Chemotherapy For mCRC Research Articles

Serial FDG–PET/CT for early outcome prediction in patients with metastatic colorectal cancer undergoing chemotherapy

The study purpose was to assess the predictive value of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computerized tomography (CT) metabolic response after a single course of chemotherapy in patients with metastatic colorectal cancer (mCRC). FDG-PET/CT scans were carried out at baseline and on day 14 in 41 patients with unresectable mCRC treated with a biweekly regimen of chemotherapy. Metabolic nonresponse was defined by <15% decrease in FDG uptake in the dominant proportion of the patient's lesions or if a lesion was found metabolically progressive. The PET-based response was correlated with radiological response (primary end point) and patient's outcome (secondary end points). RECIST response rate in metabolically responding patients was 43% (10 of 23) compared with 0% (0 of 17) in nonresponding patients (P=0.002). The metabolic assessment's predictive performance for RECIST response was sensitivity 100% [95% confidence interval (CI) 69% to 100%], specificity 57% (95% CI 37% to 75%), positive predictive value 43% (95% CI 23% to 66%), and negative predictive value 100% (95% CI 80% to 100%). Comparing metabolically responding versus nonresponding patients, the hazard ratio (HR) was 0.28 (95% CI 0.10-0.76) for overall survival and 0.57 (95% CI 0.27-1.21) for progression-free survival. The metabolic response measured by FDG-PET/CT after a single course of chemotherapy in mCRC is able to identify patients who will not benefit from the treatment.

Serious adverse events among a population-based cohort of patients receiving first-line chemotherapy for metastatic colorectal cancer (mCRC).

e14003 Background: Little is known about the toxicity of first line chemotherapy for mCRC in the general population. We sought to determine the proportion of patients who experienced at least one of the following: a serious toxicity (defined as an emergency department visit or hospitalization) or death within 30 days of receiving chemotherapy. Methods: All patients, age 18 or older, diagnosed with CRC from January 1 2007 to December 31 2009 in Ontario, Canada were identified using the Ontario Cancer Registry. Patient records were linked deterministically to multiple provincial healthcare databases to identify receipt of first-line chemotherapy for metastatic disease and to evaluate Emergency Department (ED) visits, hospitalizations, and deaths. An event was determined to be potentially treatment related if it occurred within 30 days of any cycle of chemotherapy. Results: The cohort contained 2359 patients. Mean age was 62 (range 19-89) and 59% were men. See table below. Conclusions: A significant proportion of patients visit the ED at some point during first line chemotherapy and many are hospitalized. A quarter of all patients had a hospital admission whereby an infectious complication was at least a contributing diagnosis. A significant minority of patients died within 30 days of receiving chemotherapy, raising concerns of either poor patient selection or severe treatment toxicity. [Table: see text]

Abstract No. 245: Impact of addition of bevacizumab to mCRC chemotherapy on post-PVE liver metastasis growth rate

Abstract No. 245: Impact of addition of bevacizumab to mCRC chemotherapy on post-PVE liver metastasis growth rate

Updated survival results of the randomized phase II study of S-1, oral leucovorin, and oxaliplatin combination therapy (SOL) versus mFOLFOX6 in patients with untreated metastatic colorectal cancer (mCRC).

586 Background: We previously reported short term results of a randomized phase II study comparing SOL with mFOLFOX6 in terms of progression-free survival (PFS) by central review. The median PFS for SOL and mFOLFOX6 was 9.6 and 6.9 months (HR= 0.83; 95%CI, 0.49-1.40) with median follow-up time 14 months (Ojima et al, ESMO 2011). Here, we report updated overall survival (OS) results with 29 months follow-up. Methods: The inclusion criteria were; 1) histologically proved adenocarcinoma of colon or rectum, 2) age ≥ 20 years, 3) no prior treatment, 4) at least one target lesion by RECIST ver1.0 criteria, 5) ECOG Performance Status 0-1. Patients (Pts) were randomized to receive either S-1 (40-60 mg bid) and oral LV (25 mg bid) for one week and L-OHP (85 mg/m2) on day 1, repeated every 2 weeks (SOL; Group A) or L-OHP (85 mg/m2), l-LV (200 mg/m2), and 5-FU (400 mg/m2, bolus) on day 1, followed by 5-FU (2400 mg/m2, ci, 46 hours), repeated every 2 weeks (mFOLFOX6; Group B). This trial was supported by Taiho Pharmaceutical CO., LTD and Yakult Honsha CO., LTD. ClinicalTrials.gov Identifier: NCT00721916 Results: From July 2008 to July 2009, 107 pts were randomized, and 105 were eligible (56 to Group A and 49 to Group B). When survival data were updated 2 years after the last patient’s enrollment, with no lost cases, median OS for Group A and Group B was 28.5 and 25.9 months (HR= 0.76; 95%CI, 0.45-1.31), 2-year survival rate was 71.4% and 59.2%, respectively. The incidences of grade 3/4 adverse drug reactions were; neutropenia (19.6% Group A, 41.2% Group B), lymphopenia (14.3% and 5.9%), sensory neuropathy (19.6% and 2.0%), anorexia (12.5% and 7.8%), fatigue (10.7% and 5.9%) and diarrhea (10.7% and 3.9%). Post treatments with or without molecular target agents were performed for 80.4 % of Group A, and 75.5 % of Group B. Conclusions: The results of the present analysis show that SOL might be more effective than mFOLFOX6 in terms of both PFS and OS as the first line chemotherapy for mCRC. Further investigation of the SOL regimen, a phase III trial of its combination with molecular target agents should be considered.

Final skin toxicity (ST) and patient-reported outcomes (PRO) results from PRIME: A randomized phase III study of panitumumab (pmab) plus FOLFOX4 (CT) for first-line metastatic colorectal cancer (mCRC).

531^ Background: Final PRIME results showed that pmab + CT significantly improved progression-free survival (PFS) and objective response rate vs CT alone for first-line wild type (WT) KRAS mCRC. Efficacy and PRO by ST severity from the final descriptive analysis of PRIME are presented. Methods: Patients (pts) had no prior chemotherapy for mCRC, ECOG performance status ≤ 2, and tumor tissue available for biomarker testing. The final analysis occurred 30 months after the last pt was enrolled; the primary endpoint was PFS; secondary endpoints included OS, objective response, and safety. Pts who received treatment and were alive without progression at day 28 were included in the ST analysis. Results: 1183 pts were randomized. 1057 pts with WT or MT KRAS mCRC met the criteria for inclusion in the ST analysis. Maximum grade ST was observed by day 28 in &gt; 50% of pts. Results are shown ( table ). Overall differences in change from baseline of the least square means from a mixed effects model of the EQ-5D Overall Health Rating for pmab + CT (n = 285) minus CT alone (n = 294) and for ST gr 0-1 (n = 53) minus ST gr 2-4 (n = 232) were −1.069 (95% CI: −3.6277 to 1.4896) and 0.8971 (95% CI: ‐4.0224 to 5.8167), respectively. The overall safety profile was broadly comparable across ST groups and treatment arms. Conclusions: Pts with WT KRAS mCRC receiving pmab with ST gr 2-4 had longer PFS and OS vs pts receiving CT alone. PRO were not adversely affected by ST severity. [Table: see text]

Systemic Chemotherapy with and without Anti-EGFR Antibody in the First-line Treatment of Metastatic Colorectal Cancer

To define whether or not the addition of anti-EGFR monoclonal antibodies to standard chemotherapy, compared with chemotherapy alone, can improve Overall Survival (OS) and Progression-Free Survival (PFS) in the patients with Metastatic Colorectal Cancer (mCRC), and evaluate the influence of KRAS mutant status on the efficacy of anti-EGFR antibodies in the first-line setting. Medline, Embase and the Cochrane controlled trials register were searched. Six trials were identified, covering a total of 4,988 subjects. A significant benefit of anti-EGFR based regimen as first-line treatment was found for OS (HR, 0.89, 95% CI: [0.80, 0.99]; P=0.04) and for PFS (HR, 0.85 [0.77, 0.94]; P=0.002) among the overall population. The PFS benefit are probably limited to KRAS wild-type patients (HR, 0.83 [0.69, 0.99] P=0.03). No significant benefit was found among KRAS-positive patients: The summary HRs was 1.13 [0.91, 1.39] (P=0.26) for PFS, 1.06 [0.94, 1.19] (P=0.34) for OS, respectively. In conclusion, our data demonstrated that the addition of anti-EFGR antibodies to chemotherapy for mCRC improved overall and progression-free survival for the overall population in the first-line setting. And the benefit from anti-EGFR antibodies as first-line treatment seems to be limited to patients with KRAS wild-type tumors with respect to PFS.

Impact of watching prior to commencement of chemotherapy for metastatic colorectal cancer (mCRC): Findings from the South Australian Clinical Registry (SACR) for mCRC.

e14139 Background: The role of chemotherapy in mCRC is firmly established and the option of watchful waiting (WW) has become an alternative rarely considered. Evidence from 2 pivotal studies is conflicting and of an era when only 5FU was available. Outcomes for mCRC have improved because of early detection through surveillance, surgery and more effective chemotherapy drugs. However, there may be a group of patients who are diagnosed early with low volume and asymptomatic disease that may be suitable for a WW plan. Methods: The SACR for mCRC collects data on all patients who have a diagnosis of mCRC established after 1/2/06. We examined cancer characteristics and outcomes of patients who were suitable for chemotherapy but had their treatment delayed by more than 3 months from diagnosis of metastatic disease. Results: Data from 417 mCRC patients who received chemotherapy as first intervention have been entered into the Registry to date. 41 (9.8%) of these patients had chemotherapy commencement delayed by more than 3 months from diagnosis. Median age was 76.7 yrs (range 38-87). Stage at diagnosis is as follows (n); I=2, II=8, III=25 and IV=6. For patients with initial stage I-III disease, median time to recurrence was 1.48 years (range 0.53-7.71). 30% and 32.4% had single site lung or liver metastasis respectively. Median delay from diagnosis of metastatic disease to chemotherapy was 5.32 months (range 3-28). Average number of lines of subsequent chemotherapy=1.4 (range 1-4) and 5 patients have received anti-EGFR Rx. The median survival for this group from diagnosis was 23.2 months. Survival is equivalent to that reported for the whole group (ASCO GI 2010, #472). Conclusions: WW is a controversial option. We found that almost 10% of all mCRC had a delay in the initiation of chemotherapy consistent with a WW approach. This group was older and was likely to have a single site of metastatic disease. The majority of these patients had metachronous mCRC and low volume disease, suggesting possible diagnosis by surveillance. Despite the treatment delay, the median survival was almost 2 years.

Serial FDG-PET/CT for early outcome prediction in patients with metastatic colorectal cancer undergoing chemotherapy.

3593 Background: The purpose of our study was to assess the predictive value of FDG-PET/CT metabolic response after a single course of chemotherapy in patients with metastatic colorectal cancer (mCRC). Methods: We performed two FDG-PET/CT scans (at baseline and on day 14) in 41 patients with unresectable mCRC treated with a biweekly regimen of chemotherapy. Patients were classified as metabolically non-responders when the dominant proportion of the tumor load showed a decrease in FDG uptake less than 15%, or if at least one lesion was demonstrated to be metabolically progressive. The PET-based response was correlated with RECIST-based response (primary endpoint), and progression-free and overall survival (secondary endpoints). Results: RECIST response rate in metabolically responding patients was 43% (10/23) compared to 0% (0/17) in metabolically non-responding patients (P=0.002). The predictive performance of the metabolic assessment for RECIST response was sensitivity 100% (95% CI, 69% to 100%), specificity 57% (95% CI, 37% to 75%), positive predictive value 43% (95% CI, 23% to 66%) and negative predictive value 100% (95% CI, 80% to 100%). Comparing metabolically responding versus non-responding patients, the hazard ratio was 0.28 (95% CI, 0.10 to 0.76, P=0.008) for overall survival and 0.57 (95% CI, 0.27 to 1.21, P=0.14) for progression-free survival. Conclusions: The metabolic response measured by FDG-PET/CT after a single course of chemotherapy in mCRC is able to identify the patients who will not benefit from the treatment.

Maintenance treatment with cetuximab in a series of patients treated with standard chemotherapy and cetuximab in metastatic colorectal cancer.

624 Background: New strategies are needed to improve outcomes and reduced toxicities of currently treatments for patients with advanced colorectal cancer. Nowadays maintaining treatment until disease progression is the standard option for these patients. Cetuximab is a recombinant humanized monoclonal antibody that neutralizes epidermal growth factor receptor and it has shown benefit not only in combination with standard chemotherapy in first- and second-line treatment or as a single agent in progression to standard chemotherapy in KRAS wild-type metastatic colorectal cancer (mCRC). Methods: This data describes patients who received standard chemotherapy with cetuximab every two weeks. For patients with response or stable disease, cetuximab was continued until disease progression or unacceptable toxicity. Results: Twelve patients are reported, nine were male (75%). The median age was 62 years (range, 46 to 78 years). All patients had stage IV, and liver was the most common location (75%). The majority of patients (75%) received FOLFOX VI as a first-line treatment in combination with cetuximab; only two patients were treated with FOLFIRI. Cetuximab was maintained after the first line of treatment in the 75% of patients. The median of cycles of chemotherapy and cetuximab was 12. Best response achieved in this setting was complete response (58.3%, 7/12). Median of monotherapy with cetuximab treatment was 7.5 cycles (range 3 to 12). At the moment of this analysis seven of twelve patients continued with the maintenance. In the rest of patients the treatment was followed until progression (33%, 3/12). No grade 3-4 toxicities were seen during maintenance cetuximab. The most common adverse effect during maintenance was cutaneous toxicity but the majority of patients had minor toxicity (50% grade 1). Conclusions: Cetuximab has significant antitumor activity not only as a single agent or in combination with standard chemotherapy but may also when it is used as maintenance therapy after a complete or partial response to first or second line based chemotherapy in mCRC. Maintenance cetuximab is feasible, safe, and worthy of future study in advanced colorectal cancer. No significant financial relationships to disclose.

Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy

Background:Hypertension (HTN) is a common toxicity of anti-VEGF (vascular endothelial growth factor) antibody treatment. It may be a marker of VEGF signalling pathway inhibition and therefore represent a cancer biomarker in metastatic colorectal cancer (mCRC) patients treated with chemotherapy and bevacizumab.Methods:A total of 101 consecutive patients with mCRC were treated with standard chemotherapy combined with bevacizumab at dose of 2.5 mg kg−1 per week in a single centre. The median follow-up time of the patients alive was 64 months. Blood pressure was measured before each bevacizumab infusion, and HTN was graded according to common toxicity criteria for adverse events version 3.0.Results:Overall, 57 patients (56%) developed ⩾grade 1 HTN (median blood pressure 168/97 mm Hg), whereas 44 (44%) remained normotensive when treated with bevacizumab-containing chemotherapy regimen. Overall response rate was higher among patients with HTN (30 vs 20% P=0.025). Hypertension was associated with improved progression-free survival (10.5 vs 5.3 months; P=0.008) and overall survival (25.8 vs 11.7 months; P<0.001), and development of HTN within 3 months had an independent, prognostic influence in a multivariate landmark survival analysis together with other known mCRC prognostic factors (P=0.007). There was no association between HTN and development of thromboembolic complications.Conclusion:Hypertension may predict outcome of bevacizumab-containing chemotherapy in mCRC. These data require confirmation in prospective studies including pharmacodynamic and pharmacokinetic analyses.

The role of the KRAS G13D mutation in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy plus cetuximab.

630 Background: The CRYSTAL and OPUS studies showed that adding cetuximab (cet) to first-line chemotherapy (CT) significantly improved clinical benefit in patients (pts) with KRAS wild-type (wt) mCRC. Pts with KRAS codon 12 or 13 mutations are excluded from cet treatment. Studies suggest that not all KRAS mutations are equivalent in their biologic effects. Occasional responses and prolonged disease stabilization have been recorded following cet treatment of tumors with mainly KRAS codon 13 mutations. We investigated the influence of the most common KRAS codon 13 mutation (G13D) on clinical outcome compared with pts with other KRAS mutations or wt tumors in the CRYSTAL and OPUS trials. Methods: KRAS mutations were detected in tumor DNA from archival material using a PCR clamping and melting curve technique. Treatment arms were compared by KRAS mutation status for progression-free (PFS) and overall survival (OS). Results: In the CRYSTAL study of 1,063 evaluable pts 63% were KRAS wt, 6% were G13D mutant (mt) and 32% had other mutations. In the OPUS study of 315 evaluable pts, 57% were KRAS wt, 7% were G13D mt, and 36% had other mutations. Compared with KRAS wt pts those with G13D mutations did not benefit from the addition of cet to CT (Table). Data of comparisons of the G13D mutation with other KRAS mutations in these studies will be presented. Conclusions: Patients with KRAS G13D mt tumors did not appear to benefit from the addition of cet to first-line CT for mCRC. This analysis confirms the current practice of KRAS mutation testing as the standard diagnostic tool for determining first-line treatment of mCRC pts. [Table: see text] [Table: see text]

Cetuximab for the first-line treatment of metastatic colorectal cancer

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of cetuximab for the first-line treatment of metastatic colorectal cancer (mCRC), in accordance with the licensed indication, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The ERG project ran between 22 January 2008 and 4 November 2008. The clinical evidence came from two unpublished randomised controlled trials (RCTs) of cetuximab plus chemotherapy versus chemotherapy alone in the first-line treatment of mCRC. A third RCT submitted later compared cetuximab with irinotecan in combination with 5-fluorouracil (5-FU) and folinic acid (FA) and cetuximab with oxaliplatin in combination with 5-FU and FA in patients with mCRC with liver metastases only. No published economic evaluations of cetuximab for first-line chemotherapy in mCRC were identified in the submission. A de novo model examined the cost-effectiveness of cetuximab in patients with mCRC that was epidermal growth factor receptor positive, k-ras wild type and with liver metastases. The main source of clinical effectiveness evidence came from the first two RCTs which provided follow up information for 1-2 years. Secondary information was used to estimate survival for a further 22 years. The model focused on the patients for whom the treatment had been licensed. This limited the applicability of the model to the NHS setting in which patients would be a mixture of k-ras wild type and mutations and also a mixture of patients with liver metastases and other metastases. The difference in progression-free survival for the two trials was between 0.5 to 1.2 months over a 7-10 month period. Eight months' treatment with cetuximab, given as an initial loading dose and then weekly until progression, would cost around 22,932 pounds for an average man and 18,427 pounds for an average woman. It is uncertain whether this constitutes good value for money. The guidance issued by NICE on 25 September 2008 stated that cetuximab was not recommended for the first-line treatment of mCRC and people currently receiving cetuximab for the first-line treatment of mCRC should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

Cetuximab for the first-line treatment of metastatic colorectal cancer

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of cetuximab for the first-line treatment of metastatic colorectal cancer (mCRC), in accordance with the licensed indication, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The ERG project ran between 22 January 2008 and 4 November 2008. The clinical evidence came from two unpublished randomised controlled trials (RCTs) of cetuximab plus chemotherapy versus chemotherapy alone in the first-line treatment of mCRC. A third RCT submitted later compared cetuximab with irinotecan in combination with 5-fluorouracil (5-FU) and folinic acid (FA) and cetuximab with oxaliplatin in combination with 5-FU and FA in patients with mCRC with liver metastases only. No published economic evaluations of cetuximab for first-line chemotherapy in mCRC were identified in the submission. A de novo model examined the cost-effectiveness of cetuximab in patients with mCRC that was epidermal growth factor receptor positive, k-ras wild type and with liver metastases. The main source of clinical effectiveness evidence came from the first two RCTs which provided follow up information for 1–2 years. Secondary information was used to estimate survival for a further 22 years. The model focused on the patients for whom the treatment had been licensed. This limited the applicability of the model to the NHS setting in which patients would be a mixture of k-ras wild type and mutations and also a mixture of patients with liver metastases and other metastases. The difference in progress-free survival for the two trials was between 0.5 to 1.2 months over a 7–10 month period. Eight months’ treatment with cetuximab, given as an initial loading dose and then weekly until progression, would cost around £22,932 for an average man and £18,427 for an average woman. It is uncertain whether this constitutes good value for money. The guidance issued by NICE on 25 September 2008 stated that cetuximab was not recommended for the first-line treatment of mCRC and people currently receiving cetuximab for the first-line treatment of mCRC should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

Phase II study of capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal carcinoma

e15125 Background: The purpose of this study was to evaluate the safety and efficacy of the capecitabine-oxaliplatine combination (XELOX) in Chinese patients with metastatic colorectal carcinoma (mCRC). Furthermore, we aimed to explore whether a maintenance therapy with oral capecitabine in patients responding to XELOX is able to maintain the response and improve the duration of disease control (DDC). Methods: Patients with mCRC were treated with a 3-weekly regimen of oxaliplatin at a dose of 130 mg/m2 intravenously on Day 1 plus capecitabine 1000 mg/m2 orally twice daily from Days 2 to 15. Patients who did not progress after finished the XELOX therapy were choice to stop or receive oral capecitabine until disease progression or unacceptable toxicity. Results: 124 patients received a total of 637 cycles (median, 6) of treatment. Responses rate was 49.1%. Median overall and median progression-free survival was 20.0 months and 8.0 months, respectively. Main grade 3–4 drug-related toxicities included neutrapenia (5.6%), nausea/vomiting (4%), thrombocytopenia (2.4%), and hand-foot syndrome (2.4%). 23 of 101 patients responding to XELOX received oral capecitabine as maintenance therapy.The median DDC was 8 months for patients in the group of not using maintenance therapy, versus 12 months in the group of using capecitabine as maintenance therapy. Conclusions: XELOX is a highly effective first-line treatment for mCRC and provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Furthermore, these results support the feasibility of maintaining good response and improving DDC with oral Capecitabine after combination chemotherapy in mCRC. No significant financial relationships to disclose.

Phase II trial comparing folinic acid, fluorouracil, and gemcitabine (FFG) and FOLFOX4 regimens with added bevacizumab (B) in metastatic colorectal cancer (mCRC)

e15098 Background: FOLFOX4 is a standard chemotherapy for mCRC. FFG has shown substantial activity in mCRC. This trial compared the safety and efficacy of FFG and FOLFOX4 regimens in patients (pts) with mCRC. B was added to each arm after FDA approval in 2004 as first-line treatment of mCRC. Methods: Pts with mCRC, chemonaïve except for adjuvant treatment, were randomized to two treatment arms: FFG given weekly for 6 weeks of an 8-week cycle; FOLFOX4 had a 2-week cycle. Pts in both groups received B at 5 mg/kg every 2 weeks. Treatment continued until disease progression. Planned enrollment was 150 pts. Primary endpoint was overall response rate (ORR); secondary endpoints included toxicity, overall survival (OS), and time to progression (TTP). Response was assessed by RECIST. Post-hoc analysis of disease control rate (DCR) was added. Results: Forty-two pts (18 pts given B) were randomized to each arm. Thirty-one cycles of FFG and 248 cycles of FOLFOX4 were delivered. FFG produced greater myelosuppression than FOLFOX4. Two cases each of MI and DVT were observed in the FOLFOX4(B) subgroup; one pt had DVT with FFG alone. The incidence of gastrointestinal hemorrhage was low and similar for FFG and FOLFOX4. Peripheral neuropathy was highest in the FOLFOX4(B) subgroup. ORR and DCR were significantly greater for FOLFOX4(B) than for FFG(B). Median TTP and OS were not statistically different for FFG and FOLFOX4 groups. The trial was stopped due to low enrollment; planned statistical power was not achieved. Conclusions: FFG and FOLFOX4 regimens were generally well tolerated, with greater neuropathy in FOLFOX4 and greater myelosuppression in FFG. ORR was greatest in the FOLFOX4(B) subgroup. TTP and OS results comparing FFG and FOLFOX4 groups were inconclusive due to low enrollment. Rapid changes in mCRC “standard of care” during this trial may have constrained pt accrual. [Table: see text] [Table: see text]

Magnitude of benefit of the addition of bevacizumab (BEVA) to first-line chemotherapy (CT) for advanced/metastatic colorectal cancer (MCRC): Meta-analysis of randomized clinical trials

e15021 Background: The monoclonal antibody against vascular endothelial growth factor BEVA has recently demonstrated to improve survival for MRC patients (pts). Nevertheless, the magnitude of the provided benefit in the daily practice is still controversial. In order to quantify the benefit of adding BEVA to CT for MCRC, a literature-based meta-analysis was conducted. Methods: Survival Hazard Ratios (HR) were extracted from prospective, randomized clinical trials (RCTs, either phase II/III) reports. HR and event-based relative risks (RR) with 95% confidence intervals (CI) were derived through a random-effect model. Differences in primary (progression-free- and overall-survival, PFS/OS) and secondary outcomes (overall, partial and complete response rates, ORR/PR/CR) were explored. Absolute differences (AD) and the number of patients needed to treat (NNT) were calculated. Heterogeneity test and a meta-regression analysis with clinical predictors for outcomes were conducted as well. A sensitivity analysis according to the trial phase-design was accomplished. Results: Five trials (2,728 pts), 2 phase II (313 pts) and 3 phase III (2,415 pts), were gathered. No significant interaction was found in the sensitivity analysis between phase II and III, although a trend showed a better PFS results for BEVA in phase II trials (p=0.057). At the meta-regression analysis female gender and rectal primary site were significant predictors for PFS (p=0.003, p=0.005). Toxicity analysis is ongoing. Conclusions: Although concerns regarding costs and toxicities still exist, BEVA significantly improves the outcome of untreated MCRC pts. The absolute benefit provided into an unselected population for molecular features should be considered of paramount importance for advanced disease. [Table: see text] No significant financial relationships to disclose.

A meta-analysis of randomized controlled trials comparing chemotherapy plus bevacizumab with chemotherapy alone in metastatic colorectal cancer

Bevacizumab has demonstrated survival benefit in metastatic colorectal cancer (mCRC) patients when combined with chemotherapy. Several randomized clinical studies have evaluated bevacizumab in combination with chemotherapy. Meta-analysis was performed to better assess the efficacy and safety of bevacizumab with chemotherapy for mCRC. Five clinical trials randomizing a total of 3,103 mCRC patients to chemotherapy alone or to the combined treatment of chemotherapy plus bevacizumab were identified. The efficacy data included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR), and the safety data contained the 60-day all-cause mortality rate, adverse events (AEs), and specific toxicity such as hypertension, thrombosis, bleeding, proteinuria, gastrointestinal perforation, diarrhea, and leucopenia. There was a significant PFS benefit (P = 0.00; hazards ratio [HR] = 0.66) and OS benefit (P = 0.00; HR = 0.77) in favor of the combined treatment. The ORR was significantly higher on the bevacizumab-containing arm (P = 0.021; relative risk [RR] = 1.5), while CR was comparable between the two arms (P = 0.09). A higher incidence of grade 3/4 AEs, grade 3/4 hypertension, grade 3/4 thromboembolic/thrombotic events, grade 3/4 bleeding, and gastrointestinal perforation was associated with the bevacizumab group. The two treatment groups were similar in terms of grade 3/4 proteinuria, grade 3/4 leukopenia, grade 3/4 diarrhea, and the 60-day all-cause mortality rate. The addition of bevacizumab to chemotherapy confers a clinically meaningful and statistically significant improvement in OS, PFS, and ORR. Its side effects are predictable and manageable and do not compound the incidence or severity of toxicities from chemotherapy.

Vascular Endothelial Growth Factor plus Epidermal Growth Factor Receptor Dual Targeted Therapy in Metastatic Colorectal Cancer: Synergy or Antagonism?

There has been an intensive effort to develop novel therapies for the treatment of metastatic colorectal cancer (mCRC). The anti-epidermal growth factor receptor (EGFR) antibodies panitumumab and cetuximab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab have demonstrated clinical efficacy and acceptable toxicity in the treatment of mCRC as single agents or in combination with chemotherapy. Recent clinical trials have explored the efficacy and safety of treatment regimens incorporating chemotherapy in combination with bevacizumab and either panitumumab or cetuximab in patients with mCRC. Results from the BOND-2 trial, which investigated cetuximab, bevacizumab, and chemotherapy in mCRC, provided support for this therapeutic approach. Two large randomized phase 3 trials were initiated to evaluate firstline treatment of mCRC. The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study investigated the efficacy and safety of oxaliplatin- or irinotecan-based chemotherapy and bevacizumab with or without panitumumab; CAIRO2 assessed the efficacy and safety of capecitabine/oxaliplatin and bevacizumab with or without cetuximab. In both trials, the combination of bevacizumab, an EGFR-specific antibody, and chemotherapy in first-line treatment of mCRC was associated with increased toxicity and no improvement in patient outcome. These results suggest that these specific combinations should not be used in first-line mCRC outside investigational studies.

Innovations in Chemotherapy for Metastatic Colorectal Cancer: An Update of Recent Clinical Trials

It has been estimated that cancer of the colon and rectum (CRC) would be diagnosed in 153,760 men and women in the U.S. alone in 2007. Approximately one in five patients has metastatic CRC (mCRC) at diagnosis, which, at best, is associated with a 5-year survival rate of just 10.3%. Oxaliplatin- and irinotecan-based combination regimens are standard first-line therapies for mCRC. Recent studies suggest that survival outcomes can possibly be further improved by adding biologic agents to chemotherapy. Novel treatment strategies are being investigated to optimize the opportunity for patients to receive and benefit from the increasing number of available active agents and to further improve the efficacy, safety, and tolerability of multiagent therapy. These include switching therapy before progression, maintenance therapy, and chemotherapy-free intervals. Recent innovations in chemotherapy for mCRC are reviewed, with a focus on emerging data that may significantly improve both survival and quality of life for patients with CRC in the future.

KRAS mutation predicts response to cetuximab and chemotherapy in mCRC

KRAS mutation predicts response to cetuximab and chemotherapy in mCRC