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International audience; BackgroundChemotherapy combined with radiotherapy is the standard treatment of “limited-stage” small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and chemotherapy.Material and methodsWe performed a meta-analysis of individual patient data in randomised trials comparing earlier versus later radiotherapy, or shorter vs. longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival.ResultsTwelve trials with 2,668 patients were eligible. Data from nine trials comprising 2,305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, “earlier or shorter” vs. “later or longer” thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of “earlier or shorter” radiotherapy among trials with a similar proportion of patients who were compliant with chemotherapy (defined as having received 100% or more of the planned chemotherapy cycles) in both arms (HR 0.79, 95% CI 0.69–0.91) and in favour of “later or longer” radiotherapy among trials with different chemotherapy compliance (HR 1.19, 1.05–1.34, interaction test p

In developed countries, the incidence of breast cancer increased regularly from 1975 to 2000 (Parkin et al, 2001). A decrease in mortality was first observed in the United States during the 1990s (Ries et al, 2004). Recent publications by the Cancer Intervention and Surveillance Modeling Network (CISNET) attributed the decrease in case fatality to screening and adjuvant treatments (hormone and chemotherapy) (Berry et al, 2005; CISNET, 2006). The conclusions were supported by seven different models using analytical or simulation techniques and including from 6 to 40 parameters. Several models used the decreased mortality observed in clinical trials (EBCTCG 1998a, 1998b) as model inputs to estimate the effect of therapies on mortality. In order to extend the work of the CISNET, we chose a simple approach based on the most relevant prognostic parameters: tumour size and axillary lymph node involvement. These parameters are the cornerstones of the TNM (tumour, the lymph nodes and metastasis) system and of new prognostic tools such as Adjuvant! (http://www.adjuvantonline.com) (Ravdin et al, 2001). We focused on distant metastases instead of mortality in order to avoid any problem related to the definition of breast cancer mortality or to changes in mortality patterns in a population. We used tumour size as a quantitative variable to maximise the use of the information. Our strategy is based on analyses of the relationship between tumour size and the probability of distant metastasis (Koscielny et al, 1984). This strategy was used during the 1980s to build a simulation model that predicted a roughly 30% decrease in the incidence of metastases with screening (Koscielny et al, 1985). These results, which were among the theoretical arguments used to justify screening (Tubiana and Koscielny, 1990), are actually in keeping with the results of screening trials (Nystrom et al, 2002). As the study period spans about 50 years, we also investigated the effect of the year of treatment and, consequently, of the effect of changes in management strategies (early detection, introduction of organised mass screening, adjuvant endocrine or cytotoxic therapies) on the relationship between tumour size and the risks of nodal involvement and metastasis.

Purpose: The aim of this multicenter trial was to evaluate the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy. Patients and methods: Nine hundred and twenty-six premenopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm). Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years. The analyses were performed with Cox models stratified by center. Results: Median follow-up was 9.5 years. Mean age was 43 years. Ninety per cent of patients had histologically proven positive axillary nodes, 63% positive hormonal receptors and 77% had received an anthracycline-based chemotherapy regimen. Ovarian suppression was by radiationinduced ovarian ablation (45% of patients) or with triptorelin (48%). At the time of randomization, all patients had regular menses or their follicle-stimulating hormone and estradiol levels indicated a premenopausal status. The 10-year disease-free survival rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms (P = 0.51). The 10-year overall survival rates were 66% (95% CI 61% to 70%) for the ovarian suppression arm and 68% (95% CI 63% to 73%) for the control arm (P = 0.19). There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality. However, in patients

The purpose of this study was to determine the predictive value of breast cancer molecular subclassification regarding the benefit of adjuvant anthracycline-based chemotherapy.Tumor samples from 823 patients included in two randomized trials that compared an anthracycline-based chemotherapy with no treatment were used to construct a tissue array. Estrogen receptor (ER), Her2, epidermal growth factor receptor, cytokeratine 5/6 expressions were determined by immunohistochemistry (IHC). The potential predictive factors of treatment effect on disease-free survival (DFS) were assessed by interaction tests and multivariate analysis.Sixty-four (8%), 98 (12%), 109 (14%) and 527 (66%) patients presented a Her2+/ER-, basal-like, Her2-/ER-/nonbasal and luminal-like breast cancer. ER expression, when assessed by IHC, was an independent predictive factor for the benefit of chemotherapy on DFS (test for interaction, P = 0.0015). The molecular subclassification significantly predicted the efficacy of chemotherapy (test for interaction, P = 0.01), but had no significant added value (P = 0.32) as compared to the ER by treatment interaction. Adjuvant chemotherapy was associated with an adjusted hazard ratio for relapse or death of 0.42 [95% confidence interval (CI): 0.17-1.05], 0.54 (95% CI: 0.27-1.08), 0.35 (95% CI: 0.18-0.68), 1.07 (95% CI: 0.81-1.41) for patients with Her2+/ER-, basal-like, Her2-/ER-/nonbasal and luminal-like tumors, respectively.The breast cancer molecular subclassification was predictive for chemotherapy efficacy in adjuvant setting, but did not provide significant additional information to ER.

Background We studied whether dermal lymphatic emboli (DLE) add independent prognostic information to the clinical definition of inflammatory breast cancer (IBC). Patients and Methods The study was performed in 2 centers, one each in France and Tunisia. For every patient with IBC, 1-3 patients with noninflammatory breast cancer (non-IBC) were included. All patients were to have a surgical tumor biopsy, including a sample of the skin surrounding the tumor. The endpoint was the risk of a relapse at 2 years, which was estimated using univariate and multivariate Cox models. Results Three hundred thirty-seven patients were included (150 in France and 187 in Tunisia). The IBC status was divided into 2 clinical categories according to the extent of inflammation in the breast (localized IBC, which was defined as clinical inflammation in the tumor area, vs. diffuse IBC, which was defined as inflammation of at least two thirds of the breast). In total, 57 patients presented with localized IBC, 71 with diffuse IBC, and 209 with non-IBC. Dermal lymphatic emboli were found in 7% of non-IBC cases, in 25% of localized IBC cases, and in 45% of diffuse IBC cases. We found a significant interaction between the presence of DLE and diffuse IBC (P = 0.01). In patients with diffuse IBC, the presence of DLE increased the risk of relapse 3-fold. Conversely, DLE were not associated with the risk of relapse in patients with non-IBC, nor in patients with localized IBC. In patients with diffuse IBC and no DLE, the risk of relapse was similar to that of patients with localized IBC. Conclusion A DLE status might be a useful prognostic indicator exclusively in patients with diffuse IBC. However, because all patients with localized and diffuse IBC generally receive similar types of treatment, additional information on the presence or absence of DLE will not have an impact on treatment practice.

Summary Purpose The aim of the study was to compare reproductive factors in patients with inflammatory breast cancer (IBC), and with non-inflammatory breast cancer (non-IBC). The study was performed in two centers: one French including 49 IBC patients and 140 non-IBC and another Tunisian including 97 IBC and 139 non-IBC. Unconditional logistic regression was used for the analyses. Patients and methods The French IBC patients had a lower educational level, a higher body mass index and a longer cumulative duration of breast-feeding, and they included a greater proportion of non-European women, than the non-IBC patients. In the multivariate analysis, only breast-feeding duration remained associated with the IBC status ( P = 1 0 - 3 ). These results could not be verified in the Tunisian series, because the duration of breast-feeding was unavailable in this center. Results This study suggests that the etiology of IBC might be different of that of non-IBC.

Based on encouraging results reported in alternating radiotherapy and chemotherapy in inflammatory breast carcinoma, we have tried in this study to optimize locoregional treatment with a hyperfractionated accelerated radiotherapy schedule alternating with chemotherapy.From May 1991 to May 1995, 54 patients, previously untreated, with non-metastatic inflammatory breast cancer were entered in an alternating protocol consisting of eight courses of combined chemotherapy and two series of loco-regional hyperfractionated accelerated radiotherapy with a total dose of 66 Gy. Hyperfractionated accelerated radiotherapy was started after three courses of neoadjuvant chemotherapy (Adriamycin, Vincristine, Cyclophosphamide, Methotrexate, 5-fluoro-uracile) administered every 21 days +/- G.CSF. The first series delivered 45 Gy/three weeks to the breast, the axillary, subclavicular and internal mammary nodes, with two daily sessions of 1.5 Gy separated by an interval of eight hours; the second series consisted of a boost (21 Gy/14 fractions/10 d) alternating with another regimen of anthracycline-based-chemotherapy (a total of five cycles every three weeks). Hormonal treatment was given to all patients.Of the 53 patients evaluated at the end of the treatment, 44 (83%) had a complete clinical response, seven (13%) had a partial response (50%) and two (4%) had tumoral progression. Of the 51 patients who were locally controlled, 18 (35%) presented a locoregional recurrence (LRR); eight (15%) had to undergo a mastectomy. All the patients but two with LRR developed metastases or died of local progressive disease and 26 (50%) developed metastases. With a median follow-up of 39 months (range: 4-74 months), survival rates at three and five years were respectively, 66 and 45% for overall survival and 45 and 36% for disease-free survival.Alternating a combination of chemotherapy and hyperfractionated accelerated radiotherapy is a well-tolerated regimen which provides acceptable local control. The systemic dissemination remains the major problem of inflammatory breast carcinoma and further clinical trials using alternative drug regimens are warranted.

Prophylactic cranial irradiation reduces the incidence of brain metastasis in patients with small-cell lung cancer. Whether this treatment, when given to patients in complete remission, improves survival is not known. We performed a meta-analysis to determine whether prophylactic cranial irradiation prolongs survival.We analyzed individual data on 987 patients with small-cell lung cancer in complete remission who took part in seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation. The main end point was survival.The relative risk of death in the treatment group as compared with the control group was 0.84 (95 percent confidence interval, 0.73 to 0.97; P= 0.01), which corresponds to a 5.4 percent increase in the rate of survival at three years (15.3 percent in the control group vs. 20.7 percent in the treatment group). Prophylactic cranial irradiation also increased the rate of disease-free survival (relative risk of recurrence or death, 0.75; 95 percent confidence interval, 0.65 to 0.86; P0.001) and decreased the cumulative incidence of brain metastasis (relative risk, 0.46; 95 percent confidence interval, 0.38 to 0.57; P0.001). Larger doses of radiation led to greater decreases in the risk of brain metastasis, according to an analysis of four total doses (8 Gy, 24 to 25 Gy, 30 Gy, and 36 to 40 Gy) (P for trend=0.02), but the effect on survival did not differ significantly according to the dose. We also identified a trend (P=0.01) toward a decrease in the risk of brain metastasis with earlier administration of cranial irradiation after the initiation of induction chemotherapy.Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission.

Postoperative radiotherapy is commonly used to treat patients with completely resected nonsmall cell lung carcinoma, but its effect on overall survival has not been established.After undergoing complete surgical resection, 728 patients with non-small cell lung carcinoma (221 Stage I, 180 Stage II, and 327 Stage III) were randomized to receive either postoperative radiotherapy at a total dose of 60 gray or observation only . The main end point was overall survival.At the reference date, 218 of 355 patients in the control group had died and 262 of 373 in the radiotherapy group had died. Five-year overall survival was 43% for the control group and 30% for the radiotherapy group (P = 0.002, log rank test; relative risk [RR]: 1.33; 95% confidence interval [CI]: 1.11-1.59). This result was not modified by adjustment for potential prognostic factors. The excess mortality rate for the radiotherapy group was due to an excess of intercurrent deaths (P = 0.0001; RR: 3.47; the 5-year intercurrent death rate was 8% for the control group and 31% for the radiotherapy group). Radiotherapy had no significant effect on local recurrence (RR: 0.85; 95% CI: 0.64-1.14) and no effect on metastasis (RR: 1.06; 95% CI: 0.85-1.31). The rate of non-cancer-related death increased with the dose per fraction delivered.

Tamoxifen administered in patients after breast cancer surgery is one of the most effective adjuvant treatments in this pathology. A large number of randomized studies including thousands of patients allowed to quantify the treatment benefits in terms of recurrence, contralateral breast cancer and overall survival rates. The treatment is generally given for more than 2 years. However, the optimal treatment duration is unknown. Uncertainties appeared when adverse effects were described after some years of treatment (e.g. a higher incidence of endometrial adenocarcinoma). New ongoing multicentric trials will clearly define in the next years the optimal duration of this adjuvant treatment.

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.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.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.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.

Though Hodgkin's disease (HD) is one of the malignancies in which considerable progress has been made, long-term side effects have been observed, second primary cancer being the most significant. Several recent reports have indicated an increased risk of breast cancer (BC) in girls and young women among HD patients.In a retrospective multicenter analysis, 63 women treated for HD subsequently developed BC. Results that were obtained in 13 women (21%) who developed either synchronous (five cases) or metachronous (eight cases) BC were analyzed. The median age at diagnosis of HD was 19 years. Seven patients underwent exclusive radiotherapy (RT) (including "mantle" supradiaphragmatic irradiation) and six received concomittant radiation therapy and chemotherapy.The first breast tumor occurred after a median delay of 16 years. According to the TNM classification, we showed nine stage T0 (non palpable lesions), four stage T1, five stage T2, one stage T3, two stage T4 and five stage Tx BC. Seventeen infiltrating carcinomas, two fibrosarcomas and seven ductal carcinomas in situ were observed. Among 15 axillary dissections performed for invasive carcinomas, histological involvement was found in 10 cases. Seventeen tumors were treated by mastectomy and nine patients underwent conservative surgical treatment. With a 70-month median follow-up (range: 15-125), three patients developed locoregional recurrence and four other metastases. At present, eight are alive with no evidence of disease and one died of intercurrent disease.According to previous works, BC represents 6.3 to 9% of all second cancers occurring after HD treatment. The risk is higher in young women treated before 20 years of age, especially before 15 years of age. Factors that favour the development of secondary BC are: supradiaphragmatic irradiation, very young age at treatment, chemotherapy with alkylating agents, and probably genetic factors. We conclude that young women and girls treated for HD should be carefully monitored at least 10 years after the end of the treatment for HD, using clinical examination, mammography and ultrasonography. The optimal rythm of this follow-up is not yet clearly defined. Moreover, after multidisciplinary concertation, we suggest that secondary BC be sometimes treated by conservative radiosurgical approach.

The yellow (y) mutation of Drosophila melanogaster affects the development of behavior and morphology. We have analyzed some behavioral and morphological parameters during the development of y mutants. Wild-type third instar larvae move in straighter paths than larvae of the same age homozygous for the y mutation. At 96 h of age, the tracks of y larvae have 10 times as many loops as tracks of wild-type larvae, and at 120 h of age, y larvae show bending behavior about 2.5 times more frequently than do wild-type. Consequently, they do not disperse as much as wild-type larvae. Concomitant with the behavioral changes, the larvae present a defect in the morphology of large chaetae in the larval denticle belts, particularly of 2nd and 3rd instars, both with light and scanning electron microscopes. These results suggest that a cuticular defect is probably involved in the abnormal locomotor activity observed in y larvae of Drosophila melanogaster.

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.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.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 (P0.02) or inadequate surgical excisioin (P0.02) were significant. No particular risk factors for contralateral tumor development were identified.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.

The effect of adjuvant chemotherapy after resection of nonsmall cell lung cancer (NSCLC) remains an unresolved question.From October, 1982, to November, 1986, 267 patients with resected NSCLC were included in a randomized trial. The adjuvant allocated treatments were either postoperative radiotherapy, 60 Gy in 6 weeks (radiotherapy group = 129 patients), or three courses of postoperative COPAC (cyclophosphamide, doxorubicin, cisplatin, vincristine, lomustine) chemotherapy followed by a similar radiotherapy schedule (chemotherapy/radiotherapy group = 138 patients).The sex ratio (M:F) was 19/1; mean age was 57 +/- 9 years. According to postoperative staging, 8 patients were Stage I, 70 were Stage II, and 189 were Stage III. The histologic type was squamous cell carcinoma in 175 patients, adenocarcinoma in 57, and large cell carcinoma in 35. The minimum follow-up was 6 years. Four patients were lost to follow-up. Death was recorded in 233 patients. No significant difference was observed in terms of disease free interval (P = 0.47, log-rank test), or overall survival (P = 0.68, log-rank test). With respect to the first site of relapse, distant metastasis occurred more frequently in the radiotherapy group (P = 0.09, log-rank test) whereas local relapse occurred similarly in both groups (P = 0.27). An interaction was observed between lymph node involvement and treatment in terms of overall survival.The COPAC chemotherapy as postoperative treatment failed to improve overall survival in patients with resected NSCLC receiving postoperative radiotherapy but decreased the pattern of metastatic progression, mainly in the N2 patients.

For some years, breast cancer surgery has become increasingly conservative, in order to preserve the aesthetic aspect of the treated breast and global harmony of the bosom. Unfortunately, conservative treatment is followed by 20% to 30% of unsatisfactory cosmetic results. Some studies have defined the various factors associated with an increased failure rate in terms of cosmetic results. These are related to the surgical technique, patient characteristics, or tumor specificities. In these cases with a poor aesthetic prognosis, the authors propose, following the initial tumorectomy, esther breast reduction or mammaexy, in order to reshape the volume of the breast as symmetrically as possible. In a series of 21 female patients operated at the Institut Gustave-Roussy between 1988 and 1991, the authors describe the aesthetic and carcinologic advantages of this method, and define its main indications. Although the aesthetic aspect of the operated breast was considered tube excellent in 33% of cases and good in 67% of cases, the global harmony of the breasts was excellent or good in 76% of cases. The 24 moderate or poor results were due to asymmetry of shape or volume, which is easy to improve by a secondary contralateral breast reduction.

The aim of this study is to determine the diagnostic value of magnetic resonance imaging in the diagnosis of local recurrence of breast cancer. From 1991 to 1994, 61 women were studied prospectively using magnetic resonance imaging. All examinations were made on a 1.5 Testa machine with T1 weighted images and after gadolium-dota injection and dynamic images (T1 weighted sequences every 47 seconds during injection of a gadolinium-dota bolus). All the pre-injection, images in the dynamic series were subtracted from the images after injection. A surgical biopsy was obtained in 39 patients yielding a diagnosis of local recurrence (n = 28) or a benign lesion (n = 11). Among the 28 local recurrences, pathology examination reported invasive cancer in 22 and intra-ductal carcinoma in 6. In 22 patients with normal magnetic resonance imaging, follow-up examinations were performed every 6 months. There were no local recurrences within a delay of 6 to 36 months. Twenty-six of the 28 patients with a local recurrence, cystosteatonecrosis and surgery scar tissue less than 6 months old showed contrast uptake 1 min and 34 s after gadolinium injection during the dynamic sequence. This product uptake yielded nodular images within the invasive carcinomas and linear images in the intraductal cancers. In all cases, it is easier to visualize this contrast uptake in subtraction images. In conclusion, magnetic resonance imaging is a simple reliable method for the diagnosis of local recurrence of breast cancer.

Two-hundred two patients with limited small cell lung cancer were tested by four consecutive alternating radiotherapy and chemotherapy protocols. The alternating schedule consisted of six cycles of chemotherapy (doxorubicin, etoposide, and cyclophosphamide, plus methotrexate in the first protocol; cisplatin replaced methotrexate in the other three protocols) and three courses of thoracic radiotherapy at a total dose of 45, 55, 65 and 61 Gy in the four consecutive protocols, respectively. A 1-week rest followed each chemotherapy cycle and each course of radiotherapy. Seventy-six percent of patients were in complete remission at the end of the induction treatment. Overall results showed a 2-year cumulative incidence rate of failure of 75%. The first cause of failure was local recurrence only, 33%; distant only, 25%; distant and local simultaneously, 9%; and intercurrent death, 8%. Overall survival rate at 5 years was 16%. No significant differences were observed between the four treatment groups. Alternating radio-chemotherapy approaches are feasible and currently included in Phase III trials.

This retrospective analysis was conducted on breast cancer patients treated by radiotherapy alone at The Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients had either operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Previous results showed that a radiation dose increase of 15 Gy can decrease the relative risk of tumor or lymph node recurrence twofold. In this third report, the same data were analyzed to determine the treatment-related complication rates and to correlate these to the radiation dose levels. Overall results were analyzed on 453 patients, but detailed analyses on complications were conducted on 372 patients not developing local recurrence in the first 6 months of follow-up. Each complication was graded on a 3-level previously defined scale. Most frequent complications were skin changes of different degrees, which were usually asymptomatic. More disabling complications were arm edema, impaired shoulder mobility, rib fractures and brachial plexopathy. The incidence of disabling complications was low. The only factor significantly increasing the risk of complications was the radiation dose level to the tumor and axilla. Technical factors such as overlapping fields should also be taken into account. As the more effective control of tumor and lymph nodes obtained in patients treated with higher radiation doses is counterbalanced by an increase in the complication rate, the dose to be delivered for each patient should be carefully chosen according to individual risk factors.

Seventy-five patients with locally advanced non small cell lung carcinoma were entered in a phase II study combining chemotherapy (vindesine, lomustine, cisplatin and cyclophosphamide) and radical thoracic radiotherapy delivering a total dose of 60-65 Gy. Patients were regularly assessed by radiological and fiberoptic bronchoscopy examinations in order to evaluate local control. An objective response was observed in 22 patients (29%) after initial chemotherapy (2 complete remissions and 20 partial responses). The complete response rate after the combined schedule was 30%. Toxicity of this combination was acceptable. Median survival was 13.5 months. Actuarial risk of developing distant metastases at 3 years was 60%. However, the main cause of failure was local with 80% of uncontrolled or recurrent thoracic tumor in the first 2 years of follow-up. The present study shows that local control remains a major problem in the management of patients with inoperable non metastatic non small cell lung cancer.

This Phase II study evaluated the combination of two active agents in small cell lung carcinoma (SCLC): carboplatin and ifosfamide. Thirty previously untreated patients (27 men and 3 women) with a median age of 59 years were included in this study. Twelve patients had one metastatic site and 18 had two or more metastatic sites. The median performance status was 80%. The chemotherapy (CT) regimen administered during the course of this study consisted of carboplatin (300 mg/m2) and ifosfamide (4 g/m2) plus mesna every 4 weeks. All 30 patients were evaluable: 1 achieved a complete remission (CR) and 18 achieved a partial remission (PR) (objective response rate, 63%). The median response time was 3 months and the median survival time was 8 months (range, 1 to 25+ months). Bone marrow toxicity was Grade III in three patients and Grade IV in four patients. The carboplatin and ifosfamide combination was well tolerated. No cross-resistance with the doxorubicin and etoposide regimen was established because 4 of 11 patients responded to this combination (+/- cisplatin) after failing to respond to the ifosfamide and carboplatin regimen. The ifosfamide and carboplatin combination may be considered for inclusion in non-cross-resistant alternating CT schedules.

Most patients with locally advanced non small cell lung carcinoma are treated with external thoracic radiotherapy. Because of the high incidence of distant metastasis the addition of chemotherapy has been proposed. The present randomized study was conducted from June 1983 to February 1989 and included 353 patients. The trial compared arm A, thoracic megavoltage radiotherapy alone at a total dose of 65 Gy in 26 fractions and 45 days, to arm B that comprised the same radiotherapy preceded and followed by 3 monthly cycles of VCPC (vindesine 1.5 mg/m2 d 1-2, cyclophosphamide 200 mg/m2 d 2-4, cisplatinum 100 mg/m2 d 2 and lomustine 75 mg/m2 d 3). Disease was deemed unresectable but non-metastatic after bronchoscopic, radiologic, CAT, and nuclear scans and physical examinations. Only patients in clinical, radiological, endoscopic, and histological complete remission were considered as locally controlled; these patients were monitored by fiberoptic bronchoscopy and systematic biopsies to the primary site. One hundred seventy-seven patients received thoracic radiotherapy alone and 176 received the combined modality. Twenty-seven percent of arm B patients had an objective response after 2 VCPC cycles. At the time of final assessment, performed 3 months after the end of thoracic radiotherapy in both arms, there were 20% of complete responders in arm A versus 16% in arm B. The two-year survival rate was 14% in arm A versus 21% in arm B (p = 0.08, logrank test). The distant metastasis rate was 67% in arm A versus 45% in arm B (p less than 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively). The striking effect of VCPC chemotherapy on the incidence of distant metastasis did not have a significant impact on overall survival. We conclude that thoracic tumor control remains a significant problem in unresectable non small cell lung cancer.

One-hundred seventy-three patients with limited small cell lung cancer were included in three consecutive protocols alternating radiotherapy and chemotherapy. The alternating schedule consisted of six courses of chemotherapy (doxorubicin, VP16213, cyclophosphamide, and methotrexate in the first protocol; methotrexate being replaced by cisplatinum in the other two protocols) and three series of thoracic radiotherapy delivering a total dose of 45, 55, and 65 Gy in each consecutive protocol. Radiotherapy was started after the second course of chemotherapy. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy. Seventy percent of patients were in complete remission at the end of the induction treatment. The actuarial 5-year local control was 60% and the 5-year overall survival was 18%. Sixty percent of patients developed distant metastases. The death rate unrelated to cancer was 10%. These results show that alternating radiotherapy and chemotherapy schedules are reproducible, and provide a consistent long-term local control and a long-term survival rate exceeding 15% in limited disease.

A review of 20 patients with malignant thymic tumors is presented. A simplified classification is used avoiding the term thymoma, which is considered misleading. Most of the patients were treated by a combination of surgery and radiation therapy while 7 were treated by irradiation alone. Postoperative radiation therapy is indicated when the tumor is incompletely removed. This is also advised in invasive tumors even when they are considered completely resected. Irradiation alone of inoperable tumors should be carried out with high doses (55 to 60 Gy) to decrease the risk of local recurrence.

1. Urinary kallikrein excreted by normal rats is significantly increased (P < 0·001) 2 h after: (a) water loading, (b) water loading plus frusemide, 0·27 mmol (10 mg) per rat, (c) salt loading. In water-loaded rats, 5 i.u. of renin strikingly reduced kallikrein excretion (P < 0·01) but considerably increased sodium excretion (P < 0·001). 2. Renal kallikrein, measured by its kininogenase activity within 2 h of water loading, was significantly increased (P < 0·05); after water loading and frusemide it was 40% decreased (P < 0·001) and after salt loading it was reduced by approximately 50% (P < 0·02). Renin did not change renal kallikrein. 3. Severely hypertensive (one-kidney) rats (blood pressure >150 mmHg) showed no increase of urinary kallikrein after water loading, although there was a marked natriuresis; in moderately hypertensive rats (blood pressure

Two non randomized therapeutic trials have been conducted in oat cell carcinoma of the lung with limited disease. The first protocol combined chemotherapy (adriamycin, cyclophosphamide, VM 26, procarbazine) with mediastinal and supra-clavicular radiotherapy in classical fractionation (40 grays in 4 weeks). The second combined a more intensive chemotherapy (adriamycin, VP 16, methotrexate, cyclophosphamide) with an alternating radiotherapy (3 series of 15 grays). All patients received prophylactic brain irradiation. Preliminary results show a 9 month survival rate of 34 per cent and 62.5 per cent respectively. In addition, all patients in the second protocol presented a complete response at the end of the induction treatment. These preliminary data encourage proceeding with this kind of combined treatment.

Sixty three patients with limited small cell lung carcinoma were entered into a pilot study alternating monthly cycles of combination chemotherapy (doxorubicin, VP16213, cyclophosphamide and methotrexate (group A) or cis platinum (group B) with 3 courses of mediastinal radiotherapy. The total mediastinal dose was 45 Gy for the first 28 patients (group A) and 55 Gy for the remaining 35 (group B). The complete response rate was 86% in group A (median survival 14 months) and 91% in group B (median survival 20 months). Local control at two years was 61% in group A and 82% in group B, while relapse-free 2 year survival rates were 32% and 37% respectively. The acceptable toxicity and high response rate of this combined modality therapy lead us to further research in maintenance therapy.

The results of 2 chemotherapeutic regimens used in 170 cases of inflammatory breast cancer were compared with those obtained in 60 historical controls treated with radiotherapy and hormonal therapy. Inflammatory breast cancers could be divided into evolutive phase 2 with limited signs of inflammation and evolutive phase 3 where inflammation involved the whole breast. The 60 controls had been treated between 1967 and 1974 with radiotherapy (45 Gy plus an extra dose of 20 or 30 Gy); premenopausal patients underwent ovarian irradiation. The 91 patients treated with regimen A between 1976 and 1980 received a DVM-type induction chemotherapy (doxorubicin 40 mg/m2 on day 1, vincristin 1 mg/m2 on day 2, and methotrexate 6 mg/m2 on days 3, 4, 5) every 3 or 4 weeks, and a VCF-type maintenance chemotherapy (vincristin 1 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2, 3, 4 and 5-fluorouracil 300 mg/m2 on days 2, 3, 4) every 4 weeks. Premenopausal patients had their ovaries irradiated; postmenopausal patients received tamoxifen. The therapeutic sequence was: 3 DVM - 45 Gy - DVM - 15 Gy - 4 DVM - 4-12 VCF. The 79 patients treated between 1980 and 1982 with regimen B received a DVCMF-type induction therapy (doxorubicin 50 mg/m2 on day 1, vincristin 0.6 mg/m2 on day 2, 5-fluorouracil 300 mg/m2 on days 3, 4, 5, cyclophosphamide 200 mg/m2 on days 3, 4, 5 and methotrexate 10 mg/m2 on days 3, 4, 5) every 4 weeks. Hormonal therapy was the same as with regimen A. The sequence was 3 DVCMF - 45 Gy - DVM - 20-25 Gy - 4 DVM - 4-12 VCF. The survival rate at 3 years was 42% in controls, 53% in regimen A patients and 74% in regimen B patients (P less than 0.05). The relapse-free survival rates in these three groups at 3 years were 15%, 32% and 54% respectively (P less than 0.0008). These results suggest that a multidisciplinary approach and initial chemotherapy are useful in this type of breast cancer. The value of prolonged maintenance treatment is discussed.

1. In normally hydrated rats prostaglandin F2alpha (PGF2alpha) in doses of 5 microgram/100 g body weight given subcutaneously every 2 h (three times) induced a significant increase in urinary kallikrein activity, and in sodium, potassium and water excretion for 8 h after the first injection. In moderately hyperhydrated rats loaded 2.5% of body wt. with 0.5% NaCl solution, PGF2alpha produced similar changes in kallikrein activity and electrolyte excretion. 2. In normally hydrated rats prostaglandin E2 (PGE2) in the same conditions and doses as in 1 had no effect on kallikrein activity, showing a tendency to decrease potassium and water excretion. 3. PGE2 in doses of 5, 12.5 and 25 microgram/100 g body wt. in overhydrated rats given 2.5% and 0.5% NaCl and 5% of tap water/100 g body wt. 1 h later, significantly increased kallikrein activity in the urine collected for 120 min after the injections. A significant decrease in potassium and water excretion was observed with the highest dose. 4. PGF2alpha, had no effect on kallikrein activity in overhydrated rats, but an increase in sodium and a decrease in potassium excretion was seen at the highest dose. 5. The different actions of PGE2 and PGF2alpha may be part of a regulatory mechanism associated with the kallikrein-kinin system which contributes maintainance of extracellular fluid homeostasis.

During the period 1968-79, a total of 90 thoracotomies for lung metastases was performed in 76 adult patients (42 men and 34 women, aged from 16 to 72 years) treated at the Gustave Roussy Institute, Paris. Forty-three had carcinoma, 29 had sarcoma and 4 had melanoma. Thoracotomy was performed once in 64 patients, twice in 10 patients and 3 times in 2 patients. Complete resection could be performed in 88%. The operative mortality rate was 1.1%. Four benign lesions were encountered. The survival rate was 56% at 2 years and 43% at 3 years. Several prognostic factors were identified. The indications for pulmonary metastasectomy within the overall strategy of metastatic cancer treatment are discussed.

Twenty-five cases of presumed radiation-induced brachial plexopathy were identified out of a population treated at the Institut Gustave-Roussy, in 3 different ways, during the period 1967-1980. The incidence of this complication is given for each group, and the radiation dosage and natural history is described, with results of neurolysis when it was possible. The absence of successful treatment methods makes prevention of this complication crucial. The use of fraction sizes no greater than 2.5 Gy, and the avoidance of radiation treatment to the completely dissected axilla, are advocated.

Three patients with bilateral multiple pulmonary metastases of cylindroma were treated with sequential and repeated courses of chemo- and radiotherapy. Objective symptoms of regression were observed.

Five year survival of 683 mammary carcinomas would confirm the prognostic value of T.N.M. classification (UICC), of tumor particular characteristics (size, fixation to neighbouring structures) and presence or absence of clinical nodes. A clinical-histological relationship was studied for axillary nodes: in our experience, clinical determination is more reliable for estimation of N0 and N2 than N1. Three groups of age were considered; the age, T and N corrected five year survival show a higher mortality for patients older than 60 years with T3-T4, N greater than 0 carcinomas. The study of this prospective computerised register confirms the prognostic value of developping growth tumors (PEV) described by P. Denoix. In fact, inflammatory carcinomas (PEV 2-PEV 3) show a poor 5 year survival and PEV 1 is an intermediate pronostic group between stable and inflammatory carcinomas. PEV 1 was showed to be an independant clinical factor from T and N characteristics.

Sixty-nine patients with a superior vena cava syndrome were treated by radiotherapy. Forty were also given chemotherapy before or after irradiation. Twenty-nine had bronchial carcinoma, thirteen had other solid tumors, fourteen had lymphosarcoma and thirteen had no histological diagnosis. Subjective improvement was recorded in 86% of cases and the objective response rate was 41%. The response was obtained in a mean period of 4 weeks and its duration was 39 weeks for lymphosarcomas and only 6 weeks for solid tumors. Overall 1 year survival was 18%. Poor results obtained in superior vena cava syndrome incites recommendation of more intensive radiochemotherapeutic management.

It is confirmed that urinary kallikrein is significantly and persistently decreased in totally hypophysectomized rats. In addition, kallikrein activity in the kidneys in these animals is significantly reduced (p less than .001) as compared to partially hypophysectomized and sham-operated rats. The administration of 125 mU of ACTH twice a day for 2 months, did not modify urinary kallikrein excretion. Negative effects were also obtained in subsequent periods, by injection of 10 microgram corticosterone and 10 microgram aldosterone, twice a day for 9 and 6 days, respectively. The administration of rat pituitary anterior lobe homogenates, freshly prepared, increased significantly urinary kallikrein level in hypophysectomized rats.

The authors analyze the respiratory sequelae in 19 patients with limited small cell lung carcinoma who survived for more than 30 months following an alternating chemo-radiotherapeutic combined regimen. The clinical tolerance measured with respiratory functional test is acceptable. In two patients an effort dyspnea is increased by evolutive, chronic obstructive bronchopneumopathy. Radiologic sequellae are constant and correlated with the volume of irradiation and cumulative etoposide doses. The role of a combined chemo-radiotherapeutic in pulmonary toxicity is discussed.