Efficacy of different maintenance strategies for RAS wild-type colorectal cancer: A network meta-analysis.

INTRODUCTION: In metastatic RAS wild-type colorectal cancer (CRC), induction combination chemotherapy doublets (CT) with an anti-EGFR agent are considered the primary treatment. We performed a network meta-analysis (NMA) to compare the relative efficacy of different maintenance treatments for advanced RAS wild-type CRC. MATERIALS AND METHODS: PubMed, EMBASE and Cochrane, from database inception until December 2021 were used. Randomized clinical trials enrolling adults with advanced RAS wild-type CRC and providing overall survival (OS) and/or progression-free survival (PFS) data PRISMA guidelines for NMA were followed. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (95% CrIs). Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. RESULTS: A total of 7 randomized phase 2 trials were included (for a total of 1286 patients). Compared to depotentiation treatments, continuous CT + anti-EGFR was not significantly superior to other maintenance regimens for OS and was ranked as the best option for NMA (SUCRA p-score=0.69). Conversely, in the PFS analysis, single-agent fluoropyrimidines + anti-EGFR was ranked as the best treatment (SUCRA p-score=0.60). CONCLUSIONS: Maintaining chemotherapy doublet + anti-EGFR until progression appears to be the best first-line strategy in terms of OS for advanced unresectable RAS wild-type mCRC treatment. However, fluoropyrimidines single-agent + cetuximab or panitumumab represent a reasonable choice regarding PFS.

Optimizing the first-line treatment for metastatic colorectal cancer.

Colorectal cancer represents an important oncological challenge both for its incidence, which makes it an important health problem, and for its biological complexity, which has made clinical results very difficult in terms of outcome for this category of patients. To date these diseases should not be treated as a single entity but it is necessary to distinguish colorectal cancers based on characteristics that nowadays are essential to have greater therapeutic benefits. These include the sideness of the disease, the state of microsatellites, the presence of prognostic and predictive mutations of response to treatments currently available in clinical practice, which are associated with new therapeutic targets. The greatest challenge in the future will be to circumvent the resistance mechanisms that make this disease very difficult to treat with good long-term results by studying effective combination treatments with a good toxicity profile. Once such combinations or targeted treatments are consolidated, it will be desirable to shift the best therapies to the first line treatment to make them immediately accessible to the patient. It will also be essential to refine the selection of patients who can benefit from these treatments.

Knowledge and awareness of stroke and associated factors in the Saudi general population: a cross-sectional study.

Introduction: Stroke is a major cause of death and disability globally and in Saudi Arabia as well. Prevention and management of stroke depend highly on raising knowledge and awareness about the disease. Purpose: The purpose of this study was to evaluate Saudi adult's knowledge and awareness about stroke and determine the associated factors. Materials and methods: A cross-sectional online survey was conducted in May-July 2022 among Saudi citizens. Assessments of stroke knowledge about risk factors, symptoms, and response to stroke symptoms were evaluated. Logistic regression was conducted to assess the association between the socio-demographic characteristics and knowledge. Results: A total of 389 participants were enrolled with the majority (81.7%) being male participants. Less than half of the study subjects (43.3%) identified four out of five correct answers related to general knowledge about stroke. Almost all the participants were able to identify at least one risk factor associated with stroke. The majority of the participants (81.2%) believed that physical inactivity was the most common risk factor associated with stroke. Approximately three-quarters of participants considered difficulty speaking and understanding speech, followed by the sudden loss of consciousness as the most common stroke manifestation. Participants with a history of hypertension, dyslipidemia, and obesity had significantly higher odds of identifying at least one early stroke symptom (OR 2.271 [95% CI 1.402 3.677], 2.059 [95% CI 1.273 3.328], and 2.665 [95% CI 1.431 4.963], respectively). Conclusion: Our study revealed that participants have good knowledge about stroke. Nonetheless, further efforts are required to raise awareness and educate the public to optimize and ensure better treatment outcomes.

Integrated Decision-Making in the Treatment of Colon-Rectal Cancer: The Case of KRAS-Mutated Tumors.

In recent years, precision medicine has taken an increasing place in various branches of medical oncology, including colorectal cancer. Among the potentially relevant mutations for this cancer is the KRAS mutation, initially defined as "untargetable"; today, we see the birth of new molecules that target one of the variants of the KRAS mutation, KRAS G12C, having a significant impact on the therapeutic options for other malignancies, such as metastatic lung cancer. This fundamental step forward has stimulated scientific research on other potential targets of KRAS, both indirect and direct, and combination treatments aiming to overcome the mechanisms of resistance to these drugs that decrease in efficacy in colorectal cancer. What was once a negative predictive marker of response to anti-EGFR drugs today has become a potential target for targeted treatments. In turn, the prognostic role of the mutation has become extremely interesting, making it a potentially useful element in therapeutic decision-making, not only regarding oncological treatments but also in a more complex and complete manner within a global vision of the patient, involving other figures on the multidisciplinary team, such as surgeons, radiotherapists, and interventional radiologists.

Microsatellite instability and chemosensitivity in solid tumours.

The use of biomarkers that influence a targeted choice in cancer treatments is the future of medical oncology. Within this scenario, in recent years, an important role has been played by knowledge of microsatellite instability (MSI), a molecular fingerprint that identifies defects in the mismatch repair system. This knowledge has changed clinical practice in the adjuvant setting of colon cancer, and its role in the neoadjuvant setting in gastric tumours is becoming increasingly interesting, as well as in endometrial cancers in both early and advanced diseases. Furthermore, it has undoubtedly conditioned the first lines of treatment in the metastatic setting in different types of cancers. The incidence of MSI is different in different cancer types, as well as in early cancers versus metastatic disease. Knowing the incidence of MSI in the various histologies can provide insight into the potential use of this biomarker considering its prognostic value, especially in the early stages, and its predictive role with respect to treatment response. In particular, MSI can guide the choice of chemotherapy treatments in the adjuvant setting of colon and perioperative setting in gastric tumours, which could lead to immunotherapy treatments in these patients in both the early stages of the disease and the metastatic setting where the response to immunotherapy drugs in diseases with MSI is now well established. In this review, we focus on colon, gastric and endometrial cancers, and we briefly discuss other cancer types where MSI could have a potential role in oncological treatment decisions.

Treatment de-escalation for HPV+ oropharyngeal cancer: A systematic review and meta-analysis.

Human Papillomavirus (HPV) related oropharyngeal carcinoma (OPC) carries a better prognosis compared with HPV-counterparts, thereby pushing the adoption of de-intensification treatment approaches as new strategies to preserve superior oncologic outcomes while minimizing toxicity. We evaluated the effect of treatment de-intensification in terms of overall survival (OS), progression-free survival (PFS), locoregional and distant control (LRC and DM) by selecting prospective or retrospective studies, providing outcome data with reduced intensification versus standard curative treatment in HPV+ OPC patients, with a systematic analysis till September 2020. The primary outcome of interest was OS. Secondary endpoints were PFS, LRC, and DM expressed as HR. A total of 55 studies (from 1393 screened references) were employed for quantitative synthesis for 38 929 patients. Among n = 48 studies with data available, de-intensified treatments reduced OS in HPV+ OPCs (HR = 1.33, 95% CI 1.17-1.52; p < 0.01). In de-escalated treatments, PFS was also decreased (HR = 2.11, 95% CI 1.65-2.69; p < 0.01). Compared with standard treatments, reduced intensity approaches were associated with reduced locoregional and distant disease control (HR = 2.51, 95% CI 1.75-3.59; p < 0.01; and HR = 1.9, 95% CI 1.25-2.9; p < 0.01). Chemoradiation improved survival in a definitive curative setting compared with radiotherapy alone (HR = 1.42, 95% CI 1.16-1.75; p < 0.01). When adjuvant treatments were compared, standard and de-escalation strategies provided similar OS. In conclusion, in patients with HPV+ OPC, de-escalation treatments should not be widely and agnostically adopted in clinical practice, as therein lies a concrete risk of offering a sub-optimal treatment to patients.

New drugs for the treatment of metastatic colorectal cancer.

Colorectal cancer (CRC) represents one of the most frequent malignancies in terms of incidence and mortality, thus representing the third leading cause of cancer death worldwide. In the last decade, few drugs have enriched the treatment landscape of metastatic CRC and have significantly affected prognosis. Unlike other neoplasms, metastatic CRC patients who have exhausted treatment options often still maintain a good performance status. There are many challenges to increasing potential treatment options, notably a better understanding of disease biology and the mechanisms of resistance underlying cancer treatment failure. The development of new drugs for metastatic CRC certainly represents one of the most important challenges in medical oncology. This article discusses the main limitations in the development of new drugs and potential future scenarios. In particular, we addressed three questions: (1) The main limitations of targeted therapy in the treatment of metastatic CRC (mCRC); (2) New target armamentarium that could escape primary and secondary resistance and lead to more personalized mCRC therapy; and (3) Future directions.

Tocilizumab as treatment for COVID-19: A systematic review and meta-analysis.

BACKGROUND: The majority of patients with coronavirus disease 2019 (COVID-19) have good prognoses, but some develop a critical illness that can lead to death. Evidence shows severe acute respiratory syndrome is closely related to the induced cytokine storm. Interleukin-6 is a key player; its role in systemic inflammation is well known. AIM: To evaluate the effect of tocilizumab (TCZ), an interleukin-6 receptor antagonist, on the outcomes for patients with COVID-19 pneumonia. METHODS: PubMed, EMBASE, SCOPUS, Web of Science, MedRxiv, Science Direct, and the Cochrane Library were searched from inception to 9th June 2020 for observational or prospective studies reporting results of hospitalized adult patients with COVID-19 infection treated with TCZ. Effect sizes were reported as odds ratios (ORs) with 95% confidence intervals (CIs), and an OR less than 1 was associated with a better outcome in those treated with TCZ. RESULTS: Overall 13476 patients (33 studies; n = 3264 received TCZ) with COVID-19 pneumonia and various degree of severity were included. Outcome was improved with TCZ. In the primary analysis (n = 19 studies reporting data), mortality was reduced in patients treated with TCZ (OR = 0.64, 95%CI: 0.47-0.87; P < 0.01). In 9 studies where risk of death with TCZ use was controlled for other variables mortality was reduced by 57% (OR = 0.43, 95%CI: 0.27-0.7; P < 0.01). Intensive care need (mechanical ventilation) was also reduced (OR = 0.36, 95%CI: 0.14-0.89; P = 0.02). CONCLUSION: In COVID-19-infected patients treated with TCZ, outcome may be improved compared to those not treated with TCZ.

Pancreatic adenocarcinoma: Beyond first line, where are we?

Pancreatic cancer is considered one of the most aggressive cancers, with an increasing incidence in recent years. To date, chemotherapy is still the standard of care for advanced metastatic disease, unfortunately providing only a slight advantage in terms of survival. The molecular and cellular characteristics of pancreatic cancer cells, as well as the cells that characterize the pancreatic tumour microenvironment, are the basis of the mechanisms of resistance to treatment. After progression during first-line treatment, few patients are eligible for second-line treatment due to the loss of performance status. To date, a clear survival advantage has not yet been demonstrated for second-line chemotherapy. Precision medicine could be the key to increasing responses to cancer treatment and finally impacting survival in this difficult-to-treat disease. In this review, we analyze current recommendations in the second-line setting and potential future prospects.

Drug-Related Pneumonitis in Cancer Treatment during the COVID-19 Era.

Interstitial lung disease is recognized as a group of diseases with a different etiopathogenesis characterized by chronic lung inflammation with the accumulation of inflammatory cells, lymphocytes and macrophages, and the consequent release of proinflammatory cytokines. Various degrees of pulmonary fibrosis can be associated with this inflammatory condition. Interstitial lung disease related to oncological drugs is a relevant problem in clinical practice. The etiopathogenetic mechanisms underlying this adverse event are not completely known but can be partly explained by the mechanism of action of the drug involved. Therefore, knowledge of the relevance of this potentially fatal adverse event supported by the reported safety data of pivotal studies becomes fundamental in the management of patients. The prompt diagnosis of drug-related pneumonia and the consequent differential diagnosis with other forms of pneumonia allow a rapid suspension of treatment and the establishment of an immunosuppressive treatment if necessary. In the context of the health emergency related to SARS CoV2 infection and COVID-19-related interstitial lung disease, such knowledge holds decisive relevance in the conscious choice of cancer treatments. Our intent was to describe the oncological drugs most correlated with this adverse event by reporting, where possible, the percentages of insurgency in pivotal studies to provide an overview and therefore promote greater awareness of this important toxicity related to oncological treatment.

The prognostic value of CD3+ tumor-infiltrating lymphocytes for stage II colon cancer according to use of adjuvant chemotherapy: A large single-institution cohort study.

BACKGROUND: High tumor infiltrating lymphocytes (TILs) density was previously shown to be associated with favorable prognosis for patients with colon cancer (CC). However, the impact of TILs on overall survival (OS) of stage II CC patients who received adjuvant chemotherapy (ADJ) or not (no-ADJ) is unknown. We assessed the prognostic value of CD3+ TILs in stage II CC patients according to whether they had ADJ or not. METHODS: Patients treated with curative surgery for stage II CC (2002-2013) were selected from the Santa Maria alle Scotte Hospital registry. TILs at the invasive front, center of tumor, and stroma were determined by immunohistochemistry and manually quantified as the rate of TILs/total tissue areas. High TILs (H-TILs) was defined as >20%. Patients were categorized as high or low TILs (L-TILs) and ADJ or no-ADJ. RESULTS: Of the 678 patients included, 137 (20%) received ADJ and 541 (80%) did not. The distribution of the 4 groups were: 16% (L-TIL/ADJ), 64% (L-TIL/no-ADJ), 5% (H-TIL/ADJ), 15% (H-TIL/no-ADJ). Compared to H-TILs/no-ADJ, ADJ patients showed a significantly increased OS (P<.01) regardless of the TILs rate whereas L-TILs/no-ADJ had significantly decreased OS and higher risk of death (HR=1.41; 95% CI, 1.06-1.88; P<.0001). On multivariable analysis, the unfavorable prognostic value of L-TILs (vs. H-TILs) for no-ADJ patients was confirmed (HR=1.36; 95% CI 1.02, 1.82; P=.0373). CONCLUSION: Low CD3+ TILs rate was associated with shorter OS in those with stage II colon cancer who did not receive adjuvant therapy. Low CD3+ TILs could be considered an additional risk factor for still ADJ-untreated stage II CC patients, which could facilitate clinical decision making.

Outcome of oncological patients admitted with COVID-19: experience of a hospital center in northern Italy.

BACKGROUND: Recent literature regarding the outcome of cancer patients infected with COVID-19 are not encouraging. Nevertheless, current evidence on the risk and benefits of continuing oncological treatment of cancer patients during the pandemic remains insufficient. We provide our experience in a center with high access for patients with COVID-19-associated pneumonia in Lombardy, Italy. We conducted a retrospective study using a prospectively maintained database of patients admitted to our hospital between 25 February 2020 and 9 April 2020 with a confirmed diagnosis of COVID-19 pneumonia. RESULTS: A total of 53 patients with a history or current oncological disease were included in this study. Sixteen oncological patients (30.2%) died during hospitalization. Multivariable logistic regression analysis found that age (Odds ratio [OR]: 1.17, p = 0.009), diabetes (OR: 15.05, p = 0.028) and active oncological disease (OR 13.60, p = 0.015) were independently associated with in-hospital mortality. The mortality rate of the total number of cancer patients is about twice as high as that of non-oncological patients admitted to our hospital with a diagnosis of COVID-19. CONCLUSION: The presence of active oncological disease is independently related to mortality as well as age and diabetes. The majority of patients who died were frail. Careful evaluation of the risks and benefits of treatment in frail patients is needed, considering that difficult access to intensive care may have affected the mortality rate.

Neutropenic Enterocolitis in the Treatment of Solid Tumors: A Case Report and Review of the Literature.

Neutropenic enterocolitis is a clinical condition characterized by inflammation of the colic mucosa, usually the caecum, associated with bowel wall thickening in patients with compromised immune system due to chemotherapy treatments. It can occur as well in other clinical conditions that lead to immunosuppression. Clinically, patients present with abdominal pain, fever, and neutropenia on blood tests. A number of major and minor criteria have been suggested for the clinical diagnosis of typhlitis. The most sensitive radiological investigation is represented by a computed tomography scan. There are no guidelines for treatment, but some factors may lead the clinician to medical treatments or prompt surgery as the best choice in that particular patient. The most implicated chemotherapeutic regimens are those based on taxanes. Here, we present a clinical case of a young patient with breast cancer and a review of the state of the art of knowledge regarding neutropenic enterocolitis in adult patients undergoing chemotherapy for the treatment of solid tumors.

Feasibility of modified docetaxel, oxaliplatin, capecitabine followed by capecitabine as maintenance chemotherapy as first-line therapy for patients with metastatic gastric or gastroesophageal cancer.

The aim of this study was to evaluate the efficacy and safety of modified docetaxel, oxaliplatin, capecitabine (DOC) combination chemotherapy, followed by maintenance capecitabine as first-line therapy for patients with metastatic gastric or gastroesophageal junction (GEJ) cancer. Treatment consisted of docetaxel 35 mg/m (days 1-8), l-OHP 85 mg/m (day 1), and capecitabine 750 mg/m twice daily (days 1-14), every 3 weeks. After six cycles of DOC, patients who did not progress received maintenance treatment with three-weekly capecitabine 1000 mg/m twice daily (days 1-14), until disease progression or unacceptable toxicity. Six-month disease control rate (DCR) was the primary endpoint and overall survival (OS), progression-free survival (PFS) and safety were the secondary endpoints. The Kaplan-Meier method was applied to estimate OS and PFS. Between July 2014 and September 2017, 37 patients with metastatic gastric or GEJ cancer were enrolled at our institution. Upon completion of the DOC regimen, 35 patients (94.5%) received capecitabine as maintenance chemotherapy for a median of 7 cycles (range, 3-14 cycles). The six-month DCR was 83.7% [95% confidence interval (CI), 71.8-95.6%], median PFS was 8.2 months (95% CI, 6.3-9.8 months), and median OS was 14.4 months (95% CI, 11.7-18.6 months). During DOC chemotherapy, the most common grade 3-4 adverse events were neutropenia (29.7%), anemia (10.8%), and diarrhea (10.8%). During maintenance treatment, toxicity was sporadic and mainly of grade 1-2. Modified DOC followed by capecitabine as maintenance chemotherapy seems to be an active and well tolerated first-line treatment strategy for patients with metastatic gastric and GEJ cancer.

Capecitabine Plus Oxaliplatin and Bevacizumab, Followed by Maintenance Treatment With Capecitabine and Bevacizumab for Patients Aged > 75 Years With Metastatic Colorectal Cancer.

BACKGROUND: The aim of the present study was to evaluate the efficacy and safety of the combination of CAPOX-Bev (capecitabine [Cap] plus oxaliplatin and bevacizumab [Bev]), followed by maintenance Cap and Bev, for patients with metastatic colorectal cancer (mCRC) and aged > 75 years. PATIENTS AND METHODS: The regimen consisted of intravenous oxaliplatin 130 to 100 mg/m2 on day 1, oral Cap 750 to 1000 mg/m2 twice daily on days 1 to 14, and Bev 7.5 mg/kg on day 1, every 3 weeks. After 4 cycles of CAPOX-Bev, the patients without evidence of disease progression received maintenance treatment with Cap 1000 to 1250 mg/m2 twice daily on days 1 to 14 and Bev 7.5 mg/kg on day 1, every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was the 9-month disease control rate. Progression-free survival (PFS), overall survival (OS), and safety were the secondary endpoints. RESULTS: Overall, 36 patients were enrolled from March 2012 to April 2017 at our institution. After completion of CAPOX/Bev, 15 patients (41.7%) had a partial response, 18 (50.0%) had stable disease, and 3 (8.3%) had progressive disease. Thirty-three patients (91.7%) received the Cap/Bev regimen as maintenance treatment for a median of 8.6 cycles (range, 3-14 cycles). The 9-month DCR was 58.3% (95% confidence interval [CI], 40.8-74.5), the median PFS was 8.8 months (95% CI, 6.7-10.3 months), and the median OS was 20.8 months (95% CI, 16.1-25.4 months). With the CAPOX/Bev regimen, the most common grade 3 toxicity included neutropenia (11.1%), diarrhea (5.5%), nausea/vomiting (2.8%), and fatigue (2.8%). Grade 3 neurotoxicity was not observed. With Cap/Bev maintenance therapy, grade 3 hand-foot syndrome was observed in 2 patients (6.0%). CONCLUSION: CAPOX/Bev, followed by Cap/Bev as maintenance treatment, is safe and effective in terms of PFS and OS for elderly patients aged > 75 years with mCRC.