Cost-Utility Analysis of Continuation Versus Discontinuation of First-Line Chemotherapy in Patients With Metastatic Squamous-Cell Esophageal Cancer: Economic Evaluation Alongside the E-DIS Trial.

OBJECTIVES: Continuous chemotherapy has been used to treat patients with metastatic esophageal squamous cell carcinoma (mESCC), despite weak evidence supporting a clinical benefit, associated side effects for the patients, and unjustified medical costs. In the French setting, we conducted a cost-utility analysis alongside the randomized E-DIS trial (NCT01248299), which compared first-line fluorouracil/platinum-based chemotherapy continuation (CT-CONT) to CT discontinuation (CT-DISC) in progressive-free patients after an initial 6-week treatment phase. METHODS: A partitioned survival analysis was performed using patient-level data collected during the trial for survival outcomes, quality of life (EQ-5D-3L), and medical costs. The mean quality-adjusted life-years (QALYs) and medical costs were estimated over an 18-month period to assess the incremental net monetary benefit and incremental cost-effectiveness ratio. Uncertainty was handled using the nonparametric bootstrap and univariate analysis. Sixty-seven patients with mESCC were randomized and included in the cost-utility analysis. RESULTS: On average, CT-CONT slightly decreased the number of QALYs (-0.038) and increased the cost per patient (+ €1177). At a willingness-to-pay threshold of €50 000/QALY, the incremental net monetary benefit was negative (-€3077 [95% confidence interval: -6564; 4359]), and the incremental cost-effectiveness ratio was -30 958€/QALY (CT-CONT dominated). The probability of the CT-CONT treatment option being cost-effective at a willingness-to-pay threshold of €50 000/QALY, compared to CT-DISC, was 29%. CONCLUSIONS: CT-DISC may be considered as an alternative therapeutic option to CT-CONT in patients with mESCC who have stable disease after an initial chemotherapy treatment phase. A continuous chemotherapy could indeed reduce the number of QALYs because of the disutility associated with the continuous treatment.

The FREGAT biobank: a clinico-biological database dedicated to esophageal and gastric cancers.

BACKGROUND: While the incidence of esophageal and gastric cancers is increasing, the prognosis of these cancers remains bleak. Endoscopy and surgery are the standard treatments for localized tumors, but multimodal treatments, associated chemotherapy, targeted therapies, immunotherapy, radiotherapy, and surgery are needed for the vast majority of patients who present with locally advanced or metastatic disease at diagnosis. Although survival has improved, most patients still present with advanced disease at diagnosis. In addition, most patients exhibit a poor or incomplete response to treatment, experience early recurrence and have an impaired quality of life. Compared with several other cancers, the therapeutic approach is not personalized, and research is much less developed. It is, therefore, urgent to hasten the development of research protocols, and consequently, develop a large, ambitious and innovative tool through which future scientific questions may be answered. This research must be patient-related so that rapid feedback to the bedside is achieved and should aim to identify clinical-, biological- and tumor-related factors that are associated with treatment resistance. Finally, this research should also seek to explain epidemiological and social facets of disease behavior. METHODS: The prospective FREGAT database, established by the French National Cancer Institute, is focused on adult patients with carcinomas of the esophagus and stomach and on whatever might be the tumor stage or therapeutic strategy. The database includes epidemiological, clinical, and tumor characteristics data as well as follow-up, human and social sciences quality of life data, along with a tumor and serum bank. DISCUSSION: This innovative method of research will allow for the banking of millions of data for the development of excellent basic, translational and clinical research programs for esophageal and gastric cancer. This will ultimately improve general knowledge of these diseases, therapeutic strategies and patient survival. This database was initially developed in France on a nationwide basis, but currently, the database is available for worldwide contributions with respect to the input of patient data or the request for data for scientific projects. TRIAL REGISTRATION: The FREGAT database has a dedicated website ( www.fregat-database.org ) and is registered on the Clinicaltrials.gov site, number NCT 02526095 , since August 8, 2015.

Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. METHODS: In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov, NCT01900743. FINDINGS: From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9-2·3) with regorafenib versus 1·7 months (0·9-1·8) with placebo (HR 0·89 [95% CI 0·48-1·64] p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5-5·0) with regorafenib versus 1·8 (1·0-2·8) months with placebo (HR 0·46 [95% CI 0·46-0·80] p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4-11·6) with regorafenib versus 1·0 (0·8-1·4) with placebo (HR 0·10 [95% CI 0·03-0·35] p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0-7·8) with regorafenib versus 1·0 (0·9-1·9) with placebo (HR 0·46 [95% CI 0·25-0·81] p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 [19%] events in the 89 patients in the regorafenib group vs two [2%] events in the 92 patients in the placebo group), hand and foot skin reaction (14 [15%] vs no events) and asthenia (12 [13%] vs six [6%]). One treatment-related death occurred in the regorafenib group due to liver failure. INTERPRETATION: Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib. FUNDING: Bayer HealthCare.

First-Line Chemotherapy for Metastatic Esophageal Squamous Cell Carcinoma: Clinico-Biological Predictors of Disease Control.

OBJECTIVE: This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy. METHODS: A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients. RESULTS: Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC. CONCLUSION: We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients.

Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program.

BACKGROUND: Randomized trials have shown a survival benefit for regorafenib over placebo in patients with metastatic colorectal cancer (mCRC) that progressed after standard therapies. We evaluated survival and safety outcomes in patients treated with regorafenib in a real-life setting. METHODS: REBECCA is a cohort study nested within a compassionate use program designed to evaluate survival, safety, and potential prognostic factors for outcome associated with regorafenib in patients with mCRC refractory to standard therapies. Treatment effects according to various patient and tumour characteristics were evaluated using univariate and multivariate Cox proportional hazards regression models. RESULTS: Of 1178 patients in the compassionate use program, 654 were in the full analysis set. Median follow-up was 16.5 months. Median survival was 5.6 months. The 12-month survival rate was 22 %. Survival was independently and unfavourably affected by the following variables: poor performance status, short time from initial diagnosis of metastases to the start of regorafenib, low initial regorafenib dose, >3 metastatic sites, presence of liver metastases, and KRAS mutations. We identified prognostic groups of patients with low, intermediate, and high risk of death, with a median survival of 9.2, 5.2, and 2.5 months, respectively. Five-hundred-twenty-four patients (80 %) experienced at least one regorafenib-related adverse event, most commonly, fatigue, hand-foot skin reaction, diarrhea, anorexia, arterial hypertension, and mucositis. CONCLUSION: The safety and efficacy profile of regorafenib in REBECCA are similar to those in randomized trials. Our prognostic model identified subgroups of mCRC patients who derived a minimal and maximum benefit from regorafenib. TRIAL REGISTRATION: Clinicaltrials.gov NCT02310477 .

Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial.

BACKGROUND: Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial. METHODS/DESIGN: PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio. DISCUSSION: This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors. TRIAL REGISTRATION: NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial.

BACKGROUND: The benefit or harm of trabectedin discontinuation in patients with non-progressive soft-tissue sarcoma remains unclear. We report the final analysis of a phase 2 trial investigating the clinical benefit of continuation of trabectedin treatment until progression versus interruption of therapy after six treatment cycles in patients with advanced soft-tissue sarcoma. METHODS: For this open-label, non-comparative, multicentre, phase 2 study, eligible adult patients with advanced soft-tissue sarcomas, who had previously received doxorubicin-based chemotherapy and were able to receive trabectedin, were enrolled from 14 centres of the French Sarcoma Group. Trabectedin was administered at a dose of 1·5 mg/m(2) through a central venous line as a 24-h continuous infusion every 3 weeks. After the initial six cycles of trabectedin, patients who were free from progressive disease were randomly assigned in a 1:1 ratio either to continuous treatment or therapy interruption. Randomisation was done centrally by a computer-generated system using permuted blocks of four patients, stratified by tumour grade and performance status. Patients allocated to the interruption group were allowed to restart trabectedin in case of progressive disease. The primary endpoint was progression-free survival at 6 months after randomisation, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01303094. RESULTS: In 178 evaluable patients, 91 (51%) patients had not progressed after six cycles. Of these patients, 53 patients were randomly assigned to the two treatment groups: 27 to the continuation group and 26 to the interruption group. Overall, patients in the two groups received a similar median number of trabectedin cycles (continuation group: 11 cycles [range 6-31+] vs interruption group: 11 [range 6-23+]). After randomisation, progression-free survival at 6 months was 51·9% (95% CI 31·9-68·6) in the continuation group versus 23·1% (9·4-40·3) in the interruption group (p=0·0200). The occurrence of treatment-related grade 3 adverse events (four [16%] of 25 patients in the continuation group vs three [14%] of 21 in the interruption group) and grade 4 adverse events (one [4%] vs none) was similar in both groups. The most common grade 3 and 4 toxicities were alanine aminotransferase or aspartate aminotransferase increases (one [4%] in the interruption group vs three [14%] in the continuation group), neutropenia (two [8%] vs two [10%]), and intestinal occlusion (one [4%] vs one [5%]). INTERPRETATION: We do not recommend trabectedin discontinuation in patients with advanced, doxorubicin-refractory soft-tissue sarcoma who have not progressed after six cycles of treatment. FUNDING: The French National Cancer Institute (INCa) and PharmaMar SA.

Improvement of the initial management of sarcomas after the dissemination of evidence-based guidelines depends on the primary sarcoma location: a population-based study.

BACKGROUND: Improvement of the initial management of sarcomas after the dissemination of evidence-based guidelines depends on the primary sarcoma location: a population-based study. To improve the initial management of adult sarcomas, a regional expert team in Northern France performed two actions: dissemination of evidence-based guidelines (EBG) for the management of soft tissue/visceral sarcoma and yearly educational symposia. The aim of this study was to measure the impact of the dissemination of EBG on the key-indicators of adult sarcoma management. METHODS: We conducted a before-after population-based study (before: 2005 with 63 cases, after: 2008-2009 with 86 cases) in the Lille area (Northern France urban/sub-urban area with 800,000 inhabitants). The following were the key-indicators of adult sarcoma management: pre-therapeutic biopsy, appropriate tumour and chest imaging, expert interdisciplinary discussion, expert interdisciplinary discussion before the first treatment and in operated cases, the rate of R0 resection. RESULTS: There was no statistically significant difference in patient and tumour characteristics for the two time periods in terms of gender, prior cancer, primary location, histological subtype, grade, size, metastasis and lymph node involvement. There was no statistically significant improvement in primary tumour imaging (83 versus 87%), chest imaging (67 vs 71%), pre-therapeutic biopsy (57 vs 58%). There was an improvement in expert multidisciplinary discussion (37 vs 45%) or discussion before the first treatment (26 vs 44%) but no statistically significant. However, when soft tissue and bone sarcomas were analysed separately, we observed statistically significant improvements in expert multidisciplinary discussion (50 vs 74%, p = 0.02) and R0 resection rate (58 vs 91%, p = 0.002). In contrast, in cases of visceral sarcoma, there was no improvement in expert multidisciplinary discussion (10 vs 16%, p = 0.7) or in R0 resection (88 vs 81%, p = 0.7). CONCLUSIONS: The dissemination of EBG was associated with a limited improvement in sarcoma management when measured in this before-after population-based study, and this improvement was dependent on the primary location of the tumour. Efforts to implement these guidelines by all surgical teams that could treat sarcoma, including visceral sarcoma, need to be made.

Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial.

BACKGROUND: Angiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial. METHODS/DESIGN: We are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age ≥18, not > 3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6 months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; ß = 0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; ß = 0.2 Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients. DISCUSSION: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (TRIAL REGISTRATION NUMBER: EudraCT N°: 2012-005743-24, on the 15(th) February 2012).

Sorafenib in patients with progressive epithelioid hemangioendothelioma: a phase 2 study by the French Sarcoma Group (GSF/GETO).

BACKGROUND: There is no standard treatment for progressive epithelioid hemangioendothelioma (EHE). To investigate the significant vascularization of EHE, the activity/toxicity of sorafenib in patients with progressive EHE was explored. METHODS: In this multicenter, 1-stage, phase 2 trial of sorafenib (800 mg daily), the primary endpoint, which was chosen by default, was the 9-month progression-free rate. All patients had documented progressive disease at the time of study entry. RESULTS: Fifteen patients were enrolled between June 2009 and February 2011. The median age was 57 years (range, 31-76 years), and the ratio of men to women was 9:6. The performance status was zero in 10 patients and 1 in 5 patients. Twelve patients had metastases, mainly in the lung (12 patients), liver (5 patients), and bone (3 patients). Five patients had received prior chemotherapy (doxorubicin in 5 patients and taxane in 3 patients). The median sorafenib treatment duration was 124 days (range, from 27 to >271 days). Seven patients required dose reductions or transient treatment discontinuation. The 9-month progression-free rate was 30.7% (4 of 13 patients). The 2-month, 4-month, and 6-month progression-free rate was 84.6% (11 of 13 patients), 46.4% (6 of 13 patients), and 38.4% (5 of 13 patients), respectively. Two partial responses were observed that lasted 2 months and 9 months. CONCLUSIONS: Further clinical trials exploring sorafenib as treatment of progressive EHE are needed.

Clinical complete responders to definite chemoradiation or radiation therapy for oesophageal cancer: predictors of outcome.

BACKGROUND: To identify predictors of long-term outcome for patients with clinical complete response (cCR) after definite chemoradiotherapy (CRT) or radiation therapy (RT) for oesophageal cancer (EC). METHODS: In this retrospective study, we reviewed the files of all patients from our institution that underwent definitive RCT or RT for EC, from January 1998 to December 2003. Among 402 consecutive patients with EC, 110 cCR responses were observed, i.e. without evidence of tumour on morphological examination of the biopsy specimens, 8 to 10 weeks after radiation. Baseline patient and tumour characteristics were as follows: male = 98/110, median age = 60, squamous histology = 103/110, tumour site (upper/middle/lower third) = 41/50/19, weight loss none/<10%/≥10% = 36/45/29, dysphagia grade 1/2/≥3 = 30/14/66. Patients were staged according to endosonography and/or computed tomography. There were 9 stage I, 31 stage IIA, 15 stage IIB, 41 stage III, 6 stage IV. Post treatment nutritional characteristics were as follows: weight loss during treatment none/<10% ≥ 10% = 35/38/37, remaining dysphagia grade 1/2/≥3 = 54/24/32. Univariate and multivariate analyses were performed using log-rank and Cox proportional hazards models, and survival curves were estimated using the Kaplan-Meier method. RESULTS: During follow up (median: 6 [0.4-9.8] years), 16 patients had salvage surgery. Median OS was 2.5 years, and 5-year OS was 33.5%. Histological type, stage, age, gender, and treatment characteristics had no significant impact on outcome. The risk of death was increased two-fold for patients with grade ≥ 3 dysphagia after treatment (HR = 1.9 [1.2-3.1], p = 0.007). Weight loss ≥10% during treatment also negatively affected outcome (HR = 1.8 [1.0-3.2], p = 0.040). CONCLUSION: One EC patient among 3 with cCR after definite CRT/RT is still alive at 5 years. Variables related to reduced OS were: remaining significant dysphagia after treatment and weight loss ≥10% during treatment.

Sorafenib for patients with advanced angiosarcoma: a phase II Trial from the French Sarcoma Group (GSF/GETO).

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: Sorafenib showed limited antitumor activity in pretreated patients only, for both visceral and superficial angiosarcoma, but tumor control was of short duration.

Circulating thrombospondin 1 level as a surrogate marker in patients receiving cyclophosphamide-based metronomic chemotherapy.

Several previous reports suggest that thrombospondin (TSP-1) may be a mediator of the antiangiogenic effects of low-dose metronomic cyclophosphamide-based chemotherapy (MC). We conducted a randomized phase II trial evaluating megestrol acetate (n = 44) versus MC (n = 44) in patients having exhausted all standard treatments. We measured the TSP-1 levels at baseline and D15. We did not observe significant differences in TSP-1 at baseline in the two arms (p = 0.07). TSP-1 levels decreased in patients receiving metronomic cyclophosphamide (from 16.6 ± 7.2 µg/ml to 12.8 ± 7.4 µg/ml; p = 0.057). The TSP-1 level was stable in patients receiving megestrol acetate. Nevertheless, the TSP-1 level driven by MC did not correlate to clinical benefit.

Predictors for establishing recommended phase 2 doses: analysis of 320 dose-seeking oncology phase 1 trials.

INTRODUCTION: For decades, determination of the recommended Phase 2 dose (RP2D) was based on the toxicity (especially the maximum tolerated dose or MTD) experienced by patients enrolled in dose-escalating Phase 1 trials investigating anti-cancer agents. Recent studies suggest that this toxicity-based strategy is not suitable for modern anti-cancer agents. We conducted a retrospective study to identify the risk factor(s) for failing to determine the RP2D according to the MTD. MATERIAL AND METHODS: We analyzed 320 recently published (1997-2008) Phase 1 trials using the maximum tolerated dose (MTD) to define the P2RD. We analyzed the current definitions of RP2D and then identified the risk factors for not establishing the RP2D using the odds ratio and 95% confidence intervals. Interactions between these risk factors were explored using the logistic regression model and CHAID algorithm. RESULTS: 18% of contemporary dose-seeking Phase 1 trials did not identify a RP2D. The logistic regression analysis showed that the risk factors for not identifying the RP2D were: investigation of molecular targeted therapies (RR = 3.0, p = 0.0017), lack of justification of the starting dose (RR = 5.9, p = 0.0121) and lack of definition of the MTD (RR = 8.4, p = 0.0006). The CHAID algorithm confirmed the importance of the methodological parameters. DISCUSSION: This study confirms the difficulty of determining the RP2D of molecular targeted therapy using conventional methods. However, it underlines the major importance of two methodological points: definition of the MTD and justification of the starting dose.

Nature and subjectivity of dose-limiting toxicities in contemporary phase 1 trials: comparison of cytotoxic versus non-cytotoxic drugs.

Dose-limiting toxicity (DLT) remains the preferred metric in dose-finding phase 1 trials. Nevertheless, this primary endpoint appears unsuitable for investigating non-cytotoxic drugs. We reviewed 201 recent dose-finding phase 1 trials and compared the DLT defined with cytotoxic (119 trials) and non-cytotoxic drugs (molecular-targeted therapies and immune-stimulant agents; 82 trials). DLT was less frequently identified with non-cytotoxic drugs (52 vs. 89%, p = 0.00005). Myelotoxicity remains the most frequent DLT in studies investigating cytotoxic agents (51%). Myelotoxicity was significantly less frequent in studies investigating non-cytotoxic drugs (14%, p = 0.00003). Skin toxicities (p = 0.038), coagulation perturbation (p = 0.025) and fever (p = 0.025) were the most frequent DLTs in studies investigating non-cytotoxic drugs. Moreover, DLTs identified with non-cytotoxic drugs were less frequently objectively measurable as they were based on biological anomalies (30 vs. 63%, p = 0.0026). Approximately 50% of dose-finding phase 1 trials investigating non-cytotoxic drugs led to DLT and then the maximum tolerated dose being found. However, the nature of these DLTs is different from those described with cytotoxic drugs and less objectively measurable in many cases.

Factual understanding of randomized clinical trials: a multicenter case-control study in cancer patients.

Objective Several reports have shown that despite the informed consent process, enrolled patients misunderstand the modalities and goals of randomized clinical trials (RCTs). We believe that this may be linked to a priori misconceptions in the main population. The purpose of this study is to compare the knowledge about cancer RCTs in enrolled participants (cases) versus patients treated under cancer standard care who have never taken part in RCTs (controls). Methods We submitted a validated questionnaire (ICEC-R) to both populations to explore their knowledge about RCTs. A total of 75 cases and 107 controls were included. Results Globally, the cases' knowledge was significantly better, especially about (i) the randomization process, (ii) the uncertain potential benefits, and (iii) the right to withdraw consent. Both populations presented the lowest scores for items exploring the randomization process and uncertain treatment benefits. Conclusion Enrolled patients' comprehension of the goals and means of RCTs is actually better than controls'. Nevertheless, additional efforts should be made to enhance information about clinical research to patients as well as to the main population. Practice Implications Having better knowledge about patients' difficulties in understanding RCTs would allow physicians to adjust the information they give and then to enhance patients' well-being.

Justification of the starting dose as the main determinant of accrual time in dose-seeking oncology phase 1 trials.

INTRODUCTION: New drug development is a time- and resource-consuming process. Phase 1 trials constitute a major key-step of this development. Shortening the accrual time is of major importance. METHODS: 292 published phase-1-trials were retrospectively reviewed to establish the determinants of accrual time using Log-rank test and then Cox Model. RESULTS: Out of 292 trials (1997-2008), only 107 reports (36%) described the accrual time (median: 20 months, 5-72). Phase-2-recommended dose was established in 87 studies (81%). Most studies investigated regimens including cytotoxic drugs (77%) or molecular targeted therapies (29%). Under univariate analysis, two parameters shortened the accrual time: studies conducted in USA vs. other places (19 vs. 21 months p = 0.03) and regimen with more than 2 dose-escalated drugs (13 vs. 21 months, p = 0.003). One parameter was significantly associated with longer accrual time: starting dose justified by animal toxicology data vs. previous clinical trials (22 vs. 19 months, p = 0.03). Most of parameters did not significantly affect the accrual time: nature of investigated drugs, duration of treatment cycle, phase 1 dedicated to specific tumoral subtypes, number of centers, method of drug escalation (classical 3+3 vs. accelerated titration design), type of increment (modified Fibonacci method vs. others) and presence of expansion of cohort at the phase-II-recommended dose. Cox model analysis retained one determinant: starting dose justified by animal toxicology data: HR = 2.00 [1.45-5.20], p = 0.047. CONCLUSION: Few parameters influence the accrual time of dose-escalation phase-1 trials. Real first-in-man phase 1 studies based on starting dose estimated from animal toxicological data require longer accrual time.

The ongoing French metastatic breast cancer (MBC) cohort: the example-based methodology of the Epidemiological Strategy and Medical Economics (ESME).

PURPOSE: The currently ongoing Epidemiological Strategy and Medical Economics (ESME) research programme aims at centralising real-life data on oncology care for epidemiological research purposes. We draw on results from the metastatic breast cancer (MBC) cohort to illustrate the methodology used for data collection in the ESME research programme. PARTICIPANTS: All consecutive ≥18 years patients with MBC treatment initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres were selected. Diagnostic, therapeutic and follow-up data (demographics, primary tumour, metastatic disease, treatment patterns and vital status) were collected through the course of the disease. Data collection is updated annually. FINDING TO DATE: With a recruitment target of 30 000 patients with MBC by 2019, we currently screened a total of 45 329 patients, and >16 700 patients with a metastatic disease treatment initiated after 2008 have been selected. 20.7% of patients had an hormone receptor (HR)-negative MBC, 73.7% had a HER2-negative MBC and 13.9% were classified as triple-negative BC (ie, HER2 and HR status both negative). Median follow-up duration from MBC diagnosis was 48.55 months for the whole cohort. FUTURE PLANS: These real-world data will help standardise the management of MBC and improve patient care. A dozen of ancillary research projects have been conducted and some of them are already accepted for publication or ready to be issued. The ESME research programme is expanding to ovarian cancer and advanced/metastatic lung cancer. Our ultimate goal is to achieve a continuous link to the data of the cohort to the French national Health Data System for centralising data on healthcare reimbursement (drugs, medical procedures), inpatient/outpatient stays and visits in primary/secondary care settings. TRIAL REGISTRATION NUMBER: NCT03275311; Pre-results.