Carlo Signorelli

A feasibility study of gefitinib in association with capecitabine (CAP) and oxaliplatin (OXA) as first-line treatment in patients with advanced colorectal cancer (ACRC)

3748 Background: EGF-receptor (EGF-R) is commonly overexpressed in epithelial tumors including ACRC and has thus become the target of various molecular therapeutic approaches. Gefitinib (Iressa), an EGF-R tyrosine kinase inhibitor, demonstrated activity in lung and head and neck cancer, but its clinical activity in ACRC is still unknown. We designed this trial to assess the safety and efficacy of Iressa in association with CAP-OXA regimen as first-line treatment in pts affected by metastatic colorectal cancer Methods: From October 2002 21 pts were included in a two steps trial (m:f:12/9, median age 66 yrs (54-73). Actually the twelve pts planned for first safety analysis are evaluable for toxicity and response. CAP was orally administered (1000 mg/m2) twice a day continuously for 15 days and OXA was administered (120 mg/m2) as a 2-hour infusion on day 1, repeated every 3 weeks for six courses. Gefitinib has been given orally, once daily, at 250 mg, continuously from day 1.Pts on response at the end of the treatment continued to receive gefitinib until progression or unacceptable toxicity. RESULTS 40 cycles were totally administered. The most common side-effect was Diarrhea (14/40 cycles: one G4, two G3 and five G2).Acneiform skin lesion (NCI-CTC grade 1-2 in four and one pts respectively) was frequent, but often disappeared or decreased under continued therapy with Iressa. Further major side-effects included Nausea/Vomiting G1-2 in 12/40 cycles, thrombocytopenia G1-2 6/40 cycles, neutropenia G2-3 4/40 cycles. 82,5% of cycles were given at full dose, while 17,5 were given at full dose but delayed; no reduction of dose was performed. 12 pts are evaluable for efficacy according to an intent-to-treat analysis: 1 CR, 5 PR, 1 SD, 3 PD and 2 withdrawn for SAE (asthenia, diarrhea, and vomiting). CONCLUSIONS Iressa in combination with Cape and Oxa is a feasible regimen in ACRC with an acceptable toxicity profile and an interesting, although preliminary, activity. Further studies are required to assess the potential of Iressa as treatment option in ACRC. Accrual will continue up to 35 patients as planned. No significant financial relationships to disclose.

A phase II trial of gefitinib in combination with capecitabine and oxaliplatin as first-line chemotherapy in patients with advanced colorectal cancer

ABSTRACT Objective: This study was designed as a multicentre phase II trial to assess the efficacy and safety of gefitinib in association with capecitabine and oxaliplatin in patients with untreated metastatic colorectal cancer. Research design and methods: Patients with metastatic colorectal cancer that had received no prior chemotherapy for advanced disease were treated with oral gefitinib (250 mg daily) plus oral capecitabine (1000 mg/m2 twice a day on Days 1–14) and intravenous oxaliplatin (120 mg/m2 on Day 1 of each 3‑week cycle). Results: Thirty-five patients were enrolled. In the intention-to-treat analysis, 3 (8.6%) patients experienced a complete response (CR), 14 (40%) a partial response (PR) and 11 (31.4%) had stable disease (SD). The disease control rate (CR + PR + SD) was 80%, the median time to progression was 7.3 months (95%CI: 4.76–9.2) and the estimated median overall survival was 21.9 months (95% CI: 15.1–not reached). The most common grade 3 to 4 toxicities included diarrhoea (31%) and vomiting (5.7%). Conclusions: The combination of capecitabine, oxaliplatin and gefitinib appears to have promising activity in chemotherapy-naïve metastatic colorectal cancer. A higher disease control rate and an increase in median overall survival were seen compared with previous reports with capecitabine and oxaliplatin in similar patient populations. The tolerability profile appears to be predictable and similar to capecitabine/oxaliplatin regimens.

Observational study on quality of life, safety, and effectiveness of first‐line cetuximab plus chemotherapy in KRAS wild‐type metastatic colorectal cancer patients: the ObservEr Study

Cetuximab improves efficacy when added to chemotherapy for metastatic colorectal cancer (mCRC). Effective management of skin reactions from cetuximab improves quality of life (QoL), and treatment compliance in clinical trials. No data are available from real‐world settings. The ObservEr observational, multicenter, prospective study evaluated QoL, the incidence of skin reactions, and management of chemotherapy plus cetuximab in first‐line for mCRC. The primary endpoint was QoL measured with the Dermatology Life Quality Index (DLQI) and EORTC QLQ‐C30. Secondary endpoints were the incidence of skin and serious adverse events, median overall and progression‐free survival, tumor response, and resection rates. Between May 2011 and November 2012, 228 patients with KRASwt mCRC were enrolled at 28 Italian centers, 225 evaluable, median age 65 years. QoL did not change during treatment and was not affected by the choice of prophylactic or reactive skin management. The incidence of cetuximab‐specific grade ≥3 skin reactions was 14%, with no grade 4/5 events. Skin reactions correlated with survival (P = 0.016), and their incidence was influenced by chemotherapy regimen (oxaliplatin vs. irinotecan—Incidence rate ratio [IRR] 1.72, P < 0.0001) and gender (male vs. female—IRR 1.38, P = 0.0008). Compliance at first postbaseline evaluation was 97.75%. Median overall survival was 23.6 months, median progression‐free survival 8.3 months. Cetuximab plus chemotherapy did not compromise QoL in the routine clinical setting when patients receive close monitoring plus prophylactic or reactive management of skin reactions. We observed the same correlation between overall survival (OS) and skin reactions reported in controlled clinical trials, also in this setting.

Treatment of Metastatic Colorectal Cancer Patients ≥75 Years Old in Clinical Practice: A Multicenter Analysis.

Background Colorectal cancer patients have a median age of incidence >65years although they are largely under-represented in phase-III trials. This large population contains patients unfit for treatment, those suitable for monotherapy or for doublets and the impact of chemotherapy outside clinical trial is unclear. The aim of the study was to retrospectively analyse Overall Survival(OS) of elderly metastatic colorectal cancer(mCRC) patients treated with chemotherapy in daily practice. Methods Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for differences between subgroups, Cox’s proportional hazard model to assess the impact of known prognostic factors and treatment. Results 751 patients with mCRC observed between January 2000 and January 2013 were collected. Median age was 79 year(75–93); Male/Female 61/39%, ECOG-PS 0-1/2 85/15%; colon/rectum 74/26%; multiple metastatic sites 34%, only liver metastasis in 41% of patients. KRAS status was studied in 35% of patients: 44% of them showed gene mutation. 20.5% of patients did not received any kind of treatment including surgery. Comorbidities observed: cardiovascular 34%, diabetes 14%, hypertension 50%. Primary tumor was resected in 80.6%; surgery of liver metastasis was done in 19% of patients (2.3% of patients >80years). 78% of patients underwent chemotherapy. Median follow up was 12 months(range 1–124). Median OS was 17 months (CI 95%15–19);median OS in no-treated patients was 5 months (4–6); mOS of patients with at least one treatment was 20 months (18–22). In KRAS mutated group median OS was 19months (15–23) while in KRAS wild type patients median OS was 25 months (20–30). At multivariate analysis sex(Female), age(<80y), performance status(0–1), chemotherapy, Surgery of metastasis, Surgery of primary tumor and Site of metastasis(liver) were prognostic factors for OS. Conclusion The results of our study show that in clinical practice treatment has a positive impact on OS of elderly patients, confirmed at multivariate analysis, included patients with age >80 years old or with a poor performance status (respectively p<0.0001 and p<0.0001). KRAS analysis deserve further evaluation.

600PTREATMENT (T) OF METASTATIC COLORECTAL CANCER (MCRC) PATIENTS (PTS) ≥75 YEARS (Y) OLD IN CLINICAL PRACTICE: A MULTICENTER ANALYSIS

ABSTRACT Aim: CRC pts have a median age of incidence > 65y although they are largely under-represented in phase III trials. This large population contains pts unfit for T, those suitable for monotherapy or for doublets and the impact of chemotherapy (CHT) outside clinical trial is unclear. Aim of the study was to retrospectively analyse T of elderly mCRC pts. Methods: Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for diferences between subgroups, Coxs proportional hazard model to assess the impact of known prognostic factors and T. Results: 751 pts with mCRC observed from January 2000 to January 2013 were collected. Median age was 79y (75-93); Variables HR (CI95%) P value Sex 1.21 (1.01-1.46) 0.04 Age 1.75 (1.45-2.12) ECOG PS 2.51 (1.94-3.25) CT 2.14 (1.68-2.73) S of metastasis 2.48 (1.88-3.29) S of primary tumor 1.66 (1.31-2.11) Site of metastasis 1.33 (1.09-1.63) 0.006 Conclusions: These data show that in clinical practice treatment of metastatic disease has a positive effect on elderly pts OS, confirmed at multivariate analysis. KRAS analysis deserve further evaluation. Update results will be presented. Disclosure: All authors have declared no conflicts of interest.