Irinotecan-containing Regimens Research Articles

Overall survival benefits for irinotecan‐containing regimens as first‐line treatment for advanced gastric cancer: An updated meta‐analysis of ten randomized controlled trials

The standard treatment for patients with advanced gastric cancer (AGC) is still debated, and the available data on the benefit of irinotecan-containing regimen as first-line treatment for those patients are controversial. We performed a systematic review and meta-analysis of randomized controlled trials to determine the survival benefits of irinotecan-containing regimens in this setting. A total of 1,837 patients from ten trials were included in the analysis. Our results showed that irinotecan-containing regimens significantly improved overall survival [OS: hazard ratio (HR) 0.86, 95% CI = 0.78-0.94, p = 0.002] and progression-free survival [HR = 0.82, 95% CI = 0.69-0.97, p = 0.026); however, the improvement of time to failure (HR = 0.90; 95% CI = 0.77-1.04, p = 0.15), 1-year survival rate [1-year SR: relative risk (RR) 1.10, 95% CI = 0.97-1.24, p = 0.13] and overall response rate (RR = 1.16, 95% CI = 0.91-1.49, p = 0.24] were nonsignificant. Equivalent frequencies of toxicities were found between the two groups excluding more Grade 3 or 4 fatigue (p = 0.001) in irinotecan-containing regimens. This updated meta-analysis provided strong evidence for a survival benefit of irinotecan-containing regimen as first-line treatment for AGC. A clear advantage of irinotecan-containing over nonirinotecan-containing regimen had not been established. These results should help to inform decisions about patient management and design of future trials.

The introduction of bevacizumab for the treatment of metastatic colorectal cancer (CRC) in Ontario and its effect on hepatic metastectomy.

303 Background: Where possible, the optimal treatment for CRC liver metastases is metastectomy. Perioperative chemotherapy may be associated with improved outcomes in this setting. The government of Ontario approved public funding of bevacizumab (Bev) for metastatic CRC in July 2008. For first-line treatment, funding of Bev has been limited to use in combination with FOLFIRI, an irinotecan-containing regimen. However, the best evidence in support of perioperative chemotherapy for CRC liver metastases involves the use of oxaliplatin, not irinotecan. We sought to analyze changes in prescribing patterns, histologic findings, and clinical outcomes since the funding approval for Bev in Ontario. Methods: A single centre, retrospective review was performed of all patients receiving metastectomy for CRLM between 2004 and 2010, and archival hematoxylin-eosin slides were reviewed. Results: A total of 121 patients underwent metastectomy for CRLM during the study period. Of these, 54 were treated with perioperative chemotherapy, 37 before and 16 after funding approval of Bev. A marked increase was seen in Bev and irinotecan-containing regimens since funding approval (p < 0.01). Pathologic examination of the surgical specimens did not reveal any increase in steatosis or steatohepatitis. However, there was a trend towards more R0 resections (p = 0.3) in the post-bev era. A significant reduction in the occurrence of post-operative hepatic dysfunction was observed in the post-Bev era (p = 0.04). Overall survival (OS) and disease-free survival (DFS) were similar. Conclusions: Public funding of Bev-FOLFIRI for metastatic CRC has led to an increased and yet incomplete utilization of this regimen for CRLM. Pathologic and clinical data do not suggest harm and may show early signs of benefit. Further research is needed to determine the optimal utilization of bev in the setting of CRLM. [Table: see text]

Abstract A150: Molecular mechanisms mediating the pharmacodynamic interactions between oxaliplatin (Ox) and epidermal growth factor receptor (EGFR) inhibitors in KRAS mutant colorectal cancer (CRC) cells.

Abstract Background: Platinum agents are a standard of care for treatment many cancers. Clinical data has shown that patients (pts) with CRC with mutant (MT) KRAS do not respond to EGFR inhibitors (Amado et al 2009). Furthermore, results from phase 3 clinical trials with erlotinib, cetuximab, or panitumumab have shown that pts whose tumors express MT KRAS have shorter progression-free survival and overall survival when an EGFR inhibitor is added to a platinum-containing regimen vs chemotherapy alone (Eberhard et al 2005, Bokemeyer et al 2011, Douillard et al 2010). However, KRAS status is not predictive of outcomes in pts receiving Ox- or irinotecan-containing regimens without an EGFR inhibitor (Richman et al 2009). This negative interaction has not been observed in pts whose tumors express either wild type (WT) KRAS receiving an EGFR inhibitor and chemotherapy or whose tumors express MT KRAS receiving an EGFR inhibitor with irinotecan (Peeters et al 2010, Van Cutsem et al 2009). Our goal was to gain a molecular mechanistic understanding of the negative interaction between EGFR inhibitors and Ox in KRAS MT CRC cells. Methods: To investigate the negative interaction between Ox and EGFR inhibitors, isogenic MT and WT KRAS-expressing HCT116 CRC cells were treated with Ox, SN-38 (the active metabolite of irinotecan), panitumumab, or gefitinib as single agents or in combination for 72 hrs. Viability was measured using an ATPlite assay. To determine the cellular distribution of EGFR, cells were serum-starved, labeled with a fluorescent anti-EGFR mAb, and visualized by a confocal microscopy. To analyze the effects of single agent or combination treatment on downstream phosphorylation of the PI3K or MAPK pathways, cells were treated for 24 hrs and phospho-proteins were detected by Western blotting. To investigate whether negative interaction between Ox and EGFR inhibitors could be reversed, cells were treated with Ox and gefitinib in combination with inhibitors to MEK, PI3K or Src for 72 hrs. Results: Treatment with gefitinib, but not panitumumab, reversed the anti-proliferative effects of Ox in the MT KRAS-expressing CRC cells vs Ox alone (p<0.0005). Neither treatment reversed the anti-proliferative effects of Ox observed in the WT KRAS-expressing cells or SN-38 in either the MT or WT KRAS-expressing cells. In the MT KRAS-expressing cells, EGFR was predominantly expressed intracellularly; in contrast, distinct cell surface staining was observed in the W T-KRAS expressing cells. This difference correlated with the inability of panitumumab to reverse the anti-proliferative effects of Ox in the CRC cells. Combination treatment of MT KRAS CRC cells with Ox and gefitinib increased pAKT which was not observed with Ox alone. Treatment of the mutant KRAS-expressing cells with a MEK, PI3K or Src inhibitor reversed the negative interaction between Ox and gefitinib (p<0.0005). Conclusion: We developed a preclinical model to further understand the negative interaction between MT KRAS-expressing cancer cells, platinum agents, and EGFR inhibitors. Feedback though AKT may contribute to the increased resistance to Ox in KRAS MT cells. Inhibitors of MEK, PI3K, or Src reversed the negative interaction between the EGFR inhibitors and Ox in a mutant-KRAS genetic background. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A150.

Clinical impact of anti‐epidermal growth factor receptor monoclonal antibodies in first‐line treatment of metastatic colorectal cancer

Antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (MoAbs) are indicated for the treatment of metastatic colorectal cancer patients, but some scientific issues concerning their efficacy are currently unsolved. A literature-based meta-analysis was conducted. Hazard ratios (HRs) were extracted from randomized trials for progression-free survival (PFS) and overall survival (OS); the event-based risk ratio was derived for response. Sensitivity analyses to look for interactions according to KRAS status and chemotherapy association regimens were performed. Eight trials (6609 patients) were identified. A significant interaction according to KRAS status was found for PFS (wild type vs mutant, P = .001) and response rate (wild type vs mutant, P < .0001). The addition of an anti-EGFR MoAb to first-line chemotherapy increased PFS in the KRAS wild-type population (HR, 0.91; 95% confidence interval [CI], 0.84-0.99; P = .03), and had a detrimental effect in the KRAS mutant population (HR, 1.13; 95% CI, 1.03-1.25; P = .013). A significant increase in the probability of achieving a response was evident in KRAS wild-type patients (relative risk, 1.17; 95% CI, 1.04-1.33; P = .011). In this population, the interaction in response rate according to adopted chemotherapy favored irinotecan-containing regimens (P = .01), and at meta-regression analysis the relative increase in response rate was significantly related to PFS (P = .00001) and OS (P = .00193) benefit. The addition of an anti-EGFR MoAb to first-line chemotherapy produces a clear benefit in response rate. This advantage is restricted to KRAS wild-type patients and translates into a small benefit in PFS. At present, irinotecan-based backbone chemotherapy could be a preferable option. The correlation between activity and survival parameters corroborates the hypothesis that anti-EGFR MoAbs might be more suitable for patients needing tumoral shrinkage.

KRN330, a fully human antibody against A33, in combination with irinotecan for patients with metastatic colorectal cancer (mCRC).

534 Background: KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen on normal colonic epithelium, which is uniformly expressed in 95% of colorectal cancers. A KRN330 monotherapy phase I study showed over 1 year of stable disease in 2 pts with refractory mCRC. We report results of the phase I part of a phase I/II trial of KRN330 in combination with irinotecan in pts with mCRC. Methods: Pts with mCRC who progressed on one or more prior therapies received weekly (QW) or biweekly (Q2W) intravenous doses of KRN330 at 0.5 or 1.0 mg/kg with Q2W irinotecan at 180 mg/m2 in a standard 3+3 dose escalation design. Results: Nineteen pts were treated. Four pts received 1.0 mg/kg of KRN330 Q2W and irinotecan treatment. Three pts developed DLTs, which included G4 febrile neutropenia and G3 colitis, prolonged G3 diarrhea, and, G4 neutropenia with prolonged G3 diarrhea. KRN330 was then deescalated to 0.5 mg/kg Q2W and 0.5 mg/kg QW. There were no DLTs in 7 of 8 pts in the Q2W cohort. The 1 DLT in this cohort was G3 colitis. None of the 7 pts in the QW cohort experienced DLT. The most common G3/4 toxicities included diarrhea (26.3%) and febrile neutropenia (15.9%), leucopenia (10.5%), neutropenia (10.5%), abdominal pain (10.5%), and colitis (10.5%). Of the 16 pts evaluable for efficacy, 2 pts had PR, 8 SD and 6 PD as best response. The 2 pts with PR had previously received an irinotecan-containing regimen, one with PD on an irinotecan-containing regimen. The responses are being confirmed by independent adjudicator. Conclusions: QW and Q2W intravenous doses of KRN330 at 0.5 mg/kg KRN330 with irinotecan were tolerable and demonstrated antitumor effect in pts who had received previous irinotecan-containing regimens. The phase II part of the phase I/II study of QW KRN330 plus irinotecan in pts with second line mCRC is ongoing. No significant financial relationships to disclose.

Randomized Phase II Trial of Irinotecan with Paclitaxel or Gemcitabine for Non-small Cell Lung Cancer: Association of UGT1A1*6 and UGT1A1*27 with Severe Neutropenia

Irinotecan-containing regimens are known to be active and tolerable in patients with non-small cell lung cancer (NSCLC). A randomized phase II trial was conducted to evaluate the efficacy of irinotecan plus paclitaxel or gemcitabine for previously untreated stage IIIB or stage IV NSCLC. Previously untreated patients with adequate organ function who gave written informed consent were randomly assigned to receive irinotecan (50 mg/m on days 1, 8, and 15) plus paclitaxel (180 mg/m on day 1) every 4 weeks (IP group) or irinotecan (100 mg/m on days 1 and 8) plus gemcitabine (1000 mg/m on days 1 and 8) every 3 weeks (IG group). The primary endpoint was the response rate. We also evaluated the relationship of response and toxicity to polymorphisms of the uridine diphosphate glucuronosyltransferase (UGT) gene. Eighty patients were enrolled, and 78 patients were eligible (38 in the IP group and 40 in the IG group). The response rate was 31.6% (95% confidence interval: 17.5-48.7%) in the IP group and 20.0% (9.1-35.6%) in the IG group. The median progression-free survival time was 86 days and 145 days, respectively. Both regimens were well tolerated. The most common severe adverse event was grade 4 neutropenia (36.8% and 10.0%, respectively), which was associated with UGT1A1*6 and UGT1A1*27. UGT polymorphisms did not correlate with response. Irinotecan plus paclitaxel may be more active against NSCLC than irinotecan plus gemcitabine. The UGT1A1*6 and UGT1A1*27 genotypes might be useful predictors of grade 4 neutropenia in patients who receive irinotecan-based chemotherapy.

FEB study: Efficacy treatment evaluation in metastatic colorectal cancer (mCRC) patients (pts) changing monoclonal antibody (MA) after progression with chemotherapy.

3550 Background: Monoclonal antibodies bevacizumab (B) and cetuximab (C) both improve overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) when combined with irinotecan-containing regimens. The optimal sequence of these monoclonal antibodies in combination with chemotherapy (CT) is controversial. This study analyzed the efficacy of C associated with irinotecan- based CT (FOLFIRI) after progression with the same regimen plus B in pts with mCRC. Methods: Eligibility criteria: progressive disease (PD) after CT with Folfiri-B (FB)->B; ECOG PS 0-1. Primary endpoints: ORR and disease control rate (DCR:ORR plus stable disease > 6 months); secondary endpoints: PFS, duration of response, OS and toxicity. ORR and DCR were reported with their confidence interval at 95%. Kaplan-Meier method was used for PFS and OS evaluation. Results: 50 pts were enrolled to receive Folfiri-C (FC)->C after PD to FB->B. Four pts were not evaluable for response rate. Median age was 67 (43-80), M/F 29/21, ECOG PS 0/1 was 18/ 32, WT Kras 40 (80%). Median cycles of first line FB->B was 12 (range 4- 16)/8 (range 1-23) and median cycles of second line FC->C was 7 (range 1-14)/6 (range 2-15). The ORR was 24% (CI 95% 12-36), DCR was 54% (CI 95% 40-69). In the group of patients responders to FB->B 37% of pts continued to be responsive to FC->C; in the group of non responders 15% obtained a response. Median duration of response was 5 months (range 1-9) and clinical benefit 8 months (CI 95% 4-12). PFS and OS are shown in the Table. Acne-like rash occurred in 76% of pts (42% grade ≥ 2). No grade 4 toxicity was observed. Conclusions: Efficacy in response and survival is maintained in pts with mCRC treated with the same CT regimen changing monoclonal antibodies. Data collection is ongoing and update results will be presented. Endpoints 6 months (%) 12 months(%) 24 months (%) Median (CI95%) PFS 51 23 — 7 (6-8) OS 80 61 22 17 (10-24) No significant financial relationships to disclose.

Panitumumab: a new frontier of target therapy for the treatment of metastatic colorectal cancer

Panitumumab is a fully human monoclonal IgG2 antibody targeting the EGF receptor (EGFR). This agent represents a new class of drug owing to its fully human nature, and no need for premedication and loading dose. Panitumumab selectively binds to EGFR, blocking the extracellular domain of the receptor, and has not been associated with the formation of any antibodies directed against it. The drug is indicated as monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. The safety profile is favorable and is generally well tolerated; the most common toxicities are skin rashes and diarrhea. Therefore, panitumumab’s hypersensitivity reaction rate is lower when compared with a chimeric monoclonal antibody such as cetuximab. Panitumumab increases the clinician’s repertoire of agents to treat metastatic colorectal carcinoma. The available clinical data are the most promising for a single-agent anti-EGFR monoclonal antibody in this disease at the present time. These new data open different clinical scenarios in metastatic colorectal carcinoma patients and encourage clinicians and basic researchers to investigate new therapeutic approaches for this patient subset.

Cisplatin-Based Chemotherapy Is Associated with An Unacceptably High Incidence of Thromboembolic Events: A Large Retrospective Analysis.

Abstract 456▪▪This icon denotes an abstract that is clinically relevant. Introduction:Cancer is a well established risk factor for the development of venous and arterial thromboembolic events (TEEs), including deep venous thrombosis, pulmonary embolus, cerebrovascular accident, and unstable angina/myocardial infarction. In addition to cancer itself, cytotoxic chemotherapy has been shown to potentiate the risk of TEEs. Among chemotherapeutic agents, cisplatin may be associated with a particularly high incidence of TEEs as suggested by few small series. The objective of this study was to determine the incidence of TEEs in patients treated with cisplatin based chemotherapy. Patients and Methods:We performed a large retrospective analysis of all patients treated at MSKCC for a variety of malignancies with cisplatin-based chemotherapy in 2008. Patients were included if they were at least 18 years of age, had received their first dose of their planned chemotherapy regimen between January 1, 2008 and December 31, 2008, and had at least 4 weeks of follow-up since the last dose of cisplatin. Patients were identified using the pharmacy information system. The diagnosis of TEE was based on documentation provided by angiography, magnetic resonance imaging, computed tomography, venous Doppler ultrasound, ventilation/perfusion scan, as well as clinical and laboratory documentation of myocardial infarction by EKG/troponin as per the patients' electronic medical record. A TEE was considered cisplatin-associated if it occurred between the time of the first dose of cisplatin administration and 4 weeks after the last dose. Results:Overall, 1,098 patients received at least one dose of cisplatin in 2008, of whom 936 met the inclusion criteria. The underlying cancer diagnoses included lung (21.7%), head and neck (10%), gastric (8.2%), pancreatic (8.1%), and melanoma (7.3%). The extent of disease at the time of cisplatin administration included metastatic disease (46.7%), locally advanced disease (43.6%) and early stage disease (7%). Among the 936 patients, 171 (18.3%) experienced a TEE during cisplatin administration or within 4 weeks of the last dose. TEEs occurred within 90 days of initiation of treatment in 146 out of 171 (85.4%) patients. The thrombotic events included a DVT in 86 patients (50.3%); PE in 45 patients (26.3%); a DVT and a PE in 22 patients (12.9%); an arterial TEE (CVA, MI, or distal arterial thrombosis) in 13 patients (7.6%); or DVT and an arterial TEE in 5 patients (2.9%). The incidence of TEEs varied according to the underlying primary cancer diagnosis with a TEE occurring in 38.2% of patients with pancreatic cancer, 31.2% with gastric cancer, 25% with gastroesophageal junction cancer, 20.7% with ovarian cancer, and 18.9% with germ cell cancer. The incidence of TEEs also varied according to extent of disease with TEEs most frequently seen in patients with metastatic disease (97 patients, 22.2%) compared to locally advanced (60 patients, 14.7%) or early stage disease (11 patients, 16.7%). Likewise, the incidence of TEE varied according to the type of cisplatin based chemotherapeutic combinations with TEE occurring in 27.3% for gemcitabine-containing regimens; in 26.4% for docetaxel-containing regimens; in 24.6% for bevacizumab-containing regimens; in 19.5% for irinotecan-containing regimens; and in 14.1% for vinblastine-containing regimen. Of note, a TEE occurred in 11 out of 16 patients receiving cisplatin plus docetaxel plus 5-FU/leucovorin plus bevacizumab. Conclusions:This large retrospective analysis confirms the unacceptable high incidence of TEEs in patients receiving cisplatin based chemotherapy, which is 18.3% across all underlying primary cancers. As one would expect, the incidence of TEE varied according to primary cancer, extent of disease, and chemotherapeutic regimens. It is likely that the incidences reported in this retrospective analysis represent an under-estimate of the real incidence of TEEs since some patients with TEE may have been missed because of lack of adequate documentation. It is important to highlight that the majority of events occurred within 90 days of the first dose of cisplatin. This study suggests that TEE prophylaxis may be advisable for patients receiving cisplatin-based chemotherapy. A prospective study is currently in progress. Disclosures:No relevant conflicts of interest to declare.

6056 Changing monoclonal antibody keeping unaltered the chemotherapy regimen in metastatic colorectal cancer (mCRC) patients (pts): is efficacy mantained?

Irinotecan-containing regimens are known to be active and tolerable in patients with non-small cell lung cancer (NSCLC). A randomized phase II trial was conducted to evaluate the efficacy of irinotecan plus paclitaxel or gemcitabine for previously untreated stage IIIB or stage IV NSCLC.Previously untreated patients with adequate organ function who gave written informed consent were randomly assigned to receive irinotecan (50 mg/m2 on days 1, 8, and 15) plus paclitaxel (180 mg/m2 on day 1) every 4 weeks (IP group) or irinotecan (100 mg/m2 on days 1 and 8) plus gemcitabine (1000 mg/m2 on days 1 and 8) every 3 weeks (IG group). The primary endpoint was the response rate. We also evaluated the relationship of response and toxicity to polymorphisms of the uridine diphosphate glucuronosyltransferase (UGT) gene.Eighty patients were enrolled, and 78 patients were eligible (38 in the IP group and 40 in the IG group). The response rate was 31.6% (95% confidence interval: 17.5–48.7%) in the IP group and 20.0% (9.1–35.6%) in the IG group. The median progression-free survival time was 86 days and 145 days, respectively. Both regimens were well tolerated. The most common severe adverse event was grade 4 neutropenia (36.8% and 10.0%, respectively), which was associated with UGT1A1*6 and UGT1A1*27. UGT polymorphisms did not correlate with response.Irinotecan plus paclitaxel may be more active against NSCLC than irinotecan plus gemcitabine. The UGT1A1*6 and UGT1A1*27 genotypes might be useful predictors of grade 4 neutropenia in patients who receive irinotecan-based chemotherapy.

6067 First line treatment with FOLFIRI-Bevacizumab for advanced colorectal cancer (ACRC): a single institution experience with 127 consecutive unselected patients

Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor and is indicated for patients with metastatic colorectal cancer (mCRC) who have experienced disease progression after standard chemotherapy. We conducted this phase II study to assess the ability of panitumumab to be administered with first-line irinotecan-containing regimens in patients with mCRC.This was a 2-part multicenter study of panitumumab 2.5 mg/kg weekly with irinotecan, 5-fluorouracil (5-FU), and leucovorin. Part I used bolus 5-FU (IFL), and part 2 used infusional 5-FU (FOLFIRI). Tolerability (measured by grade 3/4 diarrhea) was the primary endpoint. Objective response, progression-free survival, overall survival, and safety were also examined.Nineteen patients in part I and 24 patients in part 2 received panitumumab plus chemotherapy. Grade 3/4 diarrhea occurred in II patients (58%) in part I and 6 patients (25%) in part 2. All patients had a skin-related toxicity (no grade 4 events). Objective response rates were 46% in part I and 42% in part 2. Disease control rates were 74% in part I and 79% in part 2. Median progression-free survival (95% confidence interval) was 5.6 months (4.4–8.3 months) for part I and 10.9 months (7.7–22.5 months) for part 2. Median overall survival (95% confidence interval) was 17 months (13.7 months to not estimable) for part I and 22.5 months (14.4 months to not estimable) for part 2.In patients with mCRC, panitumumab/IFL was not well tolerated. Panitumumab/FOLFIRI was well tolerated, showed promising activity, and is undergoing further investigation.

The Role of Preoperative Chemotherapy in Patients with Resectable Colorectal Liver Metastases

Liver metastases develop in 40-50% of patients with colorectal cancer and represent the major cause of death in this disease. Surgical resection remains the only treatment procedure that can ensure long-term survival and provide cure when liver metastases can be totally resected with clear margins, when the primary cancer is controlled, and when there is no nonresectable extrahepatic disease. Five-year survival rate after surgical resection of colorectal metastases varies from 25% to 55%, but cancer relapse is observed in most patients. To review the potential benefits and disadvantages of neoadjuvant chemotherapy administered before surgery to patients with initially resectable metastases. European Organization for Research and Treatment of Cancer (EORTC) study 40983 has shown that neoadjuvant chemotherapy could reduce the risk of relapse by one-quarter, and allows to test the chemosensitivity of the cancer, to help to determine the appropriateness of further treatments, and to observe progressive disease, which contraindicates immediate surgery. Neoadjuvant chemotherapy can induce damage to the remnant liver. Oxaliplatin-based combination regimen is associated with increased risk of vascular lesions, whereas irinotecan-containing regimens have been associated with increased risks of steatosis and steatohepatitis. Analysis of EORTC study 40983 showed that administration of six cycles of neoadjuvant systemic chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was associated with moderate increase of the risk of reversible complications after surgery, but mortality rate was below 1% and not increased. If patients are not overtreated, chemotherapy before surgery is well tolerated. The integration of novel targeted agents in combination with cytotoxic drugs is a promising way to improve outcome in patients with advanced colorectal cancer. Preliminary trials have shown that targeted agents combined with cytotoxic regimens can increase tumor response rates. Another impact of preoperative chemotherapy is that metastases that respond to treatment may no longer be visible on computed tomography (CT) scan or at surgery. Patients should be carefully monitored and receive surgery before metastases disappear. Treatment of most patients with liver metastases-those with resectable metastases as well as those with initially unresectable metastases-should start with chemotherapy. If drugs are well chosen and the duration of treatment is monitored with care during multidisciplinary meetings, benefits largely outweigh potential disadvantages.

Panitumumab with Irinotecan/Leucovorin/5-Fluorouracil for First-Line Treatment of Metastatic Colorectal Cancer

Purpose Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor and is indicated for patients with metastatic colorectal cancer (mCRC) who have experienced disease progression after standard chemotherapy. We conducted this phase II study to assess the ability of panitumumab to be administered with first-line irinotecan-containing regimens in patients with mCRC. Patients and Methods This was a 2-part multicenter study of panitumumab 2.5 mg/kg weekly with irinotecan, 5-fluorouracil (5-FU), and leucovorin. Part I used bolus 5-FU (IFL), and part 2 used infusional 5-FU (FOLFIRI). Tolerability (measured by grade 3/4 diarrhea) was the primary endpoint. Objective response, progression-free survival, overall survival, and safety were also examined. Results Nineteen patients in part I and 24 patients in part 2 received panitumumab plus chemotherapy. Grade 3/4 diarrhea occurred in II patients (58%) in part I and 6 patients (25%) in part 2. All patients had a skin-related toxicity (no grade 4 events). Objective response rates were 46% in part I and 42% in part 2. Disease control rates were 74% in part I and 79% in part 2. Median progression-free survival (95% confidence interval) was 5.6 months (4.4–8.3 months) for part I and 10.9 months (7.7–22.5 months) for part 2. Median overall survival (95% confidence interval) was 17 months (13.7 months to not estimable) for part I and 22.5 months (14.4 months to not estimable) for part 2. Conclusion In patients with mCRC, panitumumab/IFL was not well tolerated. Panitumumab/FOLFIRI was well tolerated, showed promising activity, and is undergoing further investigation.

Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741.

In this report, we update survival (OS) and time-to-progression (TTP) data for the Intergroup trial N9741 after a median 5 years of follow-up by using risk-stratified and prognostic factor analyses to determine if treatment outcomes differ in specific patient subgroups. A total of 1,691 patients were randomly assigned to one of seven fluorouracil-, oxaliplatin-, and irinotecan-containing regimens. OS and TTP were calculated by treatment arm and baseline risk group (on the basis of WBC, performance status, number of sites of disease, and alkaline phosphatase). Multivariate prognostic factor analysis was used to assess clinical factors for their relationships to OS, TTP, response, and toxicity by using Cox and logistic regression models. The observed 5-year survival with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) of 9.8% was better than with irinotecan plus bolus fluorouracil and leucovorin (IFL; 3.7%; P = .04) or with bolus irinotecan/oxaliplatin (IROX; 5.1%; P = .128). OS and TTP were significantly longer for FOLFOX (20.2 months and 8.9 months, respectively) than for IFL (14.6 months and 6.1 months, respectively; P < .001 for both) or for IROX (17.3 months and 6.7 months, respectively; P < .001 for both). OS differed by risk group: 20.7 months for low risk, 17.4 months for intermediate risk, and 9.4 months for high risk (P < .001). FOLFOX treatment was superior in all risk groups and was the most powerful prognostic factor for OS, TTP, response rate, and toxicity. The 9.8% 5-year OS in patients with metastatic colorectal cancer who were treated with first-line FOLFOX sets a new benchmark. Neither baseline risk group nor any prognostic factor examined was predictive of treatment-specific outcome. However, treatment efficacy and patient longevity varied as a function of risk group.

Irinotecan Pharmacogenetics in Japanese Cancer Patients: Roles of &lt;i&gt;UGT1A1&lt;sup&gt;*&lt;/sup&gt;6&lt;/i&gt; and &lt;sup&gt;*&lt;/sup&gt;&lt;i&gt;28&lt;/i&gt;

Recent progress in pharmacogenetic research has made "personalized medicine" a reality, where a suitable drug at the appropriate dosage is prescribed based on individual genetic factors. Irinotecan, an anticancer drug, is one of the models for personalized medicine, and a number of clinical studies have revealed significant associations between UGT1A1(*)28 and irinotecan toxicity. Based on the cumulative evidence, clinical tests for the UGT1A1(*)28 marker have started in the United States since 2005. However, the appropriate criteria for irinotecan dose adjustments have not yet been fully established. Since there are considerable differences in genetic polymorphisms among different ethnic groups and in approved irinotecan-containing regimens between countries, the criteria for the choice of suitable genetic markers and dose adjustments should be standardized in each country. This mini-review outlines our recent studies on irinotecan pharmacogenetics and discusses the clinical significance of UGT1A1(*)6 and (*)28 markers for personalized irinotecan therapy in Japanese cancer patients.

Role of UGT1A1*6 in irinogenetics in Asians.

Evaluation of: Jada SR, Lim R, Wong CI et al.: Role ofUGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients. Cancer Sci. 98(9), 1461-1467 (2007). The pharmacokinetics and toxicity of irinotecan vary widely among patients. This review focuses primarily on a study of the role of UGT1A1*6, UGT1A1*28, and ABCG2 421C>A in three Asian cancer patient populations treated with a 3-weekly regimen of irinotecan. In that study, a statistically significantly higher level of SN-38 and a relatively lower degree of glucuronidation occurred in patients with the UGT1A1*6 homozygote genotype than in patients with the reference genotype. The UGT1A1*6 allele was associated with an increased risk of severe neutropenia. In addition, the study of gene allele frequencies in three healthy Asian populations indicated that the allelic frequency of UGT1A1*6 was higher in the healthy Chinese subjects than in the Malaysian or Indian subjects. UGT1A1*28 and ABCG2 421C>A were not associated with the pharmacokinetics of SN-38 or the severity of neutropenia. In this evaluation, we put this study into the context of similar studies of irinogenetics (irinotecan pharmacogenetics) in Asians and discuss the application of UGT1A1 testing in Asian cancer patients treated with irinotecan-containing regimens.

Randomized, Controlled Trial of Irinotecan Plus Infusional, Bolus, or Oral Fluoropyrimidines in First-Line Treatment of Metastatic Colorectal Cancer: Results From the BICC-C Study

This phase III study compared the safety and efficacy of the following three different irinotecan-containing regimens in the first-line treatment of metastatic colorectal cancer: irinotecan plus infusional fluorouracil (FU)/leucovorin (LV) (FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecan plus oral capecitabine (CapeIRI). A total of 430 previously untreated metastatic colorectal cancer patients were randomly assigned to receive FOLFIRI (n = 144), mIFL (n = 141), or CapeIRI (n = 145). Patients were concurrently randomly assigned to a double-blind treatment with celecoxib or placebo. After a protocol amendment, an additional 117 patients were randomly assigned to either FOLFIRI plus bevacizumab (FOLFIRI+Bev; n = 57) or mILF plus bevacizumab (mIFL+Bev; n = 60), whereas the CapeIRI arm was discontinued. The primary study end point was progression-free survival (PFS), with secondary end points of overall survival (OS), response rate, and toxicity. Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (P = .004 for the comparison with FOLFIRI), and 5.8 months for CapeIRI (P = .015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (P = .09), and 18.9 months for CapeIRI (P = .27). CapeIRI was associated with higher rates of severe vomiting, diarrhea, and dehydration. After the amendment to add bevacizumab, the median survival time has not yet been reached for FOLFIRI+Bev and was 19.2 months for mIFL+Bev (P = .007). FOLFIRI+Bev was associated with a higher rate of > or = grade 3 hypertension than mIFL+Bev. FOLFIRI and FOLFIRI+Bev offered superior activity to their comparators and were comparably safe. An infusional schedule of FU should be the preferred irinotecan-based regimen in first-line metastatic colorectal cancer.

Panitumumab with Irinotecan/Leucovorin/5-Fluorouracil for First-Line Treatment of Metastatic Colorectal Cancer

Purpose Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor and is indicated for patients with metastatic colorectal cancer (mCRC) who have experienced disease progression after standard chemotherapy. We conducted this phase II study to assess the ability of panitumumab to be administered with first-line irinotecan-containing regimens in patients with mCRC. Patients and Methods This was a 2-part multicenter study of panitumumab 2.5 mg/kg weekly with irinotecan, 5-fluorouracil (5-FU), and leucovorin. Part 1 used bolus 5-FU (IFL), and part 2 used infusional 5-FU (FOLFIRI). Tolerability (measured by grade 3/4 diarrhea) was the primary endpoint. Objective response, progression-free survival, overall survival, and safety were also examined. Results Nineteen patients in part 1 and 24 patients in part 2 received panitumumab plus chemotherapy. Grade 3/4 diarrhea occurred in 11 patients (58%) in part 1 and 6 patients (25%) in part 2. All patients had a skin-related toxicity (no grade 4 events). Objective response rates were 46% in part 1 and 42% in part 2. Disease control rates were 74% in part 1 and 79% in part 2. Median progression-free survival (95% confidence interval) was 5.6 months (4.4–8.3 months) for part 1 and 10.9 months (7.7–22.5 months) for part 2. Median overall survival (95% confidence interval) was 17 months (13.7 months to not estimable) for part 1 and 22.5 months (14.4 months to not estimable) for part 2. Conclusion In patients with mCRC, panitumumab/IFL was not well tolerated. Panitumumab/ FOLFIRI was well tolerated, showed promising activity, and is undergoing further investigation.

Benefits and Risks of Neoadjuvant Therapy for Liver Metastases

Colorectal cancer ranks second in Europe and third in the United States among the most common causes of death caused by cancer. Approximately 50% of patients with colorectal cancer will develop liver metastases during the course of their disease. Surgical resection is the only treatment and can currently ensure long-term survival in 25% to 40% of patients. However, using the current indications for surgery, only 15% to 20% of patients with colorectal cancer liver metastases are suitable for surgical resection. In the majority of patients, metastases are considered to be unresectable, and chemotherapy is the treatment of choice, but 5-year survivors with chemotherapy alone are rare. Recent progress, including more efficient chemotherapy regimens and targeted agents, has opened new perspectives in the treatment of both resectable and nonresectable colorectal liver metastases. In patients with unresectable liver metastases, emerging data have shown that neoadjuvant chemotherapy can render some metastases resectable, hence opening up the possibility of prolonged survival. In patients with initially resectable liver metastases, neoadjuvant chemotherapy is often administered, although the benefits in terms of long-term disease control have not yet been formally proven. Thus, many patients receive neoadjuvant chemotherapy before liver resection but without direct proof of benefit. Recently, the enthusiasm over the potential positive effects of neoadjuvant chemotherapy has been cooled down somewhat by the awareness of toxicity to the remnant liver caused by preoperative treatment, which could increase the risks of surgery and even preclude liver resection. There are now accumulating data showing that preoperative chemotherapy is associated with pathologic changes of liver parenchyma. The following two main types of chemotherapyassociated liver injuries have been reported: vascular changes and chemotherapy-associated steatohepatitis (CASH). The vascular changes include sinusoidal dilation with erythrocytic congestion, occasionally accompanied by perisinusoidal fibrosis and fibrotic venous occlusion, which could result in sinusoidal obstruction syndrome as observed in veno-occlusive disease. CASH is defined as the association of severe steatosis, lobular inflammation, and ballooning of hepatocytes. Few studies have evaluated the correlation between the type of liver injury and the neoadjuvant chemotherapy regimen. In this issue, Aloia et al assess the relationship between systemic chemotherapy and hepatoxicity by comparing 92 patients who received preoperative chemotherapy with 17 patients who received surgery without chemotherapy. Preoperative chemotherapy included fluorouracil (FU) plus leucovorin, either alone or combined with oxaliplatin. This study confirms, as suggested in other reports, that the oxaliplatin-based combination regimen is associated with an increased risk of vascular lesions of the liver. It is uncertain from this report whether this is specific for oxaliplatin or caused by the effects of more intensive combination chemotherapy. In other reports, irinotecan-containing regimens have also been associated with increased risks of steatosis and steatohepatitis. Steatohepatitis is observed more frequently after chemotherapy in patients with a higher body mass index. This could explain why CASH is more frequently reported in US studies, whereas vascular lesions are more often reported in studies from Europe. Therefore, it is possible that specific chemotherapy regimens do not automatically predispose to steatosis but can aggravate it when it already exists. That chemotherapy can be associated with liver injury is now well recognized. The main question is whether collective damages to the liver induced by preoperative chemotherapy have any clinical significance. Do they increase the risks of complications after surgery and lead to a change in treatment strategy? The article by Aloia et al in this issue of the Journal of Clinical Oncology addresses this question. It shows that perioperative mortality and morbidity rates were not significantly increased in patients who had received preoperative chemotherapy. However, patients who had received more than 12 cycles of preoperative chemotherapy had a higher risk of reoperation and a longer hospital stay. The safety data of European Organisation for Research and Treatment of Cancer (EORTC) study 40983, which compared perioperative chemotherapy with FU, leucovorin, and oxaliplatin (six cycles before surgery and six cycles after) with surgery alone in 364 patients, were presented at the 41st Annual Meeting of the American Society of Clinical Oncology in 2005. The results showed that the mortality rate was low (close to 1%) in the two treatment arms and that the rate of reversible complications was acceptable. Thus, administration of six cycles of FU, leucovorin, and oxaliplatin before surgery seems feasible. Another report by Karoui et al brought another insight into the relationship between duration of preoperative chemotherapy and perioperative morbidity and showed that administration of more than six cycles of neoadjuvant systemic chemotherapy increased morbidity after major liver resection but did not increase mortality. Some studies have looked at the relationship JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 31 NOVEMBER 1 2006

Chemotherapy in Advanced Gastric Cancer: A Systematic Review and Meta-Analysis Based on Aggregate Data

This systematic review and meta-analysis were performed to assess the efficacy and tolerability of chemotherapy in patients with advanced gastric cancer. Randomized phase II and III clinical trials on first-line chemotherapy in advanced gastric cancer were identified by electronic searches of Medline, Embase, the Cochrane Controlled Trials Register, and Cancerlit; hand searches of relevant abstract books and reference lists; and contact to experts. Meta-analysis was performed using the fixed-effect model. Overall survival, reported as hazard ratio (HR) with 95% CI, was the primary outcome measure. Analysis of chemotherapy versus best supportive care (HR = 0.39; 95% CI, 0.28 to 0.52) and combination versus single agent, mainly fluorouracil (FU) -based chemotherapy (HR = 0.83; 95% CI = 0.74 to 0.93) showed significant overall survival benefits in favor of chemotherapy and combination chemotherapy, respectively. In addition, comparisons of FU/cisplatin-containing regimens with versus without anthracyclines (HR = 0.77; 95% CI, 0.62 to 0.95) and FU/anthracycline-containing combinations with versus without cisplatin (HR = 0.83; 95% CI, 0.76 to 0.91) both demonstrated a significant survival benefit for the three-drug combination. Comparing irinotecan-containing versus nonirinotecan-containing combinations (mainly FU/cisplatin) resulted in a nonsignificant survival benefit in favor of the irinotecan-containing regimens (HR = 0.88; 95% CI, 0.73 to 1.06), but they have never been compared against a three-drug combination. Best survival results are achieved with three-drug regimens containing FU, an anthracycline, and cisplatin. Among these, regimens including FU as bolus exhibit a higher rate of toxic deaths than regimens using a continuous infusion of FU, such as epirubicin, cisplatin, and continuous-infusion FU.