[Show abstract][Hide abstract] ABSTRACT: Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater anti-tumor activity compared to cetuximab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy.
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Rectal and pararectal gastrointestinal stromal tumors (GISTs) are rare. The optimal management strategy for primary localized GISTs remains poorly defined.
We conducted a retrospective analysis of 41 patients with localized rectal or pararectal GISTs treated between 1991 and 2011 in 13 French Sarcoma Group centers.
Of 12 patients who received preoperative imatinib therapy for a median duration of 7 (2-12) months, 8 experienced a partial response, 3 had stable disease, and 1 had a complete response. Thirty and 11 patients underwent function-sparing conservative surgery and abdominoperineal resection, respectively. Tumor resections were mostly R0 and R1 in 35 patients. Tumor rupture occurred in 12 patients. Eleven patients received postoperative imatinib with a median follow-up of 59 (2.4-186) months. The median time to disease relapse was 36 (9.8-62) months. The 5-year overall survival rate was 86.5%. Twenty patients developed local recurrence after surgery alone, two developed recurrence after resection combined with preoperative and/or postoperative imatinib, and eight developed metastases. In univariate analysis, the mitotic index (<=5) and tumor size (<=5 cm) were associated with a significantly decreased risk of local relapse. Perioperative imatinib was associated with a significantly reduced risk of overall relapse and local relapse.
Perioperative imatinib therapy was associated with improved disease-free survival. Preoperative imatinib was effective. Tumor shrinkage has a clear benefit for local excision in terms of feasibility and function preservation. Given the complexity of rectal GISTs, referral of patients with this rare disease to expert centers to undergo a multidisciplinary approach is recommended.
BMC Cancer 03/2014; 14(1):156. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metastases are responsible for the majority of deaths from solid cancers. Metastatic phenomenon, complex, is a multi-step process where interactions between cells and with the microenvironment are essential. The organ tropism, that is the propensity of a cancer to metastasize to specific organs, can be explained by several mechanisms that we have described. Apart from the usual metastases, unusual sites can appear with heterogeneous clinical presentations. We describe known to date mechanisms that can explain these unusual metastasis. A summary of these locations has been realized. A rare location should always be considered in front of any atypical symptom.
[Show abstract][Hide abstract] ABSTRACT: Recent years have seen the emergence of new molecules for the treatment of patients with metastatic cutaneous melanoma, with significant benefits in terms of survival and the opening of new therapeutic perspectives. In addition, many techniques are currently being developed for locoregional treatment of metastatic sites. Management of metastatic melanoma is thus fast-changing and is marked by innovative therapeutic approaches. However, the availability of these new treatments has prompted debate among healthcare professionals concerning their use and their place in therapeutic strategy.
Since 2008, the French National Cancer Institute (INCa) has been leading a project to define and diffuse national clinical practice guidelines. It has performed a review of these treatment methods, which it aims to circulate, and it is seeking to develop recommendations in order to allow nationwide implementation of innovative approaches while promoting good use thereof.
The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts within a multidisciplinary working group, with feedback from specialists in cancer care delivery. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery.
This article presents the national recommendations for first- and second-line systemic treatment and for locoregional treatment of metastatic sites in patients presenting metastatic cutaneous melanoma.
Annales de Dermatologie et de Vénéréologie 02/2014; 141(2):111-21. · 0.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: la mise à disposition récente de nouvelles molécules pour le traitement du mélanome cutané métastatique avec un bénéfice significatif sur la survie des patients soulève auprès des professionnels de santé des interrogations quant à leur utilisation et place dans la stratégie thérapeutique.l’Institut national du cancer (INCa), dont l’une des missions est de définir et de favoriser la diffusion de recommandations nationales de bonnes pratiques cliniques depuis 2008, a souhaité diffuser un état des lieux des connaissances sur ces nouvelles modalités de traitement et formuler des recommandations afin de permettre une diffusion au niveau national de l’innovation tout en favorisant son bon usage.le processus d’élaboration est basé sur une revue systématique de la littérature et sur le jugement argumenté d’experts cliniciens au sein d’un groupe de travail multidisciplinaire. Avant publication, les recommandations sont revues par des experts cliniciens indépendants du groupe de travail.cet article présente les recommandations nationales relatives au traitement systémique de 1ère et de 2ème ligne des patients atteints d’un mélanome cutané métastatique (hors métastase cérébrale).
[Show abstract][Hide abstract] ABSTRACT: the last years are marked by the emergence of new molecules for the treatment of metastatic cutaneous melanoma with a significant benefit on the survival. Besides, some techniques are in development for the loco-regional treatment of the metastatic sites, bringing new therapeutic perspectives. However, their respective use and place in the therapeutic strategy are debated by healthcare professionals. the French National Cancer Institute leads a national clinical practice guidelines project since 2008. It realized a review of these modalities of treatment and developed recommendations. the clinical practice guidelines development process is based on systematic literature review and critical appraisal by a multidisciplinary expert workgroup. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery. this article presents recommendations for loco-regional treatments of the pulmonary, bone, cutaneous, hepatic and digestive metastatic sites for patients with pauci-metastatic cutaneous melanoma.
[Show abstract][Hide abstract] ABSTRACT: As a consequence of under-representation of elderly patients in clinical trials, the recommended dose of chemotherapy is often based on results observed in younger patients. We designed a risk-adapted, dose escalation study of weekly docetaxel in the first-line treatment of elderly patients with cancer in order to determine the optimal dose according to age, comorbidity and functional status.
Sixty-eight patients aged 70 or more were stratified into three risk groups according to a combination of age, performance status, and comorbidity. The study was conducted using a standard phase I design with sequential cohorts of patients receiving docetaxel at increasing doses in each risk group.
The maximum tolerated dose was not reached in the intermediate-risk group and was 45mg/m(2)/week in the high-risk group. Because of a slow recruitment rate, it was not possible to conclude the trial in the good-risk category. Neutropenia, asthenia and diarrhea were the most frequently encountered severe toxicities.
Docetaxel can be used at a dose of 40mg/m(2)/week as a first-line treatment for elderly patients with locally advanced or metastatic cancer without excessive toxicity. The risk groups defined in the study are not able to accurately distinguish between subgroups of patients with divergent toxicity profiles.
Journal of Geriatric Oncology 04/2013; 4(2):122-7. · 1.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Worldwide, head and neck carcinomas account for 5% of all malignancies. Two-thirds of patients relapse after initial multimodal therapy. Until early 2000, the median overall survival (OS) of metastatic patients was about 6months. Recently, new drugs have been incorporated in patient management, thus enabling an increase in OS. This review aims to define the comprehensive medical management of patients with relapsing head and neck carcinoma. METHODS: A comprehensive review of the literature was made targeting four topics: first- and second-line treatment, supportive care, and management of elderly patients. RESULTS: The choice of first- or second-line treatments is mainly based on performance status. In the elderly, geriatric assessment could be helpful. For PS 0.1 patients, the standard first-line treatment is 6cycles of cisplatin-5FU-cetuximab. In the event of response, cetuximab alone is prolonged until progression or unacceptable toxicity. For second-line treatment, several options are currently available: enrolment in clinical trials, single-agent therapy (methotrexate, taxane, cetuximab), and best supportive care (BSC). Supportive care has to be initiated very early in the course of the disease to prevent pain, dysphagia and malnutrition. In elderly patients, the therapeutic options are: first-line treatment with the EXTREME regimen replacing cisplatin by carboplatin for patients in good general condition or methotrexate alone for other patients. BSC continues to be given to all patients (i.e. poor general conditions). CONCLUSION: In spite of numerous pending issues requiring further investigation, these recommendations seem to be routinely applicable.
[Show abstract][Hide abstract] ABSTRACT: Background
We previously demonstrated that interruption of imatinib mesylate (IM) in responding patients (pts) with advanced gastrointestinal stromal tumours (GISTs) results in rapid reprogression. The impact of interruption on residual tumour, quality of response and secondary resistance has not been fully investigated.Patients and methodsWithin the BRF14 study, 71 non-progressing patients were randomly assigned in the interruption arms after 1, 3 or 5 years. IM was resumed in the case of progressive disease (PD). Tumour status at randomisation, relapse and after IM rechallenge, progression-free survival (PFS) and time to secondary resistance were analysed.ResultsAt data cut-off, 51 of 71 patients had restarted IM following documented PD. Eighteen patients (35%) progressed on known lesions only, while 33 patients (65%) had new lesions, with concomitant progression of known lesions in 17 patients. Only 8 (42%) of complete remission (CR) patients and 12 (52%) of partial response (PR) patients at randomisation achieved a new CR and PR. Patients progressing rapidly after interruption had a poorer prognosis. Tumour status at randomisation influenced time to progression after rechallenge.Conclusion
In advanced GIST patients interrupting IM, quality of response upon reintroduction did not reach the tumour status observed at randomisation. Rapid progression after imatinib interruption is associated with poor PFS after reintroduction.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Phase II trials demonstrate the activity of cisplatin in patients with refractory Ewing sarcoma family tumours (ESFT) and also the feasibility of giving cisplatin with oral VP16 in a variety of different cancers. This trial was conducted to evaluate the activity and toxicity profile of this combination delivered as outpatient therapy in patients with refractory/relapsed ESFT. METHODS: Cisplatin was administered on days 1, 8 and 15 and days 29, 36 and 43 (70 mg/m(2)/dose for patients <21 years of age and 50 mg/m(2)/dose ≥21 years). VP16 was administered at a dose of 50 mg/m(2) on days 1-15 and days 29-43 inclusive. A three-stage Fleming statistical design was used for analysis. RESULTS: Between January 2003 and October 2006, 45 patients aged between 5 and 46 years (median 19) were enrolled. Thirty-eight were evaluable for response. Patients had previously received one to three lines of chemotherapy (median = one). Seventy-three per cent of the patients had grade 3/4 neutropenia, 20 % developed fever, 40 % had grade 3/4 anaemia, 68 % grade 3/4 thrombocytopenia and 16 % grade 2/3 ototoxicity. Measured response after 2 cycles: 0 CR, 7 PR (18 %), 13 SD (34 %), 18 PD (48 %). There was excellent concordance between unidimensional and bidimensional criteria in 31 of 33 responses (94 %). PFS at 1 year was 39 %, with a median PFS of 6 months. Overall survival at 1 year was 44 %; median survival was 11 months. CONCLUSIONS: Cisplatin combined with oral VP16 is well tolerated and has acceptable side effects, but limited clinical activity in refractory/relapsed ESFT.
Cancer Chemotherapy and Pharmacology 11/2012; · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. This study aimed to evaluate the efficacy and toxicity of single-agent gemcitabine versus gemcitabine plus docetaxel as second-line therapy in patients with uterine and nonuterine leiomyosarcoma (LMS). Patients and Methods. Patients had metastatic or unresectable LMS and had received one prior anthracycline-based regimen. A total of 90 patients received either single-agent gemcitabine (arm A; gemcitabine, 1,000 mg/m(2) i.v. for 100 minutes on days 1, 8, and 15 of a 28-day cycle) or a combination of gemcitabine and docetaxel (arm B; gemcitabine, 900 mg/m(2) i.v. for 90 minutes on days 1 and 8, plus docetaxel, 100 mg/m(2) i.v. for 1 hour on day 8 of a 21-day cycle with lenograstim). The primary endpoint was the objective response rate. Results. The objective response rates were 19% and 24% in arm A (gemcitabine) and arm B (gemcitabine plus docetaxel), respectively, for patients with uterine LMS. For patients with nonuterine LMS, the objective response rates were 14% and 5% for arms A and B, respectively. The median progression-free survival times for arms A and B were 5.5 months and 4.7 months, respectively, for patients with uterine LMS. For patients with nonuterine LMS, the median progression-free survival times were 6.3 months and 3.8 months for arms A and B, respectively. One toxic death occurred in arm B. Conclusions. Both single-agent gemcitabine and gemcitabine plus docetaxel were found to be effective second-line therapies for leiomyosarcomas, with a 3-month progression-free survival rate of 40% for LMS with both uterine and nonuterine sites of origin. Single-agent gemcitabine yielded results similar to those of gemcitabine plus docetaxel in this trial, but patients using single-agent gemcitabine experienced less toxicity.
The Oncologist 08/2012; 17(9):1213-20. · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiosarcomas account for <2% of all soft tissue sarcomas. This subtype is one of the most aggressive forms of soft tissue sarcoma. The prognosis for angiosarcoma patients in the advanced phase remains poor with current cytotoxic agents (progression-free survival [PFS] time of ∼4 months and overall survival [OS] time of ∼8 months). We investigated the antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas in a phase II trial.
We conducted a stratified phase II trial. The primary endpoint was the progression-free rate (PFR) at 9 months according to the Response Evaluation Criteria in Solid Tumors. A two-stage design (optimal Simon design) was used. Patients received sorafenib (400 mg twice daily) for 9 months until unacceptable toxicity or tumor progression. Central pathological and radiological reviews were performed. Data on stratum A (superficial angiosarcoma) and stratum B (visceral angiosarcoma) are currently available. This trial is registered with ClinicalTrials.gov (identifier, NCT00874874).
Strata A and B recruited 26 and 15 patients, respectively. The median age was 63 years (range, 31-82 years), with 17 male and 24 female patients. Fourteen cases arose in irradiated fields. Thirty patients (73.0%) had been pretreated with conventional chemotherapy. No unexpected toxicity occurred. The PFR at 9 months was 3.8% in stratum A and 0.0% in stratum B. The median PFS times were 1.8 months and 3.8 months, respectively, whereas the median OS times were 12.0 months and 9.0 months, respectively. No responses were observed in chemotherapy-naïve patients, whereas a 40% tumor control rate and 23% response rate were observed in the pretreated population. In this cohort, no activating mutation of the KDR gene (exons 15, 16, 24) was detected.
Sorafenib showed limited antitumor activity in pretreated patients only, for both visceral and superficial angiosarcoma, but tumor control was of short duration.
The Oncologist 01/2012; 17(2):260-6. · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2-6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity.
Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib.
Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.
British Journal of Cancer 08/2011; 105(5):618-27. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients.
Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7.
From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity.
This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.
Annals of Oncology 06/2011; 23(3):777-84. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiosarcomas are a rare but aggressive form of soft tissue sarcoma. At metastatic stage, the clinical benefit of therapeutic intervention remains debatable.
We have carried a retrospective analysis of 149 cases treated between 1996 and 2009 in the French Sarcoma Group.
The median age was 60; the sex ratio was 0.80. Sixty-two percentage of cases presented with metastasis at the diagnosis. About 20% arose in irradiated fields. The median overall survival was 11 months. Treatment consisted in metastasectomy (5.4%), doxorubicin-based regimen (46.9%), weekly paclitaxel (Taxol) (31.5%), other chemotherapy regimens (10.7%) or exclusive palliative care (10.9%). Clinical prognostic factors identified by univariate analysis were presence of bone metastasis (P = 0.0107), presence of other metastasis (P = 0.0327) and performance status (P < 0.0001). The Cox model retained a performance status of two or more as the sole independent prognostic factor (HR [hazard ratio] = 2.49, P < 0.0001). After adjustment to the performance status and compared with exclusive palliative care, the following treatments significantly improve the outcome: doxorubicin-based regimen as first-line chemotherapy (HR = 0.38, P = 0.0165), weekly paclitaxel as first-line regimen (HR = 0.36, P = 0.0146) and metastasectomy (HR = 0.09, P = 0.0221).
This retrospective analysis indicates that some therapeutic interventions may significantly improve the outcome of this aggressive disease. Doxorubicin-based regimens and weekly paclitaxel seem to provide the same range of efficacy.
Annals of Oncology 05/2011; 23(2):517-23. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Imatinib evaluated as a new treatment option in patients with recurrent or established progressive aggressive fibromatosis/desmoid tumor (AF/DT).
Forty patients with unresectable and progressive symptomatic AF/DT were treated with imatinib (400 mg/day for 1 year) in a Simon's optimal two-stage phase II study (P(0) = 10%, P(1) = 30%, α = 5%, β = 10%). The primary end point was non-progressive at 3 months (RECIST).
The study population consisted of 28 women and 12 men, with a mean age of 41 (range 20-72 years). Most of the primary sites were extra-abdominal (24, 54.5%). Familial adenomatous polyposis was observed in six (15%) cases. The median follow-up was 34 months. Imatinib toxicity was similar to that previously reported in literature. Tumor assessment was validated by a central independent radiology committee for 35 patients At 3 months, one (3%) complete and three (9%) partial confirmed responses were observed. The non-progression rates at 3, 6 and 12 months were, respectively, 91%, 80% and 67%. The 2-year progression-free and overall survival rates were 55% and 95%, respectively. Two patients with mesenteric AF/DT died from progressive disease.
Imatinib is active in the treatment of recurrent and progressive AF/DT, providing objective response and long-term stable disease in a large proportion of patients.
Annals of Oncology 02/2011; 22(2):452-7. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains debated. We analyzed the outcome of patients with non metastatic locally advanced primary GIST treated with IM within the prospective BFR14 phase III trial.
The database of the BFR14 trial was searched for patients with no metastasis at time of inclusion. Patients treated for recurrent disease were excluded. Twenty-five of 434 patients met these criteria.
Fifteen of 25 patients (60%) had a partial response to IM. Nine of the 25 patients (36%) underwent surgical resection of their primary tumor after a median of 7.3 months of IM treatment (range 3.4-12.0). Per protocol patients received continuous IM treatment in the post resection period, in an adjuvant setting. With a median follow-up of 53.5 months, there was a significant improvement in progression-free survival (PFS) and overall survival (OS) for patients who underwent surgical resection versus those who did not (median not reached vs 23.6 months, p = 0.0318 for PFS and median not reached vs 42.2 months, p = 0.0217 for OS). In the group of patients who underwent resection followed by IM, the 3-year PFS and OS rates were 67% and 89% respectively
Following neoadjuvant IM for non metastatic locally advanced GIST 9 of 25 patients (36%) were selected for resection of the primary tumor. OS and PFS figures were close to those of localised intermediate or high risk GIST (70% at 5 years) in the subgroup of operated patients, while the outcome of the non-operated subgroup was similar to that of metastatic GIST.
[Show abstract][Hide abstract] ABSTRACT: The effect of imatinib discontinuation on progression-free survival and overall survival in long-lasting responders with advanced gastrointestinal stromal tumours (GIST) is unknown. We assessed treatment interruption in patients with non-progressive disease according to the Response Evaluation Criteria In Solid Tumors criteria after 3 years of imatinib in a randomised trial.
In this open-label national multicentre phase 3 study in France, patients with GIST free of progression after 3 years of imatinib 400 mg/day were randomly assigned to continue or interrupt imatinib. Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of two and four patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. An interim analysis was planned after the first 50 randomly assigned patients. Analysis was done according to the intention-to-treat principle-ie, all patients randomly assigned to a study group were included. This study is registered with ClinicalTrial.gov, number NCT00367861.
434 patients were enrolled in this trial between May 27, 2002, and May 5, 2009. Between June 13, 2005, and May 30, 2007, 50 patients with non-progressive disease who had received 3 years of treatment with imatinib were randomly assigned to continue or interrupt their treatment, 25 patients in each group. By Dec 7, 2009, after a median follow-up of 35 months (95% CI 33-38) after random assignment, 2-year progression-free survival was 80% (95% CI 58-91) in the continuation group and 16% (5-33) in the interruption group (p < 0·0001). There was no difference in adverse events grade 3 or greater (oedema and asthenia) between the two groups.
Imatinib interruption after 3 years in responders results in a high risk of rapid progression in patients with advanced GIST. Discontinuation of imatinib is not recommended outside clinical trials unless patients experience significant toxic effects.
Conticanet, the Ligue Contre Le Cancer du Rhone, and Novartis.
The Lancet Oncology 10/2010; 11(10):942-9. · 25.12 Impact Factor