3521 Background: STAR-01 is a randomized phase III trial investigating the effect of adding oxaliplatin (OXA) to preoperative (preop) 5-fluorouracil (FU)-based pelvic chemoradiation (CRT) in patients (pts) with resectable locally advanced rectal cancer (LARC). No benefit from adding OXA could be demonstrated on primary tumor response to preoperative chemoradiation (Aschele, J Clin Oncol, 2011). Methods: Eligibility required a resectable, biopsy-proven rectal adenocarcinoma within 12 cm from the anal verge with radiological evidence of perirectal fat or nodal involvement. Randomization was between infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (arm A) or the same regimen + weekly OXA (60 mg/msq x 6) (Arm B). Overall survival (OS) was the primary endpoint (252 deaths required to have a log-rank test with 80% power to detect a 30% reduction in mortality rates at the 5% two-sided significance level). Results: From November 2003 through August 2008, 739 eligible patients were enrolled at 41 Italian institutions. With a median follow up of 8.8 years (IQR 8.1-9.9), 132 and 109 deaths were recorded in Arm A and B, respectively (HR 0.82, CI 0.64-1.06, p=0.126). The corresponding 5 and 10 years OS rates were 77.6 vs 80.4 % and 62.3 vs 67.4 % (Arm A vs B). Preoperative/intraoperative progressions were thrice higher in Arm A (28, vs 10 in Arm B) while recurrences and deaths without recurrence were evenly distributed between the 2 arms (83/81 and 14/19 in Arm A/B, respectively). The corresponding event-free survival rates were 70.6 vs 74.2 % and 66.3 vs 69.2 % in Arm A vs B, at 3 and 5 years, respectively (HR 0.89, CI 0.69-1.15, p=0.374). Conclusions: This study did not meet its primary endpoint of a 30% reduction in mortality rates. The observed differences are consistent with a more limited impact on OS and warrants further investigation with pooled analyses of similar studies investigating OXA added to FP-based preop CRT. The large reduction in the number of early progressions is coherent with an effect of OXA on micrometastatic disease but was not paralleled by an improvement in recurrences after surgery.
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.
e14557 Background: Cetuximab significantly improves efficacy when added to chemotherapy in mCRC pts. The ObservEr Study evaluated quality of life (QoL), skin toxicity management and treatment compliance of cetuximab-based regimens in first-line treatment of mCRC pts. Methods: ObservEr is a non-interventional, multicenter, prospective study. Primary endpoint is change in QoL during first-line treatment, with focus on the impact of dermatological toxicity. QoL (Dermatology Life Quality Index/DLQI and EORTC QLQ C30) is assessed at baseline and weekly for the first 8 weeks of treatment, then at every evaluation visit until PD or withdrawal. Secondary endpoints are efficacy, rate of liver metastasis resections, incidence of serious adverse events. Results: Between Apr 2011 and Nov 2012, 29 Italian centers enrolled 233 pts, with 226 evaluable pts. Pt characteristics: 152(67.3%) males, 74(32.7%) females; median age 65 (39-81) years; PS ECOG 0-1 95.5%; potentially resectable liver metastasis 59(27.1%); irinotecan regimens 129(57.1%), oxaliplatin regimens 60(26.5%), other regimens 37(16.4%). Median interval between request and result of KRAS test was 10 (6-15) days. Prophylactic skin treatment with vitamin K1 cream was used in 159(70.4%) pts, reactive treatment included vitamin K1 in 59(26.1%). Grade (gr) 1-2 skin toxicity was observed in 128(56.6%) pts, gr 3 in 28(12.4%); no gr 4 was detected. No significant difference in gr 3 skin toxicity was observed between males vs females (13.8 vs 9.5%; p=0.351), age <60 vs ≥60 years (18.1 vs 9.7%; p=0.077), irinotecan vs oxaliplatin regimens (12.4 vs 18.3%; p=0.278), prophylactic vs reactive treatment (15.1 vs 6.8%; p=0.339). Dose reduction, temporary and permanent discontinuation of cetuximab due to skin toxicity was required in 9(4.0%), 32(14.2%) and 7(3.1%) pts respectively; cetuximab compliance ≥70% of dose was reached in 208(92.0%) pts. Conclusions: These results suggest that appropriate skin toxicity management and prophylactic or reactive treatment with Vitamin K1 cream can improve the gr 3 skin toxicity control and the cetuximab compliance. QoL results will be shown at the 2013 ASCO Meeting. Clinical trial information: ID239.
Patients with urothelial carcinoma are not always amenable to cisplatin-based chemotherapy. The authors previously reported that they achieved a 60% response rate in patients who failed on cisplatin-based combination chemotherapy (methotrexate, vinblastine, doxorubicin, and cisplatin) by using a convenient outpatient regimen of gemcitabine (G) and paclitaxel (P) every 2 weeks. A multicenter trial was initiated in 5 Italian centers to evaluate this regimen as first-line chemotherapy.From January 2003 to April 2005, 54 patients who had histologically proven, measurable disease (according to Response Evaluation Criteria in Solid Tumors) with a World Health Organization (WHO) performance status (PS) from 0 to 2, metastatic or inoperable urothelial carcinoma, no prior systemic cytotoxic or biologic treatment, a creatinine clearance >or=40 mL per minute, and bilirubin <20 micromol/L received G at a dose of 2500 mg/m(2) in 30 minutes and P at a dose of 150 mg/m(2) in 3 hours every 2 weeks. Granulocyte-colony-stimulating factor (G-CSF) was given for 5 to 7 days for neutropenia toxicity of grade >or=3 (grading determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 guidelines). From 6 to 12 courses were planned. All patients received at least 1 cycle of therapy and were included in all analyses.The median patient age was 67 years (range 34-78 years), and the median WHO PS was 1 (range, 0-2). Metastases occurred in the lung in 17 patients (31%), in lymph nodes in 26 patients (54%), in the bladder in 20 patients (37%), in bone in 8 patients (15%), and in the liver in 8 patients (15%). Fifty-nine percent of patients had >1 site of disease, and 13% of patients had >or=3 sites of disease. In total, 343 cycles were administered. Five patients achieved a complete response, and 15 patients achieved a partial response; thus, the overall response rate was 37% in an intent-to-treat analysis. Hematologic toxicity was predominant but manageable. G-CSF was used in only 6% of cycles. The median survival was 13.2 months, and the median time to disease progression was 5.8 months.In a multicenter study, G and P was found to be a well-tolerated outpatient regimen. This regimen demonstrated promise and may be considered in patients who are unable to receive cisplatin.
<i>Objectives:</i> Colorectal cancer is usually diagnosed in elderly patients. Since there is clear evidence that such patients are under-treated and under-represented or even excluded from clinical studies and there are no reliable and prospective data on the feasibility and efficacy of an oxaliplatin (L-OHP)-based chemotherapy in this setting, we have tested the L-OHP plus oral uracil/tegafur (UFT) and oral folinic acid (FA) combination as first-line therapy in patients with advanced or metastatic colorectal cancer (MCRC) aged 70 or older. <i>Patients and Methods:</i> Forty-seven patients with advanced or MCRC, aged over 70, were treated with L-OHP 65 mg/m<sup>2</sup> as an intravenous 3-hour infusion on day 1 and 8 plus UFT 300 mg/m<sup>2</sup> and FA 90 mg in 3 divided doses given orally on days 1–14 for each 3-week cycle. Patients were followed by a geriatric and a quality of life (QoL) assessment with specific scales and EORTC-QLQ-C30 questionnaire. <i>Results:</i> All patients were assessable for toxicity and 45 for response to treatment. Complete response was achieved in 2 patients (4%) and partial response in 22 (47%) [overall response rate, 51%; 95% confidence interval (CI): 40.7–61.2%]; 18 patients (38%) had stable disease, and 5 (11%) had disease progression. The median duration of response was 8 months (range, 3–19+ months). After a minimum follow-up of 17 months, the median time to disease progression and the median overall survival were 8.0 (95% CI: 6.7–9.3%) and 14.1 (95% CI: 11.0–17.1%) months, respectively. Regimen safety was manageable. Most adverse events were mild to moderate, and this did not result in QoL impairment. The most common grade 3–4 treatment-related adverse events were diarrhea (17%), neutro- and thrombocytopenia (2%), laryngeal spasm (2%), and peripheral neuropathy (12.7%). No treatment-related deaths occurred. <i>Conclusions:</i> These results confirmed that this tested chemotherapy combination is active with acceptable tolerability and QoL maintenance in elderly patients with advanced or MCRC.
