Highlights • Following disease progression after standard first- and second-line combination chemotherapy with monoclonal antibodies, many patients have a good performance status and a significant ...proportion are willing to undergo further therapy. • Choices of treatment beyond the second-line setting for mCRC are therefore becoming increasingly important. • Regorafenib significantly improved OS, compared with placebo, in two pivotal phase III trials (CORRECT and CONCUR) in chemo-refractory mCRC patients.TAS-102, an oral fluoropyrimidine, also resulted in significantly improved OS versus placebo in the phase III trial RECOURSE, which was conducted in a similar patient population to CONCUR and CORRECT. • Reintroduction of previously administered therapy is another valid and commonly used approach, especially for those regimens which were discontinued before progression, e.g. if associated with cumulative toxicities, such as peripheral neuropathy. • This review aims to provide guidance for mCRC treatment beyond second-line combination therapy.
The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based ...chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial.
We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3–4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (<60, 60–70, and ≥70years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis.
A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P<0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50months, in patients aged <60years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P=0.013) and systemic recurrences (P=0.023), DFS (P=0.011), and even overall survival (OS; P=0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40–70years compared with elderly patients treated with oxaliplatin.
The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60years with advanced rectal cancer. Patients aged ≥70years had no benefit.
NCT00349076
The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based ...therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC.
Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis.
Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% 95% confidence interval (CI) 17.2–34.4 for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2–30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89–9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62–9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74–1.36). The response rates were 49.1% (95% CI 39.7–58.6) and 45.9% (95% CI 36.4–55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%).
No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity.
NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.
Acne-like skin rash is a frequently occurring adverse event associated with drugs against the epidermal growth factor receptor. This randomized vehicle-controlled study investigated the addition of ...vitamin K1 cream to doxycycline in patients with metastatic colorectal cancer treated with cetuximab.
Patients receiving first-line cetuximab+FOLFIRI were randomly assigned to prophylactic treatment with doxycylin and vitamin K1 cream or doxycycline and the vehicle. The primary end point of the study was the incidence of grade≥2 skin rash (NCI CTCAE version 4.02) during 8weeks of skin treatment. Secondary end points comprised skin rash according to a more thorough tripartite skin toxicity score (WoMo), quality of life, efficacy, and compliance. The study had 80% power to show a 20% reduction of the incidence of grade≥2 skin rash.
A total of 126 patients were analyzed. The incidence of skin rash grade≥2 was comparable between the arms. Likewise, no difference was seen in the WoMo score with respect to the percentage of skin affected. However, starting in week 5 and increasing over time patients treated with vitamin K1 cream had less severe rash and fewer fissures. Quality of life as well as efficacy and compliance with study medication and anticancer treatment was comparable in both arms.
The primary end point of decreasing grade≥2 skin rash was not met. However, using vitamin K1 cream as part of prophylactic treatment decreased the severity of acne-like skin rash according to WoMo, an alternative and more thorough skin toxicity scoring tool.
Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); ...chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC.
Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1–4 or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2.
The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06–2.98; P = 0.028. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79–1.75; P = 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression 44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP; objective responses 27/73 (37.0%) were identical. The most common serious adverse events were kidney injury 3 (4.3%) versus 7 (9.7%), general health deterioration 5 (7.1%) versus 5 (6.9%) and dysphagia 4 (5.7%) versus 4 (5.6%) in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP.
EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies.
ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).
•CF is the best palliative regimen in adv. ESCC.•Panitumumab added to CF failed to improve survival.•Low sEGFR linked to better PFS.
Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We ...examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial.
Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1–4) were used to assess individual-level surrogacy of NAR for DFS.
After a median follow-up of 50months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS 75.9% (95% confidence interval CI 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P=0.034; PC 1) and resulted in a shift toward lower NAR groups (P=0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P<0.001; PC 3). NAR score remained an independent prognostic factor for DFS low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106–7.020; P<0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303–2.98; P=0.001 in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4.
Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.
Docetaxel is a widely used cytotoxic agent. This study evaluates the impact of docetaxel toxicities on patient's health-related quality of life (QoL).
We conducted a multicenter, prospective, ...non-interventional trial, in which the QoL was assessed using the EORTC QLQ-C30 questionnaires at baseline and every 4 weeks up to 40 weeks in patients receiving a docetaxel-based chemotherapy for metastatic disease. Treatment-related adverse events were correlated with the corresponding QoL scores. Uni- and multivariate analyses were applied.
From January 2008 to June 2011, a total of 2659 patients were included. The majority of patients (48.1%) had prostate cancer, followed by breast (17.1%) and non-small-cell-lung cancer (15.8%). Patients received a median of 5 docetaxel cycles with the median dose of 75 mg/m2. The presence of grade 3/4 diarrhea showed the strongest effect on global health status/QoL average scores (50.91 versus 33.06), followed by vomiting (50.91 versus 35.17), dyspnea (50.94 versus 35.81), mucositis/stomatitis (50.88 versus 36.41), nausea (50.91 versus 36.68), infection (50.90 versus 37.14), fatigue (50.90 versus 43.82) and anemia (50.91 versus 41.03), P < 0.05 for all comparisons. Grade 3/4 leukopenia/neutropenia, alopecia, constipation, neurotoxicity and nail disorders had no significant impact on the global health status/QoL or other items.
In this large non-interventional trial, docetaxel-associated grade 3 or 4 toxicities were shown to have a strong detrimental effect on patient's QoL. Notably, diarrhea and vomiting had the strongest negative impact on QoL measures. This has to be kept in mind while making therapeutic decisions and providing optimized supportive treatment measures.
This study was registered at Deutsches Krebsstudienregister (DKSR, primary registry in the WHO Registry Network) with the ID 527.
This study assessed the activity of the mAb cetuximab in combination with cisplatin and 5-fluorouracil (5-FU) in advanced esophageal squamous cell carcinoma.
For a maximum of six 29-day cycles, ...patients received cisplatin 100 mg/m2, day 1, plus 5-FU 1000 mg/m2, days 1–5 (CF), either alone or in combination with cetuximab (CET–CF; 400 mg/m2 initial dose followed by 250 mg/m2 weekly thereafter). The primary end point was tumor response. Tumor material was obtained for analysis of KRAS mutation status.
Sixty-two eligible patients were included, 32 receiving CET–CF and 30 CF. Cetuximab did not exacerbate grade 3/4 toxicity, except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rate according to RECIST criteria was 19% and 13% and the disease control rate 75% and 57% for the CET–CF and CF arms, respectively. With a median follow-up of 21.5 months, the median progression-free survival was 5.9 and 3.6 months and median overall survival 9.5 and 5.5 months for CET–CF and CF, respectively. No KRAS codon 12/13 tumor mutations were identified in 37 evaluated samples.
Cetuximab can be safely combined with CF chemotherapy and may increase the efficacy of standard CF chemotherapy.
This randomized study was designed to investigate the superiority of gemcitabine (gem) plus nimotuzumab (nimo), an anti-epidermal growth factor receptor monoclonal antibody, compared with gem plus ...placebo as first-line therapy in patients with advanced pancreatic cancer.
Patients with previously untreated, unresectable, locally advanced or metastatic pancreatic cancer were randomly assigned to receive gem: 1000 mg/m2, 30-min i.v. once weekly (d1, 8, 15; q29) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or gem plus placebo, until progression or unacceptable toxicity. The primary end point was overall survival (OS), secondary end points included time to progression, overall response rate, safety and quality of life.
A total of 192 patients were randomized, with 186 of them being assessable for efficacy and safety (average age 63.6 years). One-year OS/progression-free survival (PFS) was 34%/22% for gem plus nimo compared with 19%/10% for gem plus placebo (HR = 0.69; P = 0.03/HR = 0.68; P = 0.02). Median OS/PFS was 8.6/5.1 months for gem plus nimo versus 6.0/3.4 mo in the gem plus placebo group (HR = 0.69; P = 0.0341/HR = 0.68; P = 0.0163), with very few grade 3/4 toxicities. KRAS wildtype patients experienced a significantly better OS than those with KRAS mutations (11.6 versus 5.6 months, P = 0.03).
This randomized study showed that nimo in combination with gem is safe and well tolerated. The 1-year OS and PFS rates for the entire population were significantly improved. Especially, those patients with KRAS wildtype seem to benefit. The study was registered as protocol ID OSAG101-PCS07, NCT00561990 and EudraCT 2007-000338-38.
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