Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial

The primary aim of this study is to determine the oncological effectiveness of adjuvant HIPEC using oxaliplatin, following a curative resection of a T4 or intra-abdominally perforated colon carcinoma in preventing the development of PC.

Secondary aims are:

This will be a randomized controlled clinical trial of the Dutch Colorectal Cancer Group (DCCG) that will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible patients will be randomized (in a 1:1 ratio) to adjuvant HIPEC followed by standard adjuvant systemic chemotherapy in the experimental arm, or adjuvant systemic chemotherapy alone in the control arm (Fig. 1). Stratification factors will be tumour characteristic (T4 or perforation), surgical approach of the primary tumour resection (laparoscopy or open) and age (<65 years or ≥65 years).

Timing of adjuvant HIPEC is tailored to the different clinical entities within the study population. Patients with obvious clinical T4 stage can be asked preoperatively for informed consent with simultaneous HIPEC if randomized in the experimental arm. If patients are randomized postoperatively based on intra-operative findings, early staged adjuvant HIPEC is preferably performed as soon as possible after primary resection but at a maximum of 10 days. When early postoperative HIPEC is not feasible, delayed staged adjuvant HIPEC will be performed in week 5 to 8 from primary resection. Adjuvant HIPEC can be performed either by laparoscopy or open approach. Subsequently, patients will receive routine adjuvant systemic chemotherapy according to local treatment protocols within 3 weeks from HIPEC, preferably as soon as the clinical condition allows for systemic therapy. Follow-up will be performed routinely according to the national guideline during the first 18 months. Patients who already developed recurrent disease during this time interval will be treated accordingly. During the entire postoperative period, concomitant medications, adverse events, procedures and adjuvant therapies will be reviewed and documented. In patients who have no clinical signs of recurrent disease at 18 months on CT scan of the thorax and abdomen in combination with non-elevated CEA levels, diagnostic laparoscopy will be performed in both arms of the study. Laparoscopy enables accurate assessment of the primary endpoint of the study and may have therapeutic implications for patients in whom asymptomatic PC is proven by laparoscopically taken biopsies. These patients will subsequently be treated by CR/HIPEC according to the national guideline if fulfilling the treatment criteria, with a switch to mitomycin-C in patients who underwent adjuvant HIPEC with oxaliplatin previously. The staging laparoscopy at 18 months is supported by the increasing data in the literature on the value of second look surgery for high-risk patients [41, 42]. Patients with a negative laparoscopy will continue routine follow-up for at least 5 years from primary resection and during this period, oncological outcome in terms of local recurrence, metastases and survival as well as oncological therapies will be documented. All relevant data during work up, management and follow up will be collected in an electronic case record form. In addition, quality of life and economic evaluation questionnaires will be administered to the patient at each follow-up interval. Data will be documented in line with ‘Good Clinical Practice’ and Dutch legal requirements.

Patients diagnosed with adenocarcinoma of the colon and either one of the two following risk factors for PC or both will be considered for inclusion:

Those patients are eligible for this study when they meet the following inclusion criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

The primary endpoint of the study is peritoneal recurrence-free survival at 18 months determined by CT and if negative by laparoscopy.

Approximately 25 % of CRC patients with a pT4 or perforated primary tumour is expected to develop PC (see below). Adjuvant HIPEC is expected to result in a 60 % relative risk reduction in peritoneal recurrence based on the currently available literature (see below). To detect an absolute 15 % difference in PC recurrence-free survival at 18 months (90 % peritoneal recurrence-free under HIPEC plus systemic chemotherapy against 75 % peritoneal recurrence free under systemic chemotherapy), a total number of 176 patients (88 in each arm) is needed (Kaplan-Meier, one-sided, alpha = 0.05, power of 80 %, drop-out 5 %). Actually, the power may even be higher, because the calculation ignores longer follow-up for the patients who have been included early on in the study.

The primary endpoint, peritoneal recurrence-free survival at 18 months, will be compared between the two study groups, using Kaplan Meier survival analysis with log rank test and a significance level of 0.05.

The medical ethical committee of the Academic Medical Center Amsterdam has approved the study protocol (MEC 2014–264, NL49960.018.14) and this study will be conducted according to the principles of the Declaration of Helsinki (Fortaleza, October 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO). An interim review will be performed after inclusion of 25, 50 and 100 (of the total of 176 patients). At 6 weeks after inclusion of these patients the trial’s safety data will be evaluated. The data and safety monitoring board (DSMB) will be supplied with the number of (serious) adverse events in both groups at this time point. If there is a skewed distribution of the number of (serious) adverse events between the two groups an efficacy analysis can be performed at the discretion of the DSMB. Following these interim analyses the DSMB will advise upon continuation of the trial.

In the COLOPEC trial we will use oxaliplatin as standard chemotherapeutic agent for HIPEC. In the Netherlands, we have recently switched from mitomycin-C as the standard agent for HIPEC to oxaliplatin in all HIPEC centres. Oxaliplatin and mitomycin-C are both cell cycle independent alkylating agents, interfering with DNA and DNA-synthesis. Because of a large molecular weight, there is limited systemic absorption of both agents. The enhancement of cytotoxicity under hyperthermia and a maximal tissue penetration of 2 mm. are also comparable. Although there are no randomized studies comparing oxaliplatin and mitomycin-C for CR/HIPEC, the literature suggests an equal antitumor effectiveness [45]. The advantage of oxaliplatin is the absence of neutropenia and shorter perfusion time (30 versus 90 min.) compared to mitomycin-C.

In this project, there is the possibility to deliver HIPEC by both the conventional open approach and a minimally invasive approach. If compared to an open procedure, laparoscopic HIPEC avoids the risk and recovery time associated with a laparotomy while the temperature profiles and peritoneal perfusion flow rates are similar [46]. Experimental studies in pigs suggest even better penetration of chemotherapy in a closed abdomen probably due to increased abdominal pressure [47, 48].

Prophylactic resection of organs at risk of harbouring tumour cells, such as omentectomy and ovariectomy, has been performed in addition to adjuvant HIPEC [49]. There is currently no evidence to support this. Because HIPEC is applied in adjuvant setting with the majority of patients not expected to benefit from this intervention, we aim to minimise invasiveness of the therapy. Therefore, we decided not to perform prophylactic omentectomy, ovariectomy or any other prophylactic surgery . Moreover, we hypothesise that potential micro metastases at these sites are sufficiently treated with HIPEC .

Timing of the adjuvant HIPEC procedure will be tailored to the individual patient within the COLOPEC trial. Both a simultaneous and a staged approach can be chosen. A theoretical disadvantage of a staged approach is the suggested phenomenon of residual cancer cells being encapsulated with fibrin, which probably makes these cells less accessible for chemotherapy at an interval of more than two weeks after surgery [20, 50‐52]. Therefore, it is often stated that HIPEC should ideally be performed simultaneously with primary tumour resection, although this is not an evidence-based recommendation. Simultaneous adjuvant HIPEC is often not feasible because pT4 stage is only found at definitive pathology, HIPEC is not available at time of primary tumour resection in an emergency setting for a perforated tumour, or primary resection is being performed outside a HIPEC centre. In order to make results from a RCT transferable to daily clinical practice in the end, the possibility of early postoperative HIPEC has been included in the study protocol. Staged HIPEC may be performed within 10 days in case of adequate patient condition and logistics, or may be delayed to 5–8 weeks from primary resection. The theoretical advantage of staged adjuvant HIPEC is that healing of the anastomosis is not compromised by immunosuppression as a result of the administration of chemotherapeutic agents, and the more favourable logistics. Disadvantages of staged adjuvant HIPEC are the necessity of adhesiolysis, the risk of suboptimal distribution of chemotherapy in the abdominal cavity, and the potential delay of routine adjuvant systemic treatment.

Although 3-year disease-free survival (3-years-DFS) using CT imaging is a commonly used endpoint in adjuvant setting, 18 month laparoscopy is more appropriate in this trial because of the restricted sensitivity of imaging modalities to detect PC at an early stage. Also, second look surgery is increasingly applied in patients at high risk of developing PC in- and outside trial setting. Positive findings during laparoscopy may have therapeutic implications, which justifies an invasive method to determine the primary outcome parameter. It is likely that a significant reduction in peritoneal recurrence rate at 18 months will eventually translate into an overall survival benefit given the worse prognosis associated with peritoneal dissemination.

There needs to be a good balance between associated costs and morbidity on one hand and effectiveness on the other hand for an adjuvant treatment modality. For routine adjuvant systemic chemotherapy in colon cancer, an absolute survival benefit as low as 5 % is considered to be worthwhile despite duration of treatment for six months with treatment related toxicity such as hand-foot syndrome.

Based on reported incidences of PC between 14 and 58 % for perforated tumours [41, 53, 54] and between 17 and 50 % for pT4 stage [55‐58], the estimated incidence of PC in the study population will be 25 %. Reported incidences may have been underestimated because of the inaccuracy of routine follow-up examinations to detect PC and incomplete autopsy rates of patients who died of CRC. The relative risk reduction in a comparative study of 25 patients undergoing prophylactic HIPEC compared to a 1:2 matched control group was 82 % [59]. Older randomized studies using intraperitoneal 5-FU showed relative risk reductions of peritoneal recurrence of 78 % [38] and 62 % in favour of the intraperitoneal chemotherapy groups [37]. Based on these data, a conservative expected relative risk reduction of adjuvant HIPEC is 60 %. The expected advantage of the experimental intervention is therefore an absolute reduction of 15 % in PC (from 25 % to 10 %).

As a consequence of a 15 % absolute risk reduction, from each cohort of 100 patients, 85 patients will undergo an additional treatment without any benefit. This is only acceptable if the associated morbidity is relatively low, which appears to be so based on systematic review of the literature and our own feasibility study [39, 40].

With regard to cost-effectiveness, additional costs of routine adjuvant HIPEC should be weighed against gained life years and reduced costs of patients in whom PC has been prevented to develop. A 15 % reduction of peritoneal recurrence is expected to result in at least a 5 % survival benefit, given the dismal prognosis associated with development of PC and based on an update of the study by Sammartino et al. [49]. Reduced costs may be related to less expensive treatment for clinically manifest PC, such as CR/HIPEC (approximately €50.000 per procedure) and palliative systemic treatment including expensive targeted agents such as bevacizumab (€2.400 per month per patient). Furthermore, reduced costs may be related to a reduced use of other palliative treatment modalities (ascites drainage, palliative surgery) and less need for palliative care in a hospital or other institutional setting, or at home.