Impact of Sarcopenia on Survival in Patients Treated with FOLFIRINOX in a First-Line Setting for Metastatic Pancreatic Carcinoma.

Sarcopenia, defined as decreased muscle mass and strength, can be evaluated by a computed tomography (CT) examination and might be associated with reduced survival in patients with carcinoma. The prognosis of patients with metastatic pancreatic carcinoma is poor. The FOLFIRINOX (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) chemotherapy regimen is a validated first-line treatment option. We investigated the impact of sarcopenia on overall survival (OS) and progression-free survival (PFS) in patients with metastatic pancreatic carcinoma. Clinical data and CT examinations of patients treated with FOLFIRINOX were retrospectively reviewed. Sarcopenia was estimated using baseline CT examinations. Seventy-five patients were included. Forty-three (57.3%) were classified as sarcopenic. The median OS of non-sarcopenic and sarcopenic patients were 15.6 and 14.1 months, respectively (p = 0.36). The median PFS was 10.3 in non-sarcopenic patients and 9.3 in sarcopenic patients (p = 0.83). No differences in toxicity of FOLFIRINOX were observed. There was a trend towards a higher probability of short-term death (within 4 months of diagnosis) in sarcopenic patients. In this study, the detection of sarcopenia failed to predict a longer OS or PFS in selected patients deemed eligible by a physician for triplet chemotherapy and receiving the FOLFIRINOX regimen in a first-line setting, confirming the major importance of a comprehensive patient assessment by physicians in selecting the best treatment option.

Impact of Sarcopenia on Patients with Localized Pancreatic Ductal Adenocarcinoma Receiving FOLFIRINOX or Gemcitabine as Adjuvant Chemotherapy.

Background: Despite its toxicity, modified FOLFIRINOX is the main chemotherapy for localized, operable pancreatic adenocarcinomas. Sarcopenia is known as a factor in lower overall survival (OS). The purpose of this study was to assess the impact of sarcopenia on OS in patients with localized pancreatic ductal adenocarcinoma (PDAC) who received modified FOLFIRINOX or gemcitabine as adjuvant chemotherapy. Methods: Patients with operated PDAC who received gemcitabine-based (GEM group) or oxaliplatin-based (OXA group) adjuvant chemotherapy between 2008 and 2021 were retrospectively included. Sarcopenia was estimated on a baseline computed tomography (CT) examination using the skeletal muscular index (SMI). The primary evaluation criterion was OS. Secondary evaluation criteria were disease-free survival (DFS) and toxicity. Results: Seventy patients treated with gemcitabine-based (n = 49) and oxaliplatin-based (n = 21) chemotherapy were included, with a total of fifteen sarcopenic patients (eight in the GEM group and seven in the OXA group). The median OS was shorter in sarcopenic patients (25 months) compared to non-sarcopenic patients (158 months) (p = 0.01). A longer OS was observed in GEM non-sarcopenic patients (158 months) compared to OXA sarcopenic patients (14.4 months) (p < 0.01). The median OS was 157.7 months in the GEM group vs. 34.1 months in the OXA group (p = 0.13). No differences in median DFS were found between the GEM group and OXA group. More toxicity events were observed in the OXA group (50%) than in the GEM group (10%), including vomiting (p = 0.02), mucositis (p = 0.01) and neuropathy (p = 0.01). Conclusion: Sarcopenia is associated with a worse prognosis in patients with localized operated PDAC whatever the delivered adjuvant chemotherapy.

Therapeutic Management of Advanced Hepatocellular Carcinoma: An Updated Review.

Hepatocellular carcinoma (HCC) usually occurs in the setting of liver cirrhosis and more rarely in a healthy liver. Its incidence has increased in the past years, especially in western countries with the rising prevalence of non-alcoholic fatty liver disease. The prognosis of advanced HCC is low. In the first-line setting of advanced HCC, sorafenib, a tyrosine kinase inhibitor, was the only validated treatment for many years. In 2020, the combination of atezolizumab, an immune checkpoint inhibitor, and bevacizumab showed superiority to sorafenib alone in survival, making it the first-line recommended treatment. Regorafenib and lenvatinib, other multikinase inhibitors, were also validated in the second and first-line settings, respectively. Transarterial chemoembolization can be an alternative treatment for patients with intermediate-stage HCC and preserved liver function, including unresectable multinodular HCC without extrahepatic spread. The current challenge in advanced HCC lies in the selection of a patient for the optimal treatment, taking into account the underlying liver disease and liver function. Indeed, all trial patients present with a Child-Pugh score of A, and the optimal approach for other patients is still unclear. Furthermore, the combination of atezolizumab and bevacizumab should be considered in the absence of medical contraindication. Many trials testing immune checkpoint inhibitors in association with anti-angiogenic agents are ongoing, and primary results are promising. The landscape in advanced HCC management is undergoing profound change, and many challenges remain for optimal patient management in the years to come. This review aimed to provide an overview of current systemic treatment options for patients with advanced unresectable HCC who are not candidates for liver-directed therapy.

Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives.

Major breakthroughs have been achieved in the management of metastatic pancreatic ductal adenocarcinoma (PDAC) with FOLFIRINOX (5-fluorouracil + irinotecan + oxaliplatin) and gemcitabine plus nab-paclitaxel approved as a first-line therapy, although the prognosis is still poor. At progression, patients who maintain a good performance status (PS) can benefit from second-line chemotherapy. To address the concern of achieving tumor control while maintaining a good quality of life, maintenance therapy is a concept that has now emerged. After a FOLFIRINOX induction treatment, maintenance with 5-fluorouracil (5-FU) seems to offer a promising approach. Although not confirmed in large, prospective trials, gemcitabine alone as a maintenance therapy following induction treatment with gemcitabine plus nab-paclitaxel could be an option, while a small subset of patients with a germline mutation of breast cancer gene (BRCA) can benefit from the polyadenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib. The rate of PDAC with molecular alterations that could lead to a specific therapy is up to 25%. The Food and Drug Administration (FDA) recently approved larotrectinib for patients with any tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and pembrolizumab for patients with a mismatch repair deficiency in a second-line setting, including PDAC. Research focused on targeted therapy and immunotherapy is active and could improve patients' outcomes in the near future.

Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions.

Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.

Indications of Peptide Receptor Radionuclide Therapy (PRRT) in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors: An Updated Review.

Radionuclide therapy for neuroendocrine tumors is a form of systemic radiotherapy that allows the administration of targeted radionuclides into tumor cells that express a large quantity of somatostatin receptors. The two most commonly used radio-peptides for radionuclide therapy in neuroendocrine tumors are 90Y-DOTATOC and 177Lu-DOTATATE. Radio-peptides have been used for several years in the treatment of advanced neuroendocrine tumors. Recently, the randomized Phase III study NETTER-1 compared177Lu-DOTATATE versus high-dose (double-dose) octreotide LAR in patients with metastatic midgut neuroendocrine tumors, and demonstrated its efficacy in this setting. Strong signals in favor of efficiency seem to exist for other tumors, in particular for pancreatic and pulmonary neuroendocrine tumors. This focus on radionuclide therapy in gastroenteropancreatic and pulmonary neuroendocrine tumors addresses the treatment modalities, the validated and potential indications, and the safety of the therapy.

Endoscopic ultrasound efficacy in staging gastric linitis plastica lesion: a retrospective multicentric French study.

BACKGROUND: Endoscopic ultrasound (EUS) is a key imaging technique in gastric cancer (GC). The aim of this study was to evaluate the performance of EUS in the staging of parietal and lymph node involvement in linitis plastica (LP) compared to "classical" GC. METHODS: A retrospective multicentric French study was conducted on patients with no metastatic LP and operated by gastrectomy. A 2/1 matching based on pTNM stage and center was performed with GC. RESULTS: Forty-three patients were included, sixteen patients in the LP group and 27 in the control group. Sensitivity and specificity of EUS for diagnosis of T3-T4 parietal invasion were 77% and 100% respectively in the LP group and 89% and 56% respectively in the control group. Sensitivity and specificity of EUS for diagnosis of lymph node involvement were 73% and 80%, respectively in the LP group and 88% and 50%, respectively in the control group. Patients from LP group had significantly more advanced histological lesion, and frequent undiagnosed peritoneal carcinomatosis. CONCLUSIONS: This study evaluated for the first time in a European population, the preoperative EUS performance in LP. Our study identified a similar sensitivity and specificity of the EUS in LP compared to "classical" GC paving for a broader use of EUS in preoperative settings.

Organ Preservation after Endoscopic Resection of Early Esophageal Cancer with a High Risk of Lymph Node Involvement.

Background: Esophagectomy is recommended after endoscopic resection of an early esophageal cancer when pejorative histoprognostic criteria indicate a high risk of lymph node involvement. Our aim was to analyze the clinical outcomes of a non-surgical, organ preserving management in this clinical setting. Patients and Methods: This retrospective study was performed in two tertiary centers from 2015 to 2020. Patients were included if they had histologically complete resection of an early esophageal cancer, with poor differentiation, lymphovascular invasion or deep submucosal invasion. Endoscopic resection was followed by chemoradiotherapy or follow-up in case of surgical contraindications or patient refusal. Outcome measures were disease-free survival (DFS), overall survival (OS), cancer specific survival (CSS) and toxicity of chemoradiotherapy. Results: Forty-one patients (36 with squamous cell carcinoma and 5 with adenocarcinomas) were included. The estimated high risk of lymph node involvement was based on poor differentiation (10/41; 24%), lympho-vascular invasion (11/41; 27%), muscularis mucosa invasion or deep sub-mucosal invasion (38/41; 93%). Thirteen patients (13/41; 32%) were closely monitored, and 28 (28/41; 68%) were treated by chemoradiotherapy or radiotherapy alone. In the close follow-up group, DFS, OS and CSS were 92%, 92% and 100%, respectively vs. 75%, 79% and 96%, respectively in the chemoradiotherapy group at the end of the follow-up. Serious adverse events related to chemoradiotherapy occurred in 10% of the patients. There were no treatment-related deaths. Conclusions: Our study shows that close follow-up may be an alternative to systematic esophagectomy after endoscopic resection of early esophageal cancer with a predicted high risk of lymph node involvement.

Medical Treatment of Advanced Pancreatic Neuroendocrine Neoplasms.

Pancreatic neuroendocrine neoplasms (panNENs) are relatively rare but their incidence has increased almost sevenfold over the last four decades. Neuroendocrine neoplasms are classified according to their histologic differentiation and their grade. Their grade is based on their Ki-67 proliferation index and mitotic index. Their prognosis is highly variable according to these elements and treatments also vary according to their classification. Surgery is the only curative treatment for localized and advanced panNENs and offers a better prognosis than non-surgical treatments. In the case of an advanced panNEN without the possibility of resection and/or ablation, medical treatment remains the cornerstone for improving survival and preserving quality-of-life. PanNENs are considered as chemosensitive tumors, unlike midgut neuroendocrine tumors. Thus, panNENs can be treated with chemotherapy, but targeted therapies and somatostatin analogs are also treatment options. The scarcity and heterogeneity of NENs make their management difficult. The present review aims to clarify the medical treatments currently available for advanced panNENs, based on their characteristics, and to propose a treatment algorithm.

Oral therapies in digestive oncology (Review).

Targeted therapy and oral chemotherapy indications are increasing in the realm of digestive oncology. Oral intake of cancer agents is sometimes compulsory (no i.v. equivalent) or is preferred by the patient or the physician. Although oral chemotherapy facilitates the treatment of oncology patients, the treatment diversity, risk of pharmaceutical interactions and monitoring of side effects are potentially challenging and need to be fully acknowledged by the physician. We offer here a literature review of the indications, doses, side effects and monitoring of every oral therapy indicated in Digestive Oncology. We suggest a prescription algorithm including therapeutic education by the physician or a trained nurse, and pharmaceutical counseling.

Non-Pharmacological Therapeutic Options for Liver Metastases in Advanced Neuroendocrine Tumors.

The incidence of liver metastasis in digestive neuroendocrine tumors is high. Their presence appears as an important prognostic factor in terms of quality of life and survival. These tumors may be symptomatic because of the tumor burden itself and/or the hormonal hyper-secretion induced by the tumor. Surgery is the treatment of choice for resectable tumors and metastasis. Nevertheless, surgery is only possible in a small number of cases. The management of non-resectable liver metastasis is a challenge. The literature is rich but consists predominantly in small retrospective series with a low level of proof. Thus, the choice of one technique over another could be difficult. Local ablative techniques (radiofrequency) or trans-catheter intra-arterial liver-directed treatments (hepatic artery embolization, chemo-embolization, and radio-embolization) are frequently considered for liver metastasis. In the present review, we focus on these different therapeutic approaches in advanced neuroendocrine tumors, results (clinical and radiological), and overall efficacy, and summarize recommendations to help physicians in their clinical practice.

Impact of a dedicated multidisciplinary meeting on the management of superficial cancers of the digestive tract.

Background The recent development of endoscopic resection for superficial gastrointestinal cancers could justify the need for a dedicated oncological multidisciplinary meeting (MDM). The aim of our study was to evaluate the impact of the dedicated MDM on the management of superficial cancers of the digestive tract. Methods A dedicated MDM was developed at our tertiary referral center. A retrospective review of the MDM conclusions for all patients referred from March 2015 to March 2017 was performed. Outcomes measurements were the outcomes of endoscopic resection, and the concordance rate between the MDM recommendations, European Society of Gastrointestinal Endoscopy (ESGE) guidelines, and final patient management. Results In total, 153 patients with a median age of 69 years were included. Half of the patients had major comorbidities. The mean lesion size was 25 mm, and R0 and curative resection rate were 73.9 % and 56.9 %, respectively. Forty-three patients had an indication for surgery after endoscopic resection. The concordance rate between ESGE guidelines and MDM recommendation was 92.2 %, and 12 patients did not receive the treatment recommended due to comorbidities. Conclusion A MDM dedicated to superficial tumors helped tailor the ESGE guidelines to each patient in order to avoid unnecessary surgery.

Computed tomography scan efficacy in staging gastric linitis plastica lesion: a retrospective multicentric French study.

BACKGROUND: Computed tomography (CT) scan is a key imaging technique in the staging of gastric adenocarcinoma and therapeutic management of patients. The aim of this study was to evaluate the performance of CT scan in the staging of parietal and metastatic invasion in gastric linitis plastica group. METHODS: A retrospective multicentric French study was conducted from January 2006 to December 2015 on patients with no metastatic gastric linitis plastica and operated by gastrec-tomy. A 2/1 matching based on pTNM stage and center was performed. RESULTS: Fifty patients were included in the linitis plastica group and 100 in the control group. Patients from the linitis group were significantly different from those from the control group with a lower age at diagnosis, a more advanced histological lesion, a more frequent undiagnosed peritoneal carcinomatosis, and a higher risk of R1 resection. Sensitivity and specificity of CT scan for the diagnosis of lymph node involvement were 44% and 75%, respectively, in the linitis plastica group and 55% and 60%, respectively, in the control group. The sensitivity and specificity of CT scan for the T3-T4 parietal invasion were 26% and 100%, respectively, in the linitis group and 40% and 72%, respectively, in the control group. CONCLUSION: CT scan has an equal sensitivity and specificity for the evaluation of lymph node and parietal involvement in gastric adenocarcinoma, including linitis plastica. CT scan remains the cornerstone of preoperative evaluation in gastric adenocarcinoma, including linitis plastica. However, CT presents a lack of sensitivity to diagnose low-volume peritoneal carcinomatosis.

[Therapeutic advances in the management of biliary tract carcinoma]. / Les progrès dans la prise en charge des cholangiocarcinomes.

Cancers of the bile ducts or cholangiocarcinomas are a rare entity whose incidence is increasing in France. Surgical resection of cholangiocarcinoma remains the only curative therapy. Adjuvant therapy with capecitabine at a fixed dose of 1250mg/m2 twice daily from day 1 to day 14 (21-day cycle) for a 6 months period is now the standard of care after curative surgery. At a metastatic stage, the reference treatment consists of the combination of a platinum salt in addition to gemcitabine. No biomarker has been identified to predict the response to chemotherapy. DNA sequencing of the tumor can identify specific tumor mutations in bile duct cancers that are the focus of targeted studies.

Addition of an antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers.

Background The prognosis of patients with metastatic carcinoma of the biliary tract (mBTC) is poor and a systemic therapy with gemcitabine and platinum-based is the gold standard. The addition of bevacizumab to the chemotherapy might increase patients' survival. Our aim was to assess and compare the efficacy of GEMOX (gemcitabine and oxaliplatin regimen) plus bevacizumab to GEMOX alone in mBTC. Methods Patients with mBTC who received the GEMOX-bevacizumab (n = 32; Group A) or GEMOX (n = 25; Group B) regimen as first-line treatment were compared. Treatment was repeated every two weeks until disease progression or unacceptable adverse effects occurred. The primary evaluation criterion was the progression-free survival (PFS). Results A quarter of patients (8/32) from Group A and a fifth of patients (13/25) from Group B had an objective response. The median PFS was 6.48 months and 3.72 months in Group A and B, respectively (p = 0.049). The median OS was 11.31 months and 10.34 months in Group A and B, respectively. Grade 3/4 sepsis was identified in 9.4% and 12% in Group A and B, respectively, (p = 0.64). Conclusion In mBTC, the addition of bevacizumab to GEMOX increased the progression-free survival and was associated with manageable toxicity. These data pave the way for further evaluation of antiangiogenic agents in mBTC.

Tumour growth increased following antiangiogenic interruption: the challenge of tumour evaluation.

Vascular endothelial growth factor inhibitors, led by bevacizumab, are considered the cornerstone of the therapy in metastatic colorectal carcinoma. We present the case of a patient with metastatic colorectal cancer who experienced rapid tumour growth with liver broad invasion after the withdrawal of an antivascular endothelial growth factor therapy, aflibercept. The rebound effect caused by the residual tumour inducing a regrowth after an initial controlled disease has already been stressed in mice and metastatic colorectal cancer patients following bevacizumab interruption. The use of liver volume evaluation was consistent with the Response Evaluation Criteria in Solid Tumours 1.1 criteria evaluation and might be a useful tool in patients with more than a half liver invasion. We describe for the first time the case of a major liver disease progression, confirmed by Response Evaluation Criteria in Solid Tumours 1.1 criteria and liver volume evaluation, after an antiangiogenic interruption in second line.

Immune Checkpoint Inhibitor-Induced Colitis: Diagnosis and Management.

Immune checkpoint inhibitors are monoclonal antibodies indicated for an increasing number of malignant diseases. These agents can cause specific side effects, which need to be anticipated while clear patterns of management need to be established. Immune checkpoint inhibitor-mediated gastrointestinal side effects, including diarrhea and colitis, occur in up to 30% of patients. Severe colitis can lead to severe dehydration or intestinal perforation. Endoscopic lesions and histopathological features of immune checkpoint inhibitor-induced colitis are similar to an inflammatory bowel disease (IBD) flare. Patients with immune checkpoint inhibitor-induced diarrhea and colitis are treated with corticosteroids. Infliximab can be used in cases of corticosteroid failure. Rectosigmoïdoscopy or colonoscopy should be performed when severe immune checkpoint inhibitor-induced colitis is suspected, but endoscopic investigations should not delay treatment. Specific patient education as well as co-operation between oncologists and gastroenterologists is essential.

[Mid gut neuroendocrine tumors: News on medical treatment]. / Tumeurs neuroendocrines de l'intestin grêle : actualités sur le traitement médical.

CONTEXT: Mid gut neuroendocrine tumors (NET) are rare tumors whose incidence is increasing. Curative surgery remains the gold standard for the treatment of NETs of the small intestine. Surgery should be considered as soon as possible even if a metastatic stage is diagnosed. The management of unresectable well-differentiated metastatic NETs of the small intestine recently changed with the publication of trials demonstrating the benefit of targeted therapies and metabolic radiotherapy, leading to a change of practices and update of French and international recommendations. OBJECTIVE: The objective of this review is to present the recent data consisting of three phase III studies, which modify the management of well-differentiated metastatic midgut NETs and make an inventory of the available treatment options. DOCUMENTARY SOURCES: The documentary sources used were gathered through the PubMed website using keyword searching (neurendocrine tumor, mid gut, treatment). We also referred to recommendations of the European Society of neuroendocrine tumors (ENETS) trials presented at ESMO Congress 2015 (European Society for Medical Oncology). STUDY SELECTION: We excluded studies of exclusive extra-digestive NETs, poorly differentiated NETs, surgical treatments and phase I studies. RESULTS: We discussed three randomized phase III trials: CLARINET, RADIANT and NETTER studies. These studies demonstrated the efficacy of respectively somatostatin analogues, mTOR inhibitors and metabolic radiotherapy. CONCLUSION: This review highlights the validation by randomized studies of an mTOR inhibitor and metabolic radiotherapy in metastatic non-pancreatic digestive NETs unresectable well-differentiated grade of G1/2 in progression under somatostatin analogues.