The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 ...resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen.
Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m(2) intravenously on days 1 and 8) and capecitabine (1,500 mg/m(2) per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m(2) per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively.
A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage.
This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.
Women have more adverse events (AEs) from chemotherapy than men, but few studies have investigated sex differences in immune or targeted therapies. We examined AEs by sex across different treatment ...domains.
We analyzed treatment-related AEs by sex in SWOG phase II and III clinical trials conducted between 1980 and 2019, excluding sex-specific cancers. AE codes and grade were categorized using the Common Terminology Criteria for Adverse Events. Symptomatic AEs were defined as those aligned with the National Cancer Institute's Patient-Reported Outcome-Common Terminology Criteria for Adverse Events; laboratory-based or observable/measurable AEs were designated as objective (hematologic
nonhematologic). Multivariable logistic regression was used, adjusting for age, race, and disease prognosis. Thirteen symptomatic and 14 objective AE categories were examined.
In total, N = 23,296 patients (women, 8,838 37.9%; men, 14,458 62.1%) from 202 trials experiencing 274,688 AEs were analyzed; 17,417 received chemotherapy, 2,319 received immunotherapy, and 3,560 received targeted therapy. Overall, 64.6% (n = 15,051) experienced one or more severe (grade ≥ 3) AEs. Women had a 34% increased risk of severe AEs compared with men (odds ratio OR = 1.34; 95% CI, 1.27 to 1.42;
< .001), including a 49% increased risk among those receiving immunotherapy (OR = 1.49; 95% CI, 1.24 to 1.78;
< .001). Women experienced an increased risk of severe symptomatic AEs among all treatments, especially immunotherapy (OR = 1.66; 95% CI, 1.37 to 2.01;
< .001). Women receiving chemotherapy or immunotherapy experienced increased severe hematologic AE. No statistically significant sex differences in risk of nonhematologic AEs were found.
The greater severity of both symptomatic AEs and hematologic AEs in women across multiple treatment modalities indicates that broad-based sex differences exist. This could be due to differences in AE reported, pharmacogenomics of drug metabolism/disposition, total dose received, and/or adherence to therapy. Particularly large sex differences were observed for patients receiving immunotherapy, suggesting that studying AEs from these agents is a priority.
Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine ...neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).
We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate ORR; RECIST v1.1; complete response (CR) and partial response (PR); secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.
Thirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%;
= 15) and lung (19%;
= 6). The overall ORR was 25% 95% confidence interval (CI) 13-64%; CR, 3%,
= 1; PR, 22%,
= 7. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients;
= 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.
Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.
Safeguards for medical aid in dying Blanke, Charles D
British journal of hospital medicine (London, England : 2005),
2024-Feb-02, Letnik:
85, Številka:
2
Journal Article
Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a ...randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses.
In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy.
Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect.
Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.
Abstract
Background
The incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal ...cancer (mCRC).
Methods
We studied the association of age with survival in 2326 mCRC patients enrolled in the Cancer and Leukemia Group B and SWOG 80405 trial, a multicenter, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan-Meier method and compared among younger vs older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided.
Results
Of 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs 62.5 years in patients aged 50 years and older. There was no statistically significant difference in OS between yoCRC vs older-onset patients (median = 27.07 vs 26.12 months; adjusted HR = 0.98, 95% CI = 0.88 to 1.10; P = .78). The median PFS was also similar in yoCRC vs older patients (10.87 vs 10.55 months) with an adjusted hazard ratio of 1.02 (95% CI = 0.92 to 1.13; P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs 26.12 months in older-onset patients with an adjusted hazard ratio of 1.08 (95% CI = 0.81 to 1.44; Ptrend = .93).
Conclusion
In this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients aged 50 years and older.
CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with ...chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS.
Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested.
Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio HR, 0.73 95% CI, 0.57 to 0.95;
= .02). In patients with microsatellite instability-high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 95% CI, 0.06 to 0.30; interaction
< .001 for interaction between microsatellite status and the two arms). Patients with
mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 95% CI, 1.49 to 2.71;
< .001). Patients with extended
mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 95% CI, 1.26 to 1.84;
< .001). Patients with triple-negative tumors (WT for
/
/
) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors (
< .001).
In patients with metastatic colorectal cancer treated in first line, low TMB, and
and
mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.
To determine the predictive and prognostic value of the consensus molecular subtypes (CMSs) of colorectal cancer (CRC) that represent a merging of gene expression-based features largely in primary ...tumors from six independent classification systems and provide a framework for capturing the intrinsic heterogeneity of CRC in patients enrolled in CALGB/SWOG 80405.
CALGB/SWOG 80405 is a phase III trial that compared the addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment of advanced CRC. We characterized the CMS classification using a novel NanoString gene expression panel on primary CRCs from 581 patients enrolled in this study to assess the prognostic and predictive value of CMSs in these patients.
The CMSs are highly prognostic for overall survival (OS;
< .001) and progression-free survival (PFS;
< .001). Furthermore, CMSs were predictive for both OS (
for interaction < .001) and PFS (
for interaction = .0032). In the CMS1 cohort, patients treated with bevacizumab had a significantly longer OS than those treated with cetuximab (
< .001). In the CMS2 cohort, patients treated with cetuximab had a significantly longer OS than patients treated with bevacizumab (
= .0046).
These findings highlight the possible clinical utility of CMSs and suggests that refinement of the CMS classification may provide a path toward identifying patients with metastatic CRC who are most likely to benefit from specific targeted therapy as part of the initial treatment.
PURPOSE To study the pharmacokinetics (PK) of imatinib (IM) in patients with advanced GI stromal tumors (GISTs) treated in a randomized phase II study and to explore the potential relationship ...between IM plasma levels and long-term clinical outcomes. PATIENTS AND METHODS Patients were randomly assigned to receive IM at 400 mg versus 600 mg daily. IM plasma levels were analyzed in a subset of patients (n = 73) for whom PK data on day 1 and at steady-state (SS, day 29) were available. IM PK was evaluated using a population PK approach. The relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough concentration (C(min)). The clinical outcome parameters evaluated include overall objective benefit rate (OOBR; complete response plus partial response plus stable disease) time to progression (TTP), and KIT genotyping. Results IM PK exposure showed a high inter-patient variability, and clinical outcomes were correlated with IM trough levels at SS. The median TTP was 11.3 months for patients in the lowest C(min) quartile (Q1, < 1,110 ng/mL) compared with more than 30 months for Q2 to Q4 (P = .0029). OOBR was also inferior in Q1 patients. In patients with GIST with KIT exon 11 mutations (n = 39), the OOBR was 67% for Q1 patients versus 100% for all others (P = .001). CONCLUSION In patients with advanced GIST, IM trough levels at SS were associated with clinical benefit. Patients with IM C(min) below 1,100 ng/mL showed a shorter TTP and lower rate of clinical benefit (OOBR). Further studies are justified to test whether monitoring IM plasma levels might optimize clinical outcomes for patients with GIST.
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