Surgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant ...benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients.
We previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated.
Patients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex.
This pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC.
•Role of sex in individual patient data analysis on MSI/MSS resectable gastric cancer.•MSI-high GC patients have better prognosis than MSS/MSI-low ones irrespective of sex.•In MSS/MSI-low GC females had non-significantly improved DFS and OS than males.•MSI-high GC females had a higher trend of detriment from multimodal therapy than males.
To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin, and fluorouracil (FOLFIRI) in patients with
-mutated, methyl-guanine ...methyltransferase (
)-methylated metastatic colorectal cancer (mCRC).
In this randomized, phase II trial, we enrolled patients with
-mutated,
-methylated mCRC after failure of oxaliplatin-based regimen. Patients with centrally confirmed
methylation were stratified by first-line progression-free survival (PFS) and prior bevacizumab and randomized to either capecitabine plus temozolomide (arm A, CAPTEM) or FOLFIRI (arm B). The primary endpoint was PFS analyzed on intention-to-treat basis, with 90% power and one-sided significance level of 0.05 to detect an increase of median time from 2 months in arm B to 4 months in arm A.
Between November 2014 and May 2019, 86 patients were randomly assigned to arm A (
= 43) or arm B (
= 43). After a median follow-up of 30.5 months (interquartile range, 12.2-36.3), 79 disease progression or death events occurred. Superiority of arm A was not demonstrated (one-sided
= 0.223). Progression-free survival and overall survival were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) in arm A versus 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B HR = 1.19 (0.82-1.72) and HR = 0.97 (0.58-1.61), respectively. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. Patients with positive MGMT expression by IHC did not benefit from CAPTEM.
Temozolomide-based therapy warrants further investigation in molecularly hyperselected subgroups.
In patients with metastatic colorectal cancer (mCRC) receiving highly active first-line combination treatments, early tumor shrinkage (ETS) and depth of response (DoR) are associated with survival, ...but their influence on outcomes during maintenance therapy is unknown. The Valentino study showed inferior PFS in 229 RAS wild-type mCRC patients randomized to panitumumab plus FOLFOX followed by maintenance with panitumumab vs. panitumumab + 5-FU/LV.
After blinded independent central review of ETS (≥20% reduction of the sum of target lesions) and DoR in patients enrolled in Valentino, the prognostic and predictive role of such parameters was investigated, along with their combination with PRESSING panel (uncommon genomic alterations associated with anti-EGFRs resistance beyond RAS and BRAF).
One hundred and ninety-six patients were included (ETS in 132 67.3%, median DoR: 44.1%). Both ETS and DoR ≥34% were associated with longer mPFS (p = 0.010 and p < 0.001) and mOS (p = 0.006 and p < 0.001). The PFS benefit of 5-FU/LV added to panitumumab maintenance, reported in the study, was independent from ETS and DoR status (interaction tests NS for both PFS and OS). However, outcomes were extremely poor in patients who received single-agent panitumumab and had no-ETS (mPFS and mOS: 7.7 and 18.7 months) or DoR < 34% (mPFS and mOS: 6.5 and 18 months). Combining PRESSING panel (‘molecular hyperselection’) and response dynamics allowed to stratify both PFS (p < 0.001 and p < 0.001 for ETS and DoR, respectively) and OS (p < 0.001 and p = 0.017 for ETS and DoR, respectively).
ETS and DoR allow on-treatment anticipation of outcomes following an anti-EGFR-based strategy planning de-escalation, and poor radiological response may guide enrolment in crossover strategy trials. As in vivo markers of drug sensitivity, ETS and DoR may be integrated with several patient- and tumor-related factors to wisely drive decision-making on upfront treatment duration and intensity.
•In Valentino trial, early tumor shrinkage/depth of response (ETS/DoR) is prognostic.•Poorest outcomes seen if no ETS/poor DoR + single-agent panitumumab maintenance.•Poorest outcomes seen if no ETS/poor DoR + resistance alterations beyond RAS/BRAF.•Tumor dynamics may be integrated in clinical trials or clinical decision-making.
Quality of life (QoL) patient-reported outcomes (PROs) data from pivotal first-line trials in metastatic colorectal cancer (mCRC) are poor. The Valentino study showed that de-escalation to ...single-agent panitumumab after 4-month induction with panitumumab-FOLFOX is inferior to panitumumab-5-FU/LV in patients with RAS wild-type mCRC, although slightly reducing toxicity. We report QoL, a secondary end-point.
PROs were assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQ-C30), EORTC QLQ-CR29, EuroQol EQ-5D questionnaires, at baseline and every 8 weeks until disease progression. First two evaluations correspond to induction treatment (identical in both arms), while subsequent to maintenance. To describe QoL changes over time, mean changes from baseline at each time point were calculated in overall population. To compare maintenance between two arms, mean changes and proportion of improved/stable/worse patients versus baseline were compared for each item.
In arm A/B, 91.5%/92.0% of enrolled patients completed questionnaires at baseline. No significant differences in the two arms were reported in compliance, baseline scores and mean changes versus baseline for the three questionnaires during maintenance (24/32/40 weeks). Overall, mean changes versus baseline showed an early deterioration during induction with partial recovering during maintenance for global QoL, functional scales and several symptoms/items of QLQ-C30 (fatigue, nausea/vomiting, appetite loss, diarrhoea) and QLQ-CR29 (body image, dry mouth, hair loss, taste, faecal incontinence, sore skin), and EQ-5D Visual Analogue Scale (VAS) score.
In patients with RAS wild-type mCRC, induction with oxaliplatin-containing chemotherapy plus anti-EGFRs induces a transient significant QoL deterioration. After induction phase, treatment deintensification determines an overall recovery of health-related QoL, besides the expected prevention of oxaliplatin-related neurotoxicity.
•This study reports on a pre-specified secondary analysis of the randomized open-label phase II Valentino trial.•Quality of Life (QoL) changes are reported through patient-reported outcomes.•Patients affected by RAS wild type metastatic colorectal cancer were treated in first-line with panitumumab (pan) plus/minus fluorouracil/leucovorin maintenance after FOLFOX-pan induction.•The results of this study showed an early deterioration of QoL during induction with partial recovery during maintenance.•No significant QoL differences between the two maintenance treatment arms are reported.
Neuroendocrine neoplasms of the lung represent about 20% to 30% of all neuroendocrine tumors. On the basis of clinical and pathologic characteristics, 2 different categories of tumors may be defined: ...poorly differentiated neuroendocrine neoplasms, characterized by a high rate of recurrences and poor prognosis, and well-differentiated neuroendocrine neoplasms (typical carcinoids and atypical carcinoids), which generally display an indolent course. Lung carcinoids represent only 1% to 5% of all lung malignancies, but their incidence has significantly increased over the past 30 years. Surgery is the reference standard of treatment for lung carcinoids with locoregional disease. For advanced or unresectable lung carcinoids, several therapeutic options are available, but the choice should be shared within a multidisciplinary team to ensure optimal therapeutic outcomes. We describe the current management of these rare neoplasms.
Background
Epstein‐Barr virus (EBV)‐positive gastric cancers (GCs) have been recently identified as a molecular subgroup showing excellent outcomes after surgery for early‐stage disease and ...responsiveness to immune checkpoint inhibitors (ICIs) for metastatic stage. No data are available on the prevalence, clinical characteristics, and prognosis of this subgroup of GCs in the metastatic setting.
Materials and Methods
In this cohort study, we assessed the impact of EBV status in patients with metastatic GC treated with chemotherapy at two Italian institutions.
Results
Among the 175 cases analyzed, only 7 (4%) were EBV positive and all showed long‐lasting and even complete responses to first‐line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV‐negative patients (3‐year overall survival: 80% vs. 20.1%; hazard ratio: 0.12).
Conclusion
If confirmed in larger data sets, our results may give a strong rationale for investigating the addition of ICIs to chemotherapy, in order to maximize the chance of achieving durable and complete responses in this uncommon subtype of GC.
Implications for Practice
To date, no data are available on the prevalence and clinical characteristics of patients with Epstein‐Barr virus (EBV)‐positive metastatic gastric cancer (GC), a specific subtype of GC showing excellent outcomes after radical surgery in early‐stage disease and responsiveness to immune checkpoint inhibitors (ICIs). This cohort study showed that patients with EBV‐positive GC who did not receive ICIs had exceptional, long‐lasting, and even complete responses to first‐line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV‐negative patients. If confirmed in larger series, these results may give a strong rationale for investigating the combination of chemotherapy and ICIs to achieve durable and potentially complete response in this uncommon subtype of GC.
This article assesses the effect of Epstein‐Barr virus status in patients with metastatic gastric cancer.
Background
Outcomes of patients with metastatic melanoma discontinuing BRAF‐targeted therapy for cumulative toxicity after sustained response are unknown.
Materials and Methods
This retrospective ...case series analysis conducted at a single Cancer Center in Italy included patients with BRAF mutated metastatic melanoma treated with a BRAF inhibitor as a single agent or in combination with a MEK inhibitor between June 1, 2011 and January 1, 2020 and interrupted treatment due to cumulative toxicity after achieving complete response (CR) or long‐lasting partial response (PR; i.e. >12 months).
Results
We included 24 patients with a median treatment duration of 59.4 months (95% confidence interval CI, 55.4–63.4; range, 12–88). CR and PR were achieved in 71% and 29% of patients, respectively. At a median follow‐up after treatment discontinuation of 37.8 months (95% CI, 33.7–41.9), the 12‐month progression‐free survival after discontinuation (dPFS) rate was 70.8% (95% CI 54.8–91.6) and 24‐month dPFS rate was 58.3% (95% CI, 41.6–81.8). Baseline patient and tumor characteristics as well as treatment duration and best response did not significantly impact on dPFS. Patients with CR and negative circulating tumor DNA (ctDNA) at time of discontinuation had a significantly improved dPFS compared with patients with either radiological residual disease or ctDNA positivity (p = .007). No patient in CR with undetectable ctDNA experienced progression.
Conclusion
The risk of progression is high even in patients with sustained sensitivity to BRAF/MEK inhibitors. Integration of liquid biopsy in clinical trials investigating the optimal management of patients with sustained sensitivity to BRAF/MEK inhibitors is warranted.
Implications for Practice
Outcomes of patients with metastatic melanoma discontinuing BRAF‐targeted therapy for cumulative toxicity are unknown. This study analyzed patients with sustained responses (median treatment duration 59.4 months). Twelve‐ and 24‐month progression‐free survival following discontinuation were 70.8% and 58.3%, respectively. Complete response and negative circulating tumor DNA at time of discontinuation are promising prognostic biomarkers in this setting.
This article reports clinical outcomes of patients with metastatic melanoma treated with BRAF/MEK inhibitors who interrupted the treatment after achieving a long‐lasting objective response, exploring the role of circulating tumor DNA assessed at time of discontinuation as a biomarker for post‐discontinuation progression‐free survival.
In patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of ...anti-EGFR-based reinduction therapy during the upfront strategy.
We included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan-Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score-based matching was used.
Liver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score-matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction.
Reinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical-molecular selection for re-treatments and the need for prospective strategy trials in selected populations.
Background:
The RECOURSE trial (Study of TAS-102 in Patients With Metastatic Colorectal Cancer Refractory to Standard Chemotherapies) demonstrated an overall survival (OS) benefit of ...trifluridine/tipiracil (FTD/TPI) vs placebo in refractory metastatic colorectal cancer (mCRC). Given the limited benefit of later line treatments, we developed the Colon Life nomogram to assess the 12-week death probability in the refractory setting.
Methods:
This post hoc analysis of RECOURSE included patients with available data to calculate the nomogram score: Eastern Cooperative Oncology Group Performance Status, primary tumor resection, lactate dehydrogenase, and peritoneal metastases. The nomogram calibration was assessed by calibration plots and C-index. The nomogram prognostic and predictive ability was assessed by Cox model analyses and the nomogram score predictive value was explored according to the cutoff identified at maximum value of the Youden index in time-dependent receiver operating characteristic curve analysis.
Results:
Overall, 251 trial patients were evaluable: 90 in the placebo arm and 161 in the FTD/TPI arm. The calibration was optimal in the placebo arm (C-index 0.807) and suboptimal in the FTD/TPI arm (0.657). The cutoff of the nomogram score of 23 showed the best discriminative ability for 12-week OS (hazard ratio 3.46, 95% confidence interval 2.17–5.51 for scores 40 vs 15) and had maximum value of the Youden index (0.381). Median OS and 3-month PFS were 9.0 vs 7.5 months and 39.3% vs 5.2%, respectively, for FTD/TPI vs placebo in the low-risk group (score <23) and 4.8 vs 3.4 months and 22.3% vs 9.8% in the high-risk group (score ⩾23) (interaction NS).
Conclusion:
The Colon Life nomogram is an accurate tool for estimating life expectancy in refractory mCRC. The benefit of FTD/TPI was independent of the predicted risk of early death.
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