High-dose Oxaliplatin Research Articles

Multicenter randomized phase II study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases (YCOG1001).

The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX). In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3weeks. The dose of S-1 was fixed at 80mg/m2. The doses in the low- and high-dose oxaliplatin groups were 100mg/m2 (low-dose group) and 130mg/m2 (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs). Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705). SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.

2022 Peritoneal Surface Oncology Group International Consensus on HIPEC Regimens for Peritoneal Malignancies: Colorectal Cancer

BackgroundSelected patients with peritoneal metastases of colorectal cancer (PM-CRC) can benefit from potentially curative cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC), with a median overall survival (OS) of more than 40 months.ObjectiveThe aims of this evidence-based consensus were to define the indications for HIPEC, to select the preferred HIPEC regimens, and to define research priorities regarding the use of HIPEC for PM-CRC.MethodsThe consensus steering committee elaborated and formulated pertinent clinical questions according to the PICO (patient, intervention, comparator, outcome) method and assessed the evidence according to the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Standardized evidence tables were presented to an international expert panel to reach a consensus (4-point, weak and strong positive/negative) on HIPEC regimens and research priorities through a two-round Delphi process. The consensus was defined as ≥ 50% agreement for the 4-point consensus grading or ≥ 70% for either of the two combinations.ResultsEvidence was weak or very weak for 9/10 clinical questions. In total, 70/90 eligible panelists replied to both Delphi rounds (78%), with a consensus for 10/10 questions on HIPEC regimens. There was strong negative consensus concerning the short duration, high-dose oxaliplatin (OX) protocol (55.7%), and a weak positive vote (53.8–64.3%) in favor of mitomycin-C (MMC)-based HIPEC (preferred choice: Dutch protocol: 35 mg/m2, 90 min, three fractions), both for primary cytoreduction and recurrence. Determining the role of HIPEC after CRS was considered the most important research question, regarded as essential by 85.7% of the panelists. Furthermore, over 90% of experts suggest performing HIPEC after primary and secondary CRS for recurrence > 1 year after the index surgery.ConclusionsBased on the available evidence, despite the negative results of PRODIGE 7, HIPEC could be conditionally recommended to patients with PM-CRC after CRS. While more preclinical and clinical data are eagerly awaited to harmonize the procedure further, the MMC-based Dutch protocol remains the preferred regimen after primary and secondary CRS.

First clinical study reporting safety and outcomes of high dose oxaliplatin use in PIPAC for colorectal peritoneal carcinomatosis.

e15606 Background: PIPAC in inoperable colorectal peritoneal carcinomatosis has showed better oncological outcomes at existing doses of 92mg/m2. However the maximum dose that can be used and its clinical outcomes is not defined yet. Methods: PIPAC was done at dose 120 mg /m2 oxaliplatin which was established from a phase 2 study. The patient demographics, perioperative findings, adverse events, and outcomes were prospectively recorded. Response rate was graded as Peritoneal Regression Grading Score (PRGS). QoL of the patients was studied according to the EORTC QLQ - C30 score. Results: 42 PIPAC administrations were performed in 15 patients. The median hospital stay was 1.5 day (1-3 day). CTCAE grade 3 was observed in 5 patients, for abdominal pain and nausea, grade 3 fatigue in 4 patients. Transient increase in C- reactive protein was seen in 8 patients, haematological, renal and hepatic functions were not impaired in any patients except for mild transient elevation in AST and ALT levels in 7 patients. 12 patients completed 3 cycles of PIPAC. Of the 15 patients, 3 had complete response (PRGS 1) and 8 had major (PRGS 2), 3 had minor response (PRGS 3). There was improvement in functional scale, symptom scale and overall global health status for all patients. Conclusions: PIPAC can be performed safely at dose of oxaliplatin 120mg/m2. There is better objective &amp; pathological response with this dose with no major complications or side effects to the patients. There is also improvement in quality of life. This dose should be new standard of care for further studies.

Personalized Identification of Optimal HIPEC Perfusion Protocol in Patient-Derived Tumor Organoid Platform.

Chemotherapy dosing duration and perfusion temperature vary significantly in HIPEC protocols. This study investigates patient-derived tumor organoids as a platform to identify the most efficacious perfusion protocol in a personalized approach. Peritoneal tumor tissue from 15 appendiceal and 8 colon cancer patients who underwent CRS/HIPEC were used for personalized organoid development. Organoids were perfused in parallel at 37 and 42°C with low- and high-dose oxaliplatin (200mg/m2 over 2h vs. 460mg/m2 over 30min) and MMC (40mg/3L over 2h). Viability assays were performed and pooled for statistical analysis. An adequate organoid number was generated for 75% (6/8) of colon and 73% (11/15) of appendiceal patients. All 42°C treatments displayed lower viability than 37°C treatments. On pooled analysis, MMC and 200mg/m2 oxaliplatin displayed no treatment difference for either appendiceal or colon organoids (19% vs. 25%, p = 0.22 and 27% vs. 31%, p = 0.55, respectively), whereas heated MMC was superior to 460mg/m2 oxaliplatin in both primaries (19% vs. 54%, p < 0.001 and 27% vs. 53%, p = 0.002, respectively). In both appendiceal and colon tumor organoids, heated 200mg/m2 oxaliplatin displayed increased cytotoxicity as compared with 460mg/m2 oxaliplatin (25% vs. 54%, p < 0.001 and 31% vs. 53%, p = 0.008, respectively). Organoids treated with MMC or 200mg/m2 heated oxaliplatin for 2 h displayed increased susceptibility in comparison with 30-min 460mg/m2 oxaliplatin. Optimal perfusion protocol varies among patients, and organoid technology may offer a platform for tailoring HIPEC conditions to the individual patient level.

HIPEC with oxaliplatin for colorectal peritoneal metastasis: The end of the road?

In patients with colorectal peritoneal metastases (PM), the use of cytoreductive surgery (CRS) and HIPEC with oxaliplatin (OX) is increasingly used. The results of the recently reported randomized Prodige 7 trial failed to show a difference in overall survival between patients undergoing CRS alone versus CRS combined with HIPEC using high dose OX. The trial was not designed or powered, however, to detect a potentially clinically meaningful benefit in locoregional disease control. Here, I address some potential explanations for the lack of benefit in the Prodige 7 trial, including OX efficacy issues, adverse effects of intraperitoneal high dose glucose, and potential drawbacks of the use of hyperthermia.

Phase I/II study of oxaliplatin dose escalation via a laparoscopic approach using pressurized aerosol intraperitoneal chemotherapy (PIPOX trial) for nonresectable peritoneal metastases of digestive cancers (stomach, small bowel and colorectal): Rationale and design.

BackgroundThe annual incidence of gastrointestinal carcinomas (stomach, small bowel, colon and rectum) is increasing in Western countries, reaching 50,000 new cases each year in France. Peritoneal carcinomatosis (PC) is diagnosed in 15% of these patients. Complete cytoreductive surgery (CCS) plus Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) is the only therapy that can offer patients with PC a chance for long-term survival with a 5 year overall survival (OS) rate of 30–60% versus 0–5% with systemic chemotherapy alone. However, CCS plus HIPEC still presents serious limitations and very few patients (10%) are candidates for these radical treatments. PC remains a palliative setting for 90% of patients with a median survival ranging from 15 to 25 months. Innovative surgical therapies such as Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) therefore need to be developed to improve the prognosis. Potential benefits were obtained after intraperitoneal nebulization of oxaliplatin in patients with advanced PC from colorectal cancer. Innovative surgical therapies such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been proposed as palliative locoregional treatment with some promising results. The dose of oxaliplatin currently established by nebulization (PIPAC) is really low at 92 mg/m2. However, the peritoneum acts as a barrier limiting the systemic passage of intraperitoneal drug. Oxaliplatin used at higher doses during PIPAC procedures could be a safe option and allow better intratumoral penetration of chemotherapy.Method and designThe proposed study is a multicenter phase I/II trial of oxaliplatin dose escalation during PIPAC. The aim is to determine the maximum tolerated dose of pressurized oxaliplatin administered by the intraperitoneal route (PIPAC) during two consecutive procedures at a 4–6 week interval for patients with extended peritoneal carcinomatosis from the gastrointestinal tract. Dose started at 90 mg/m2 and escalation was in 50 mg/m2 steps up to a maximum of 300 mg/m2.DiscussionOxaliplatin is an effective drug in gastrointestinal cancer and high doses given by the intraperitoneal route during HIPEC are well tolerated. In this phase I trial, we hypothesized that high-dose oxaliplatin during PIPAC is feasible and safe. The repeated local administration of high doses of oxaliplatin could improve tumor response and prognosis.Trial registrationProspective study. ClinicalTrials.gov: NCT03294252. EudraCT: 2016-003666-49

Abstract 4105: Localized and triggered release of oxaliplatin for the treatment of colorectal liver metastasis

Abstract Though systemic chemotherapy is the standard of care for the treatment of unresectable metastatic colorectal cancer, new drug delivery platforms are needed to mitigate the associated toxicities. The aim of this study was to develop and evaluate a liposome formulation that delivers oxaliplatin under magnetic field stimulus in a rat model of colorectal liver metastases. The drug delivery platform was synthesized by encapsulating iron oxide nanocubes and oxaliplatin in sterically stabilized polyethylene glycol (PEG)-coated liposomes of ~140 nm size. Magnetic properties and efficacy of drug release were determined by exposing the liposomes to an alternating magnetic field (AMF). In vitro efficacy of the liposomes was tested by performing viability assay on rat colorectal liver metastasis cell line (CC-531 cell line). For in vivo studies, rats implanted with CC-531 cells were divided into various groups and the efficacy of systemically delivered oxaliplatin was compared to localized and triggered delivery. Localized delivery and triggered release of drug was imaged by quantitative magnetic resonance and optical imaging methods. The rats were euthanized after 3 weeks, tumors harvested and H&amp;E and Prussian blue staining was performed. Kinetics of oxaliplatin bioavailability was performed by ICP-MS analysis for platinum at various time points and in different tissues. The analysis of feasibility and efficacy of multiple cycles of triggered release is currently in progress. Drug-loaded magnetic liposomes presented an oxaliplatin loading content of ~2 %. Magnetic liposomes separated from the solution within 30 min, when exposed to a permanent magnet. An increase in drug release (~18%) was observed by both HPLC and optical imaging methods when the samples were exposed to the AMF. Viability assay demonstrated that under high-dose oxaliplatin conditions (0.17-0.33 mg/mL), the cell viability after liposome treatment and exposure to AMF was significantly lower than those not exposed to AMF (p&amp;lt; 0.001). MR imaging revealed that all the rats developed tumors within 1 week. Optical imaging on rats showed that nanomaterial could be infused locally via mesenteric vein into liver and there is a consistent increase in the release of drug when exposed AMF. Although the tumors showed metastasis by the end of third week, triggered release of drug was well tolerated and shrinkage of primary tumor with necrotic regions was prominent in the MR imaging. Prussian blue staining and quantitative MR imaging showed delivery of liposomal cargo to the tumor site when exposed to AMF. H&amp;E staining revealed marked necrotic regions in the tumor among the animals exposed to magnetic field. In conclusion, AMF triggered oxaliplatin release from liposome for increased cell death of CC-531 cell line. Triggering was well tolerated by rats and, further, can be employed to targeted killing of tumor by optimizing the dose of drug. Citation Format: Venkateswara R. Gogineni, Woo Ram Park, Jaidip Jagtap, Abdul Parchur, Gayatri Sharma, Amit Joshi, Dong-Hyun Kim, Andrew C. Larson, Sarah B. White. Localized and triggered release of oxaliplatin for the treatment of colorectal liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4105.

Hyperthermic intraperitoneal chemoperfusion with high dose oxaliplatin: Influence of perfusion temperature on postoperative outcome and survival.

Introduction : Hyperthermic intraperitoneal chemotherapy (HIPEC) is becoming a standard therapy in the treatment of peritoneal carcinomatosis (PC). Compared to systemic chemotherapy, HIPEC improves survival in patients with PC. This therapy has high morbidity rates (up to 41%). In vitro it has been demonstrated that hyperthermia has a toxic effect on malign cells. However, hyperthermia also affects normal tissue. To my knowledge, any additional effect of hyperthermia combined with chemotherapy has never been demonstrated in a clinical setting. In this study, the effects of hyperthermia on outcome and survival were analyzed. Methods : Patients with PC from any origin who were treated with HIPEC were included in this retrospective, non-randomized study. Data on patient characteristics, tumor characteristics, features of the surgery and postoperative complications were extracted from patient files. Models predicting time to removal of nasogastric tube (TRNT), post-operative major complications, the occurrence of anastomotic leaks and post-operative survival were built, using negative binomial regression, logistic regression or Cox proportional hazards regression as appropriate. 138 patients treated with HIPEC were included. Maximal temperature during the operation was not statistically significantly associated with anastomotic leaks or post-operative major complications. Maximal temperature during the operation was negatively associated with post-operative survival (P=0.01). Conclusion : The results suggest that hyperthermia may negatively affect survival in patients who are treated with HIPEC for PC of various origins. This study has the classical limitations of a retrospective study. Therefore, randomized trials are required to confirm the results.

Hyperthermic intraperitoneal chemoperfusion with high dose oxaliplatin: Influence of perfusion temperature on postoperative outcome and survival

Introduction : Hyperthermic intraperitoneal chemotherapy (HIPEC) is becoming a standard therapy in the treatment of peritoneal carcinomatosis (PC). Compared to systemic chemotherapy, HIPEC improves survival in patients with PC. This therapy has high morbidity rates (up to 41%). In vitro it has been demonstrated that hyperthermia has a toxic effect on malign cells. However, hyperthermia also affects normal tissue. To my knowledge, any additional effect of hyperthermia combined with chemotherapy has never been demonstrated in a clinical setting. In this study, the effects of hyperthermia on outcome and survival were analyzed. Methods : Patients with PC from any origin who were treated with HIPEC were included in this retrospective, non-randomized study. Data on patient characteristics, tumor characteristics, features of the surgery and postoperative complications were extracted from patient files. Models predicting time to removal of nasogastric tube (TRNT), post-operative major complications, the occurrence of anastomotic leaks and post-operative survival were built, using negative binomial regression, logistic regression or Cox proportional hazards regression as appropriate. Results: 138 patients treated with HIPEC were included. Maximal temperature during the operation was not statistically significantly associated with anastomotic leaks or post-operative major complications. Maximal temperature during the operation was negatively associated with post-operative survival (P=0.01). Conclusion : The results suggest that hyperthermia may negatively affect survival in patients who are treated with HIPEC for PC of various origins. This study has the classical limitations of a retrospective study. Therefore, randomized trials are required to confirm the results.

Hyperthermic intraperitoneal chemoperfusion with high dose oxaliplatin: Influence of perfusion temperature on postoperative outcome and survival

Introduction: Hyperthermic intraperitoneal chemotherapy (HIPEC) is becoming a standard therapy in the treatment of peritoneal carcinomatosis (PC). Compared to systemic chemotherapy, HIPEC improves survival in patients with PC. This therapy has high morbidity rates (up to 41%). In vitro it has been demonstrated that hyperthermia has a toxic effect on malign cells. However, hyperthermia also affects normal tissue. To my knowledge, any additional effect of hyperthermia combined with chemotherapy has never been demonstrated in a clinical setting. In this study, the effects of hyperthermia on outcome and survival were analyzed.Methods: Patients with PC from any origin who were treated with HIPEC were included in this retrospective, non-randomized study. Data on patient characteristics, tumor characteristics, features of the surgery and postoperative complications were extracted from patient files. Models predicting time to removal of nasogastric tube (TRNT), post-operative major complications, the occurrence of anastomotic leaks and post-operative survival were built, using negative binomial regression, logistic regression or Cox proportional hazards regression as appropriate.Results: 138 patients treated with HIPEC were included. Maximal temperature during the operation was not statistically significantly associated with anastomotic leaks or post-operative major complications. Maximal temperature during the operation was negatively associated with post-operative survival (P=0.01).Conclusion: The results suggest that hyperthermia may negatively affect survival in patients who are treated with HIPEC for PC of various origins. This study has the classical limitations of a retrospective study. Therefore, randomized trials are required to confirm the results.

“Natural history” of complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy

Background Combining complete cytoreductive surgery (CCRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a new approach allowing curatively intended treatment of multiple malignant peritoneal tumour seedings. This aggressive treatment is frequently followed by a complicated or an unusual postoperative course, that has yet to be described. Aim To describe the clinical and biological post-therapeutic course of patients treated with CCRS plus HIPEC, who were considered uncomplicated cases, and were discharged from hospital before the 15th postoperative day. Patients and methods Thirty-two patients were retrospectively selected on these criteria among 232 treated patients, most of whom had received intraperitoneal high-dose oxaliplatin and intravenous 5-fluorouracil. The daily postoperative clinical and biological parameters are presented in graphs using boxplots. Results Hyperthermia at 38 °C was the rule during the first postoperative week. The daily flow rate of the abdominal drains decreased progressively from 500 ml to 50 ml from day 1 to day 7. The flow rate of the nasogastric tube was high and close to 1000 ml/24 h until day 6. Resumption of digestive transit occurred between day 4 and day 6; it was always a diarrheic transit until day 12. Severe hypophosphoremia was observed at day 2 and day 3. White blood cells gradually decreased until day 12 to half the normal value, haemoglobin remained stable and the platelet count, which was low after surgery, continued to decrease progressively until day 3. Other data are presented. Conclusion These results, in this selected group of patients, allow a description of the “natural history” of CCRS plus HIPEC, which is not similar to classic uncomplicated postoperative courses following surgery. Knowledge of these “natural” changes may help avoid unnecessary explorations, and allow the early detection of postoperative complications.

FOLFOX in patients aged between 76 and 80 years with metastatic colorectal cancer

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer randomized studies. The OPTIMOX1 study evaluated FOLFOX7, a simplified (s) leucovorin (LV) and 5-fluorouracil (5FU) regimen (sLV5FU2) with high-dose oxaliplatin, in a new oxaliplatin stop-and-go strategy. An exploratory cohort of patients aged 76 to 80 years was included in the study. In all, 620 previously untreated patients were randomized between FOLFOX4 until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). A total of 37 patients aged 76 to 80 years were included, 20 in arm A and 17 in arm B. The overall response rate (ORR) was 59.4%, comparable to younger patients (59%). Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 20.7 months. These results did not differ from that in younger patients < or =75 years in the OPTIMOX1 study with PFS 9.0 months (P = .63) and OS 20.2 months (P = .57). They experienced slightly more grade 3 of 4 toxicity than younger patients: 65% versus 48% (P = .06), mainly with more neutropenia (41% vs 24%, P = .03) and neurotoxicity (22% vs 11%, P = .06). Tolerability, however, was manageable and no toxic death occurred in this elderly population. The efficacy of FOLFOX-based treatment was maintained in patients >75 years with both FOLFOX regimens. The oxaliplatin stop-and-go management strategy performed well in this population.

Safety and Efficacy of Hyperthermic Intraperitoneal Chemoperfusion with High-Dose Oxaliplatin in Patients with Peritoneal Carcinomatosis

Cytoreduction with hyperthermic intraperitoneal chemoperfusion (HIPEC) has an established role in selected patients with peritoneal carcinomatosis (PC). We analyzed the safety and efficacy of HIPEC using high-dose oxaliplatin, a cytotoxic agent commonly used in metastatic colorectal cancer and showing promising activity in ovarian cancer and mesothelioma. Following complete cytoreduction, HIPEC was performed using 460 mg/m(2 )oxaliplatin in 5% dextrose for 30 min at a temperature of 41-42 degrees C. Open perfusion (coliseum technique) was performed in all patients. Metabolic, electrolyte, and hemodynamic changes were recorded during chemoperfusion as well as postoperative morbidity, mortality, late toxicity, and survival. From July 2005 to January 2007, 52 patients were treated. Chemoperfusion with 5% dextrose resulted in temporary significant hyperglycemia, hyponatremia, and metabolic acidosis. Major morbidity developed in 24% of patients, while 30-day mortality did not occur. One patient developed unexplained repeated episodes of hemoperitoneum. Chemoperfusion with oxaliplatin resulted in mild hepatic toxicity evidenced by persistent elevation of glutamyl transferase and alkaline phosphatase 1 month after surgery. After a mean follow-up time of 14.5 months, nine patients died from disease progression. In colorectal cancer patients, actuarial overall survival was 80% at 1 year. Cytoreduction with HIPEC using high-dose oxaliplatin leads to manageable metabolic and electrolyte disturbances and frequent mild hepatic toxicity without discernible impact on postoperative morbidity. Longer follow-up in a larger patient cohort will be required to assess the real risk of unexplained hemoperitoneum observed in one patient, and to establish the long-term effect on local relapse and survival.

OPTIMOX1: A Randomized Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal Cancer—A GERCOR Study

In metastatic colorectal cancer, a combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7, a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin. Previously untreated patients were randomly assigned to either FOLFOX4 administered every 2 weeks until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). Six hundred twenty patients were enrolled, including an exploratory cohort of 95 elderly or poor prognosis patients. Median progression-free survival and survival times were 9.0 and 19.3 months, respectively, in patients allocated to arm A compared with 8.7 and 21.2 months, respectively, in patients allocated to arm B (P = not significant). Response rates were 58.5% with arm A and 59.2% with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was observed in 54.4% of the patients in arm A v 48.7% of patients in arm B. From cycle 7, fewer patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in 17.9% of the patients in arm A v 13.3% of patients in arm B (P = .12). In arm B, oxaliplatin was reintroduced in only 40.1% of the patients but achieved responses or stabilizations in 69.4% of these patients. Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. Further study is needed to fully evaluate oxaliplatin reintroduction.

The evolving role of oxaliplatin in the management of colorectal cancer

The introduction of oxaliplatin into the chemotherapy of advanced colorectal cancer has substantially increased the frequency and magnitude of clinical response compared with that achieved using 5-FU/leucovorin, and has extended progression-free and overall survival. Research is now in progress on several fronts to determine how oxaliplatin-based therapy can be optimized. A phase III multicentre trial recently compared the efficacy and safety of the FUFOX regimen, based on high dose infusional 5-FU/leucovorin and 50 mg/m2 oxaliplatin given weekly for 4 weeks in a 5-week cycle (n = 123) with the Mayo clinic 5-FU/leucovorin regimen (n = 129) in the first-line therapy of metastatic disease. The response rate with the FUFOX regimen was 48.3%, more than twice that in the Mayo regimen (22.6%; P < 0.0001) and median survival was 20.4 months, despite the fact that the FUFOX regimen had lower toxicity. The value of high dose oxaliplatin and 5-FU/leucovorin has also been demonstrated in the FOLFOX series of studies, where patients who received more than 85 mg/m2 oxaliplatin per 2-week cycle had double the response rate of patients receiving less than 85 mg/m2. In the FOLFOX7 regimen based on a simplified high dose bolus/infusional regimen of 5-FU/leucovorin (sLV5FU2) plus 130 mg/m2 oxaliplatin, a response rate of over 40% has been achieved in second line therapy. Studies have also compared first-line therapy based on oxaliplatin with irinotecan-based first-line therapy. A large trial coordinated by the North Central Cancer Treatment Group (NCCTG) recently compared the IFL regimen, which is currently the standard irinotecan-based first-line treatment for advanced colorectal cancer in the United States, with oxaliplatin-based treatment using the FOLFOX4 regimen. Compared with irinotecan-based chemotherapy, oxaliplatin was associated with a 30% increase in overall survival (19.5 months vs. 15.0 months; P = 0.0001), a higher response rate (45% vs. 31%, P = 0.002) and lower toxicity. Further studies are investigating how therapy can be optimized over multiple lines. In a phase III two-line study comparing first-line therapy with FOLFOX6 and second line therapy with irinotecan-based therapy (FOLFIRI) (n = 109) with the reverse sequence (n = 111), progression-free and overall survival were comparable whichever regimen was used first, although patient numbers were smaller than in the NCCTG study and less able to detect treatment differences. FOLFOX6 was also more effective than FOLFIRI in second-line therapy. Currently, studies based on FOLFOX7, novel FOLFIRI regimens and sLV5FU2 are in progress to determine how disease control can be sustained in the long-term, and the development of drug resistance delayed, in multiline therapeutic management. In parallel with these studies, two large phase III trials are now investigating the role of oxaliplatin in the adjuvant treatment of nonmetastatic colorectal cancer. The first of these studies, MOSAIC, has already shown a very encouraging 23% decrease in the risk of relapse at 3 years (P = 0.002) with FOLFOX4 compared to LV5FU2.