Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial.

BACKGROUND: Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. PATIENTS AND METHODS: Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. RESULTS: Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). CONCLUSIONS: pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis. CLINICALTRIALSGOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.

[Techniques and complications of non-genetic risk reducing mastectomies: Guidelines of the National College of French Gynecologists and Obstetricians (CNGOF)]. / Modalités et morbidité des mastectomies de réduction de risque en dehors du risque avéré de prédisposition héréditaire : recommandations du Collège national des gynécologues et obstétriciens français (CNGOF).

OBJECTIVE: Based on an updated review of the international literature covering the different surgical techniques and complications of risk reducing mastectomies (RRM) in non-genetic context, the Commission of Senology (CS) of the College National des Gynécologues Obstétriciens Français (CNGOF) aimed to establish recommendations on the techniques to be chosen and their implementation. DESIGN: The CNGOF CS, composed of 24 experts, developed these recommendations. A policy of declaration and monitoring of links of interest was applied throughout the process of making the recommendations. Similarly, the development of these recommendations did not benefit from any funding from a company marketing a health product. The CS adhered to and followed the AGREE II (Advancing guideline development, reporting and evaluation in healthcare) criteria and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method to assess the quality of the evidence on which the recommendations were based. The potential drawbacks of making recommendations in the presence of poor quality or insufficient evidence were highlighted. METHODS: The CS considered 6 questions in 4 thematic areas, focusing on oncologic safety, risk of complications, aesthetic satisfaction and psychological impact, and preoperative modalities. RESULTS: The application of the GRADE method resulted in 7 recommendations, 6 with a high level of evidence (GRADE 1±) and 1 with a low level of evidence (GRADE 2±). CONCLUSION: There was significant agreement among the CS members on recommendations for preferred surgical techniques and practical implementation.

Clinical and pathologic characteristics of breast cancer patients carrying the c.3481_3491del11 mutation.

Tumor characteristics are used today to evaluate the possibility of mutation and to target mutation screening in families with high risk of breast and/or ovarian cancer. We studied the breast tumor profile associated to the c.3481_3491del11 French founder effect mutation on the BRCA1 gene to an attempt to identify any particularity or difference when comparing it to that related to other BRCA1 mutations. Within the population who were referred to our oncogenetic clinic at the Lorraine Oncology Institute in France and who underwent genetic testing between 1994 and 2012, we identified 404 women carrying a BRCA1 mutation. Interestingly, 45% (180/404) women had the germline c.3481_3491del11 mutation. These included 91 patients affected by first breast cancer. Clinical and pathologic data were retrieved from medical files. Descriptive statistics were conducted using the SPSS software (version 20.0). For the entire cohort of 91 women, the mean age was 43.64 years (SD 10.04). Tumors were identified in 37.4% of cases aged < 40 years. Estrogen receptor status and progesterone receptor status were reported to 67 patients. Seventy-four percent were ER negative. Hormonal receptors status was negative in 68.6% of tumors. HER2 status was available for 32 tumors. The triple-negative subtype was found in 21 cases, which accounts for 65.6% of the patients. High tumor grade was found in 81% of triple negative breast cancer patients. Based on our results compared to those of previous international studies, we concluded that the breast cancer associated to the c.3481_3491del11 is not different from that associated to other BRCA1 mutations. A larger cohort with complete information on the breast cancer pathologic characteristics and including other BRCA1 mutations would allow us to statistically compare the breast tumor profile associated to the c.3481_3491del11 to that related to other BRCA1 mutations.

[PALB2, a major susceptibility gene for breast cancer]. / PALB2, gène majeur de susceptibilité au cancer du sein.

OBJECTIVES: About 5% of breast cancers are linked to an inherited predisposition, the two most known susceptibility genes being BRCA1 and BRCA2. Recently, new susceptibility genes, including PALB2, have been identified. The risk of breast cancer associated with a deleterious mutation of PALB2, the age of onset of these cancers, their prognosis and associated cancers have so far been the subject of controversy. Our objective was to clarify these different questions from an updated review of the literature. METHODS: The analyzed articles were taken from the PUBMED database between January 2008 and December 2015. The keywords used were "breast cancer" and "PALB2". RESULTS: Women with PALB2 mutations have a higher risk than the general population of developing breast cancer. The relative risk is significant, varying according to the different studies between 3,4 (IC 95%: 2,4-5,9) and 9,47 (IC 95%: 5,72-14,39). The different mutations as well as environmental and geographical factors should be taking into account when interpreting these results. There is currently no proven link between a PALB2 mutation and the occurrence of ovarian or pancreas cancer. CONCLUSION: PALB2 must be considered as a high-penetrance breast cancer predisposing gene. Women with a PALB2 mutation face an increased risk of triple negative breast cancer and higher risk of death from breast cancer.

Is there a genetic anticipation in breast and/or ovarian cancer families with the germline c.3481_3491del11 mutation?

The aim of the current analysis is to evaluate any differences of breast or ovarian cancer age at diagnosis between mothers and daughters carrying the c.3481_3491del11 mutation in the BRCA1 gene. A study cohort of 38 women carrying the c.3481_3491del11 mutation and affected by first breast or ovarian cancer who reported a first breast or ovarian cancer in their mother carrying the c.3481_3491del11 mutation, was identified in 37 different families including members with breast and/or ovarian cancer at the Oncology Institute of Lorraine. Twelve mothers underwent genetic testing. Twenty-five pairs of the 38 mothers-daughters pairs with c.3481_3491del11 mutation were affected by breast cancer and 13 pairs by ovarian cancer. Clinical and genetic data were collected from medical files and family pedigrees. Analyses were conducted for each cancer type. We investigated an early breast cancer detection effect due to early screening programs and also an increased breast tumor aggression. Since major improvements in breast cancer clinical management and imaging techniques appeared after 1980, we compared the age at breast cancer diagnosis and the age at death in mothers and daughters before and after 1980, first, in the group of women including mothers and daughters taken together and then in mothers and daughters separately. The mean age at breast cancer diagnosis was 45.28 ± 10.27 years in mothers and 39.80 ± 7.79 years in daughters (p = 0.026). The difference of age at ovarian cancer diagnosis in mother-daughter pairs was 8.62 ± 12.76 years (p = 0.032). When considering the group of women including mothers and daughters taken together, no significant difference of age at breast cancer diagnosis was found between women affected before 1980 and those affected after 1980 (p = 0.577). However, the age at death increased in these women after 1980 (p = 0.026). Comparison of age at breast cancer diagnosis in mothers and daughters separately, showed that daughters were affected at an earlier age after 1980 (p = 0.002). Daughters had a poor prognosis and died earlier than mothers after 1980. Our results may have reflected genetic anticipation in c.3481_3491del11 mutation breast and ovarian cancer families. In order to confirm our findings, a larger cohort would provide more precision to the difference of ages at breast or ovarian cancer diagnosis between mothers and daughters and more powerful statistical analyses. Increased aggression in daughters' tumors compared to those of mothers could be also considered as a parameter of genetic anticipation. Complete information on tumor profile and proliferation would allow us to study genetic anticipation by comparing the tumor phenotypes between mothers and daughters in the future.

[Role for aromatase inhibitors as adjuvant treatment of breast cancer in menopaused women: facts and questions in 2005]. / Place des inhibiteurs de l'aromatase dans le cancer du sein de la femme ménopausée, en situation adjuvante: les acquis et les incertitudes en 2005.

After a dominant role for more than 30 years, tamoxifen has been progressively replaced by aromatase inhibitors as adjuvant treatment for breast cancer in the menopaused woman. We present here a recall of the mechanisms of action involved together with a review of clinical trials leading to the current situation. Giving trial results in detail, we discuss the current evidence as well as open questions. The populations concerned and trial methodologies are analyzed. Comparative tolerance is detailed. Several questions remain open, either due to the lack of evidence to be obtained from ongoing trials or sufficient follow-up. The evidence presented is commented in light of the American (ASCO) and European (Saint-Gallen) or French (Saint-Paul) guidelines.

French version of FACT-G: validation and comparison with other cancer-specific instruments.

The aim of this study was to assess the validity of the French version of the Functional Assessment of Cancer Therapy - General (FACT-G), and to compare its psychometric properties with those of two other cancer-specific quality of life questionnaires, European Organisation for Research and Treatment of Cancer Quality of Life - Core 30 (EORTC QLQ-C30) and Functional Living Index - Cancer (FLIC). Two hundred and twenty three patients with breast or colorectal cancer completed the FACT-G questionnaire in French followed by (in random order) the QLQ-C30 and FLIC. An additional 87 patients with head and neck (H&N) cancer completed the FACT-H&N followed by the QLQ-C30 and H&N-Besançon. The French version of FACT-G was internally consistent, and its reproducibility was excellent. FACT-G Physical Well-Being and global scores correlated with all QLQ-C30 subscales. There was evidence of discriminant validity. Compared with the other tools, FACT-G included a statistically significantly higher proportion of items patients considered to be confusing or upsetting. Patients with breast or colorectal cancer expressed a preference for QLQ-C30. Use of the specific H&N additional items increased the responsiveness to change of FACT-G. The French version of FACT-G is valid and has psychometric properties similar to those of FLIC and QLQ-C30.

Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer.

This comparative phase III trial of mitoxantrone+vinorelbine (MV) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin (FAC/FEC) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy, while resulting in an improved tolerance in relation to alopecia and nausea/vomiting. This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.

Radiation therapy alone for medically inoperable patients with adenocarcinoma of the endometrium.

Surgery with adjuvant radiation is the definitive method for treating patients with Stage I and II FIGO endometrial carcinoma. However, radiation therapy alone becomes the only curative alternative for patients who presented with severe, acute, and chronic medical illnesses which prevented surgical management. We report on 104 such patients treated at Centre Alexis Vautrin in Nancy (FRANCE) between 1975 and 1984. The minimum follow-up was 2 years, the maximum was 11 years. Fifty-two patients were treated by association of external irradiation (RT) and curietherapy (CUR), and 52 by curietherapy alone. The median age of the patients was 68.8 years with a minimum of 43 and maximum of 89 years old. Ninety-six patients (92.3%) were obese. Forty-nine (47.1%) were hypertensive. Forty-one (39.4%) had cardiovascular diseases, 25 (24%) had diabetes mellitus, and 13 (12.5%) had history of phlebitis. Seventy-nine patients (75.9%) were Stage I FIGO, 15 (14.4%) were Stage II, 4 patients (3.8%) were Stage III, and 6 patients (5.7%) were Stage IV. The 5- and 10-year overall absolute survival was 51.6% and 35.9% respectively. The 5- and 10-year determinate survival was 65.9% and 58.6% respectively. The 5- and 10-year absolute survival of patients treated by combination RT + CUR was 59.6 and 49.8% respectively. The 5- and 10-year survival of patients treated by CUR alone was 42.3% and 27% significantly worse (p = 0.025). The 5- and 10-year determinate survival for Stage Ia was 82.1%, 71.4% and for Stage Ib 64.6% and 64.6% respectively. The difference was not significant (p = 0.18). While the 5- and 10-year determinate survival for Stage II was 56.2% and 56.3%, significantly worse than Stage I patients (p = 0.043). Tumor differentiation (G) was found to be a significant prognostic factor in survival (p less than 0.05). Local failure was seen in 9 patients (8.6%) 5 in association with distant metastasis (DM). The 5- and 10-year actuarial local control were 87.6% and 85.1% respectively. Severe complications occurred in 18 patients (17.3%). Five of these patients are still alive with a mean follow-up of 8.8 years (minimum 6 years and maximum 11 years). The rate of complications had considerably diminished after 1980, as techniques improved and computerized dosimetry was used.

Effectiveness of brachytherapy in treating carcinoma of the vulva.

PURPOSE: Radical radiotherapeutic management of vulvar cancer often incorporates brachytherapy as a portion of the treatment regimen. However, few studies using this modality alone to manage vulvar cancer have been published. METHODS AND MATERIALS: Thirty four patients were treated with iridium-192 (192Ir) brachytherapy for vulvar cancer between 1975 and 1993 at Centre Alexis Vautrin. Twenty-one patients were treated at first presentation when surgery was contraindicated or declined. Of these patients, 12 had International Federation of Gynecology and Obstetrics Classification Stage III or IV disease, 8 were Stage II, 1 was Stage I, and 1 was Stage 0. Thirteen patients were treated for recurrent disease. Paris system rules for implantation and dose prescription were followed. The median reference dose was 60 Gy (range 53 to 88 Gy). At the time of analysis, 10 of 34 patients were alive. Median follow-up in these 10 patients was 31 months (range: 21 months to 107 months). Fourteen of the 24 deaths were from causes other than vulvar cancer. RESULTS: Kaplan-Meier actuarial 5-year local control was 47% (95% confidence interval (CI) = 23 to 73%) and 5-year actuarial loco-regional control was 45% (95% CI = 21 to 70%). Kaplan-Meier actuarial 5-year disease-specific survival was 56% (95% CI = 33 to 76%) and actuarial 5-year survival was 29% (95% CI = 15 to 49%). Median time to death was 14 months. Subset analysis revealed a higher actuarial 5-year local control in patients treated at first presentation than those treated for recurrence (80 vs. 19%, log rank, p = 0.04). Similarly, actuarial 5-year loco-regional control was higher in patients treated at first presentation (80 vs. 16%, log rank, p = 0.01). The two groups did not differ significantly in disease-specific or overall survival. The actuarial 5-year disease specific survival of 56% is somewhat less than the expected 5-year disease-specific survival after surgery in a group having a similar proportion of early stage, advanced stage, and recurrent vulvar cancer. CONCLUSIONS: Brachytherapy is an effective treatment for patients with carcinoma of the vulva who decline surgery or in whom surgery is contraindicated.

The study of tumoral, radiobiological, and general health factors that influence results and complications in a series of 448 oral tongue carcinomas treated exclusively by irradiation.

PURPOSE: Our aim was to study the different factors that influence the results and complications in a series of 448 carcinomas of the oral tongue treated from January 31, 1972 to December 31, 1986, by brachytherapy (Br) +/- neck dissection (181 cases) or combination of external beam irradiation and brachytherapy (EBI + Br) (267 cases). METHODS AND MATERIALS: The patients distribution (TNM classification 1979) was: 125 T1, 186 T2, 128 T3, 9 T4Tx, 78% N0, and 22% N+. We used guide gutter or plastic tubes technique (Paris system dosimetry). Results at 5 and 10 years are: local control 68% and 64%, locoregional control 58% and 53%, specific survival 45% and 39%, and overall survival 44% and 27%. RESULTS: In the univariate analysis for local control (LC) and overall survival (OS), we considered the tumoral factors. At 5 years, the LC for T1, T2, T3 are 93%, 65%, and 49%, and the OS 69%, 41%, and 25%, respectively (p < 0.002). The lesions of the undersurface of the tongue have a better LC (77%) than other localizations (64%) (p = 0.02). For general factors, the index of general health condition, age, and sex were not significant for LC, but proved significant for OS (p = 0.01). Significant radiobiological factors: the safety margin (expressed by the ratio treated surface on tumoral surface > or = 1.2) is significant for LC and OS. This is the same if the interval between EBI and Br is < or = 20 days. Neither the dose rate, the spacing between the sources, the total dose, nor Br dose were significant, but the last two were adapted according to the infiltration. In the univariate study for grade 2 and 3 complications (tissue and bone), the surface treated (> 12 cm2), and the dose rate > 0.7 Gy/h were significant. CONCLUSION: The multivariate study showed that the small size of the lesion is the most important factor for local control, with brachytherapy alone for T1T2N0 and the number of days between EBI and brachytherapy < or = 20 days. For the complications, the most important factors are the total dose > 80 Gy and a treated surface > 12 cm2.

Place of radiotherapy in the treatment of Graves' orbitopathy.

PURPOSE: The aim of this study is to evaluate the response of Graves' orbitopathy to irradiation, and to specify the prognostic factors allowing one to better define the indications of orbital radiotherapy. METHODS AND MATERIALS: From 1977 to 1996, 199 patients received bilateral orbital irradiation delivering 20 Gy in 10 fractions and 2 weeks for a progressive Graves' orbitopathy. 195 patients were seen between 1 and 6 months after radiotherapy. The different symptoms were studied and their response to radiation was analyzed. Factors such as age, sex, evolution of thyroid disease, history of symptoms, and previous or combined treatments were analyzed. RESULTS: The results revealed that 50 patients (26%) had a good or excellent response, 98 (50%) had a partial response, 37 (19%) were stable, 10 (5%) had a progression of disease. The signs that best responded to radiotherapy were the infiltration of soft tissues and the corneal involvement. Responses of proptosis or oculomotor disorders were more complete when these signs were not advanced at the time of treatment. Irradiation seemed to have the same efficacy when applied as first-line treatment or after failure of corticosteroids. Neither modality of treatment of hyperthyroidism nor thyroid status at the time of orbital irradiation modified the results. The best results were recorded for early or moderately advanced presentation (p = 0.05). Patients treated within a delay of 7 months after the beginning of the ophthalmopathy had better responses than patients treated later (p = 0.10). CONCLUSION: Radiation therapy was successful in Graves' orbitopathy by stopping the progression of disease in almost all cases, by improving the comfort of patients, by obtaining objective responses, and by avoiding surgical treatments particularly when signs were moderate.

Cervical lymph node relapses of head-and-neck squamous cell carcinoma: is brachytherapy a therapeutic option?

PURPOSE: To report the results of interstitial brachytherapy (IBT) without salvage surgery for isolated cervical lymph node relapses. PATIENT AND METHODS: From 1970 to 1989, 84 patients were treated; 76 patients had relapsed in sites of previous external beam radiation. In 72 patients, IBT was sole salvage treatment (mean, 56.5 Gy). In 12 patients IBT (mean, 38 Gy) was combined with further external beam radiotherapy (mean, 41 Gy). RESULTS: Local control in the neck was 49% at 1 year, 31% at 2 years, and 0% at 5 years. Overall survival was 33% at 1 year, 13% at 2 years, and 1% at 5 years. Significant toxicity occurred in 35% (7% fatal). Multivariate analysis shows survival after salvage was better for patients who had achieved initial control for > or =18 months before relapse (0% vs. 13% at 3 years, p < 0.0002). Lymph node control was better for patients who received total salvage dose > or =60 Gy (0% vs. 56% at 3 years, p = 0.0004). CONCLUSION: Given its poor efficiency and its toxicity, IBT must be considered only when surgery is contraindicated and if lymph node relapse occurs after a minimal interval of 18 months.

Velotonsillar squamous cell carcinoma: 277 cases treated by combined external irradiation and brachytherapy--results according to extension, localization, and dose rate.

From 1977 to 1987, 277 patients with velotonsillar cancer (oropharyngeal cancer excluding base of tongue and valleculae) were treated by brachytherapy either alone (14 patients) or combined with external beam irradiation (263 patients) using a new afterloading Iridium-192 technique. The distribution of patients according to the localisation was as follows: 106 tonsillar region, 98 soft palate, 45 anterior pillar, 8 posterior pillar and 20 pharyngoglossal sulcus. According to the UICC TNM classification of 1979, the patients were staged as follows: 65 T1, 103 T2, 101 T3, 8 TX. 172 patients were NO, 74 N1, 3 N2, 20 N3 et 8 NX. According to the tumor extension, the 5 year actuarial local control, locoregional control, specific survival and overall survival by T stage (T1 [65 pts], T2 [103 pts.], T3 [101 pts]) were respectively: local control: 89%, 86%, 69%; locoregional control: 84%, 80%, 67%; specific survival (excluding patients dead with intercurrent disease or second cancer): 78%, 62%, 46%; overall survival: 62%, 53%, 43%. No local recurrence was detected after 3 years. According to the localization, the tumors arising from the tonsillar region, the soft palate and the posterior pillars (A Group) had a better prognosis than the tumors arising from the anterior pillars and glossotonsillar sulcus (B Group). The complications were classified into four grades according to their extension and duration: Grade 1 (minor) with very small tissue ulcer which healed within 2 months with medical treatment (20%). Grade 2 (moderate) (5%), grade 3 (severe) (1.4%), grade 4 (fatal) (0.4%). The dose rate seemed to be relatively higher in patients with grade 2 and 3 complications (70 cGy per hour on average) versus the dose rate of patients without complications (50 cGy per hour) but the difference was not significant. In conclusion, the brachytherapy boost after external irradiation can be performed under favourable conditions with an acceptable rate of complications. It was set out in order to attempt to improve the local control of the tumor while preserving the salivary function and lessening the muscular fibrosis. It shows how experienced the team is, however only a randomized study would allow to state whether this technique brings about a real improvement especially as for tumors T2 or T3.

Complications following definitive irradiation for cancers of the oral cavity and the oropharynx (in a series of 1134 patients).

PURPOSE: To study the rate and severity of complications in a series of 1134 patients treated by definitive irradiation for tumors of the oral cavity (772 cases) or the oropharynx (361 cases). METHODS AND MATERIALS: Patients were staged as 29.5% T1, 42% T2, 26% T3, 2.5% T4-Tx, and 74.5% N0 tumors. We treated 364 patients with brachytherapy only (192Ir) for the primary lesion. External irradiation and brachytherapy were combined for 770 patients. RESULTS: The results included local control and survival. Out of 1134 patients, 330 had 376 complications. Grade 1 complications occurred in 20% of the patients, Grade 2 in 9%; Grade 3 in 4%; and Grade 4 in 0.2%. Of the Grade 1 complications, 78% were soft tissue and only 24% were bone complications. For the more severe grades (2, 3, and 4), there were 56 soft tissue complications and 90 bone complications out of 1340 patients. The statistical analysis included tumor-related factors and treatment-related factors. For the first two factors, only tumor location was significant. The treatment-related factors significant for complications were studied in univariate and multivariate study. This multivariate study confirmed that for soft tissue complications dose rate and volume treated were important (p < 0.001). It also confirmed that for bone complications, total dose > 80 Gy, dose rate > 0.7 Gy/h, and the absence of leaded protection of the mandible were all important factors. CONCLUSION: This statistical study should allow future reduction of severe complications (Grades 2, 3, 4), if treatment factors inducing them can be taken into account. This is not always possible for very large tumors.

Influence of tumoral, radiobiological, and general factors on local control and survival of a series of 361 tumors of the velotonsillar area treated by exclusive irradiation (external beam irradiation+brachytherapy or brachytherapy alone)

PURPOSE: To evaluate statistically the factors influencing the therapeutic results. METHODS AND MATERIALS: A statistical study was carried out concerning 361 patients treated from 1977 to 1991 for velotonsillar carcinoma. They received either brachytherapy alone (18) or a combination of external beam irradiation and brachytherapy (343 patients) using an afterloading iridium technique in plastic tubes. The distribution of patients according to the localization was: 128 tonsils, 134 soft palates, 9 posterior pillars, 63 anterior pillars, and 27 glossotonsillar sulcus. The patients were staged as follows: 90 T1, 141 T2, 119 T3, 2 T4, 9 Tx with 230 N0, 93 N1, 9 N2, 20 N3, and 9 Nx. RESULTS: The results at 5 and 10 years show: local control 80% and 74%, locoregional control 75% and 70%, overall survival 53% and 27%, specific survival 63% and 52%, respectively. The univariate study shows at 5 years a better local control for T1T2 (87%) compared with T3 (67%) with p = 0.00004. The locoregional control is better for N0 (80%) than for N+ (55%) with p = 0.002. This is the same for the overall survival (59% vs. 42%, p = 0.002). Tumors with an extension to the mobile tongue or the base have a poor prognosis (p < 0.002). The radiobiological factors show less recurrences if the total duration of the treatment is < 55 days, the number of days between External Beam Irradiation and brachytherapy is < 20. The security margin seems important also. CONCLUSIONS: For the combination external irradiation and brachytherapy, the multivariate study for local control shows that ony T, localization, and the total duration of treatment are significant. For complications, classified into four grades, only the dose rate is significant.

Conservative treatment by irradiation of epidermoid cancers of the anal canal: prognostic factors of tumoral control and complications.

UNLABELLED: We analyzed in a retrospective series of patients treated by conservative irradiation for an epidermoid cancer of the anal canal (ECAC) the prognostic factors of locoregional control (LRC), survival, late severe complications (LSC), and sphincter conservation (SC). METHODS AND MATERIALS: From 1976 until 1994, 118 patients presenting with an ECAC were conservatively treated (mean age, 65 years). According to the 1987 International Union Against Cancer (TNM) classification, they were: 19 T1, 70 T2, 22 T3, 7 T4, 94 N0, and 24 N1-3. The treatment started with external beam irradiation (EBI) (36 Gy in 3 weeks or 45 Gy in 5 weeks). Concomitant chemotherapy (5-fluorouracil and mitomycin C) was delivered to 31 patients. Two months later, a boost of 20 Gy was delivered by interstitial 192Ir brachytherapy to 101 patients and EBI in 5. Twelve other patients had an abdominoperineal resection (APR). The mean follow-up was 6 years. RESULTS: At 5 years the overall survival was 60%, and specific survival (SS) was 75%; it was 94% for T1, 79% for T2, 53% for T3, and 19% for T4. In multivariate analysis, tumor size (> or = 4 cm), node involvement, and no response to the EBI were factors of poor prognosis for SS. Thirty-two locoregional recurrences occurred of which 21 were local recurrences in the 106 patients treated by a conservative schedule. Only tumor size and response to the EBI were prognostic factors on multivariate analysis for local and LRC. A total of 17 patients presented with LSC (Grade 3, 16 patients; and Grade 4, 1 patient), which was treated by APR in 4 patients and colostomy in 11 (of which 7 were definitive). The only significant prognostic factor for LSC in the multivariate analysis was the total extrapolated response dose of irradiation. The definitive rate of SC after conservative treatment in cured patients was 100% for T1, 82% for T2, 58% for T3, and 100% for T4. Since 1989, improvements of the technique have allowed reduction of the LSC in maintaining the same local control. CONCLUSION: The results of this series are similar to those of the literature. The confirmation of pretherapeutic prognostic factors related to response to the treatment should allow us to adapt the therapeutic intensity for each case to obtain better tumor control, with as few sequelae as possible, to yield a better rate of SC.

Salvage irradiation by brachytherapy of velotonsillar squamous cell carcinoma in a previously irradiated field: results in 73 cases.

PURPOSE: The salvage brachytherapy performed in patients presenting velotonsillar carcinoma in a previously irradiated field is evaluated in terms of local control, complications and survival. METHODS AND MATERIALS: Between 1976 and 1990, 73 patients presenting with velotonsillar squamous cell carcinoma in a previously irradiated area were treated at Center Alexis Vautrin with brachytherapy along using an 192Ir implant (afterloading technique) with curative intent. According to the UICC 1987 TNM classification, there were 45 T1 N0, 20 T2 N0, one T3 NO, one T3 N2 and six Tx Nx. RESULTS: The 5-year actuarial local control for T1 N0 and T2 N0 are 80% and 67% respectively. The regional relapse rate was 10% in both groups. Grade 2 complications occurred in 13% of patients and these were neither related to the volume treated nor the dose rate. There were no Grade 3 or 4 complications. The 5-year specific survival is 64%, with a plateau after the 5th year, but the 5-year overall survival is only 30%. Fourty-two percent of the patients in this series died from another carcinoma. All but two of these were related to continued alcohol and tobacco intoxication. CONCLUSION: We conclude that brachytherapy alone (60 Gy) is optimal treatment for patients presenting with velontonsillar carcinoma in a previously irradiated field. The greatest challenge is the screening of these patients and the prevention of subsequent head and neck cancers. Recognizing the fact that these patients are at high risk for subsequent malignancies of upper aerodigestive tract, lung and esophagus, close surveillance is necessary for: (a) early diagnosis and prompt treatment; and (b) development of prevention strategies of field cancerization.

Prognostic implications of downstaging following preoperative radiation therapy for operable T3-T4 rectal cancer.

PURPOSE: To evaluate the prognostic value of tumor downstaging after preoperative radiation for resectable rectal cancer. METHODS AND MATERIALS: Eighty-eight patients with non-metastatic resectable rectal cancers (76 T3 and 12 T4) were treated with preoperative irradiation. Median dose was 40 Gy (30-46 Gy) delivered over 32 days (range 11-40). Seventeen patients received preoperative chemotherapy, two courses of 5-fluorouracil (5FU) 350 mg/m2/day and folinic acid 20 mg/m2/day; 5 days per week during the first and fifth weeks of radiotherapy. Surgery was performed with a mean delay of 46 days after completion of irradiation and included 66 abdominoperineal resections and 22 anal sphincter-preserving procedures. Postoperative chemotherapy was administered in 44 patients. RESULTS: Histological tumor stages were: complete histological response in 7%, pT2N0 in 19%, pT3N0 in 46%, and pT2-3N1 in 28%. Tumor downstaging occurred in 26%. No predictive factor of downstaging was statistically significant. The median follow-up was 33 months. The 3- and 5-year cancer-specific survival rates were 100% for the pT0N0 and pT2N0, respectively, 89% and 68% for pT3N0, and 64% and 0% for pT2T3N1. After preoperative irradiation, the pathological tumor stages remained a prognostic factor. Patients with downstaging (pT0T2N0) had significantly higher cancer-specific survival rates than the group without downstaging: 100% and 80% at 3 years, and 100% and 45% at 5 years; respectively (p = 0.011). The 3- and 5-year recurrence free-survival rates were 94% for the group with downstaging and 56% and 50%, respectively, for the group without downstaging (p = 0.002). CONCLUSION: Downstaging after preoperative irradiation in this retrospective study results in an improvement in local control and survival.

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

PURPOSE: To evaluate the feasibility of dose escalation in a multi-institutional study in prostate cancer patients. METHODS AND MATERIALS: Between October 1995 and October 1998, 164 patients with localized adenocarcinoma of the prostate were treated with 3-dimensional conformal radiotherapy at one of five French institutions. The dose of radiation was escalated from 66 to 80 Gy (ICRU point). The maximum dose to the rectal wall was limited to 75 Gy. RESULTS: Results were compared in two groups, one (group 1) receiving the standard dose (n = 46 patients; 66 to 70 Gy) and the other (group 2) receiving the escalated dose (n = 118 patients; 74 to 80 Gy). There was no difference in the characteristics of patients between the two groups. The mean follow-up time was 32 months in group 1 and 17.5 months in group 2. No statistical difference between the two groups was observed in the incidence of late gastrointestinal and urinary toxicities. The probability of achieving a posttreatment prostate-specific antigen nadir of