ABSTRACT
Background: Metastatic colorectal cancer is one of the most common causes of cancer death worldwide, and its incidence increases with age. Treating an older RAS and BRAF wild-type patient represents a challenge for the medical oncologist, even more so for those patients defined as "vulnerable" and undergoing at least two lines of therapy. In this context, recent evidence supports the role of retreatment with anti-EGFR inhibitors and the use of liquid biopsy. However, frequent skin toxicity constitutes a limitation of therapy, especially in older people. Since it has been described that continuous administration of these monoclonal antibodies leads to acquired resistance to anti-EGFRs, with consequent therapeutic failure, an intermittent strategy with chemotherapy plus an anti-EGFR could help maintain the efficacy of the treatment over time, delaying the resistance and improving patients' quality of life. Case presentation: In this case report, we describe the case of an older RAS and BRAF wild-type patient reporting a clinical response after first-line chemotherapy with FOLFOX + panitumumab, subsequently interrupted in the absence of disease progression. After radiological worsening and two additional lines of therapy, the reintroduction of panitumumab plus 5-fluorouracil, administered with a stop-and-go strategy, allowed the patient to benefit from the same drugs for 2 years from diagnosis, to achieve a clinical response during fourth-line treatment lasting more than 3 years, to delay resistance and to avoid unacceptable anti-EGFR skin toxicity. This patient, who died from a myocardial infarction more than 5 years after diagnosis, represents the case of a good synergy between molecular profile of disease and reintroduction of an anti-EGFR with intermittent strategy.
ABSTRACT
PURPOSE: The intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS: In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS: Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION: The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Rectal Neoplasms , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/adverse effects , Cetuximab/adverse effects , Colonic Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Fluorouracil/adverse effects , Irinotecan/therapeutic use , Leucovorin/adverse effects , Proto-Oncogene Proteins B-raf/genetics , Rectal Neoplasms/drug therapyABSTRACT
Breast cancer is the most common type of cancer in women worldwide. Many studies indicate that breast cancer increases in elderly patients (≥70 years) and suggest that the higher cancer mortality in this population relative to that observed in younger women could be related to organ dysfunction, an advanced and delayed diagnosis, and other morbidities. Endocrine therapy (ET) represents the favorite treatment for patients affected by hormone receptor positive (HR+) metastatic breast cancer (MBC). Unfortunately, half of these patients are resistant to ET. In recent years, new therapeutic options, such as orally highly selective inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6), have been widely investigated in patients suffering from MBC with good outcomes. They are able to bypass resistance from hormonal therapy, by restoring hormone sensitivity and by delaying chemotherapeutic agent use. Thus, CDK4/6 inhibitors, combined with hormonal therapy, represent an alternative treatment for MBC. Unfortunately, the elderly population with MBC remains mostly excluded from clinical trials. Moreover, few data on the efficacy, safety, and short and longterm outcomes of therapies based on the combined treatment of ET and CDK4/6 inhibitors are available. This narrative review highlights the use of CDK 4/6 inhibitor-based therapy for MBC in elderly patients and suggests new therapeutic perspectives.
Subject(s)
Breast Neoplasms , Humans , Female , Aged , Breast Neoplasms/pathology , Protein Kinase Inhibitors/adverse effects , Cyclin-Dependent Kinase 6 , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Receptor, ErbB-2 , Cyclin-Dependent Kinase 4/therapeutic useABSTRACT
Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Frontotemporal Dementia , Rectal Neoplasms , Humans , Proto-Oncogene Proteins p21(ras)/genetics , Uracil/therapeutic use , Trifluridine/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Pyrrolidines/therapeutic use , Colonic Neoplasms/drug therapy , Rectal Neoplasms/drug therapy , Drug Combinations , Mutation/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
BACKGROUND: High body mass index (BMI) plays a key role in the development of colon cancer (CC). Our post-hoc analysis from the TOSCA trial analyzed the association between BMI and survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS) in stage II/III CC patients. PATIENTS AND METHODS: Patients enrolled in the TOSCA trial between 2007-2013 with BMI data entered the study. The prognostic impact of BMI on survival outcomes was investigated through uni- and multivariable Cox regression analyses. RESULTS: Overall, 1455 patients with stage II/III CC patients were included. The median follow-up was of 61.5 months; 16.1% of patients relapsed, 11.2% died and 19.5% patients relapsed or died. No impact of BMI on RFS was detected at univariate or multivariable analyses. By univariate analysis for OS, a significantly impact of a BMI > 30 kg/m2 was reported (HR [>30 vs <25] 1.57, 95% CI 1.00-2.47, p = 0.049; HR [>30 vs <30] 1.55, 95% CI 1.01-2.37, p = 0.045). Multivariable analyses did not confirm this data. In the subgroup of stage III patients, a negative survival impact of BMI was found in univariate and multivariable models both for RFS and for OS. CONCLUSIONS: In our study, obesity with BMI > 30 kg/m2 was an independent prognostic factor for RFS and OS in CC patients treated with adjuvant chemotherapy, regardless of its duration (3 or 6 months). However, the prognostic impact of adiposity and body composition measurement should be considered to better classify patients with high visceral fat and refine their risk assessment.
Subject(s)
Colonic Neoplasms , Humans , Body Mass Index , Chemotherapy, Adjuvant/adverse effects , Neoplasm Staging , Obesity/complications , PrognosisABSTRACT
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers, and most NSCLC is diagnosed in the advanced stage. The advent of immune check point inhibitors (ICIs) changed the therapeutic scenario both in metastatic disease (in first and subsequent lines) and earlier settings. Comorbidities, reduced organ function, cognitive deterioration, and social impairment give reasons for a greater probability of adverse events, making the treatment of elderly patients challenging. The reduced toxicity of ICIs compared to standard chemotherapy makes this approach attractive in this population. The effectiveness of ICIs varies according to age, and patients older than 75 years may benefit less than younger patients. This may be related to the so-called immunosenescence, a phenomenon that refers to the reduced activity of immunity with older age. Elders are often under-represented in clinical trials, even if they are a large part of the patients in a clinical practice. In this review, we aim to explore the biological aspects of immunosenescence and to report and analyze the most relevant and recent literature findings on the role of immunotherapy in elderly patients with NSCLC.
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Although colorectal cancer is increasingly being diagnosed in older patients, their number is largely underrepresented in phase II or III clinical trials. Consequently, guidelines and the SIOG recommendations are not sufficiently clear regarding the treatment of these patients, particularly when chemotherapy is combined with monoclonal antibodies (bevacizumab, cetuximab, and panitumumab). Targeted therapy based on the use of anti-epidermal growth factor receptors (EGFRs) is conditioned by the potential for increased toxicity, making it more difficult to treat an older, rat sarcoma virus (RAS) and B rapidly accelerated fibrosarcoma (BRAF) wild-type patient. In light of a more detailed characterization of the older population, modernly differentiable between fit, vulnerable, or frail patients on the basis of the comprehensive geriatric assessment, and of the analysis of more recent studies, this review fully collects data from the literature, differentiating the results on functional status patients.
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Cancer is the most widespread and prominent health issue worldwide and its incidence is only exceeded by cardiovascular diseases [...].
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Cetuximab in combination with chemotherapy is a standard first-line treatment regimen for patients with metastatic colorectal cancer (mCRC) RAS wild-type (wt); however, the efficacy of cetuximab plus leucovorin, fluorouracil and oxaliplatin (FOLFOX) had never been demonstrated in a prospective, randomized, controlled phase III study. The TAILOR study is the first randomized, multicenter, prospective Phase III study evaluating the addition of cetuximab to FOLFOX in a RAS wt Chinese population and thus providing confirmatory data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Rectal Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab/adverse effects , Colonic Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Fluorouracil/adverse effects , Humans , Leucovorin/adverse effects , Neoplasm Metastasis/drug therapy , Organoplatinum Compounds/adverse effects , Prospective Studies , Rectal Neoplasms/chemically induced , Rectal Neoplasms/drug therapyABSTRACT
Novel targeted therapies for metastatic colorectal cancer are needed to personalize treatments by guiding specific biomarkers selected on the genetic profile of patients. RAS and BRAF inhibitors have been developed for patients who become unresponsive to standard therapies. Sotorasib and adagrasib showed promising results in phase I/II basket trial and a phase III trial was planned with a combination of these RAS inhibitors and anti-EGFR monoclonal antibodies. Encorafenib and binimetinib were administered in phase II clinical trials for BRAF mutated patients. Pembrolizumab is now recommended in patients exhibiting microsatellite instability. Larotrectinib and entrectinib showed a fast and durable response with few and reversible adverse events in cases with NTRK fusions. Trastuzumab and trastuzumab deruxtecan exhibited promising and durable activity in HER-2-positive patients. In this review, the reasons for an extension of the molecular profile of patients were assessed and placed in the context of the advancements in the understanding of genetics. We highlight the differential effect of new targeted therapies through an ever-deeper characterization of tumor tissue. An overview of ongoing clinical trials is also provided.
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BACKGROUND: EOX (epirubicin, oxaliplatin, and capecitabine) is one of the standard regimens for metastatic or locally advanced gastric cancer (GC). A new combination based on fractional docetaxel (low-TOX) has been developed in an attempt to increase the efficacy of EOX and reduce the heavy toxicity of classical docetaxel regimens. METHODS: Overall, 169 previously untreated GC patients were randomized between EOX (arm A) and low-TOX (arm B). The primary endpoint was progression-free survival (PFS), while secondary ones were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and tolerability. The study was designed to detect a 35% (80% power at a two-sided 5% significance level) PFS increase with low-TOX and an interim analysis for futility was planned after the first 127 events. RESULTS: At the cut-off date of interim analysis, median PFS was 6.3 months [95% confidence interval (CI) 5.0-8.1] in arm A vs 6.3 months (95% CI 5.0-7.8) in arm B, without statistical difference. OS was comparable in the two arms: 12.4 in arm A (95% CI 9.1-19.2) vs 11.5 months in arm B (95% CI 8.6-15.0). ORR was 33% and 24%, while DCR was 68% and 67%, respectively. Treatment modification (91% vs 78%, P = 0.017) and number of patients with CTC grade ≥ 3 adverse events (42 vs 35) were higher in arm B. CONCLUSIONS: A triplet regimen based on the fractional dose of docetaxel achieves no improvement over EOX which remains a potential standard treatment in many patients with inoperable, locally advanced or metastatic GC.
Subject(s)
Stomach Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Capecitabine/adverse effects , Docetaxel , Epirubicin , Fluorouracil/adverse effects , Humans , Oxaliplatin , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
A new reality is being observed around the world as the population ages: family caregivers, who are themselves older adults helping their ill older relatives. The aim of this study is to assess the burden of the older family caregiver assisting older patients in his or her end-of-life who are suffering from dementia or cancer. In this context, the elderly person is involved in the dual role of patient and caregiver. In this comparative study, a total of 87 older family caregivers (age ≥ 65 years) completed the Caregiver Burden Inventory (CBI) measurement. The sample was divided into 2 subgroups based on the individuals' advanced disease: Alzheimer's disease (AD) or cancer. Compared to cancer caregivers, the AD subgroup reported significantly higher scores in the CBI-emotional subscale (P = 0.006), confirmed by the evaluation of the generalized linear model (multivariate). There were no significant differences in the other CBI subscales and overall scores. According to the findings of this study, elderly who help elderly with AD are at a higher risk of experiencing an emotional burden than cancer caregivers. This data could be considered in designing interventions to reduce the caregiver burden of older family caregivers as they provide informal end-of-life care.
Subject(s)
Alzheimer Disease , Neoplasms , Aged , Alzheimer Disease/psychology , Caregiver Burden , Caregivers/psychology , Cost of Illness , Death , Female , Humans , Male , Neoplasms/epidemiologyABSTRACT
Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.
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OBJECTIVES: Older people are not traditionally expected to become caregivers. For this reason, the experience of caregiving in older persons has not been explored adequately in the research on gender differences. The objective of this study was to assess the caregiver burden among older family members who care for cancer patients facing the end of their lives, in order to compare their differences according to gender (male vs. female). METHODS: This is a cross-sectional study. A total of 102 older caregivers (aged ≥65 years) of hospice patients were interviewed through the Caregiver Burden Inventory (CBI). The sample group was divided into two gender subgroups. RESULTS: Compared with male caregivers, the older female group reported significantly higher scores in the CBI-physical subscale (P = 0.028), and in the CBI, the overall score (P = 0.0399) confirmed by the generalized linear model (multivariate) evaluation that included possible predictors in the model. There were no significant differences in the other CBI subscale scores (time-dependent, developmental, social, and emotional). SIGNIFICANCE OF RESULTS: Older female caregivers are at higher risk of experiencing burden and worse physical health compared with men. Further research is needed in modern palliative care to assess the role of gender differences in the experience of caregiving when the caregiver is an older person.
Subject(s)
Caregivers , Family , Aged , Aged, 80 and over , Caregivers/psychology , Cost of Illness , Cross-Sectional Studies , Death , Family/psychology , Female , Humans , Male , Sex FactorsABSTRACT
OBJECTIVES: To assess the toxicity patterns and effectiveness of doublet chemotherapy when administered at reduced doses of 20% (FOLFOX or FOLFIRI) in combination with anti-EGFR antibodies (cetuximab or panitumumab) in old, vulnerable patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We performed a retrospective observational study of RAS and BRAF wild-type, vulnerable patients aged ≥70 years with previously untreated mCRC. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: One hundred and eighteen patients were collected from 14 selected Italian centres. The median age was 75 (range, 70-85). Geriatric screening by G8 tool gave a score ≤ 14 in all patients. In total, 75 and 43 patients received FOLFOX or FOLFIRI, respectively, in combination with panitumumab (53%) or cetuximab (47%). The overall incidence of grade (G) 3-4 neutropenia was 11.8%, and for skin rash 11%. The most frequent adverse events were G1-2 skin rash (49.1%), G1-2 diarrhea (21.1%) and G1-2 nausea (17.7%). The ORR was 57.3%. Stable disease was observed in 29.1% of patients, with a disease control rate of 86.4%. With a median follow-up of 18 months, the median PFS was 10.0 months (95% confidence interval [CI]: 8.5-11.4), while the median OS was 18.0 months (95% CI: 16.0-19.9). No statistically significant difference was observed between the regimens in terms of ORR, PFS (p = 0.908), and OS (p = 0.832). CONCLUSION: This study shows that with an appropriate design, including reduced doses, vulnerable older patients best tolerate chemotherapy when combined with anti-EGFR antibodies.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Exanthema , Rectal Neoplasms , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab/adverse effects , Colonic Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Exanthema/chemically induced , Exanthema/drug therapy , Fluorouracil , Humans , Leucovorin/adverse effects , Panitumumab/therapeutic useABSTRACT
Importance: Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited. Objective: To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis. Design, Setting, and Participants: This open-label, randomized clinical phase 3 trial was conducted from May 8, 2012, to December 9, 2015, at 3 Italian centers. Patients aged 18 to 75 years with unresectable, previously untreated, or single line-treated mCRC were recruited. Follow-up was completed December 31, 2019, and data were analyzed from February 26 to July 24, 2020. Interventions: Patients received 12 biweekly cycles of standard oxaliplatin-based regimens (modified FOLFOX-6 [levo-folinic acid, fluorouracil, and oxaliplatin]/modified CAPOX [capecitabine and oxaliplatin]) plus bevacizumab administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm). Main Outcomes and Measures: The primary end point was the objective response rate (ORR) measured with Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival, overall survival, safety, and quality of life (QOL). Results: Overall, 230 patients (136 men [59.1%]; median age, 62.3 [interquartile range, 53.3-67.6] years) were randomly assigned to the standard arm (n = 115) or the experimental arm (n = 115). The median duration of follow-up was 68.3 (95% CI, 61.0-70.0) months. No difference in ORR (57.4% [95% CI, 47.8%-66.6%] in the standard arm and 56.5% [95% CI, 47.0-65.7] in the experimental arm; P = .89) or progression-free survival (10.5 [95% CI, 9.1-12.3] months in the standard arm and 11.7 [95% CI, 9.9-12.9] months in the experimental arm; P = .15) was observed. However, the median overall survival was 29.8 (95% CI, 22.5-41.1) months in the experimental arm compared with 24.1 (95% CI, 18.6-29.8) months in the standard arm (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.99; P = .04). Moreover, the experimental arm was associated with a significant reduction in the rate of severe diarrhea (6 [5.3%] vs 19 [16.5%]; P = .006) and nausea (2 [1.8%] vs 8 [7.0%]; P = .05) and improved physical functioning (mean [SD] change from baseline, 0.65 [1.96] vs -7.41 [2.95] at 24 weeks; P = .02), and constipation scores (mean [SD] change from baseline, -17.2 [3.73] vs -0.62 [4.44]; P = .003). Conclusions and Relevance: In this randomized clinical trial, sequential administration of bevacizumab plus chemotherapy did not improve ORR, the primary end point. However, the overall survival advantage, fewer adverse effects, and better health-related QOL associated with sequential bevacizumab administration might provide the basis for exploring antiangiogenic combination treatments with innovative perspectives. Trial Registration: EudraCT Identifier: 2011-004997-27; ClinicalTrials.gov Identifier: NCT01718873.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/administration & dosage , Colorectal Neoplasms/drug therapy , Oxaliplatin/administration & dosage , Adolescent , Adult , Aged , Angiogenesis Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/adverse effects , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Diarrhea/chemically induced , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Male , Middle Aged , Nausea/chemically induced , Neoplasm Metastasis , Oxaliplatin/adverse effects , Progression-Free Survival , Quality of Life , Treatment Outcome , Young AdultABSTRACT
Introduction: Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option.Areas covered: A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations.Expert opinion: Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines and upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Immunotherapy/methods , Stomach Neoplasms/therapy , Humans , Immune Checkpoint Inhibitors/administration & dosage , Patient Selection , Quality of Life , Stomach Neoplasms/immunology , SurvivalABSTRACT
BACKGROUND: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. PATIENTS AND METHODS: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged <70 years and 693 ≥ 70 years) randomised to receive 3 or 6 months of FOLFOX or CAPOX within the frame of the phase III, TOSCA study. RESULTS: Older patients compared with younger ones presented more frequently an Eastern Cooperative Oncology Group performance status equal to 1 (10.5% vs 3.3%, p < 0.001), a greater number of right-sided tumours (40.9% vs 26.6%, p < 0.001), and were at higher clinical risk (37.2% vs 33.2%, p = 0.062). The treatments were almost identical in the two cohorts (p = 0.965). We found a greater proportion of dose reductions (46.7% vs 41.4%, p = 0.018), treatment interruptions (26.1% vs 19.3%, p < 0.001) and a higher proportion of recurrences (24.2% vs 20.3%, p = 0.033) in the older patients. The multivariable analysis of the TTR did not indicate a statistically significant effect of age (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 0.98-1.44; p = 0.082). The HR comparing older with younger patients was 1.34 (95% CI: 1.12-1.59; p = 0.001) for DFS, 1.58 (95% CI: 1.26-1.99; p < 0.001) for OS, and 1.28 (95% CI: 0.96-1.70; p = 0.089) for CSS. CONCLUSIONS: Worse prognostic factors and reduced treatment compliance have a negative impact on the efficacy of oxaliplatin-based adjuvant therapy in older patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant/mortality , Colonic Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Aged, 80 and over , Capecitabine/administration & dosage , Colonic Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Oxaliplatin/administration & dosage , Prognosis , Survival RateABSTRACT
PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.