Group.

BACKGROUND: Breast conservation is now established treatment for patients with small breast cancers. The authors reviewed a large series of patients with long term follow-up who underwent conservative treatment. Clinical and pathologic factors were analyzed to identify patients at an increased risk of relapse in the breast (local relapse) or development of a contralateral tumor. METHODS: Seven hundred fifty-seven patients with unilateral invasive breast cancer (T0-2, N0-1, M0) were treated conservatively (wide local excision and radiotherapy) at the Institut Gustave-Roussy between 1970 and 1982. The median follow-up was 9 years. The risk of local relapse or development of a contralateral tumor (as first event) was studied by univariate analysis for the main clinical, pathologic, and treatment factors. Those found to be significant were entered into a Cox proportional regression analysis. RESULTS: Fifty-one patients relapsed in the treated breast (actuarial local relapse rates at 5 and 10 years were 5% and 8%, respectively) and 34 in the contralateral breast (actuarial contralateral tumor rates at 5 and 10 years were 3% and 6%, respectively). Multivariate analysis of the risk factors for local relapse showed that only age younger than 40 years (P < 0.02) or inadequate surgical excisioin (P < 0.02) were significant. No particular risk factors for contralateral tumor development were identified. CONCLUSIONS: Overall, for most patients, the risk of local relapse or of developing a contralateral tumor was low. A small number of young patients with inadequately excised tumors are at higher risk of local relapse, need more meticulous surgery, and may merit higher dose radiotherapy.

[Immunohistochemical study of 11 epithelial tumors of the thymus or thymomas with anti-keratin antibodies: KL-1]. / Etude immunohistochimique de 11 tumeurs épithéliales du thymus (TET) ou thymome avec un anticorps anti-kératine: KL-1.

Eleven cases of epithelial tumours of the thymus or thymoma and two thymuses without tumour were studied, using immunohistochemistry with anti-keratin antibodies (KL-1) which recognise cyto-keratin with a high molecular weight. In the normal thymus, KL-1 positivity seems to be limited to medullary epithelial elements and in particular Hassal's corpuscles. All the epithelial thymic tumours studied showed a net positivity for KL-1 overall in the tumour cells. This result and the demonstration of more or less well differentiated Hassal's corpuscles in these tumours make one think that these epithelial thymic tumours express some characters in relation with a differentiation of medullary type.

Invasive carcinoma of the thymus. A multicenter retrospective review of 56 cases.

This multicenter retrospective study included 56 cases of histologically reviewed invasive epithelial thymic tumors. All these patients underwent surgical treatment or exploration and were referred for complementary radiotherapy. The majority received a dose higher than 4000 rad. Twenty-three out of 50 patients (46%) with incomplete resection received some chemotherapy. The local recurrence rate at 2 yr was 34%. The overall 5-yr actuarial survival was 46%. There was no evidence of any relationship between radiation dose and local control. No difference in survival was observed with or without chemotherapy, nor according to histological type or lymphocytic infiltration, except cases with very undifferentiated carcinomas which presented a worse prognosis. Nor was any difference in survival observed between patients benefiting from incomplete resection and those only having undergone exploratory thoracotomy and biopsy. Radiotherapy seems to decrease the rate of local recurrence in invasive carcinoma of the thymus. The role of chemotherapy is still debatable, but it could have a role in decreasing tumor volume before radiotherapy. This study has shown the necessity of histological review by a panel of histopathologists in an attempt to better define terminology and diagnosis. A prospective study is necessary in order to solve the problems of concepts and management in epithelial thymic tumors.