Impact of sarcopenia on dose limiting toxicities in metastatic colorectal cancer patients (mCRC pts) receiving palliative systemic treatment

Background: Evidence is increasing that severe skeletal muscle (SM) loss (sarcopenia) is associated with reduced overall survival (OS) in mCRC pts. We recently found, using data of the randomized phase 3 CAIRO3 study (Lancet, 2015), that SM loss was related to shorter time to progression during first line maintenance treatment (Tx) with capecitabine+bevacizumab (CAP-B) or observation. Subsequently, SM loss during more intensive reinduction Tx by adding oxaliplatin (CAPOX-B) was associated to shorter overall survival (ASCO, 2017). As a potential risk factor for reduced survival we explored whether sarcopenia was associated with dose reductions at start of CAPOX-B reinduction Tx and dose limiting toxicities (DLT) during CAPOX-B reinduction Tx. Methods: Here, CAIRO3 pts were included who received CAPOX-B reinduction Tx. DLT were defined as any dose delay, reduction, or discontinuation of systemic treatment because of reported CTCAE (v3.0) toxicities at start or during Tx. Poisson regression models adjusted for relevant confounders were used to study the association between sarcopenia and DLT. Results: A total of 254 pts received CAPOX-B reinduction Tx. 39% of pts were sarcopenic and compared to normal SM pts we found no statistically significant differences in age and sex (sarcopenic vs normal SM: mean age 63.6±9.1 vs 61.9±8.5 yrs, p=.20 and 39% vs 31% females p=.31). BMI was significantly lower in sarcopenic pts, but pts were on average still overweight (25.9±3.8 vs 27.2±3.8 p=.01). Overall, 67% experienced ≥1 DLT. At start of CAPOX-B, 25% had already received a dose reduction and the risk of dose reduction at start was significantly higher for sarcopenic compared to normal SM pts (RR 1.8 95%CI 1.08-2.90). Despite more frequent dose reductions at start, sarcopenic pts did not have a significantly lower risk of DLT during CAPOX-B Tx (RR sarcopenic vs normal SM pts 0.86 95% CI 0.46-1.45). Conclusions: Sarcopenia was significantly associated with dose reductions at start of CAPOX-B reinduction Tx, and not with DLT during CAPOX-B reinduction Tx. Possible explanations for dose reductions at start might be more frequent toxicities during previous Tx including neuropathy

Impact of sarcopenia on dose limiting toxicities in metastatic colorectal cancer patients (mCRC pts) receiving palliative systemic treatment

Background: Evidence is increasing that severe skeletal muscle (SM) loss (sarcopenia) is associated with reduced overall survival (OS) in mCRC pts. We recently found, using data of the randomized phase 3 CAIRO3 study (Lancet, 2015), that SM loss was related to shorter time to progression during first line maintenance treatment (Tx) with capecitabine+bevacizumab (CAP-B) or observation. Subsequently, SM loss during more intensive reinduction Tx by adding oxaliplatin (CAPOX-B) was associated to shorter overall survival (ASCO, 2017). As a potential risk factor for reduced survival we explored whether sarcopenia was associated with dose reductions at start of CAPOX-B reinduction Tx and dose limiting toxicities (DLT) during CAPOX-B reinduction Tx. Methods: Here, CAIRO3 pts were included who received CAPOX-B reinduction Tx. DLT were defined as any dose delay, reduction, or discontinuation of systemic treatment because of reported CTCAE (v3.0) toxicities at start or during Tx. Poisson regression models adjusted for relevant confounders were used to study the association between sarcopenia and DLT. Results: A total of 254 pts received CAPOX-B reinduction Tx. 39% of pts were sarcopenic and compared to normal SM pts we found no statistically significant differences in age and sex (sarcopenic vs normal SM: mean age 63.6±9.1 vs 61.9±8.5 yrs, p=.20 and 39% vs 31% females p=.31). BMI was significantly lower in sarcopenic pts, but pts were on average still overweight (25.9±3.8 vs 27.2±3.8 p=.01). Overall, 67% experienced ≥1 DLT. At start of CAPOX-B, 25% had already received a dose reduction and the risk of dose reduction at start was significantly higher for sarcopenic compared to normal SM pts (RR 1.8 95%CI 1.08-2.90). Despite more frequent dose reductions at start, sarcopenic pts did not have a significantly lower risk of DLT during CAPOX-B Tx (RR sarcopenic vs normal SM pts 0.86 95% CI 0.46-1.45). Conclusions: Sarcopenia was significantly associated with dose reductions at start of CAPOX-B reinduction Tx, and not with DLT during CAPOX-B reinduction Tx. Possible explanations for dose reductions at start might be more frequent toxicities during previous Tx including neuropathy

Mobility impairment, muscle imbalance, muscle weakness scapular asymmetry and shoulder injury in elite volleyball athletes

BACKGROUND: The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS: In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS: Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8.5 months in the observation group and 11.7 months in the maintenance group (HR 0.67, 95% CI 0.56-0.81, p<0.0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%] patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. INTERPRETATION: Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. FUNDING: Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis

Survival of patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era

Contains fulltext : 230109.pdf (Publisher’s version ) (Closed access)BACKGROUND: Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy. METHODS: Two hundred and eighty-one dMMR mCRC patients (n = 54 from three prospective Phase 3 CAIRO trials; n = 227 from the Netherlands Cancer Registry). Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors. As comparison for OS 2746 MMR proficient mCRC patients were identified. RESULTS: Of 281 dMMR patients, 62% received first-line and 26% second-line treatment. Median OS was 16.0 months (13.8-19.6) with antitumour therapy and 2.5 months (1.8-3.5) in untreated patients. OS1 was 12.8 months (10.7-15.2) and OS2 6.2 months (5.4-8.9) in treated dMMR patients. Treated dMMR patients had a 7.6-month shorter median OS than pMMR patients. CONCLUSION: Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients