European Journal of Surgical Oncology
Volume 36, Issue 7 , Pages 599-603, July 2010

Curative treatment of colorectal peritoneal carcinomatosis: Current status and future trends

Department of Surgical Oncology, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France

Accepted 4 May 2010.

Article Outline

Abstract 

A new therapeutic approach to treat colorectal peritoneal carcinomatosis (PC) is becoming increasingly popular. Its main principle is to treat the macroscopic (visible) malignant peritoneal disease with complete cytoreductive surgery and, immediately after, to treat the remaining microscopic (non visible) malignant peritoneal disease with hyperthermic intraperitoneal chemotherapy (HIPEC).

This combined treatment has become the gold standard approach when feasible. It is associated with good oncologic results, considering a 5-year survival rate close to 40% when complete cytoreductive surgery is achieved, and acceptable surgical results, considering a postoperative mortality rate ranging from 3 to 5% and a postoperative morbidity rate ranging from 30 to 50%.

The exact effects of each steps of this combined treatment are currently unknown; therefore a randomized controlled trial is on going evaluating the real impact of HIPEC by itself (randomization with or without HIPEC after a complete cytoreductive surgery). One of the future indications of this combined approach might be its use in the very early development of PC. Indeed, early PC is currently only detectable and treatable during a second-look surgery, as recently demonstrated in high-risk patients. A trial is currently comparing the oncologic benefits of this second-look approach with HIPEC to the usual simple survey in patients with a high risk to develop PC.

Keywords: Colorectal cancer, Peritoneal carcinomatosis, Cytoreductive surgery, Chemo-hyperthermia, New trends

 

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Introduction 

Peritoneal dissemination or “carcinomatosis” from colorectal carcinoma is a form of disease progression which can affect 30–40% of patients.1, 2 Natural history studies show that peritoneal carcinomatosis (PC) is uniformly fatal, with median survival not exceeding 6 months.3 For more than a decade, as an alternative approach to overcome this disease, a handful of centers have pursued aggressive cytoreductive surgery to resect macroscopic disease as much as possible, combining it with intraperitoneal chemotherapy (initially without and then with hyperthermia), to treat any residual occult disease.

The aim of this review is to report the current status of this novel combined treatment, focusing on issues that have been solved and those which continue to pose problem and attempting to foresee future developments.

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A new therapeutic concept becoming increasingly popular 

Concept 

In 1980, Spratt was the first to describe the combination of maximal cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) to treat a recurring peritoneal pseudomyxoma,4 but the main apostle of this method was PH Sugarbaker.5 The main principles are: treating the macroscopic (visible) malignant peritoneal disease with complete cytoreductive surgery (CCRS), and immediately after, treating the remaining microscopic (non-visible) malignant peritoneal disease with HIPEC.

It is essential that surgery resects all tumor seeding greater than 1mm because the chemotherapy bath cannot penetrate tumor seeding beyond 1–2mm in depth.6, 7 Hyperthermia, in addition to intraperitoneal chemotherapy, has clearly demonstrated its ability to potentiate the penetration and activity of local chemotherapy in cancer cells in vitro, and this role was confirmed in vivo in several studies.8, 9

Finally, HIPEC must be performed immediately after surgery to avoid peritoneal adhesions in which cancer cells become trapped and could constitute a tumor sanctuary.10, 11

HIPEC is becoming widespread 

Publications devoted to HIPEC have increased exponentially between 1994 and 2009. To date, approximately five hundred have concerned colorectal PC. At the same time, the number of centers using HIPEC has progressively increased worldwide. In France, it increased from 3 in 1994 to 25 in 2009. This reflects the enhanced interest of physicians in this new therapeutic approach.

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Validated and nonvalidated aspect of this combined treatment 

Global results 

This combined treatment (CCRS immediately followed by HIPEC) works, as definitively demonstrated by the randomized study of the Amsterdam group: 105 patients presenting colorectal PC were randomized between surgery+HIPEC (and systemic chemotherapy) versus systemic chemotherapy alone.12 In that study, 50% of the patients in the experimental arm were ultimately not good candidates for HIPEC because their PC could not be completely surgically resected. In spite of this selection bias, the reported median survival was 22 months in the experimental arm versus 13 months in the control group (p=0.032) (Fig. 1).

A more recent retrospective study compared similar patients with resectable PC treated with CCRS and HIPEC to standard systemic chemotherapy: the median survival rate was 63 months in the CCRS+HIPEC group versus 24 months in the systemic chemotherapy group (Fig. 2).13

Complete cytoreductive surgery 

The impact of the completeness of cytoreductive surgery is very strong in this combined treatment. This is clearly apparent in all studies from experienced as well as less experienced centers. For example, we report in Fig. 3 the survival rates according to the radicality of surgery in the 523 patients collected by the AFC (Association Française de Chirurgie) registry.14 This study underlined the strong impact of the completeness of cytoreductive surgery on overall survival: 5 years after surgery, no patient was alive if the size of the remaining tumor nodules after surgery was ≥2.5mm whereas nearly 30% of the patients were alive if CCRS was possible (p<0.0001). Furthermore, CCRS was identified as an independent prognostic factor for disease-free survival (p=0.05).

Hyperthermic intraperitoneal chemotherapy 

The exact effect of HIPEC alone in this package is currently unknown in human beings. Its role is to cure the residual microscopic PC after complete cytoreductive surgery. In a randomized trial in rats, those treated with HIPEC survived longer than those treated with intraperitoneal chemotherapy alone or exclusively with intraperitoneal hyperthermia.8 Until now, no comparable trial has been proposed to patients, but a French randomized multicentric trial (Prodige 7) is ongoing which is comparing HIPEC versus no HIPEC after complete cytoreductive surgery.

HIPEC techniques are heterogeneous but their elaboration is highly complex. The combination of drugs can be modified, as can their concentration, but also the composition as well as the volume of the perfusion, the duration, and the temperature. A high number of combinations of these six parameters are possible, and it is not possible to test all of them. Each modification of one of these parameters implies conducting a new pharmacokinetic study. Schematically, there are two main trends worldwide for HIPEC: one uses mitomycin C over 60–90min at 41°C with a closed-abdomen technique, and the other uses oxaliplatin (±irinotecan) over 30–40min at 43°C with an opened-abdomen technique.

In the future, there is a rationale for conducting HIPEC with other drugs and newly targeted therapy (without hyperthermia, if monoclonal antibodies are used).

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What indications and what results in 2010? 

Indications 

Indications are based on absolute and relative contraindications. An absolute contraindication for CCRS plus HIPEC is a poor general status, the presence of extra-peritoneal metastases and huge and diffuse PC. Relative contraindications are: a subocclusive syndrome due to more than one digestive stenosis, peritoneal disease progressing under chemotherapy and the presence of more than 3 resectable liver metastases (LM are not contraindicated if there are <4 and they are easily resectable).15

Oncologic results 

Results obtained with CCRS+HIPEC are interesting and promising. In the AFC study, overall 5-year survival was 27%. This result takes into account all the learning curves of 28 different centers and will be the worst possibly obtained. The results of experienced centers, concerning patients who underwent CCRS+HIPEC are consistent, with overall 5-year survival rates close to 40%.16, 17, 18 It was 32% for the 70 patients reported on by da Silva et al.,17 43% for the 59 patients reported by Verwaal et al.,16 and 48% for the 30 patients in the study by Elias et al.18 Such a survival rate has never been published before about PC, even if it concerns only selected patients. It is thus a real therapeutic revolution. Furthermore, these results are exactly similar to those obtained with hepatectomy for liver metastases.13 The message appears to be that selected patients with PC should be treated with this combined therapy in the same way as selected patients with LM should be treated with hepatectomy, given that the same survival rates are obtained.19

Post-operative mortality and morbidity 

The first studies concerning CCRS and HIPEC reported high post-operative mortality and morbidity rates, creating a obstacle to its diffusion. However, in the AFC study, the postoperative mortality rate was comparable to that of standard colorectal surgery (3%) and grade 3 or 4 complications (according to the National Cancer Institute Common Toxicity Criteria) occurred in 31% of the patients.13 These acceptable operative results were confirmed in a recent Australian study, which reported a postoperative mortality rate of 3% and a severe morbidity rate of 43%.20 Thus, fear of a severe post-operative course is no longer an acceptable reason for not using CCRS and HIPEC.

Prognostic factors 

Some studies recently underlined the prognostic impact of the extent of the peritoneal disease (measured with the peritoneal cancer index: PCI).14, 17 This index ranges from 1 to 39 (a score from 0 to 3 is given for each of the 13 intra-abdominal areas).21 Among the 523 patients in the AFC registry, a peritoneal index >20 appeared as one of the main prognostic factors for survival in the multivariate analysis.14 The results of the AFC registry are reported in Fig. 4. Five-year overall survival is directly correlated with the PCI, ranging from 44% with a very low PCI (less than 6) to 7% with the highest PCI (more than 19). We currently believe that a PCI exceeding 20 should be considered as a relative contraindication for CCRS with HIPEC.

The main prognostic factors for survival selected by various studies through multivariate analysis are as follows: the completeness of cytoreductive surgery, a PCI score >20, the presence of positive lymph nodes and the delivery of adjuvant chemotherapy.13, 17 When they are resectable simultaneously with HIPEC, associated liver metastases merely exert a borderline non-significant impact.13 Until now, no CCRS plus HIPEC technique has demonstrated clear superiority over another. The technique commonly used in our department has been extensively described elsewhere.22, 23

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New trends for HIPEC in the future 

Established macroscopic PC:

a) Standardization of the techniques
A comparative study of the main techniques is desirable, but difficult to perform and time-consuming. While awaiting the results of such a study, treatment decision-making is based on a consensus among experts. Ongoing multicentric studies are a way of standardizing these techniques. The relation between the duration and the temperature of HIPEC should be carefully explored. In addition, the intraperitoneal use of newly targeted drugs ought to be explored.


b) Progress with new targeting molecules
If new and more efficient molecules capable of treating colorectal cancers become available, then the place of HIPEC will be re-analyzed. A prospective multicentric trial will be necessary to compare CCRS and HIPEC to a non-surgical treatment using these new drugs.


c) Cost-efficiency of CCRS-HIPEC
This combined treatment is complex and costly (approximately 35,000 Euros per patient). It cures only 20% of the patients with PC, but significantly increases median survival. Its cost-efficiency can be measured with the QALY method which measures the price of one year of survival gained with the treatment.24 After that, each country will have to decide if it is rich enough to pay the price and whether treating this advanced disease is a priority or not. Also, The results of such treatment will have to be weighed against the cost of new systemic chemotherapy molecules (close to 5000 Euros per month).


d) A surgical procedure reserved for specialized centers
CCRS and HIPEC are technically challenging, with a rather long learning curve.13 Moreover, as mentioned above, it is an expensive treatment. High volume and experienced centers obtain better results than others13 and quality control measurement does not currently exist. Controlling the quality of surgery is currently difficult to implement and apply to gastric and rectal cancers. It will be even more difficult for this complex technique. This is why there is a strong rationale for authorizing this activity exclusively in a few specialized centers in the future.


Prophylactic HIPEC for high-risk patients:

All the series concerning the treatment of established macroscopic PC conclude that survival results are far better when peritoneal disease is less bulky.13, 16, 17 Also postoperative morbidity and mortality are significantly lower when the peritoneal index is lower, because surgery is less extensive.14, 15 These two points are strong arguments in favor of operating patients with the lowest peritoneal index. However, early PC is currently not detectable clinically, biologically or with imaging. Early PC is only detectable by a second-look laparotomy. Second-look laparoscopy is not recommended because it does not allow the surgeon to “re-expose” all the dissection planes of the first surgery, and because palpation cannot be used. The aim of this second-look procedure is to detect the beginning of PC early and to treat it with cytoreductive surgery plus HIPEC. As this a rather aggressive and expensive treatment, it should be proposed exclusively to patients presenting a high risk of developing PC after resection of the primary. A major proportion of the at-risk population has recently be defined by Elias et al.25 and concerns: (1) patients presenting a few nodules of synchronous PC which are completely resected with the primary tumor, (2) patients with ovarian metastasis, and (3) patients with a perforated primary tumor (spontaneous or iatrogenic). A second-look procedure performed one year after the first surgery and 6 months after the end of systemic adjuvant chemotherapy, in asymptomatic patients with a completely negative work-up, was able to detect macroscopic PC in, respectively, 63%, 75% and 33% of these sub-groups. Patients with macroscopic PC were treated with cytoreductive surgery plus HIPEC, with no mortality, low morbidity and a promising survival rate (2-year disease-free survival exceeding 50%). Patients without macroscopic PC were treated prophylactically with or without HIPEC. The subgroup receiving HIPEC presented far fewer peritoneal recurrences than those who did not receive HIPEC (17% versus 43%, respectively).Based on this preliminary study, a multicentric randomized trial was designed which will begin in France in 2010. All high-risk patients (see definition above) will receive the standard adjuvant systemic chemotherapy with FOLFOX over 6 months. Afterwards, a complete work-up will be performed. If it is negative, patients will be randomized between a simple survey (control group) and a second-look with in principle HIPEC. The main evaluation criterion will be the rate of peritoneal recurrences at 3 years.To date, the risk of developing PC has not been clearly established for patients with a pT4 lesion of the colon or an occlusive tumor. Data in the literature are discordant and a new prospective study on this issue would be useful.

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Conclusion 

In conclusion, comparable to the rise in the use of hepatectomy for colorectal LM observed 15 years ago, CCRS and HIPEC is becoming the standard treatment for colorectal PC.

This combined treatment is a complex and costly therapeutic package that is slowly being adopted by surgical teams. However, it is associated with promising long-term survival and is currently the only treatment able to cure patients with PC. Its future evolution may lead to even better oncologic and surgical results.

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Acknowledgement 

The authors thank Ms lorna Saint-Ange for editing.

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Conflict of interest 

None declared.

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PII: S0748-7983(10)00115-0

doi:10.1016/j.ejso.2010.05.007

European Journal of Surgical Oncology
Volume 36, Issue 7 , Pages 599-603, July 2010

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