Jocelyn Gal

Can we increase the chance of sphincter saving surgery in rectal cancer with neoadjuvant treatments: Lessons from a systematic review of recent randomized trials

PURPOSE A common hypothesis is that neo-adjuvant treatment in rectal cancer, is able to increase sphincter saving surgery. This review studies data relevant to this question. STUDY SELECTION A total of 17 randomized trials were analysed. RESULTS Since 1976, the rate of sphincter saving surgery increased from 20% to 75%. In none of the 17 trials it was possible to demonstrate a significant benefit of the neo-adjuvant regimens on the rate of sphincter saving surgery. There was a reduction in the risk of 5-year local recurrence partly due to these neo-adjuvant treatments. These neo-adjuvant regimens had no significant impact on the overall 5-year survival. CONCLUSIONS None of the neo-adjuvant treatments tested was able to demonstrate an increase in the rate of sphincter saving surgery. The improvement in conservative surgery is mainly due to technical changes in surgery. Organ preservation after complete clinical response appears as an interesting hypothesis to test.

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

Background Pembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK). Patients and methods We retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2. Results From September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR < 2: 37%, P = 0.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not with overall survival (P = 0.77). Conclusions Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.

Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials) ☆

BACKGROUND Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. METHODS Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). RESULTS For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. CONCLUSION The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.

Organ preservation in rectal adenocarcinoma (T1) T2-T3 Nx M0. Historical overview of the Lyon Sud - nice experience using contact x-ray brachytherapy and external beam radiotherapy for 120 patients.

In most institutions, standard treatment of T2-T3 rectal adenocarcinoma is radical surgery using total mesorectal excision (TME) with or without neoadjuvant treatment [radiotherapy or chemoradiotherapy (CRT)]. Abdomino-perineal excision (APE) is considered by most patients as a severe mutilation but even with low anterior resection (LAR) morbidity is not negligible [1]. Further, postoperative mortality, especially in elderly patients is of great concern [2]. To improve quality of life and individualize treatment, an increasing number of experienced colorectal surgeons are advocating organ preservation using CRT followed either by local excision (LE) [3,4] or only close surveillance after clinical complete response (cCR) usually in T2 or ‘ early T3 ’ tumors [5,6]. In Sao Paulo, Habr-Gama has since many years been the pioneer of such an approach recommending careful evaluation of the clinical tumor response [7] using a long interval after the end of CRT. In case of cCR, her strategy is to adopt a ‘ watch and wait ’ (W-W) policy [8]. In Lyon, Papillon using contact x-ray brachytherapy (CXB) alone was able in the 1970s to achieve close to 90% cCR in more than 300 T1 N0 lesions and gave his name to this technique [9]. Since the mid-1980s, CXB was combined with external beam radiation therapy (EBRT) in order to treat, mainly in inoperable patients, T2-3 tumors at higher risk of perirectal nodal extension [10,11]. Similar approaches were used in various French, British and American institutions [12 – 15]. Since the mid-1990s, CXB was progressively abandoned for four reasons: the Philips RT 50 TM Contact machine was not manufactured anymore, technological innovations drove the interest of radiation oncologists towards three-dimensional (3D) image-guided radiotherapy, they progressively lost the clinical expertise of rigid rectoscopy and LE became the primary treatment of malignant polyps or T1N0 tumors. In 2009 a new Contact machine named Papillon 50 TM , producing a similar 50 kV x-ray beam was introduced in UK and France and initiated a renaissance of this technique [16]. We report here an overview of the use of CXB during a time period of 35 years by a homogeneous team of radiation oncologists working successively in CHU Lyon Sud and Centre Antoine Lacassagne in Nice. The report will focus exclusively on the combined treatment using CXB with EBRT to achieve organ preservation in T2 to early T3 rectal adenocarcinomas.

Local Recurrence after Breast Cancer Affects Specific Survival Differently according to Patient Age

Purpose: Young age is known to be an independent factor for developing local recurrence (LR) in breast cancer patients. It has also been shown that the occurrence of LR negatively affects patient outcome, especially if LR occurs within 3 years after treatment of the primary tumour. The question whether the impact of LR on patient outcome differs according to the patient’s age has not been addressed before. The purpose of the present study is to investigate cancer-specific survival (CSS) as well as overall survival after LR in young patients (<50 years old) and to compare it to older patients. The age cut-off level was taken as 50 to avoid strong imbalance in patient numbers between the 2 groups. Patients and Methods: Between 1974 and 2003, 2,130 breast cancer patients were treated with conservative surgery and axillary dissection. All of them received post-operative radiotherapy. Adjuvant chemo- and/or hormonal therapy was given according to the prognostic factors and the treatment policy at the time of diagnosis. Only biopsy-confirmed ipsilateral LRs were taken into account. Early LRs were those observed within 36 months after surgery, and late LRs were those which occurred thereafter. The median follow-up was 100 months. Survival analysis was conducted with the Kaplan-Meier method. Results: The median age was 59 years. There were 472 patients aged <50 years versus 1,658 older patients. Pathological tumour size, hormone receptor status and lymph node involvement were evenly distributed in the 2 groups. The 5- and 10-year CSS was 92.3 and 83.9% in young patients, and 94.4 and 87.6% in older patients (p = 0.061), respectively. Overall, 200 LRs were observed; 52 of them (26%) were early LRs. The rate of LR was significantly higher in young patients: at 5 years, it was 10.5 versus 3.7% in patients ≧50 years; the respective rates at 10 years were 17.8 and 8.8% (p < 0.0001). The 5- and 10-year CSS in patients who developed LR was 86.8 and 76.0%, versus 94.7 and 88.2% in patients who did not develop LR (p < 0.0001). The 5-year CSS after LR in young and older patients was 77.6 and 65.7%, respectively (p = 0.028). Conclusion: Although young patients experience more LR than older ones, once LR occurs, young patients have a better outcome than the others. Possible hypotheses are: (1) more aggressive treatment in young patients after LR; (2) the treatment is better sustained in young patients; (3) biological differences in the characteristics of LR.

Predictive factors for early and late local toxicities in anal cancer treated by radiotherapy in combination with or without chemotherapy.

BACKGROUND: The treatment of anal cancer is based on concomitant radiotherapy and chemotherapy and is associated with a nonnegligible rate of local severe toxicities that can strongly impair the quality of life. OBJECTIVE: A retrospective analysis was performed to screen the following factors as potential predictive factors for local skin and digestive toxicities, and as potential prognostic factors for cumulative colostomy incidence: sex, age, tumor size, clinical T and N stage, circumferential extension, invasion of anal margin, HIV status, type of chemotherapy, and type of radiotherapy and dose delivered. METHODS: One hundred five patients in our database treated between January 2000 and February 2010 met the eligibility criteria. RESULTS: Median follow-up was 54.1 months (range, 1–133). Early and late severe local toxicities occurred in 33 patients (31.4%) and 18 patients (17.1%). The 5-year cumulative rate of colostomy was 26.6%. Predictive factors for local severe early toxicities were as follows: clinical stage III/IV (p = 0.01), no brachytherapy boost (p = 0.003), and use of chemotherapy (p = 0.01). Only brachytherapy retained its independence in multivariate analysis (OR = 4.8 (1.4–16.3), p = 0.01). Human immunodeficiency virus positivity (p = 0.04) was the only predictive factor for late toxicities in univariate analysis; it was linked independently to the occurrence of ulcer (OR = 0.1 (0.01–0.66), p = 0.01). Tumor size ≥4 cm (p < 0.001) and occurrence of grade 2 to 3 ulcers (p < 0.001) were correlated with greater cumulative colostomy incidence. CONCLUSIONS: In this cohort, nonuse of brachytherapy was an independent predictive factor for local acute toxicity. Human immunodeficiency virus positivity was the only predictive factor for local late toxicities and strongly influenced the onset of ulcer.

Effectiveness and Tolerability of Maintenance Capecitabine Administrated to Patients with Metastatic Pancreatic Cancer Treated with First-Line FOLFIRINOX

Objective: Treating metastatic pancreatic cancer (MPC) remains a challenging issue. Maintenance therapy is a growing concept used in different types of cancer. Our retrospective analysis aims to evaluate the effectiveness and tolerability of early maintenance capecitabine administrated to patients with MPC treated with first-line FOLFIRINOX. Methods: 103 patients treated for MPC between November 2009 and July 2014 were retrospectively identified in our institution. Among them, 30 patients initially treated with a minimum of 4 and no more than 8 cycles of FOLFIRINOX, without signs of progression (every 14 days), received maintenance therapy with capecitabine until progression. Upon first progression (first progression-free survival, PFS1), patients were retreated with FOLFIRINOX or another scheme until second progression (second progression-free survival, PFS2). Results: Median OS was 17 months. Survival rates were 73% at 1 year (95% CI 0.59-0.91) and 25% at 2 years (95% CI 0.13-0.50). Median PFS1 was 5 months. Twenty-nine patients experienced disease progression during capecitabine treatment (96.7%). After disease progression, median PFS2 was 10 months. Considering the interval between the starting date of FOLFIRINOX treatment and second disease progression, the median time to treatment failure is 17 months. Conclusions: Maintenance with capecitabine seems effective without compromising FOLFIRINOX efficacy and allows obtaining very promising OS and PFS.

Multicenter prospective micro-costing study evaluating mandibular free-flap reconstruction

Free-flap mandibular reconstruction is a highly specialized procedure associated with severe complications necessitating re-interventions and re-hospitalizations. This surgery is expensive in terms of health workers’ time, equipment, medical devices and drugs. Our main objective was to assess the direct hospital cost generated by osseocutaneous free-flap surgery in a multicentric prospective micro-costing study. Direct medical costs evaluated from a hospital perspective were assessed using a micro-costing method from the first consultation with the surgeon until the patient returns home, thus confirming the success or failure of the free-flap procedure. The mean total cost for free-flap intervention was 34,009€ (5151–119,604€), the most expensive item being the duration of hospital bed occupation, representing 30–90% of the total cost. In the event of complications, the mean cost increased by 77.3%, due primarily to hospitalization in ICU and the conventional unit. This surgery is effective and provides good results but remains highly complex and costly.

SynthèseLe rôle des cohortes d’expansion dans les essais de phase I en cancérologie : des recommandations du HUB phase IThe role of the expansion cohort in phase I trials in oncology: Guidelines of the phase I HUB

At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors.

Le rôle des cohortes d’expansion dans les essais de phase I en cancérologie : des recommandations du HUB phase I

At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors.