Emmanuel Chamorey

Prognostic factors in 1038 women with metastatic breast cancer

BACKGROUND Treatment of metastatic breast cancer (MBC) remains palliative. Patients with MBC represent a heterogeneous group whose prognosis and outcome may be dependent on host factors. The purpose of the present study was dual: first, to draw up a list of factors easily available in everyday clinical practice requiring no sophisticated or costly methods and second, to provide results from a large cohort of women who underwent diagnostic and treatment at a single institution. PATIENTS AND METHODS From 1975 to 2005, a total of 1,038 women with MBC during their follow-up were included in this retrospective analysis. Patients were subsequently assigned to five groups according to the period of metastatic diagnosis. RESULTS It is shown that age at initial diagnosis, hormonal receptor status and site of metastasis are the most relevant prognostic factors for predicting survival from the time of metastastic occurrence. It is also shown that a metastasis-free interval is an easily and immediately available multifactorial prognostic index reflecting the multiparametric variability of the disease. CONCLUSION These fundamental observations may assist physicians in evaluating the survival potential of patients and in directing them toward the appropriate therapeutic decision.

HIF‐1α and CA IX staining in invasive breast carcinomas: Prognosis and treatment outcome

Hypoxia stabilizes HIF‐1α (Hypoxia Inducible Factor‐1α), which then triggers the expression of several genes involved in many aspects of cancer progression, including metabolic adaptation, cell survival and angiogenesis. The aim of our study was to evaluate the impact of HIF‐1α and CA IX (carbonic anhydrase IX) (one of its target genes) expression on prognosis and treatment outcome of patients with breast cancer. Because of the extreme O2‐dependent instability of the protein, we first validated HIF‐1α staining using xenograft tumours that were subjected to experimental conditions mimicking surgical clamping or sitting at room temperature under normoxic conditions after surgical excision but before fixation. Afterwards, the immunohistochemical staining of HIF‐1α and CA IX was evaluated in 132 invasive breast carcinomas with a 10‐year follow‐up, and correlated to classical clinicopathological parameters and response to adjuvant therapy. No significant correlation was found between tumour size or nodal status and the expression of HIF‐1α or CA IX. Statistically significant association was found between HIF‐1α or CA IX staining and the grade, hormonal receptors loss and the presence of carcinoma in situ. Overexpression of HIF‐1α and CA IX correlates with a poor prognosis in breast cancer. We show that HIF‐1α is an independent prognostic factor for distant metastasis‐free survival and disease‐free survival in multivariate analysis. Furthermore, overexpression of HIF‐1α or CA IX correlates with a poor outcome after conventional adjuvant therapy. CA IX is, however, a weaker prognostic and predictive factor than HIF‐1α, and its association with HIF‐1α does not modify the survival curve neither response to therapy, compared to HIF‐1α alone.

Free-flap head and neck reconstruction and quality of life: a 2-year prospective study.

Objectives: This prospective study was designed to evaluate quality of life (QOL) after free‐flap head and neck reconstruction.

Radical ablative surgery and radial forearm free flap (RFFF) reconstruction for patients with oral or oropharyngeal cancer: postoperative outcomes and oncologic and functional results

Conclusions. Radical ablative surgery and radial forearm free flap (RFFF) reconstruction provide promising oncologic and functional results in patients with oral or oropharyngeal cancer. Objectives. To assess the postoperative outcomes and the oncologic and functional results, with their main predictive factors, after radical ablative surgery and RFFF reconstruction for patients with oral or oropharyngeal cancer. Patients and methods. Between 2000 and 2006, we prospectively analyzed the postoperative, oncologic and functional outcomes of all previously untreated patients who underwent this type of surgery. Results. A total of 132 patients were enrolled in this study. There were three RFFF failures. The rate of surgical complications was 20%. The 5-year locoregional control and overall survival rates were 68% and 52%, respectively. Advanced age, high comorbidity index, elevated overall stage and tumoral involvement of the inner part of the cheek were correlated with a lower overall survival rate. A good functional result was obtained for oral diet, speech, mouth opening and aesthetic outcome in 87%, 80%, 86% and 88% of the patients, respectively. High comorbidity index, large flap surface, radiotherapy and tumoral involvement of the mobile tongue were significant predictors of poorer functional or aesthetic outcomes.

Proton beam radiotherapy for uveal melanomas at nice teaching hospital: 16 years' experience.

PURPOSE To present the results of uveal melanomas treated at Nice Teaching Hospital. METHODS AND MATERIALS This retrospective study included 886 consecutive patients referred to our clinic for the treatment of uveal melanomas by proton beam radiotherapy from June 1991 to December 2007. Survival rates were determined by using Kaplan-Meier estimates, and prognostic factors were evaluated using the log-rank test or Cox model. RESULTS The number (percent total) of subjects staged according to the TNM classification system (6th edition) of malignant tumors included 39 stage T1 (4.4%), 420 stage T2 (47.40%), 409 stage T3 (46.16%), and 18 stage T4 (2.03%) patients. The median follow-up was 63.7 months. The Kaplan-Meier overall survival rate at 5 years according to the sixth edition TNM classification was 92% for T1, 89% for T2, 67% for T3, and 62% for T4; and at 10 years, 86% for T1, 78% for T2, 43% for T3, and 41% for T4. Five factors were found to be associated with an increased death rate: advanced age, tumor thickness, largest tumor basal diameter, tumor volume, and tumor volume-to-eyeball volume ratio. The metastasis-free survival rates were 88.3 % at 5 years and 76.4 % at 10 years. The local control rates were 93.9% at 5 years and 92.1% at 10 years. The ocular conservation rates were 91.1% at 5 years and 87.3% at 10 years. CONCLUSIONS We report the results of a large series of patients treated for uveal melanomas with a very long follow-up. Despite the large tumor volume treated, our results were similar to previously published findings relating to proton beam therapy.

The CXCL7/CXCR1/2 Axis Is a Key Driver in the Growth of Clear Cell Renal Cell Carcinoma

Mutations in the von Hippel-Lindau gene upregulate expression of the central angiogenic factor VEGF, which drives abnormal angiogenesis in clear cell renal cell carcinomas (ccRCC). However, the overexpression of VEGF in these tumors was not found to correlate with overall survival. Here, we show that the proangiogenic, proinflammatory cytokine CXCL7 is an independent prognostic factor for overall survival in this setting. CXCL7 antibodies strongly reduced the growth of ccRCC tumors in nude mice. Conversely, conditional overexpression of CXCL7 accelerated ccRCC development. CXCL7 promoted cell proliferation in vivo and in vitro, in which expression of CXCL7 was induced by the central proinflammatory cytokine interleukin (IL)-1β. ccRCC cells normally secrete low amounts of CXCL7; it was more highly expressed in tumors due to high levels of IL-1β there. We found that a pharmacological inhibitor of the CXCL7 receptors CXCR1 and CXCR2 (SB225002) was sufficient to inhibit endothelial cell proliferation and ccRCC growth. Because CXCR1 and CXCR2 are present on both endothelial and ccRCC cells, their inhibition affected both the tumor vasculature and the proliferation of tumor cells. Our results highlight the CXCL7/CXCR1/CXCR2 axis as a pertinent target for the treatment of ccRCC.

Phase 1 Clinical Trial of Stereotactic Body Radiation Therapy Concomitant With Neoadjuvant Chemotherapy for Breast Cancer

PURPOSE Stereotactic body radiation therapy (SBRT) allows stereotactic irradiation of thoracic tumors. It may have a real impact on patients who may not otherwise qualify for breast-conserving surgery. We conducted a phase 1 trial that tested 5 dose levels of SBRT concomitant with neoadjuvant chemotherapy (NACT) before to surgery. The purpose of the current dose escalation study was to determine the maximum tolerable dose of SBRT in the treatment of breast cancer. METHODS AND MATERIALS To define toxicity, we performed dermatologic examinations that included clinical examinations by 2 separate physicians and technical evaluations using colorimetry, dermoscopy, and skin ultrasonography. Dermatologic examinations were performed before NACT, 36 and 56 days after the beginning of NACT, and before surgery. Surgery was performed 4 to 8 weeks after the last chemotherapy session. Efficacy, the primary endpoint, was determined by the pathologic complete response (pCR) rate. RESULTS Maximum tolerable dose was not reached. Only 1 case of dose-limiting toxicity was reported (grade 3 dermatologic toxicity), and SBRT was overall well tolerated. The pCR rate was 36%, with none being observed at the first 2 dose levels, and the highest rate being obtained at dose level 3 (25.5 Gy delivered in 3 fractions). Furthermore, the breast-conserving surgery rate was up to 92% compared with an 8% total mastectomy rate. No surgical complications were reported. CONCLUSIONS This study demonstrates that SBRT can be safely combined with NACT. Regarding the efficacy endpoints, this trial showed promising results in terms of pCR rate (36%) and breast-conserving rate (92%). The findings provide a strong rationale for extending the study into a phase 2 trial. In view of the absence of correlation between dose and pCR, and given that the data from dose level 3 met the statistical requirements, a dose of 25.5 Gy in 3 fractions should be used for the phase 2 trial.

Contact X-ray Therapy for Rectal Cancer: Experience in Centre Antoine-Lacassagne, Nice, 2002–2006

PURPOSE To report the results of using contact X-ray (CXR), which has been used in the Centre-Lacassagne since 2002 for rectal cancer. METHODS AND MATERIALS A total of 44 patients were treated between 2002 and 2006 using four distinct clinical approaches. Patients with Stage T1N0 tumors were treated with transanal local excision (TLE) and adjuvant CXR (45 Gy in three fractions) (n = 7). The 11 inoperable (or who had refused surgery) patients with Stage T2-T3 disease were treated with CXR plus external beam radiotherapy (EBRT). Those with Stage T3N0-N2 tumors were treated with preoperative CXR plus EBRT (with or without concurrent chemotherapy) followed by surgery (n = 21). Finally, the patients with Stage T2 disease were treated with CXR plus EBRT followed by TLE (n = 5). RESULTS The median follow-up was 25 months. In the 7 patients who underwent TLE first, no local failure was observed, and their anorectal function was good. Of the 11 inoperable patients who underwent CXR plus EBRT alone, 10 achieved local control. In the third group (preoperative CXR plus EBRT), anterior resection was performed in 16 of 21 patients. Complete sterilization of the operative specimen was seen in 4 cases (19%). No local recurrence occurred. Finally, of the 5 patients treated with CXR plus EBRT followed by TLE, a complete or near complete clinical response was observed in all. TLE with a R0 resection margin was performed in all cases. The rectum was preserved with good function in all 5 patients. CONCLUSION These early results have confirmed that CXR combined with surgery (or alone with EBRT) can play a major role in the conservative and curative treatment of rectal cancer.

Phase II Trial Evaluating a Docetaxel-Capecitabine Combination as Treatment for Hormone-Refractory Prostate Cancer

Docetaxel is a well‐recognized drug in patients with hormone‐refractory prostate cancer (HRPC), either alone or combined with estramustine. In this indication, a Phase II trial was conducted investigating a docetaxel‐capecitabine combination.

Modeling of Salivary Production Recovery After Radiotherapy Using Mixed Models: Determination of Optimal Dose Constraint for IMRT Planning and Construction of Convenient Tools to Predict Salivary Function

PURPOSE The mathematical relationship between the dose to the parotid glands and salivary gland production needs to be elucidated. This study, which included data from patients included in a French prospective study assessing the benefit of intensity-modulated radiotherapy (RT), sought to elaborate a convenient and original model of salivary recovery. METHODS AND MATERIALS Between January 2001 and December 2004, 44 patients were included (35 with oropharyngeal and 9 with nasopharyngeal cancer). Of the 44 patients, 24 were treated with intensity-modulated RT, 17 with three-dimensional conformal RT, and 2 with two-dimensional RT. Stimulated salivary production was collected for </=24 months after RT. The data of salivary production, time of follow-up, and dose to parotid gland were modeled using a mixed model. Several models were developed to assess the best-fitting variable for the dose level to the parotid gland. RESULTS Models developed with the dose to the contralateral parotid fit the data slightly better than those with the dose to both parotids, suggesting that contralateral and ipsilateral parotid glands are not functionally equivalent even with the same dose level to the glands. The best predictive dose-value variable for salivary flow recovery was the volume of the contralateral parotid gland receiving >40 Gy. CONCLUSION The results of this study show that the recommendation of a dose constraint for intensity-modulated RT planning should be established at the volume of the contralateral parotid gland receiving >40 Gy rather than the mean dose. For complete salivary production recovery after 24 months, the volume of the contralateral parotid gland receiving >40 Gy should be <33%. Our results permitted us to establish two convenient tools to predict the saliva production recovery function according to the dose received by the contralateral parotid gland.