Management of colorectal peritoneal metastases: Expert opinion.

When peritoneal metastases are diagnosed (strong agreement of experts): (i) seek advice from a multidisciplinary coordination meeting (MCM) with large experience in peritoneal disease (e.g. BIG RENAPE network); (ii) transfer (or not) the patient to a referral center with experience in hyperthermic intraperitoneal chemotherapy (HIPEC), according to the advice of the MCM. With regard to systemic chemotherapy (strong agreement of experts): (i) it should be performed both before and after surgery, (ii) for no longer than 6 months; (iii) without postoperative anti-angiogenetic drugs. With regard to cytoreductive surgery (strong agreement of experts): (i) Radical surgery requires a xiphopubic midline incision; (ii) no cytoreductive surgery via laparoscopy. With regard to HIPEC: HIPEC can be proposed for trials outside an HIPEC referral center (weak agreement between experts): (i) if surgery is radical; (ii) if the expected morbidity is "reasonable"; (iii) if the indication for HIPEC was suggested by a MCM, and; (iv) mitomycin is preferred to oxaliplatin (which cannot be recommended) for this indication.

Organoids as preclinical models to improve intraperitoneal chemotherapy effectiveness for colorectal cancer patients with peritoneal metastases: Preclinical models to improve HIPEC.

BACKGROUND: Peritoneal metastases (PM), corresponding to tumor implants into the peritoneal cavity, are associated with impaired prognosis and low responsiveness to systemic chemotherapy. A new therapeutic approach has dramatically changed the prognosis of patients with PM from colorectal cancer (CRC), consisting in the association of a complete cytoreductive surgery followed by intraperitoneal chemotherapy associated to hyperthermia (HIPEC). Many drugs have been administered intraperitoneally, but no clear consensus has been approved. Therefore, relevant preclinical models are essentials for the efficient translation of treatments option into affected patients. METHOD: Organoids, the last generation of preclinical models, were used to rationalize and improve intraperitoneal chemotherapy. We tested several cytotoxics, combination, effect of hyperthermia, exposure duration and frequency. RESULTS: Organoids were a representative model of response to chemotherapies used for the treatment of PM from CRC; 460mg/m2 of oxaliplatin being the most efficient cytotoxic treatment. Repeated incubations with oxaliplatin; mimicking cycles of intraperitoneal treatment, resulted in an increased efficacy. CONCLUSION & DISCUSSION: Organoids are relevant models to study the chemosensitivity of peritoneal metastases from CRCs. These models could be used for large scale drug screening strategies or personalized medicine, for colorectal carcinoma but also for PM from other origins.

Long-term survival after aggressive treatment of relapsed serosal or distant pseudomyxoma peritonei.

INTRODUCTION: Complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have dramatically changed the prognosis of patients with pseudomyxoma peritonei (PMP). However, recurrences can still occur and no consensus has been reached regarding their optimal treatments. This study aimed to analyze the patterns of recurrence after CCRS plus HIPEC for PMP and potential subsequent treatments of these lesions. PATIENTS AND METHODS: Between 1992 and 2014, patients who had relapsed after treatment of PMP were selected from a prospective database of 251 patients who had undergone CCRS plus HIPEC with a curative intent. RESULTS: After a median follow-up of 85 months, 66 patients (26%) had relapsed with a median free interval of 25 months. The first recurrence was mostly located in the peritoneum, isolated in 50 patients (76%) and associated with extraperitoneal disease in 6 patients. Curatively intended treatment of the relapse, combining surgery and chemotherapy was achievable in 76% of the patients, leading to a 5-year overall survival (OS) rate of 83% from the date of treatment of the first recurrence. In contrast, the 5-year OS rate was only 27% (p < 0.001) for patients treated with non-curative therapy. An isolated peritoneal recurrence was predictive of greater amenability to curative therapy and a better prognosis. CONCLUSION: After CCRS plus HIPEC, serosal recurrences were more common than their distant counterparts. Distant relapses' emergence has raised the question of their optimal treatments. Very long-term survival can be obtained after further treatment of recurrent PMP for patients with limited disease and good general status.

Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV.

BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228.

Modified selection criteria for complete cytoreductive surgery plus HIPEC based on peritoneal cancer index and small bowel involvement for peritoneal carcinomatosis of colorectal origin.

BACKGROUND: Complete cytoreductive surgery (CCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is on the verge of becoming the gold standard treatment for selected patients presenting peritoneal metastases (PM) of colorectal origin. PM is scored with the peritoneal cancer index (PCI), which is the main prognostic factor. However, small bowel (SB) involvement could exert an independent prognostic impact. AIM: To define an adequate cut-off for the PCI and to appraise whether SB involvement exerts an impact on this cut-off. PATIENTS AND METHODS: Patients (n = 139) treated with CCRS plus HIPEC were prospectively verified and retrospectively analyzed. One hundred presented with SB involvement of different extents and at different locations. RESULTS: All the patients with a PCI ≥ 15 exhibited SB involvement. Five-year overall survival was 48% when the PCI was <15 vs 12% when it was ≥ 15 (p < 0.0001. The multivariate analysis retained two prognostic factors: PCI ≥ 15 (p = 0.02, HR = 1.8), and the involvement of area 12 (lower ileum) (p = 0.001, HR = 3.1). When area 12 was invaded, it significantly worsened the prognosis: 5-year overall survival of patients with a PCI <15 and area 12 involved was 15%, close to that of patients with a PCI ≥ 15 (12%) and far lower than that of patients with a PCI <15 and no area 12 involvement (70%). CONCLUSION: A PCI greater than 15 appears to be a relative contraindication for treatment of colorectal PM with CCRS + HIPEC. Involvement of the lower ileum is also a negative prognostic factor to be taken into consideration.

Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases.

The peritoneal cavity must be oncologically considered as an organ in its own right and peritoneal metastases (PM) must be treated with the same curative intent (and the same results) as liver metastases. The package combining complete cytoreductive surgery (CCRS) (treating the visible disease) plus hyperthermic intraoperative peritoneal chemotherapy (HIPEC) (treating the remaining non-visible disease) achieves cure in many patients. Twenty years of publication allow us to assemble sufficient background information and data to point out the good and poor indications for CCRS+HIPEC. HIPEC is the standard of care for the treatment of peritoneal pseudomyxomas and peritoneal mesotheliomas and also, recently for the treatment of colorectal PM with limited peritoneal extension. HIPEC is in the evaluation phase for gastric PM and ovarian PM after initially disappointing results, but it is highly probable that it will be useful in particular settings. PM from neuroendocrine tumours are in the same situation. HIPEC is not currently indicated for the treatment of PM from sarcomas, from GIST, and for small round-cell desmoplastic tumours, given the poor results obtained. HIPEC can be useful, on a case-by-case basis, to treat rare tumours complicated by isolated peritoneal diffusion (e.g. Frantz's tumours). HIPEC can be used in the prophylactic setting to prevent PM in patients with a high risk of developing PM, and the first results of the 'second-look' approach are promising. Finally, CCRS+HIPEC appear to be indispensable tools in the oncologist's armentarium.

Prognostic significance of visible cardiophrenic angle lymph nodes in the presence of peritoneal metastases from colorectal cancers.

BACKGROUND: Visible cardiophrenic angle lymph nodes (CPALN) (enlarged or not), detected on CT scan are correlated with the presence of peritoneal metastases (PM), and contribute to the diagnosis of PM in colorectal cancer patients. OBJECTIVE: To study whether visible CPALN exert a prognostic impact on survival after complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CCRS + HIPEC) treating PM. PATIENTS AND METHODS: From 1999 to 2010, 114 patients with colorectal cancer and PM were treated with CCRS + HIPEC. CPALN were depicted in 64% of cases. The impact of visible CPALN on survival was investigated retrospectively. RESULTS: The mean peritoneal cancer index (PCI) score was 9.2, 21% of the patients had presented with associated liver metastases, and 71% of the women with ovarian metastases. Median follow-up was 3.9 years. Visible CPALN had no impact on OS nor on DFS, unlike the PCI score which was unequivocably the most potent prognostic factor in the multivariate analysis. CONCLUSION: Although some arguments might suggest that CPALN are malignant, paradoxically, we found that visible CPALN did not exert a positive nor a negative impact on survival after CCRS + HIPEC. SYNOPSIS: Visible cardiophrenic angle lymph nodes (CPALN) on CT-scan are strongly associated with the presence of peritoneal metastases. But this study demonstrates that the presence of CPALN has no prognostic impact after optimal cytoreductive surgery plus HIPEC.

Results of systematic second-look surgery plus HIPEC in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis.

PURPOSE: To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC). PATIENTS AND METHODS: From 1999 to 2009, 41 patients without any sign of recurrence on imaging studies underwent second-look surgery aimed at treating limited PC earlier and more easily. They were selected based on 3 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 25), synchronous ovarian metastases (n = 8), and perforation (n = 8). RESULTS: PC was found and treated with complete surgery plus HIPEC in 23 of the 41 (56%) patients. The other patients underwent complete abdominal exploration plus systematic HIPEC. Median follow-up was 30 (9-109) months. One patient died postoperatively at day 69. Grade 3-4 morbidity was low (9.7%). The 5-year overall survival rate was 90% and the 5-year disease-free survival rate was 44%. Peritoneal recurrences occurred in 7 patients (17%), 6 of whom had macroscopic PC discovered during the second-look (26%), and one patient had no macroscopic PC (6%). In the univariate analysis, the presence of PC at second-look surgery was a significant risk factor for recurrence (P = 0.006). CONCLUSION: Selection criteria for high-risk patients appear to be accurate. In these patients, the second-look strategy treated peritoneal carcinomatosis preventively or at an early stage, yielding promising results. This study has allowed us to design a multicentric randomized trial (comparing the second-look + HIPEC approach versus standard follow-up alone), which is beginning.

A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802).

BACKGROUND: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. PATIENTS AND METHODS: A total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A-LV5FU2 [leucovorin 200 mg/m(2), 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m(2) bolus, 600 mg/m(2) 22-h continuous infusion, days 1 and 2] or B-LV5FU2 + IRI (irinotecan 180 mg/m(2) 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). RESULTS: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% [95% confidence interval (CI) 53% to 66%] and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed [hazard ratio (HR) = 1.12, 95% CI 0.85-1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74-1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. CONCLUSION: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

Hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis of digestive and peritoneal origin: rationale.

Up to a few years ago peritoneal carcinomatosis was considered as an "incurable" disease. The aim of this paper is to review the surgical approach with curative intent to carcinomatosis: it consists of complete resection of macroscopic disease (R1), associated with hyperthermic intraperitoneal chemotherapy (HIPEC) to treat residual microscopic disease, and to evaluate its indications. Overall 5-year survival of patients with peritoneal carcinomatosis treated by HIPEC is similar to that of patients with hepatic metastases treated with curative intent. Those patients should no longer be considered as patients with a terminal disease but as patients with a potentially treatable localized disease.

Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer. Final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial.

LV5FU2 with high-dose leucovorin (LV), weekly infusional 5-fluorouracil (5FU) (AIO schedule) and raltitrexed have been demonstrated to be active agents in first-line treatment of colorectal cancer. We performed a 4-arm randomised trial to compare (1) a low-dose intravenous bolus of LV (20 mg/m2), followed by an intravenous bolus of 5FU (400 mg/m2), followed by a 22-hour continuous infusion of 5FU (600 mg/m2) on day 1 and day 2/2 weeks (ldLV5FU2 arm), (2) a weekly continuous infusion of high-dose 5FU (2.6 g/m2/week) for 6 weeks followed by a rest week (HD-FU arm) and (3) raltitrexed (Tomudex arm; 3 mg/m2/3 weeks) to standard LV5FU2. From 1997 to 2001, 294 patients were included. The 4 arms were well balanced for sex ratio, age, WHO performance status, the primary tumour site and prior adjuvant chemotherapy. Treatment was stopped due to low accrual. Two toxicity-related deaths were observed in the Tomudex arm. The treatments gave rise to different rates of grade 3-4 neutropenia (3, 4, 11 and 14% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively, p = 0.028), leucopenia and vomiting. At least one episode of grade 3-4 toxicity was observed in 27, 25, 38 and 47% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.016). An objective response was observed in 28, 21, 22 and 10% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.04). Progression-free survival (PFS) of the patients in the Tomudex arm was statistically lower compared to that of patients treated with LV5FU2 or ldLV5FU2 (combined group; p = 0.013, log rank test). In conclusion, Tomudex is more toxic and yields shorter PFS than infusional 5FU. Despite the early closure of the study and the lack of power of the comparison, it seems that ldLV5FU2 could be considered as an active, easier and less expensive option for the treatment of metastatic colorectal cancer compared to classic LV5FU2 or weekly HD-FU.

Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801).

BACKGROUND: The aim of this study was to evaluate the efficacy of adjuvant chemotherapy after resection for gastric cancer in a randomized controlled trial. PATIENTS AND METHODS: After curative resection, stage II-III-IVM0 gastric cancer patients were randomly assigned to postoperative chemotherapy or surgery alone. 5-Fluorouracil (5-FU) 800 mg/m(2) daily (5-day continuous infusion) was initiated before day 14 after resection. One month later, four 5-day cycles of 5-FU (1 g/m(2) per day) plus cisplatin (100 mg/m(2) on day 2) were administered every 4 weeks. RESULTS: The study was closed prematurely after enrollment of 260 patients (79.7% N+), owing to poor accrual. At 97.8 months median follow-up, 5- and 7-year overall survival were 41.9% and 34.9% in the control group versus 46.6% and 44.6% in the chemotherapy group (P=0.22). Cox model hazard ratios were 0.74 [95% confidence interval (CI) 0.54-1.02; P=0.063] for death and 0.70 (95% CI 0.51-0.97; P=0.032) for recurrence. An invaded/removed lymph nodes ratio >0.3 was the main independent poor prognostic factor identified by multivariate analysis (P=0.0001). Because of toxicity, only 48.8% of patients received more than 80% of the planned dose. CONCLUSION: There was no statistically significant survival benefit with this toxic cisplatin-based adjuvant chemotherapy, but a risk reduction in recurrence was observed.

A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial.

UNLABELLED: Previous small phase II trials have demonstrated that the combination of 5-fluorouracil (5FU) and cisplatin(CDDP) could have clinical activity in metastatic biliary tract cancer. This randomised phase II trial was designed to assess the activity and safety of a high-dose infusional weekly 5FU alone (HDFU) and the combination of 5FU, folinic acid (FA) and CDDP. Patients were included if they had histologically proven locally advanced or metastatic biliary tract carcinoma, World Health Organisation (WHO) performance status < or = 2, bilirubin <2 x upper normal limit, adequate haematological and renal functions and had not received prior chemotherapy, even in the adjuvant setting. TREATMENTS: Arm A (HDFU) consisted of cycles of 5FU 3 g/m(2) intravenously (i.v.), 24 h infusion, weekly, for 6 weeks, followed by 1 week rest, every 7 weeks; Arm B (5FU+FA+CDDP) consisted of cycles of 5FU 2.0 g/m(2) i.v. with folinic acid 500 mg/m(2), 2 h-infusion, weekly, for 6 weeks, followed by 1 week rest plus cisplatin 50 mg/m(2), once every two weeks, for 6 weeks, followed by 1 week rest, every 7 weeks. From February 1997 to June 1999, 58 patients were randomised (29 in each arm). Patients had a median age of 58 years in Arm A and 62 years in Arm B, locally advanced disease was present in 21% of the patients in Arm A and 11% in Arm B. WHO performance status of 0/1/2 was noted in 48%/45%/7% of the patients in Arm A and 54%/43%/4% in Arm B. In both arms, the most common metastatic sites were the liver and peritoneum. Twenty-eight patients were eligible in each arm and one patient did not start the allocated therapy in Arm B. The median number of cycles was 2 [range 1-12] in Arm A and 2 [range 1-6] in Arm B. Responses for the eligible patients who started their allocated therapy were as follows: Complete Response (CR) 0% in Arm A, 4% in Arm B, Partial Response (PR) 7% in Arm A, 15% in Arm B resulting in an overall response rate [95% CI] of 7.1% in Arm A [0.9-23.5%] and 19% [6.3-38.1%] in Arm B. Disease stabilisation was observed in 46% in Arm A and 44% in Arm B. National Cancer Institute of Canada (NCIC) grade 3-4 adverse events (% of patients in Arm A/Arm B) were neutropenia 4%/26%, thrombopenia 0%/7%, stomatitis 0%/4%, vomiting 7%/14%, diarrhoea 0%/11% and neurotoxicity 4%/0%. There was one early toxic death in Arm B. The median overall survival (OS) [95% CI] was in Arm A/Arm B: 5.0 [4.0-7.4] months/8.0 [5.8-11.8] months and the median progression-free survival (PFS) was 3.3 [1.7-4.7] months/3.3 [2.3-6.7] months. Cisplatin in combination with 5FU+FA showed a higher activity than HDFU, but was more toxic. These results are not sufficient to start a phase III trial. However, our group is planning a phase III trial comparing 5FU+folinic acid versus the same schedule+oxaliplatin a platinum analogue.

Heated intra-operative intraperitoneal oxaliplatin plus irinotecan after complete resection of peritoneal carcinomatosis: pharmacokinetics, tissue distribution and tolerance.

BACKGROUND: The purpose of this study was to report the pharmacokinetics (PK) and tolerance profile of intraoperative intraperitoneal chemo-hyperthermia (IPCH) with oxaliplatin and irinotecan. PATIENTS AND METHODS: Thirty-nine patients with peritoneal carcinomatosis (PC) of either gastrointestinal or peritoneal origin underwent complete cytoreductive surgery followed by IPCH with a stable dose of oxaliplatin (460 mg/m(2)), plus one among seven escalating doses of irinotecan (from 300 to 700 mg/m(2)). IPCH was carried out with the abdomen open, for 30 min at 43 degrees C, with 2 l/m(2) of a 5% dextrose instillation in a closed continuous circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of oxaliplatin and irinotecan. RESULTS: Irinotecan concentration in tumoral tissue increased until 400 mg/m(2) and then remained stable despite dose escalations. It was 16-23 times higher than in non-bathed tissues. Increasing doses of intraperitoneal irinotecan did not modify the PK of intraperitoneal oxaliplatin, and the drug concentration ratio was 17.8 higher in tumoral tissue (bathed) than in non-bathed tissues. The hospital mortality rate was 2.5% and the non-hematological complication rate was 25%. However, grade 3-4 hematological toxicity rate was 58%. CONCLUSION: Intraperitoneal heated oxaliplatin (460 mg/m(2)) plus irinotecan (400 mg/m(2)) presented an advantageous PK profile and was tolerated by patients, despite a high hematological toxicity rate.

Efficacy of intraperitoneal chemohyperthermia with oxaliplatin in colorectal peritoneal carcinomatosis. Preliminary results in 24 patients.

BACKGROUND: The complete resection of macroscopic colorectal peritoneal carcinomatosis (PC), followed by intraoperative intraperitoneal chemohyperthermia (IPCH) to treat residual microscopic disease, leads to cure in some patients. We report preliminary results on survival in a phase II study using oxaliplatin (LOHP). PATIENTS AND METHODS: Twenty-four patients with macroscopic colorectal PC underwent complete resection of the PC followed by IPCH with LOHP performed in an open abdominal cavity. The dose of LOHP was 460 mg/m(2) in 2 l/m(2), during 30 min at 43 degrees C, at a flow rate of 2 l/min. During the hour preceding IPCH, they received an intravenous administration of 5-fluorouracil (400 mg/m(2)) and leucovorin (20 mg/m(2)). RESULTS: Mean peritoneal tumoral extension (Sugarbaker's Index) was 16.9 +/- 9.5, median operative duration was 490 min and median blood loss was 965 ml. There were two postoperative deaths (8%) by intracerebral hemorrhage, and morbidity rate was 41.6%. Minimal follow-up was 18 months and median follow-up was 27.4 months (range 18.3-49.6). At 1, 2 and 3 years, overall survival rates were 83%, 74% and 65%, and disease-free survival rates were 70%, 50% and 50%, respectively. Only 32% of the 22 postoperative living patients presented a peritoneal recurrence. A peritoneal index >24 influenced survival, with a 17% recurrence rate at 2 years versus 63% when it was <24 (P = 0.005). CONCLUSION: This new modality of treatment, when feasible, gives encouraging preliminary results, with a promising 3-year survival rate of 65%.

[Resectional treatment of peritoneal carcinomatosis followed by intraperitoneal chemotherapy, practical aspects]. / Traitement des carcinoses péritonéales par résection suivie de chimiothérapie intrapéritonéale, aspects pratiques.

Surgical resection with curative intent for peritoneal carcinomatosis (PC) requires the excision of all macroscopic disease followed by immediate intraperitoneal chemotherapy to treat the residual microscopic metastases. Hyperthermia improves the effectiveness of this approach. The techniques for excision of PC are rather specific and are not undertaken unless it is possible to remove all visible disease larger than 1 mm. and to assure a post-operative quality of life which is more or less normal. Intraperitoneal hyperthermic chemotherapy techniques must be draconian in order to be effective. If these conditions can be met, peritoneal metastases can be definitively cured in two thirds of colorectal PC and pseudomyxoma peritonei, and in nearly half of mesotheliomas.

Hepatic arterial infusion using pirarubicin combined with systemic chemotherapy: a phase II study in patients with nonresectable liver metastases from colorectal cancer.

BACKGROUND: A prospective phase II study was performed to determine the feasibility, efficacy and safety of arterial hepatic infusion (HAI) using pirarubicin combined with intravenous chemotherapy. PATIENTS AND METHODS: From December 1991 to April 1994, 75 patients with unresectable colorectal metastases confined to the liver were included in this multicenter study to receive intra-arterial hepatic pirarubicin and a systemic monthly regimen of 5-fluorouracil (5-FU) and folinic acid. Sixty-four patients were analyzed in the intention-to-treat analysis and 61 in the per-protocol analysis. RESULTS: Tolerance of this regimen was rather good; however, functional catheter problems were observed in 29 patients (45%) resulting in failure of HAI in 21 cases (33%) after a median of three cycles; vomiting grade 3 was present in 12.5% of patients, neutropenia grade 4 in 23% and alopecia grade 3 in 19%. The overall response rate was 31.9% in intention-to-treat analysis, and 39.3% in per-protocol analysis. Extrahepatic progression was reported in only 21.7% of patients. Time to hepatic progression and extra-hepatic progression was 8.3 and 15 months, respectively, in intention-to-treat analysis, and 11 and 18 months, respectively, in per-protocol analysis. Median survival was 19 and 20 months in intention-to-treat analysis and per-protocol, respectively. CONCLUSIONS: In our study, the combination of intra-arterial pirarubicin and intravenous chemotherapy demonstrated some efficacy and good tolerance in the treatment of isolated colorectal liver metastases. This treatment seems to prevent extra-hepatic spread and prolong survival time. The results of this study have to be confirmed by new trials using more active systemic chemotherapy.

Human pharmacokinetic study of heated intraperitoneal oxaliplatin in increasingly hypotonic solutions after complete resection of peritoneal carcinomatosis.

PURPOSE: We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions. METHODS: Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied. RESULTS: Pharmacokinetics: The mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions. SAFETY: There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups. CONCLUSION: Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.

Adjuvant chemotherapy for colon cancer.

Colorectal cancer is one of the most frequent cancers in the world, especially in occidental countries. The primary curative therapy is surgical resection of the tumour. Within the last 15 years, appropriately powered prospective randomized trials have demonstrated that adjuvant post-operative chemotherapy should be the standard treatment for stage III cancers (node-positive disease). 5-Fluorouracil(5FU)/levamisole was used in the early 1990s but has now been replaced by 5FU/leucovorin. The recommended duration of treatment is 6 months. Combining levamisole with 5FU/leucovorin does not improve efficacy. In patients with stage II colon cancer it is still unclear whether adjuvant chemotherapy is effective. In an attempt to define groups of stage II cases that may benefit from adjuvant chemotherapy, considerable efforts have been made to determine molecular genetic factors (tumour-ploidy and mutations or alterations in oncogenes and tumour-suppressor genes). Regional therapy (particularly portal vein infusion) is one of the other therapeutic strategies still considered to be investigational. Current clinical trials are evaluating the role of non-fluorinated pyrimidine agents in an adjuvant setting.