A. de la Rochefordière

Age as prognostic factor in premenopausal breast carcinoma

Whether or not young age at diagnosis is an adverse prognostic factor in breast cancer has long been controversial, in part because much previous work has not taken due account of menopausal status and confounding factors. We have analysed the influence of age on prognosis in a consecutive series of 1703 patients with stage I-III breast cancer. All were premenopausal and all were treated in one centre (Institut Curie, Paris) between 1981 and 1985. Mean age was 44 years (range 23-55) and median follow-up was 82 months. Younger patients had significantly lower survival rates and higher local and distant relapse rates than older patients. The hazard rate of relapse decreased over time in the youngest age group (< or = 33) to reach that of older patients after 5 years. The relation between the hazard of recurrence and age was a continuous one, best fitted by a log-linear function and indicating a 4% decrease in recurrence for every year of age. Multivariate analysis of both survival and disease-free interval demonstrated that the worse prognosis of young age was independent of other factors such as clinical tumour size, clinical node status, histological grade, hormone receptor status, locoregional treatment procedure, and adjuvant systemic therapy. This difference in outlook has yet to be explained biologically but it does suggest the need for a closer look at the natural history of breast cancer in young women.

Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomised trial: S6

The aim of this study was to assess a potential advantage in survival by neoadjuvant as compared to adjuvant chemotherapy. 414 premenopausal patients with T2-T3 N0-N1 M0 breast cancer were randomised to receive either four cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, 5-fluorouracil), followed by local-regional treatment (group I) or four cycles of adjuvant chemotherapy after primary irradiation +/- surgery (group II). Surgery was limited to those patients with a persisting mass after irradiation, and aimed to be as conservative as possible. 390 patients were evaluable. With a median follow-up of 54 months, we observed a statistically significant difference (P = 0.039) in survival in favour of the neoadjuvant chemotherapy group. A similar trend was seen when the time to metastatic recurrence was evaluated (P = 0.09). At this stage, no difference in disease-free interval or local recurrence between these two groups could be observed. The mean total dose of chemotherapy administered was similar in both groups. On average, group I had more intensive chemotherapy regimes (doxorubicin P = 0.02) but fewer treatment courses (P = 0.008) as compared to the treated patients in group II. Haematological tolerance was reduced when chemotherapy succeeded to exclusive irradiation. Breast conservation was identical for both groups at the end of primary treatment (82 and 77% for groups I and II, respectively). Of the 191 evaluable patients in the neoadjuvant treatment arm, 65% had an objective response (> 50% regression) following four cycles of chemotherapy. The objective response rate to primary irradiation (55 Gy) was 85%. Improved survival figures in the neoadjuvant treatment arm could be the result of the early initiation of chemotherapy, but we cannot exclude that this difference might be attributable to a slightly more aggressive treatment. So far, the trend in favour of decreased metastases was not statistically significant. The local control appeared similar in both subgroups.

Neoadjuvant chemotherapy in young breast cancer patients: correlation between response and relapse?

The aim of this analysis was to assess how the clinical response to chemotherapy corresponded to long-term prognosis in patients of less than 35 years of age. A retrospective analysis was made of response and survival data of 609 premenopausal patients who had been treated by four cycles of neoadjuvant chemotherapy followed by surgery and/or radiotherapy. Patients were stratified into three age groups (group 1, < or = 35 years; group 2, 35-40 years; group 3, > or = 41 years). Objective and complete clinical response rates were significantly higher in the youngest patients (below 35 yrs: P = 0.005 and P = 0.001, respectively) in stark contrast to a particularly poor outcome of this subpopulation. Five-year local recurrence rates were 31% in the youngest patients, compared with 26% and 16% in groups 2 and 3, respectively (P = 0.0007). Group 1 patients also had significantly higher 5-year metastatic relapse rates (41% versus 35% and 28%; P = 0.007) and 5-year survival figures were 70%, 82% and 84% for groups 1, 2 and 3 respectively (P = 0.002). Finally, stratification by age and by response revealed that, whilst the outcome of the youngest patients was highly dependent on their response to primary chemotherapy, complete responders showed disease-free survival rates at 5 years that were lower than these of older patients, whatever their response. Despite a seemingly better control of the primary tumour by chemotherapy, the patients in the youngest age group remained at a high risk for local and metastatic relapse. This apparent paradox may be in part attributable to rapid disease progression of micrometastatic tumour subpopulations that are refractory to chemotherapy.

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.

Medullary breast carcinoma: Prognostic implications of p53 expression

Medullary breast carcinoma (MBC) is a rare pathological type of breast cancer. The rate of p53 protein accumulation is higher in MBC than in common invasive ductal carcinoma. Whether this particular feature of MBC influences the outcome after treatment is unknown. We retrospectively analyzed the characteristics, treatment and outcome of 71 patients with MBC treated between 1981 and 1996. The median age was 51 years (range 27-81) and the median clinical tumor size was 25 mm (range 0-70 mm). Breast-conserving treatment was offered when possible: 55 patients had undergone a tumorectomy and radiotherapy while 16 patients had undergone a mastectomy. p53 protein accumulation was determined by immunohistochemistry on paraffin-embedded tumor specimens from 58/71 samples available for this study. The median follow-up for the 56 survivors was 113 months (range 30-241). The 10-year survival and metastasis-free survival rates were 81% and 81.4%, respectively. The local recurrence rate was 16.4%. The two factors predicting outcome were pathological axillary node involvement in the 60 patients who underwent axillary dissection and adjuvant chemotherapy. p53 accumulation was found in 33/58 patients (57%). p53 status was not predictive of survival nor of distant or local recurrences. We confirm that medullary breast carcinoma has a favorable prognosis despite its aggressive pathological features. p53 protein accumulation, found in the majority of MBCs, was not related to outcome.

Outcome in early cervical cancer following pre-operative low dose rate brachytherapy: A ten-year follow up of 257 patients treated at a single institution

OBJECTIVE To report the outcome of preoperative low dose rate uterovaginal brachytherapy (LDR-UVBT) followed by radical surgery in the treatment of early cervical carcinoma. METHODS 257 patients treated at Institut Curie from 1985 to 2008 for cervical carcinoma less than 4cm (FIGO stages Ib1, IIA and IIB) were studied. Patients received preoperative LDR-UVBT followed by hysterectomy Piver II type, with pelvic lymph nodes dissection (PLND). Predictive factors for pathological response to brachytherapy were analyzed with logistic regression, as well as survival rates. RESULTS 44% of patients had residual tumor, 4.3% of patients had parametrial invasion and 17.9% of patients had lymph node involvement. Predictive factors for an incomplete pathological response were: initial clinical tumor size 20mm (OR 2.1), pN1 (OR 2.77), glandular carcinoma (OR 2.51) and lymphovascular invasion (OR 4.35). 7.4% and 2.7% of patients had respectively grade 2 and grade 3 post-therapeutic late complications. Median follow up was 122 months [1-282]. Five-year actuarial overall survival and disease free survival were respectively 83% CI [78.3-87.5] and 80.9% CI [76.3-85.7]. In multivariate analysis, factors affecting significantly the overall survival and disease free survival rates were: lymph node involvement (RR 4.53 and 8.96 respectively), parametrial involvement (RR 5.69 and 5.62 respectively), smoking (RR 3.07 and 2.63 respectively). CONCLUSIONS Preoperative LDR-UVBT results in good disease control with a low complications rate. Its accuracy could be improved by a better selection of patients. Lymph nodes and parametrial evaluation remains a challenging issue that should be achieved with imaging and minimal invasive surgery.

Clinico-pathology and prognosis of endometrial cancer in patients previously treated for breast cancer, with or without tamoxifen: A comparative study in 363 patients

OBJECTIVE To compare the clinic-pathologic variables and the prognosis of endometrial cancer in patients with and without previous breast cancer, with and without Tamoxifen. METHODS We analyzed patients treated for an endometrial carcinoma from 1994 to 2004: patients without breast cancer (group 1), patients with a previous breast cancer without tamoxifen (group 2) and patients treated for breast cancer with tamoxifen (group 3). Survival rates were calculated according to Kaplan-Meier method and compared using a Log rank test, multivariate analysis was performed with a Cox regression model. RESULTS 363 patients were analyzed. 80 patients had a previous history of breast cancer (43 received tamoxifen). Although it was not statistically significant, more carcinosarcomas were observed in patients in group 3 than patients in groups 1 and 2 (11.7% versus 4.2% and 5.4% respectively, p = 0.17).) Median follow-up was 87 months [2-185]. 5-year overall survival rate was respectively in groups 1, 2 and 3: 82%, 73.2%, and 61% (p = 0.0006). 5-year local relapse-free survival rate was respectively: 95.9%, 93.1% and 82.5% (p = 0.02). In multivariate analysis, factors affecting overall survival rate were: age ≥65 ans (HR 3.62, p < 0.0001), FIGO stage (HR 3.33 p < 0.0001 for locally advanced stage versus early stage, HR 8.87 p = 0.03 for distant extension versus early stage), and group 3 (HR 2.83 p < 0.001 versus group 1). CONCLUSION Patients with endometrial cancer previously treated for breast cancer show a worse prognostic, particularly if they reveived tamoxifen.

Chimioradiothérapie concomitante préopératoire dans les carcinomes du col utérin de stades IB2 à IIB: expérience de l'institut Curie

PURPOSE To evaluate the treatment results of patients (pts) with Figo stage IB2, IIA, IIB cervical carcinoma (CC) treated with preoperative radiochemotherapy, followed by extended radical hysterectomy. PATIENTS AND METHODS Retrospective study of 148 women treated at the Institut Curie for operable Figo Stage IB2 to IIB, biopsy proved CC. Among them, 70 pts, median age 46 years, were treated using the same regimen associating primary radiocisplatinum based chemotherapy, intracavitary LDR brachytherapy, followed by extended radical hysterectomy. Kaplan-Meier estimates were used to draw survival curves. Comparisons of survival distribution were assessed by the log-rank test. RESULTS Complete histological local-regional response was obtained in 56% of the pts (n=39). Residual macroscopic or microscopic disease in the cervix was observed in 28 pts (40%). All but one had in situ microscopic residual CC. Lateral residual disease in the parametria was also present in nine pts, all with residual CC. Pelvic lymph nodes were free from microscopic disease in 56 pts (80%). Eight of 55 (11%) radiological N0 patients had microscopic nodal involvement, as compared to 6/15 (40%) radiological N1 (p=0.03). Seventeen pts (25%) had residual cervix disease but negative nodes. After median follow-up of 40 months (range, 8-141), 38/70 patients (54.1%) are still alive and free of disease, six (8.6%) alive with disease, and 11 (15.8%) patients were lost for follow-up but free of disease. CONCLUSION The treatment of locally advanced CC needs a new multidisciplinary diagnostic and treatment approach using new therapeutic arms to improve the survival and treatment tolerance among women presenting this disease.

What is the impact of neoadjuvant chemoradiation on outcomes in gastro-intestinal cancer?

Multimodal therapeutic strategies combining chemotherapy, radiation therapy and surgery have been shown to be feasible and to have a positive impact on outcomes by decreasing the risk of locoregional recurrence and often by increasing overall survival. The advantages of neoadjuvant chemo(radio)therapy include optimal tumor control combined with better tolerance and compliance to treatment while also increasing the number of candidates for surgery. Whereas indications for neoadjuvant therapy are increasing, its impact on surgical treatment and postoperative outcomes are not well-known. Surgeons frequently believe that chemo(radio)therapy may amplify intraoperative difficulties, thereby increasing postoperative morbidity and mortality. The aim of this review was to report the state of the art regarding: (i) the role of chemo(radio)therapy; (ii) its impact on surgical indications and modalities; and (iii) its impact on postoperative outcomes for the most frequently encountered gastro-intestinal cancers, i.e. esophageal, rectal, pancreatic, and anal canal cancer.

Toxicity and early clinical outcomes in cervical cancer following extended field helical tomotherapy to para-aortic lymph nodes ☆

PURPOSE To evaluate toxicity and early disease outcome among patients treated for cervical cancer with extended-field helical tomotherapy to the para-aortic nodes. PATIENTS AND METHODS Thirty-eight patients (International Federation of Gynecology and Obstetrics [FIGO] stage IB2-IVA) from four institutions received extended-field helical tomotherapy and were retrospectively evaluated. All had nodal disease. Para-aortic lymph nodes were involved in 31 patients. Patients were assessed for toxicity using version 4 of the National Cancer Institutes common terminology criteria for adverse events. Survival curves were plotted using Kaplan-Meier estimates. RESULTS All patients underwent radiation to the tumor region (median dose: 45Gy; range: 44-66Gy), pelvic lymph nodes and para-aortic lymph nodes (median dose: 45Gy; range: 44-60Gy). The median dose to positive lymph nodes was 55Gy (range: 45-65Gy). All received platinum-based chemotherapy (31 concurrently). The median follow-up was 15months. Acute toxicity events observed included one patient with grade 5 febrile neutropenia, 11 patients (29%) with grade 3 hematologic complications. Grades 3-4 gastrointestinal and genitourinary toxicities occurred in six (16%) and four (11%) patients, respectively. Three patients had grade 3 pelvic pain (8%). The 6- and 18-month overall survival rates were 94.7 and 63.9%, respectively. The 18-month locoregional control, disease-free survival, and late grade 3 toxicity rates were 60.2, 43.3 and 7.3%, respectively. CONCLUSION Extended-field helical tomotherapy was associated with low rates of acute gastrointestinal and genitourinary toxicities with early survival and locoregional control similar to other published series.