Neoadjuvant treatment: A window of opportunity for nutritional prehabilitation in patients with pancreatic ductal adenocarcinoma.

Patients affected by pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced disease at the time of diagnosis, limiting an upfront surgical approach. Neoadjuvant treatment (NAT) has become the standard of care to downstage non-metastatic locally advanced PDAC. However, this treatment increases the risk of a nutritional status decline, which in turn, may impact therapeutic tolerance, postoperative outcomes, or even prevent the possibility of surgery. Literature on prehabilitation programs on surgical PDAC patients show a reduction of postoperative complications, length of hospital stay, and readmission rate, while data on prehabilitation in NAT patients are scarce and randomized controlled trials are still missing. Particularly, appropriate nutritional management represents an important therapeutic strategy to promote tissue healing and to enhance patient recovery after surgical trauma. In this regard, NAT may represent a new interesting window of opportunity to implement a nutritional prehabilitation program, aiming to increase the PDAC patient's capacity to complete the planned therapy and potentially improve clinical and survival outcomes. Given these perspectives, this review attempts to provide an in-depth view of the nutritional derangements during NAT and nutritional prehabilitation program as well as their impact on PDAC patient outcomes.

Prognostic value of skeletal muscle mass during tyrosine kinase inhibitor (TKI) therapy in cancer patients: a systematic review and meta-analysis.

Low muscle mass has been associated with worse clinical outcomes in various cancers. This work investigated whether, during tyrosine kinases inhibitors (TKIs) therapy, low muscle mass was associated with treatment toxicity and survival outcomes. A systematic literature search was performed in Pubmed, Web of Science, and Scopus databases from inception to June 2020, based on fixed inclusion and exclusion criteria. Effect sizes were estimated with hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI) and heterogeneity was assessed by measuring inconsistency (I2) based on the Chi squared test. A total of 24 retrospective studies were identified, enrolling patients treated with sorafenib (n = 12), sunitinib (n = 6), lenvatinib (n = 3), regorafenib (n = 2), gefitinib (n = 1), imatinib (n = 1), and pazopanib (n = 1). Thirteen studies were deemed eligible for pooled analyses. Meta-analyses found a significant effect of low muscle mass on dose-limiting toxicity (DLT) (OR 2.40, 95% CI 1.26-4.58, p = 0.008, I2 = 51%) in patients treated with TKI therapy. A subgroup analysis by treatment showed an association between DLT and low muscle during sorafenib or sunitinib, although not significant. A significant association between low skeletal muscle index and poorer overall survival was observed in HCC patients treated with sorafenib (HR 1.45, 95% CI 1.07-1.96, p = 0.02). For other TKIs, although some results showed an association between low muscle mass and worse outcomes, the number of studies for each TKI therapy was too small to reach conclusions. Skeletal muscle mass could influence the prognosis of some TKI-treated patients. This effect is demonstrated in sorafenib-treated HCC patients but remains almost unexplored in other cancer patients undergoing TKI therapy. Further prospective studies with large sample size and sufficient follow-up are needed to clarify the role of muscle mass in the metabolism of TKI-based cancer treatment, and its association with toxicity and survival.

Skeletal Muscle Loss during Multikinase Inhibitors Therapy: Molecular Pathways, Clinical Implications, and Nutritional Challenges.

In cancer patients, loss of muscle mass is significantly associated with low tolerability of chemotherapy and poor survival. Despite the great strides in the treatment of cancer, targeted therapies such as tyrosine kinase inhibitors (TKIs) could exacerbate muscle wasting. Over recent years, the impact of skeletal muscle loss during TKI therapy on clinical outcomes has been in the spotlight. In this review, we focus on the different molecular pathways of TKIs potentially involved in muscle wasting. Then, we report the results of the studies assessing the effects of different TKI therapies-such as sorafenib, regorafenib, sunitinib, and lenvatinib-on muscle mass, and highlight their potential clinical implications. Finally, we discuss an integrative nutritional approach to be adopted during TKI treatment. The assessment of muscle mass from computerized tomography imaging could be helpful in predicting toxicity and prognosis in patients treated with TKI such as sorafenib. Early recognition of low muscle mass and effective personalized nutritional support could prevent or attenuate muscle mass wasting. However, the role of nutrition is still overlooked, and future clinical trials are needed to find the optimal nutritional support to countermeasure muscle mass depletion during TKI therapy.

Critical appraisal of ramucirumab (IMC-1121B) for cancer treatment: from benchside to clinical use.

Although antiangiogenic treatments have produced milestone advances in the treatment of several diseases, and have significantly extended the median survival of cancer patients, these agents share some weaknesses, including a limited impact on the overall cure rate, a fleeting effect because of redundant pathways or early appearance of resistance mechanisms, and the lack of predictive factors for treatment selection. Recent data suggest that antibodies targeting the vascular endothelial growth factor axis exert their activity through the inhibition of vascular endothelial growth factor receptor-2 phosphorylation, which has a pivotal role in the neoangiogenic process. Ramucirumab, a fully humanized monoclonal antibody specifically directed against the extracellular domain of the receptor, administered intravenously every 2 or 3 weeks, is emerging as a novel antiangiogenic opportunity. Starting with preclinical data and early clinical results, this concise review focuses on the development of the novel compound across multiple cancers (including gastrointestinal malignancies, breast cancer, lung carcinoma, and genitourinary tumors), and presents available data from randomized phase II and phase III trials. REGARD was the first phase III study to report on the efficacy of single-agent ramucirumab in patients with advanced cancer. Many other ongoing phase III trials are testing the efficacy of this interesting antiangiogenic compound as a single agent or in combination with chemotherapy in different cancer types.

Recurrent disease four years after surgery and adjuvant chemotherapy.

A 71-year-old man with previous primary resection was found to have extensive liver metastases. Chemotherapy was initiated with FOLFIRI plus bevacizumab, in hopes of reducing the hepatic tumor burden; this resulted in manageable toxicity and was sufficiently effective to allow resection. After 6 weeks, 6 cycles of chemotherapy with FOLFIRI plus bevacizumab were administered; the patient was free of new lesions for the next 19 months. Readministration of FOLFIRI plus bevacizumab resulted in minor response and symptom control for another 9 months before further progression was observed. The subsequent administration of FOLFOX for 8 cycles and FOLFIRI plus cetuximab were unable to prevent further decline. Detailed explanation of the selection of appropriate surgical and chemotherapeutic options are provided throughout the case discussion.

Adjuvant treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and epidoxorubicin in a randomized controlled trial.

BACKGROUND: Promising findings obtained using a weekly regimen of 5-fluorouracil (5-FU), epidoxorubicin, leucovorin (LV), and cisplatin (PELFw) to treat locally advanced and metastatic gastric cancer prompted the Italian Group for the Study of Digestive Tract Cancer (GISCAD) to investigate the efficacy of this regimen as adjuvant treatment for high-risk radically resected gastric cancer patients. METHODS: From January 1998 to January 2003, 400 gastric cancer patients at high risk for recurrence including patients with serosal invasion (stage pT3 N0) and/or lymph node metastasis (stage pT2 or pT3 N1, N2, or N3), were enrolled in a trial of adjuvant chemotherapies; 201 patients were randomly assigned to receive the PELFw regimen, consisting of eight weekly administrations of cisplatin (40 mg/m2), LV (250 mg/m2), epidoxorubicin (35 mg/m2), 5-FU (500 mg/m2), and glutathione (1.5 g/m2) with the support of filgrastim, and 196 patients were assigned to a regimen consisting of six monthly administrations of a 5-day course of 5-FU (375 mg/m2 daily) and LV (20 mg/m2 daily, 5-FU/LV). Disease-free and overall survival were estimated and compared between arms using hazard ratios (HRs) and Kaplan-Meier estimates. All statistical tests were two-sided. RESULTS: The 5-year survival rates were 52% in the PELFw arm and 50% in the 5-FU/LV arm. Compared with the 5-FU/LV regimen, the PELFw regimen did not reduce the risk of death (HR = 0.95, 95% confidence interval [CI] = 0.70 to 1.29) or relapse (HR = 0.98, 95% CI = 0.75 to 1.29). Less than 10% of patients in either arm experienced a grade 3 or 4 toxic episode. Neutropenia (occurring more often in the PELFw arm) and diarrhea and mucositis (more prevalent in the 5-FU/LV arm) were the most common serious side effects. Nevertheless, only 19 patients (9.4%) completed the treatment in the PELFw arm and 85 (43%) patients completed the treatment in the 5-FU/LV arm. CONCLUSIONS: Our study found no benefit from an intensive weekly chemotherapy in gastric cancer. The extent of toxicity experienced by the patients in the adjuvant setting suggests that, in gastric cancer, chemotherapy may be more safely administered preoperatively.

Prognostic indicators in locally advanced gastric cancer (LAGC) treated with preoperative chemotherapy and D2-gastrectomy.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy is increasingly considered an effective treatment option for patients with gastric carcinoma. Aim of the study is to evaluate the prognostic significance of the pathological response and of known prognostic factors in a group of accurately staged locally advanced gastric cancer (LAGC) patients. METHODS: Thirty-three patients with LAGC, staged by laparoscopy, underwent D2-gastrectomy after preoperative chemotherapy. Survival was calculated by Kaplan-Meier method and differences were assessed by the Log-rank and Breslow test. Multivariate analysis was performed using the Cox proportional hazard model in backward stepwise regression. RESULTS: Curative resection (R0) was achieved in 81.8% of patients. A complete or subtotal pathological response was documented in 3 and 6%, respectively. Nineteen out of thirty-three (57.6%) patients were alive and 16 of them were free of relapse at last follow-up. Survival rates were 81, 67, and 59% at 12, 24, and 36 months, respectively. At univariate and multivariate analysis, only R0 resection was found to be an independent prognostic factor. CONCLUSIONS: In the current study, R0 resection is the most important prognostic factor for resectable LAGC; according to our results we feel encouraged to consider neoadjuvant chemotherapy a promising modality for increasing the R0-percentage of gastric carcinoma patients who could benefit from a curative surgery.