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Annals of Surgical Oncology 10:508-513 (2003)
© 2003 Society of Surgical Oncology

NEW APPROACHES TO THE TREATMENT OF HEPATIC MALIGNANCIES

Cytoreductive Surgery Combined With Hyperthermic Intraperitoneal Intraoperative Chemotherapy for Peritoneal Carcinomatosis Arising From Colon Adenocarcinoma

Pierluigi Pilati, MD, Simone Mocellin, MD, Carlo Riccardo Rossi, MD, Mirto Foletto, MD, Luca Campana, MD, Donato Nitti, MD and Mario Lise, MD

From the Surgery Branch, Department of Oncological and Surgical Sciences, University of Padova, Padova, Italy.

Correspondence: Address correspondence and reprint requests to: Carlo Riccardo Rossi, MD, Università di Padova, Dipartimento di Scienze Oncologiche e Chirurgiche, Sezione di Clinica Chirurgica II, Via Giustiniani, 2, 35128 Padova, Italy; Fax: 39-049-651891; E-mail: carlor.rossi{at}unipd.it

ABSTRACT

Background: Hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) has been recently proposed to treat peritoneal carcinomatosis arising from colon adenocarcinoma, which is usually regarded as a lethal clinical entity. The purpose of this study was to evaluate the clinical outcome of this combined treatment.

Methods: A retrospective study of 46 patients treated for peritoneal carcinomatosis from colon adenocarcinoma was performed. Thirty-four patients were treated with complete cytoreductive surgery immediately followed by intraoperative HIIC with mitomycin C and cisplatin. The clinical outcome of these 34 patients was analyzed; the median follow-up period was 14.5 months.

Results: No postoperative deaths were reported. The postoperative morbidity rate was 35%. No severe locoregional or systemic toxicity was observed. The 2-year overall survival was 31%, and the median survival time and the median time to local disease progression were 18 and 13 months, respectively. Survival and local disease control in patients with well- and moderately differentiated colon adenocarcinoma were significantly better than in those with poorly differentiated tumors.

Conclusions: Considering the dismal prognosis of this condition, HIIC seems to achieve encouraging results in a selected group of patients affected with resectable peritoneal carcinomatosis arising from colon adenocarcinoma. These findings support the conduction of formal phase III randomized trials.

Key Words: Peritoneal carcinomatosis • Colon adenocarcinoma • Cytoreductive surgery • Hyperthermic intraperitoneal intraoperative chemotherapy

Peritoneal carcinomatosis is the most frequent cause of death in patients affected with colon adenocarcinoma. The overall prognosis of this disease is extremely poor, with a median survival of 5 months.1

Surgery alone, even when macroscopically complete, is not adequate. In fact, microscopic residual disease is the cause of local recurrence in almost all patients.2 It has not yet been demonstrated whether systemic chemotherapy, the current treatment for this condition, affects survival.3,4 An improved understanding of the biology of gastrointestinal tumors with intraperitoneal spread without evidence of systemic metastases has prompted the search for new therapeutic approaches.5–9 In particular, the locoregional administration of antiblastic drugs is a promising approach that is potentially able to sterilize small or microscopic residuals of disease after cytoreductive surgery (CS). In fact, because of the low drug absorption through the plasma-peritoneal barrier,10 intraperitoneal drug concentrations are 18- to 620-fold higher than systemic levels.5,11 However, early postoperative intraperitoneal chemotherapy does not seem to meet the expectations.12–15 The inefficacy of postoperative intraperitoneal drug administration may be correlated with heterogeneous drug distribution caused by early postoperative adhesions in the peritoneal cavity.16 In fact, during the early postoperative period, tumor cells may be entrapped by fibrin during the wound-healing process of surgically dissected areas and, therefore, may not be adequately exposed to the antiblastic agent.12 In an attempt to improve these results, some investigators have proposed the use of intraoperative hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) after CS. The intraoperative setting allows a better drug distribution and exploits the anticancer synergism between drugs and heat,17–20 as pioneered by Spratt et al.21 Pharmacokinetics studies have shown that the penetration of drugs into tumor tissue is extremely limited, ranging from several cell layers to 1 to 3 mm from the surface.22,23 This suggests that HIIC should be planned only after complete tumor cytoreduction (macroscopic disease absent or tumor deposits <3 mm) to optimally exploit intraperitoneal chemotherapy.24

Several authors have tested the combination of CS with HIIC to treat patients with peritoneal carcinomatosis of gastrointestinal origin.25–35 There are considerable differences between series regarding both tumor-related (i.e., tumor histology and tumor stage at laparotomy) and technical (e.g., extent of CS, HIIC drugs, and temperatures) features. The 2-year survival rates range from 28% to 60%, whereas in the largest series the mortality rate is 5%.31 Given the heterogeneity of the series and the absence of phase III randomized trials, no definitive conclusions can be drawn regarding the activity of this multimodal treatment.

Here we report our experience on CS and HIIC applied to patients with colon adenocarcinoma spread to the peritoneal surface. Although this was not a large prospective study, our findings support the hypothesis that such patients may benefit from this therapeutic approach, thus prompting formal phase III studies.

PATIENTS AND METHODS

From September 1995 to October 2001, 46 patients affected with peritoneal carcinomatosis arising from colon adenocarcinoma were observed at our institution. In seven cases, the spread of cancer to the peritoneal surface was discovered at the time of the laparotomy performed to treat the primary tumor. For the remaining patients, the peritoneal invasion was metachronous. In the latter cases, preoperative evaluation of tumor spread consisted of total body computed tomography scan (n = 40) and/or positron emission tomography (n = 12). Six patients with distant disease, such as liver and/or lung metastases or invaded lymph nodes along the aorta or inferior vena cava, were considered not eligible for HIIC.

Forty patients underwent exploratory laparotomy. In six cases, peritoneal carcinomatosis was not amenable to complete CS, and, therefore, HIIC was not performed. Thirty-four patients were treated with complete CS and HIIC: they constitute the patient population of the following analysis. There were 20 men and 14 women, with a mean age of 50.1 years (range, 31–75 years). Carcinomatosis arose from grade 1, 2, and 3 adenocarcinoma of the colon in 10, 10, and 14 cases, respectively.

The treatment consisted of complete CS followed by HIIC with mitomycin C and cisplatin. This treatment was part of a therapeutic protocol approved by the local ethics committee. All patients signed a fully informed consent form.

None of the patients had received preoperative chemotherapy. Patients who experienced local and/or systemic recurrence after HIIC were treated with 5-fluoruracil–based systemic chemotherapy.

Surgery
Complete CS was required before HIIC was started and was defined as the tumor ablation (or electrocauterization) of all macroscopically visible disease, leaving in place tumor residues <3 mm in diameter. Tumor remnants >=3 mm in their maximum diameter were considered a contraindication to HIIC.

The extent of peritoneal carcinomatosis was scored with the peritoneal index, as described by Sugarbaker.36 Briefly, the peritoneal cavity was divided into 13 regions, each of which was assigned a score from 0 to 3 according to the size and extent of tumor implants (total score range, 1–39). The mean number of regions with tumor spread was 6.3 ± 2.2, and the mean peritoneal index was 13.5 ± 4.1.

Hyperthermic Intraperitoneal Intraoperative Chemotherapy
In the first 10 cases, HIIC was performed after the laparotomy was closed (closed technique), whereas for the following 24 patients we used the open technique, which is based on the use of a peritoneal cavity expander to allow the operator to mix the perfusate as described by Fujimura et al.25 A continuous closed-circuit operated by a roller pump was used, with four (two inflow and two outflow) catheters passing through the abdominal wall. Six thermal probes were placed inside the peritoneal cavity: two floated freely in the abdominal cavity, and four were placed immediately under the peritoneal layer (above and below the transverse mesocolon and in the pelvis). Chemotherapeutic agent (i.e., mitomycin C and cisplatin) dosages were based on body-surface area (i.e., 3.3 and 25 mg/m2/L of perfusate, respectively). The mean drug doses were 26.2 mg (range, 20.1–31.6 mg) and 193.7 mg (range, 170–241.1 mg), respectively.

Clinical Outcome Evaluation
Postoperative morbidity and mortality (surgery-related complications, locoregional toxicity, and systemic toxicity) rates were recorded. Locoregional toxicity was graded according to a modified version of the system of Ozols et al.37 (Table 1). Systemic toxicity was classified with the World Health Organization scale.


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  		TABLE 1. Modified Ozols’ classification of locoregional toxicity after intraperitoneal chemotherapy
 
Response to treatment was evaluated as time to local disease progression and overall survival. Local disease progression was established by means of computed tomography scan, positron emission tomography (performed every 3 months after HIIC), or both.

Data Analysis
No patient was lost to follow-up. The median follow-up was 14.5 months (range, 6–34 months). A Kaplan-Meier survival curve was fitted to the data, and a Mantel-Cox log-rank test was used to identify differences between curves. Differences were considered significant if P < .05.

RESULTS

Surgery
CS, which was complete in all cases (no visible disease, n = 25; residual tumor deposits <3 mm in diameter, n = 9), included gastrointestinal resection (colon, n = 18; stomach, n = 6; jejunum, n = 12), other intra-abdominal organ resection (spleen, n = 6; ovary and uterus, n = 7), total peritonectomy (n = 4), and partial peritonectomy (n = 29).

For all patients, HIIC lasted 90 minutes. During HIIC, the mean peritoneal temperature was 41.5°C (range, 41.2°C–42.1°C). The mean temperature difference between the upper and lower abdomen was higher (1.3°C; range, .6°C–1.9 °C) in the first 10 cases treated with the closed technique than in the following cases (.5°C; range, .3°C–.7 °C), in which the peritoneal cavity expander was used. We usually achieved a perfusate working temperature of 41.5°C to 42°C within 15 to 20 minutes, while the inflow temperature was approximately 44°C to 45°C. The perfusate flow was maintained between 700 and 1000 mL/minute. The perfusate volume depended on the patient’s body weight and ranged from 4 to 6 L. The mean operating time (CS plus HIIC) was 7.7 hours (range, 5.7–10.2 hours).

Morbidity and Mortality
No deaths were recorded during the postoperative period. Three patients had intra-abdominal complications (two abdominal abscesses and one hemoperitoneum), which required reoperation. Pleural effusion or pneumonia was recorded in four cases. According to the modified Ozols’ classification, grade I, II, III, and IV locoregional toxicity was observed in 18, 3, 1, and 1 patient, respectively. Hematological toxicity (grade I or II anemia, according to the World Health Organization classification) occurred in four cases. Excluding grade I locoregional toxicity, 12 of 34 patients experienced locoregional side effects and/or 1 or more postoperative complications (morbidity rate, 35%). The mean hospitalization time was 11 days (range, 8–32 days).

Survival
After a median follow-up of 14.5 months (range, 6–34 months), 4 patients are alive without evidence of disease, 8 are alive with disease (7 with abdominal recurrence and 1 with local relapse and distant metastases), and 22 died of disease (with abdominal recurrence, distant metastasis, or both in 13, 3, and 6 cases, respectively).

Considering the global population, the 2-year overall survival and local progression-free survival rates were 31% and 10%, respectively (Fig. 1). The estimated median survival time and median time to local disease progression were 18 and 13 months, respectively (Fig. 1).



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  		FIG. 1. Kaplan-Meier overall (OS) and local progression-free survival (LPFS) analysis of 34 patients affected with peritoneal carcinomatosis arising from colon adenocarcinoma. All patients were treated with complete cytoreductive surgery and hyperthermic intraperitoneal intraoperative chemotherapy with mitomycin C and cisplatin. The 2-year OS and LPFS rates were 31% and 10%, respectively; the median survival time and median time to local progression were 18 and 13 months, respectively.

 
A statistically different clinical outcome was observed when patients with well-differentiated (n = 10) and moderately differentiated (n = 10) colon adenocarcinoma were compared with those with poorly differentiated colon adenocarcinoma (n = 14). Median overall survival and local progression-free survival time were 20 vs. 10 months and 14 vs. 6 months, respectively (P = .013 and .001, respectively; Figs. 2 and 3Go).



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  		FIG. 2. The overall survival of patients with G1/G2 colon adenocarcinoma (n = 20) was compared with that of patients with G3 colon adenocarcinoma (n = 14). The Mantel-Cox analysis showed a significant difference between the two groups (median survival time, 20 vs. 10 months, respectively; log-rank test; P = .013).

 


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  		FIG. 3. The time to local progression in patients with G1/G2 colon adenocarcinoma (n = 20) compared favorably to that of patients with G3 colon adenocarcinoma (n = 14). The Mantel-Cox analysis showed a significant difference between the two groups (median time to progression, 14 vs. 6 months, respectively; log-rank test; P = .001).

 
Regarding the patients (n = 6) who underwent exploratory laparotomy only, the mean follow-up was 6.5 months (range, 2–9 months). All patients died of disease; four developed local progression only, and two developed local and distant metastases.

DISCUSSION

CS combined with HIIC has been proposed as a promising strategy for the treatment of peritoneal carcinomatosis. This combination treatment exploits the therapeutic advantages of surgery with those of locoregional chemotherapy and heat. Some authors, describing the application of this therapeutic approach to colon adenocarcinoma, reported 2-year survival rates of 45% to 60%.33,34,38 In case of carcinomatosis arising from less aggressive tumor types, such as appendiceal carcinomas, the clinical outcome is even better, with a 5-year overall survival ranging from 50% to 75%.35,39,40

Despite these considerations, CS combined with HIIC must still be considered an investigational treatment. Several technical aspects are still matter of debate, and reliable conclusions cannot yet be drawn because (1) the maximum-tolerated dose has been defined only for mitomycin C41; (2) phase II studies have been performed in series that are heterogeneous for tumor histological type, grading, tumor spread, extent of surgical cytoreduction, and HIIC procedures (e.g., differences in duration, temperature, drug type, and dosage); (3) only one randomized study has been performed, for which only preliminary results are available42; and (4) some authors routinely include systemic chemotherapy in their therapeutic protocols,34,39 thus undermining a correct evaluation of HIIC activity. Phase I and II studies defining the maximum-tolerated dose and activity of drugs other than mitomycin C and cisplatin are needed to maximize the antitumor activity of HIIC. For instance, in a phase I study, Bartlett et al.43 have demonstrated the possibility of administering a biological response modifier such as tumor necrosis factor-{alpha} during HIIC. However, no phase II studies on tumor necrosis factor-{alpha}–based HIIC have been reported.

In our experience, the clinical outcome was encouraging. We observed no postoperative deaths. The postoperative morbidity rate was acceptable and comparable to that reported by other investigators.31,44 The surgery-related complication rate can be considered similar to that observed in major surgery series, supporting the hypothesis that HIIC does not increase the risk of postoperative complications. The mild locoregional toxicity, together with the low rate of systemic adverse effects, strengthens our opinion that HIIC is a safe procedure. Considering the dismal prognosis of such patients, the median survival and time to progression were favorable. The clinical outcome of patients with well- or moderately differentiated colon adenocarcinomas compared favorably to that of patients with poorly differentiated tumors. Nevertheless, even in patients with G3 colon adenocarcinoma, the median overall survival was better (10 months) than that reported in the literature, regardless of histological differentiation (5 months).1 Despite these findings, it must be remembered that in our study, we enrolled only patients affected with resectable carcinomatosis, whereas epidemiological studies dealing with the natural history of peritoneal carcinomatosis include all patients affected with this condition, regardless of the disease extent within the peritoneal cavity.

In conclusion, our results confirm those obtained by other authors and support the opinion that CS plus HIIC is a feasible and safe procedure that might represent a useful therapeutic option for patients with peritoneal carcinomatosis from colon adenocarcinoma. However, given the previously described considerations, a reliable assessment of the therapeutic value of this multimodal therapy will be possible only if the technique is standardized and comparative phase III clinical studies are undertaken.

Footnotes

In this study on cytoreductive surgery followed by hyperthermic intraoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis from colon adenocarcinoma, we observed encouraging results, particularly in patients with well-differentiated tumors. These findings support the conduction of comparative phase III trials.

Received for publication August 5, 2002. Accepted for publication February 3, 2003.

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