Management of refractory metastatic colorectal cancer: consensus recommendations from Italian oncologists

Capecitabine is an oral pro-drug of 5-fluorouracil (5FU) that has demonstrated an efficacy at least equivalent to standard leucovorin (LV)-modulated 5FU I.V. bolus regimen in the management of metastatic colorectal cancer (MCRC) patients as well as in the adjuvant setting. Despite a mild increase of some side effects, capecitabine is usually better tolerated than 5FU/LV, and could be preferable in the treatment of elderly patients. Moreover, usually the patients compliance with an oral treatment is better than with a regimen requiring the placement of a central venous catheter and infusional devices. The combination of capecitabine with oxaliplatin (XELOX regimen) was shown to be as effective as the combination of 5FU/LV with oxaliplatin (FOLFOX4 regimen) in MCRC. The XELOX regimen represents now a new standard of care for MCRC patients, and it will be probably considered in the next future an “user-friendly” alternative to the FOLFOX4 also in resected patients. The addition of bevacizumab to the XELOX regimen was demonstrated to further prolong the progression-free survival of metastatic patients, and is anticipated to reduce the risk of recurrence in resected colon cancer. Despite a higher acquisition cost than 5FU/LV, capecitabine is also cost-effective, because of the reduced costs for drug administration and management of adverse events.

Colorectal cancer is a leading cause of cancer death worldwide. Recently the results of a number of well-designed clinical trials conducted across the world have led to important advances in the management of advanced colorectal cancer. These iterative studies fostered the evolution from a standard single-agent approach using fluorouracil (5-FU) to new combination regimens including capecitabine, irinotecan, and oxaliplatin in addition to 5-FU. These developments have significantly expanded the expectations of oncologists managing the disease and the options available to individuals, leading to a likelihood of extended survival compared to previous statistics. The identification of new combination chemotherapy regimens and the integration of novel targeted therapies with cytotoxic chemotherapies are areas of active clinical investigation. In this paper selected phase III studies from around the globe that tested these new chemotherapy options and led to new standards of care and better expectations for patients with advanced colorectal cancer are reviewed.

Globally, cancer is among the principal causes of death, and the incidence of colorectal cancer is increasing annually around the world, and it is currently ranked third most diagnosed cancer type. Despite the development in the treatment procedures for colorectal cancer including chemotherapy, surgery, immunotherapy and radiotherapy, the death rates from this cancer type are still elevated due to the adverse effects associated with treatment that may affect patients' quality of life. Recently, the global interest in probiotics research has grown with significant positive results. METHODS: This review discusses the role of probiotics in normal colorectal physiology and cancer. Probiotics will become an essential part in the prevention and management of colorectal cancer in the near future as they are expected to provide a solution to the problems associated with cancer treatment. Probiotics' properties open the way for multiple effective uses in colorectal cancer prevention strategies. Additionally, probiotics can reduce the problems associated with chemotherapy and surgery when used synergistically. Probiotics can also increase the efficacy of chemotherapeutic medications. Targeted drug delivery and TRAIL collaboration techniques are other effective and promising methods that involve probiotics. Probiotics have properties that make them useful in the management and prevention of colorectal cancer and can provide new avenue to reduce the occurrence of this malignancy and enhance the patients' quality of life.

The Asian Approach to the Management of Gastrintestinal Cancer Patients During the COVID-19 Pandemic Era

A prescription for psychosocial cancer care

BackgroundIn the 2021 Statistics Canada census, 18.5% of the Canadian population were senior (65 years and older), among those 1.7 million (4.5%) were aged 80 years and older. Colorectal cancer (CRC) is the third most common cancer in both men and women, with its highest incidence rate in septu- and octogenarians. As clinicians encounter a growing number of very elderly patients (80 years and older) with resectable colorectal cancer, justifying major surgery in a comorbid population with limited life expectancy is difficult. Therefore, this study aims to systemically review the available literature to compare non-operative management to surgical resection with respect to overall survival and quality of life.MethodWe designed and registered a study protocol for a systematic review. We will include all patients above the age of 80 with resectable colorectal cancer. We will search MEDLINE, EMBASE, and the Cochrane Database of Controlled Trials from January 2000 onwards. We will include randomized, non-randomized controlled trials and observational studies comparing non-operative versus operative management of resectable colorectal cancer in elderly patients. The primary outcomes will be overall survival and mortality. Secondary outcomes will include quality of life, and health services/ resources utilization (e.g., treatments, change of level of care…). Two reviewers will independently screen all citations, full-text articles, and abstract data. Potential conflicts will be resolved through discussion. The study methodological quality (or bias) will be appraised using the ROB-2 and ROBIN-I tools. If feasible, we will conduct random effects meta-analysis. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., study design and methodological quality).DiscussionThis systematic review will synthesize the existing data on the management of colorectal cancer in the very elderly patients, and identify the gap in the literature for potential future research. More specifically, we aim to streamline non-operative outcome data on resectable colorectal cancers to aid clinicians’ decision-making with respect to survival outcomes and quality of life. The results of this study will be of interest to multiple audiences including patients, their families, caregivers, healthcare professionals, and policy makers. Results will be published in a peer-reviewed journal.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Ottawa, Ontario, October 22-23, 2010. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer, such as the use of epidermal growth factor inhibitors in metastatic colon cancer, the benefit of calcium and magnesium with oxaliplatin chemotherapy, the role of microsatellites in treatment decisions for stage II colon cancer, the staging and treatment of rectal cancer, and the management of colorectal and metastatic pancreatic cancers.

Towards a new standard of care for patients with myeloma?

BRAF-mutated colorectal adenocarcinomas: Pathological heterogeneity and clinical implications

Prostate cancer (PC) is the most frequently diagnosed male malignancy and the 2 nd or 3 rd leading cause of cancer deaths in men in the developed countries. The disease progresses from locally invasive carcinoma to metastatic prostate cancer (mPC). While PC metastasizes to the liver and lung, bone is the most frequent site of PC metastasis. Distant metastasis likely marks the point of no return progress towards the worst prognosis. Owning to the landmark discovery that metastatic PC requires androgen receptor (AR) signaling by Charles Huggins in 1941, androgen deprivation therapy (ADT) remains the standard of care for mPC patients. Although the treatment provides initial benefits in the majority of patients with mPC, metastatic castration-resistant prostate cancer (mCRPC) inevitably arises. Prior to 2011, docetaxel was the only second line-therapy (1), and prolonged median overall survival (OS) in patients with mCRPC by 3 months. Since then, the second generation anti-androgens (abiraterone and enzalutamide), radium-223, cabazitaxel, and Sipuleucel-T have become available in the clinic. Although these therapies are not curative, they extend OS in patients with mCRPC (2). As these drugs have different mechanisms of action, they could be used in a variety of combinations either sequentially or simultaneously to maximize benefits to patients with mPC or mCRPC. For example, ADT plus docetaxel is superior to either alone (3) and is becoming the new standard of care for patients with mPC with good performance status. Clearly, improving our knowledge on the course of mCRPC will contribute to the development of rational treatment plans with the currently available medicines and thereby improves patient management. In this regard, identifying parameters to accurately predict survival of patients with mCRPC is an area of active research; there are 113 and 40 published studies related to the topic of mCRPC and prognostic biomarkers or prognostic models in PubMed (https://www.ncbi.nlm.nih.gov/pubmed/advanced) up to Dec 3, 2016. In order to yield a robust predictive model, it will be essential for a team with combined expertise in clinic and machine learning to analyze comprehensive sets of clinical data.

PurposeRegorafenib, an oral multi-targeted tyrosine kinase inhibitor, is considered the new standard of care in patients with chemotherapy-refractory colorectal cancers (CRCs). However, there are no data on this drug in Korean patients.Materials and MethodsWe evaluated patients who received oral regorafenib 160 mg once daily during the first 3 weeks of each 4-week cycle between August 2013 and September 2013. All patients had previously progressed fluorouracil, irinotecan, and oxaliplatin with or without biologic agents such as cetuximab or bevacizumab.ResultsThirty-two patients were enrolled (median age, 57 years; male:female ratio, 20:12; Eastern Cooperative Oncology Group performance status [0-1:2], 31:1; colon:rectum, 21:11). The overall response rate was 3.1% and the disease control rate was 50.0% (95% confidence interval [CI]) with one partial response and 15 patients with stable disease. The median progression-free survival was 4.2 months (95% CI, 3.1 to 5.2 months) and the median overall survival has not yet been reached. The most common adverse events of grade two or higher related to regorafenib were hand-foot skin reaction (25%), mucositis (19%), abdominal pain (9%), and liver function test (LFT) abnormalities (9%). Grade 3 or 4 toxicities included LFT abnormalities (9%), abdominal pain (9%), rash (6%), anemia (3%), leukopenia (3%), neutropenic fever (3%), and fatigue (3%). There was no treatment-related death.ConclusionRegorafenib appears to have promising activity and tolerable toxicity profiles in Korean patients with refractory CRC, consistent with the CORRECT trial findings.

Adults Are Not Just Large Kids: Caring for Adults in Pediatric Hospitals.

Over 40,000 people will be diagnosed with rectal cancer in the United States in 2014, and colorectal cancer remains the second leading cause of cancer death nationally despite renewed focus on diagnosis and management (1). That being said, the incidence of colorectal cancer has dropped significantly over the last several decades largely attributable to more successful screening programs (2). In addition, cancer-related mortality among those diagnosed with colorectal cancer has also dropped in recent years, which is likely a function of earlier intervention and improved treatment modalities (3). The management of rectal cancer has evolved significantly over the last several decades and through this evolution, patients are now managed with a comprehensive multidisciplinary approach. From routine age-appropriate screening and history-taking through diagnostic work-up, cancer treatment, and survivorship, care of patients with rectal cancer requires a tremendous amount of resources and the expertise of an array of specialties working together to maximize patients’ quality and quantity of life. In this focus issue, our contributors delve into the different aspects of rectal cancer prevention, treatment, and aftercare that are largely responsible for the reduced incidence and mortality associated with this disease. After years of analysis, we now believe that as many as one in five patients diagnosed with colorectal cancer are genetically predisposed to developing invasive disease (4). Recognizing this at-risk population before they develop cancer, educating them, and enrolling them in proper screening protocols should help both in terms of disease prevention and earlier detection of invasive disease. In this issue, cancer genetics pioneer Dr. Lynch and fellow collaborators, Drs. Schlussel, Gagliano, Seto-Donlon, Eggerding, Donlon, and Berenberg have provided two manuscripts which together provide a definitive look at the evolution of colorectal cancer genetics. Part 1 details the background and history of colorectal cancer genetics and how that information has been incorporated into clinical practice (5). In part 2, Dr. Schlussel et al. review the hereditary cancer syndromes and the clinical implications and impact that providers need to be aware of when formulating a management strategy for patients and their families (6). For those patients that are diagnosed with rectal cancer, definitive treatment carries significant morbidity and mortality risks and techniques are continually being refined to reduce these treatment-related risks (7). As knowledge and understanding of rectal cancer continues to grow, identifying and screening at-risk populations in a timely fashion is leading to earlier detection and treatment. With earlier detection come more favorable outcomes and the potential to obviate the need for more traditional radical therapies. Drs. Heafner and Glasgow present a detailed review of the role of local excision in the treatment of early rectal cancers (8). In this review, the authors outline the rationale behind less invasive surgery in rectal cancer, the different techniques utilized, the risks and benefits associated with local excision, and the population that should be considered for this less invasive approach. Despite improvements in screening, prevention, and early detection, a large portion of patients with rectal cancer present with more advanced stages of disease. For patients with locally advanced disease, treatment has long featured combined modality therapy given the propensity of rectal cancer to recur both locally and distantly. Internationally, numerous trials have sought to determine the optimal sequence, duration, and intensity of therapy in an attempt to maximize outcomes while limiting treatment-related toxicities. In the United States, the standard of care in patients with locally advanced disease (at least T3 or node positive) is preoperative 5-flurouracil-based chemotherapy concurrent with external beam irradiation to a dose of approximately 5,000 cGy followed by transabdominal resection 5-12 weeks after completion of neoadjuvant therapy followed by postoperative chemotherapy. This recommended course of therapy is based on the results of the German Rectal Cancer Study which showed improved local control rates and a more favorable morbidity profile with neoadjuvant chemoradiation when compared to adjuvant chemoradiation (9). Building on this and many other trials, there are several studies ongoing, and internationally, there continues to be much debate over the ideal sequencing of treatment. Dr. Fung-Kee-Fung explores the concept of combined modality therapy for locally advanced rectal cancer from a historical perspective, showing how we have arrived at the current standards and postulating on where we are heading in the future (10). Local control following treatment is a major priority in rectal cancer both because of the historically high prevalence of local failure and due to the impact and morbidity associated with recurrent disease in the pelvis. Thus, many clinical trials for rectal cancer have focused on local control as a primary or secondary endpoint and based on the success of these studies, current treatment regimens yield long-term local control rates in excess of 90% (11). While local control rates in rectal cancer are now excellent, studies are finding that distant failure remains a persistent issue. There are a number of reasons to explain why, one being that after aggressive neoadjuvant chemoradiation and surgery, many patients never get their full course of adjuvant systemic therapy. In this issue, Drs. Boland and Fakih present the emerging role of neoadjuvant chemotherapy and how this change in therapy sequencing may further improve outcomes, particularly in terms of reducing rates of distant metastatic disease (12). With improving systemic therapy approaches, refined surgical techniques, and emerging radiation technologies, patients with all stages of rectal cancer are experiencing better treatment outcomes than they had historically, even those with advanced stages of disease (3). Advances in systemic therapy have made long-term disease control a reality for patients with a small metastatic burden, opening the door for aggressive local therapy for the treatment of limited metastatic disease. The majority of studies investigating local treatment of metastatic colorectal cancer have focused on disease metastatic to the liver. The liver is the most common site for colorectal metastases and spread to the liver is responsible for the majority of colorectal cancer-related deaths (13,14). In their manuscript, Drs. Clark and Smith lead a comprehensive discussion on liver-directed therapies in metastatic colorectal cancer (15). They take a step-wise approach to this complex treatment algorithm, focusing on the when, why and how of each treatment strategy along with the potential alternatives depending on the specific scenario. Rectal cancer is a challenging disease, and as outlined above and throughout this issue, the treatments themselves can be quite complex. Over the course of treatment, there is a significant physical and emotional toll on patients and their loved ones. And with improving outcomes, more and more patients are becoming long term survivors of this disease. And while these improving outcomes are cause for excitement, there is often disease- and treatment-related morbidity which complicates their recovery and impacts on their post-treatment quality of life. From the perceived stigma of dealing with a permanent ostomy to chronic sexual dysfunction, patients face an array of life-altering morbidity in the post-treatment setting and these issues many times go undetected by providers and thus are left untreated. In this focus issue, Drs. Averyt and Nishimoto have developed two unique manuscripts designed to help providers understand what patients are going through after treatment and to provide them with tools to help break down the barriers that are often faced in colorectal cancer survivorship. The first manuscript focuses specifically on addressing the sexual dysfunction that patients face following diagnosis and treatment (16). This topic is often largely ignored by providers and patients are many times reluctant to address this subject on their own in their routine follow-up. The authors present very effective tools to aid clinicians in opening a dialogue with patients early on in their treatment course and throughout their therapy and the end result is getting these patients the help and therapy that they need and ultimately improving their quality of life. The second manuscript takes the reader into the mind of the patient, giving insight into the top 10 questions that patients may be thinking but not asking (17). This manuscript serves as a valuable reference for providers to utilize, helping them build a strong and trusting relationship with their patients. As outlined, rectal cancer represents a comprehensive multidisciplinary challenge for many different providers who must work in concert to maximize the patient care experience. The goals of this focus issue of the Journal of Gastrointestinal Oncology are to educate our readership about many of the issues that are faced when treating rectal cancer and to provide the necessary tools needed to enhance their care of these unique patients.

Angiogenesis inhibition in metastatic colorectal cancer continuum of care

Colorectal cancers are the third most common cancers in the world. Management of both primary and metastatic colorectal cancers has evolved over the last couple of decades. Extensive research in molecular oncology has helped us understand and identify these complex intricacies in colorectal cancer biology and disease progression. These advances coupled with improved knowledge on various mutations have helped develop targeted chemotherapeutics and has allowed planning an effective treatment regimen in this era of immunotherapy with precision. The diverse chemotherapeutic and biological agents at our disposal can make decision making a very complex process. Molecular profile, including CIN, RAS, BRAF mutations, microsatellite instability, ctDNA, and consensus molecular subtypes, are some of the important factors which are to be considered while planning an individualized treatment regimen. This article summarizes the current status of molecular oncology in the management of colorectal cancer and should serve as a practical guide for the clinical team.