Jérôme Desramé

Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6)

Purpose A pathologic complete response (pCR; ypT0N0) of a rectal tumor after neoadjuvant radiochemotherapy (RCT) is associated with an excellent prognosis. Several retrospective studies have investigated the effect of increasing the delay after RCT. The aim of this study was to evaluate the effect of increasing the interval between the end of RCT and surgery on the pCR rate. Methods GRECCAR6 was a phase III, multicenter, randomized, open-label, parallel-group controlled trial. Patients with cT3/T4 or Tx N+ tumors of the mid or lower rectum who had received RCT (45 to 50 Gy with fluorouracil or capecitabine) were included. Patients were randomly included in the 7-week or the 11-week (11w) group. Primary end point was the pCR rate defined as a ypT0N0 specimen (NCT01648894). Results A total of 265 patients from 24 centers were enrolled between October 2012 and February 2015. The majority of the tumors were cT3 (82%). After RCT, surgery was not performed in nine patients (3.4%) because of the occurrence of distant metastasis (n = 5) or other reasons. Two patients underwent local resection of the tumor scar. A total of 47 (18.6%) specimens were classified as ypT0 (four had invaded lymph nodes [8.5%]). The primary end point (ypT0N0) was not different (7 weeks: 20 of 133, 15.0% v 11w: 23 of 132, 17.4%; P = .5983). Morbidity was significantly increased in the 11w group (44.5% v 32%; P = .0404) as a result of increased medical complications (32.8% v 19.2%; P = .0137). The 11w group had a worse quality of mesorectal resection (complete mesorectum [I] 78.7% v 90%; P = .0156). Conclusion Waiting 11 weeks after RCT did not increase the rate of pCR after surgical resection. A longer waiting period may be associated with higher morbidity and more difficult surgical resection.

Simplified Prognostic Model in Patients with Oxaliplatin-Based or Irinotecan-Based First-Line Chemotherapy for Metastatic Colorectal Cancer: A GERCOR Study

BACKGROUND The present study was done to establish a prognostic model for patients and trials using an oxaliplatin-based or irinotecan-based first-line chemotherapy in metastatic colorectal cancer. PATIENTS AND METHODS Eight hundred three patients treated with FOLFOX or FOLFIRI in three prospective trials were randomly separated into learning (n = 535) and validation (n = 268) samples. Eleven baseline variables were evaluated in univariate and multivariate analysis as prognostic factors for overall survival, and a prognostic score was developed. RESULTS Independent prognostic factors identified in multivariate analysis for overall survival were performance status (PS) (p < .001), serum lactate dehydrogenase (LDH) (p < .001), and number of metastatic sites (p = .005). A prognostic score based on these three variables was found efficient (Harrells C index 0.61). This new model was improved by selecting only PS and LDH (Harrells C index 0.64). Three risk groups for death could be identified: a low-risk group (n = 184; median overall survival [OS] 29.8 months), an intermediate-risk group (n = 223; median OS 19.5 months), and a high-risk group (n = 128; median OS 13.9 months). Median survival for the low-, intermediate-, and high-risk groups were 26.8, 21.1, and 16.5 months, respectively, in the validation sample (Harrells C index 0.63). CONCLUSIONS Serum LDH level was the main prognostic factor in predicting survival, followed by WHO PS. We identified three risk groups for death depending on these two baseline parameters. This simple prognostic model can be useful for clinicians use and patient stratification in future clinical trials.

Second‐line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine‐platinum combination: A large multicenter study by the Association des Gastro‐Entérologues Oncologues

Few data are available on second‐line chemotherapy (CT2) for advanced biliary tract cancer (ABTC). The aim of this multicenter study was to describe the CT2 regimens used, the response rates, and the outcomes of patients treated with various CT2 regimens.

FFCD-1004 Clinical Trial: Impact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated Patients.

Purpose Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships. Experimental design One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine. Results Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter-individual variability has been observed in patients. Conclusion This study, which included only 4.6% of CDA-deficient patients, failed in identifying CDA status as a predictive marker of toxicities with gemcitabine. A lack of statistical power because of smoothing effect of CDA variability as compared with real life conditions could explain this absence of impact. Trial Registration ClinicalTrials.gov NCT01416662

Histiocytose langerhansienne de l'adulte avec cholangite sclérosante et atrophie cérébelleuse

Resume L’histiocytose langerhansienne est une maladie de l’enfant et de l’adulte jeune caracterisee par une proliferation clonale histiocytaire, positive en immunohistochimie pour le CD1a, touchant un ou plusieurs organes. Les formes de l’adulte sont rares. Nous rapportons un cas d’histiocytose langerhansienne multisystemique de l’adulte associant une cholangite sclerosante compliquee d’une degradation rapide de la fonction hepatocytaire, d’evolution rapidement mortelle et d’une atrophie cerebelleuse progressive. L’histiocytose langerhansienne est une cause tres rare de cholangite sclerosante de l’adulte.

Métastases pancréatiques du cancer du rein : à propos de trois observations

Resume Introduction. – Le pancreas constitue un site de localisation rare des metastases du cancer du rein. Exegese. – A partir de trois observations, nous degageons les elements recents du diagnostic, du pronostic et du traitement de ce type de metastases. Le delai moyen entre la nephrectomie et la decouverte des metastases pancreatiques a ete de 16 ans. Elles ont ete decouvertes fortuitement dans 2 cas, chez des patients ne presentant pas de symptomatologie en rapport avec une affection pancreatique, au cours d’une echographie abdominale realisee pour une autre cause. Dans le troisieme cas, des symptomes pancreatiques ont conduit au diagnostic. L’echoendoscopie a permis de mettre en evidence des lesions multiples non objectivees par le scanner ou l’IRM. Les aspects echoendoscopiques sont caracteristiques, mais l’interpretation des examens histologiques et cytologiques des biopsies sous echoendoscopie est difficile compte tenu du caractere hypervascularise de ces metastases. Conclusion. – Devant un syndrome tumoral pancreatique, chez un patient aux antecedents lointains de cancer du rein, il faut savoir evoquer le diagnostic de metastase. Compte tenu de leur caractere hypervasculaire, la negativite de ponctions echoendoscopiquement guidees pourrait orienter fortement le diagnostic. Le traitement chirurgical permet une survie meilleure que celle des adenocarcinomes pancreatiques primitifs et meme que celle des metastases pancreatiques d’autre origine.

Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial

BACKGROUND Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50-60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil. METHODS We did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m2) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m2) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m2 on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the modified intention-to-treat (ITT) population, defined as all randomly assigned and assessable patients regardless of their eligibility and received treatments. This trial is registered at ClinicalTrials.gov, number NCT01964534. The trial has ended and we report the final analysis here. FINDINGS Between Dec 12, 2013, and Oct 31, 2014, we randomly assigned 114 patients to treatment: 75 patients to the leucovorin and fluorouracil group and 39 to the gemcitabine group. One patient in the leucovorin and fluorouracil group did not have a 4-month assessment, and was thus excluded from the modified ITT analysis. Median follow-up was 13·1 months (95% CI 12·5-14·1). At 4 months, 40 (56%, 90% CI 45-66) of 72 patients in the leucovorin and fluorouracil group were alive and free from disease progression (21 [54%, 40-68] of 39 patients in the gemcitabine group were also alive and progression-free at 4 months). Grade 3-4 adverse events occurred in 33 (87%) of 38 patients in the gemcitabine group and in 56 (77%) of 73 patients in the leucovorin and fluorouracil group, with different toxicity profiles. The most common grade 3-4 adverse events in the leucovorin and fluorouracil group were neutropenia without fever (17 [23%]), fatigue (16 [22%]), paraesthesia (14 [19%]), diarrhoea (nine [12%]), and mucositis (seven [10%]); in the gemcitabine group they were neutropenia without fever (12 [32%]), thrombocytopenia (seven [18%]), fatigue (eight [21%]), anaemia (five [13%]), increased alanine aminotransferase and aspartate aminotransferase concentrations (five [13%] for both), and paraesthesia (four [11%]). Two participants died; one in the leucovorin and fluorouracil group from septic shock, and one in the gemcitabine group from diabetes compensation with acidosis; these deaths were deemed to be not related to treatment. Treatment-related serious adverse events occurred in 28 (38%) of 73 patients in the leucovorin and fluorouracil group and in 14 (37%) of 38 in the gemcitabine group. INTERPRETATION Nab-paclitaxel plus simplified leucovorin and fluorouracil fulfilled the primary endpoint in that more than the required 50% of our study population were progression-free at 4 months, with a tolerable toxicity profile. This regimen thus deserves further assessment in a phase 3 trial. FUNDING GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) and Celgene through grants to GERCOR.

Complete pathological response of unresectable liver metastases from colorectal cancer after trans-arterial chemoembolization with drug-eluting beads loaded with irinotecan (DEBIRI) and concomitant systemic FOLFOX: A case report from the FFCD 1201 trial.

INTRODUCTION Most liver metastases from colorectal cancer (CRC) are unresectable at diagnosis. Systemic chemotherapy allows secondary surgical resection in 10 to 20% of patients. Hepatic intra-arterial treatments could enhance response and resection rate. We therefore designed a prospective phase II trial testing the transarterial chemoembolization (TACE) using drug-eluting beads loaded with irinotecan (DEBIRI) with concomitant systemic FOLFOX regimen, the FFCD 1201 trial, in patients with liver limited metastatic CRC. CASE REPORT A 48-year old patient was operated from an occlusive sigmoid adenocarcinoma. Magnetic resonance imaging showed 6 bilobar liver metastasis. The patient was considered as non-eligible for surgery initially. Patient was included in the FFCD 1201 trial and received 5 cycles of FOLFOX and 2 sessions of DEBIRI, with a quite good tolerability. Post-treatment evaluation showed a partial response and sufficient tumor shrinkage to make liver metastasis resectable. Right hepatectomy associated with wedge resection in the left liver was performed and pathological findings showed a complete pathological response (CPR). CONCLUSION Combination of DEBIRI with FOLFOX could increase tumor shrinkage leading to secondary resection of liver metastases from CRC. This combination may also, as shown here for the first time in a patient with unresectable LM, induce CPR of all LM, known to be associated with better outcome. Our case also emphasizes the difficulty to morphologically assess pathological response and the need for new tool to better select patients who should be resected. Further results of the FFCD 1201 trial will bring more information on this new combination therapy.

Hypercalcémie humorale révélant un lymphome malin non hodgkinien

INTRODUCTION Hypercalcemia is a rare complication of non-Hodgkin lymphoma. Usually, hypercalcemia occurs late in the disease course, except for high-grade lymphoma. Most often hypercalcemia is related to excessive level of circulating PTH-rP or sometimes, 1,25(OH)2D3. Concomitant high plasmatic concentration of PTH-rP and 1,25(OH)2D3 is uncommon. EXEGESIS We report the case of a 82-year-old man who presented with abdominal pain and weight loss, leading to the diagnosis of diffuse large-B-cell lymphoma (high-grade lymphoma) associated with symptomatic hypercalcemia (3.21mmol/l). PTH-rP and 1,25(OH)2D3 plasmatic levels were high. Calcium concentration was normalized with glucocorticoids and sequential chemotherapy. CONCLUSION This case report confirms that hypercalcemia, as consequence of excessive plasmatic level of PTH-rP secreted by tumoral cells, can occur early in the course of high-grade lymphoma. Glucocorticoids and chemotherapy are the best treatment options.

3 Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.