|TREATMENT OF PERITONEAL CARCINOMATOSIS FROM COLONIC CANCER BY CYTOREDUCTION, PERITONECTOMY AND HYPERTHERMIC ANTIBLASTIC PERITONEAL PERFUSION
Giovanni De Marco, Marco Vaira, Tommaso Cioppa, Camilla Bing, Silvia D'Amico, Alessandro Bruscino, Francesca Littori, Andrea Caridi, Michele De Simone
Key Words: Peritoneal carcinomatosis, HAPP, Cytoreductive Surgery, Colorectal Cancer
Abbreviated running title: Treatment of peritoneal carcinomatosis from colonic cancer
Peritoneal carcinomatosis was treated with poor results by surgery alone till a few years ago. In the ‘80s, some authors developed a technique to manage peritoneal carcinomatosis, based on surgical cytoreduction of the primitive cancer, peritonectomy and hyperthermic antiblastic peritoneal perfusion (HAPP)
From 1996 to January 2006, we performed 181 HAPPs in 176 patients affected by carcinomatosis, 36 patients were affected by colonic cancer, median age was 52,6 years (range: 19-70), 21 male (58,3%), 15 female (41,7%).
As for the HAPP to explain more clearly we have divided the patients into two groups (A and B) of treatment. Most common complications were sepsis (5 patients), postoperative haemorrhage (1 patient), dehiscence of intestinal anastomosis or bowel perforation (3 patients), biliary fistula (1 patient), pleuric effusion in 2 cases. Perioperative mortality was 2,8% (1 patient, that presented hemorrage, then sepsis, then DIC).
Regarding the first 21 patients treated with CDDP and C-mytomicin (Group A), the results where not very satisfactory, with a median survival time of 14,5 months, lower than we expected.
So we selected the last 15 patients with a PCI lower than 15 (Group B), and adopted Elias’ protocol in 11 patients (in 3 cases we could not use oxaliplatinum because of patients’ intolerance, in 1 case there was recurrence after HAPP with Oxaliplatinum). In this case, infact, the median survival of patients is 28,3 months.
Our experience based on better selection of patients ( maximum PCI index of 15), associated with complete cytoreduction (CC-0) seems to be encouraging in the patients with a complete cytoreduction and a lower PCI.
Peritoneal carcinomatosis may appear as synchronous disease or in the evolution of gastrointestinal or ovarian cancer and in pseudomyxoma peritonei (PMP) (1). Peritoneal carcinomatosis was treated with poor results by surgery alone till a few years ago. In the ‘80s, some authors developed a technique to manage peritoneal carcinomatosis, based on surgical cytoreduction of the primitive cancer, peritonectomy (stripping of implants on peritoneal surface) and hyperthermic antiblastic peritoneal perfusion (HAPP). Many studies reported an impact on overall survival and disease-free interval in patients affected by carcinomatosis arising from colonic cancer (2). The combination of hyperthermia and loco-regional chemotherapy has antineoplastic effects because the peritoneal cavity can be considered a "pharmacological sanctuary" due to the "peritoneal-plasma barrier". This barrier prevents leakage into systemic circulation of high molecular weight drugs, providing dose intensive therapy. On the other hand, hyperthermia increases drug penetration into tissues, the cytotoxicity of selected drugs, has an anti-tumor effect itself. HAPP has maximal efficacy when all the macroscopic disease has been removed (3-7).
There are three techniques described to perform HAPP : "closed", "open" and "semi-closed". We perform the semi-closed one; in this technique of ours (7), the abdominal wall is partially closed and hung onto an autostatic retractor, with only the central part of the incision remaining open. Through this small opening, the surgeon can mix the perfusate solution and check the peritoneal cavity. This allows both the homogeneous distribution of temperature and drugs and low risk of drug leakage from the abdominal cavity. From 1996 to January 2006, we performed 181 HAPPs in 176 patients affected by carcinomatosis, 36 patients were affected by colonic cancer.
MATERIALS AND METHODS
Peritoneal perfusion is effective only if it follows complete cytoreduction. The techniques of "centripetal" aggression of tumor have been codified by Sugarbaker. They are known as peritonectomy procedures, and allow removal of both visceral and peritoneal lesions. Six different techniques of peritonectomy are described: 1) Central peritonectomy consists in removal of eventual previous scars, greater omentectomy, performed by stripping of the superficial peritoneal layer of transverse mesocolon and a close dissection to the greater curvature of stomach. Sometimes splenectomy could be necessary en bloc with the greater omentum and the left diaphragmatic peritoneum; 2) Left upper quadrant peritonectomy: stripping of peritoneal tumor tissue from beneath the left hemidiaphragm, left adrenal gland, distal portion of the pancreas, and cephalad one-half of Gerota’s fascia; 3) Right upper quadrant peritonectomy consists in: right hemidiaphragmatic peritoneal stripping, removal of tumor from right subhepatic space and from the surface of the liver by stripping of Glisson’s capsule. Peritonectomy is concluded by removal of the peritoneum covering the right kidney and Morrison’s pouch; 4) Lesser omentum peritonectomy: after the cholecistectomy, the cancerous tissue which covers the common duct and hepatic artery is stripped from the base of gall bladder bed towards the duodenum. This phase is concluded by the stripping of omental bursa; 5) Pelvic peritonectomy with en bloc removal of pelvic peritoneum, sigmoid colon, rectum, uterus and adnexa; 6) Peritonectomy of lateral abdominal wall. Peritonectomies are variously combined with resections of viscera involved by tumor.
SEMICLOSED HAPP TECHNIQUE
When complete cytoreduction has been achieved, the procedure is completed by HAPP. The "semi-closed" technique (8) consists of placing 5 drain tubes into the abdominal cavity: there are two inflow ones, and they have multiple holes. They are Y-shaped and present 4 diffusion lines for the homogeneous distribution of drugs into the abdominal cavity (1 subdiaphragmatic branch, 1 sovramesocolic branch, 1 among the ileal loops, 1 in the pelvis). Three outflow tubes are placed respectively in the pelvis and in the subdiaphragmatic spaces. Backaus forceps are used to close the cranial and caudal portion of abdominal wound. The skin is then suspended to self-retainig retractor, placed at more or less 15 cm from abdomen, by plastic self-blocking strings. This kind of placement creates the virtual cavity needed to perform HAPP. The central portion of the wound is suspended to the retractor too and covered with a PVC sheet with a hole in the middle. The drain tubes are connected to a perfusion system formed by two pumps and a heat exchanger to heat the perfusion liquid. The pumps (inflow and outflow), are connected through a reservoir, so it’s possible to achieve continuous circulation of the perfusate at the speed of more or less 1 lt/min. The pumps are controlled by a computed system, that allows checking of the flow rate and the temperature of the heat exchanger. Three intraperitoneal temperatures are checked by probes; the inflow, outflow, and the patient oesophageal temperature. The amount of the circulating perfusate (solution for peritoneal dialysis) is calculated according to patient body surface. There are different drugs employed and these are chosen according to the neoplasia hystological type. During perfusion, the surgeon mixes the perfusate by hand through the hole in the PVC sheet. When ideal intraperitoneal temperature is reached, the drugs are added to the circuit and H.A.P.P. is performed for 30 or 60 minutes, depending on protocol used.
From October 1995 to January 2006 we performed 277 Operations for "Peritoneal Carcinomatosis"; 37 Explorative Laparotomy, 48 Debulking (Peritonectomy) without HAPP; 11 Citoreduction with EPIC (Early Postoperative Intraperitoneal Chemotherapy) and 181 HAPP on 176 patients. In those 181 cases, the peritoneal carcinomatosis arose from colorectal cancer in 36 cases; from PMP in 44 cases; from ovarian cancer in 47 cases; from peritoneal mesothelioma in 27 cases; from abdominal sarcoma in 15 cases; from gastric cancer in 6 cases; from other cancers in 6 cases (e.g. endometrial carcinoma, small cell desmoplastic tumor).
Regarding the 36 patients with carcinomatosis from colonic cancer, the median age was 52,6 years (range: 19-70), 21 were male (58,3%), 15 female (41,7%). The primitive cancer arose from left colon and rectum in 22 cases (61,1%), from right colon in 11 cases (30,5%), from transverse colon in 2 cases (5,5%), from unknown segment of colon in 1 case ( 2,7%). For all patients histology was colonic adenocarcinoma, 15 patient (41,6%) presented the histological feature of signet ring cell. 32 patient (88,8%) had undergone previous surgical procedures (6 diagnostic laparoscopy or laparotomy, 26 bowel resection or debulking operations). 18 patients (50%) had received systemic chemotherapy before our operation. 4 patients (11,1%) had bowel obstruction before the operation. The median PCI (peritoneal carcinomatosis index, an index of peritoneal carcinomatosis diffusion with a range from 0 to 39, where 0 means absence of disease) was 14,6.
We performed a variable number of visceral resection (bowel, greater omentum, hystero-oophorectomy, cholecistectomy, spleen resection), combined with multiple peritonectomies: 28 epigastric, 15 right diaphragm, 8 left diaphragm, 29 central, 29 pelvic, 14 left abdominal wall, 12 right abdominal wall peritonectomies.
The CC (Completeness of Cytoreduction, a score that varies from 0 to 2, where 0 means absence of residual disease) was CC-0 in 26 patients (72%), CC-1 in 2 patients ( 5,5%), CC-2 in 8 patients (22,2%). We performed 1 bowel anastomosis in 18 patient (50%), 2 bowel anastomosis in 10 patient (27,7%), in 8 patient were not performed bowel anastomosis (22,2%).
In 5 cases we protected the anastomosis with lateral temporary ileostomy, in 5 cases we performed a definitive colostomy.
As for the HAPP to explain more clearly we have divided the patients into two groups (A and B).
In group A , 21 patients were treated with a protocol based on administration of Cisplatinum 100 mg/sm plus C-Mitomycin 16 mg/sm for 60 minutes, with a peritoneal temperature of 41,7°C.
In group B, 15 patients were selected with PCI<15; 11 patients were treated following Elias’protocol combining i.v. administration of folinic acid 20 mg/sm plus 5-FU 400 mg/sm associated with peritoneal administration of Oxaliplatinum 460 mg/sm for 30 minutes with a peritoneal temperature of 41°C (9). The other 4 patients were treated with C-Mitomycin 35mg/sm for 60 minutes with a peritoneal temperature of 40,5°C, according to the Netherland protocol (10): 3 patients because of serious side effects from preoperative systemic chemotherapy with platinum compounds, 1 patient for recurrence after HAPP with Oxaliplatinum. The overall median duration of the operation, included HAPP, was 10,5 hours (range: 6-14).
Because of the massive involvement of viscera and peritoneum, in some selected patients we performed the treatment in steps. In fact 3 patients were treated in 2 steps, and one patient in 3 steps. In these cases, we perform the upper abdomen cytoreduction in the first step, then the patient is submitted to systemic chemotherapy for 2 or 3 months. The second step consists in lower abdomen cytoreduction and peritoneal perfusion of all the peritoneal cavity.
In the 36 patients who underwent cytoreduction + HAPP, morbidity rate was 28,8% and in 5 cases re-intervention was necessary (3 for bowel perforations, 1 for hemorrage, 1 for biliary fistula from round ligament).
Most common complications were sepsis (5 patients), postoperative haemorrhage (1 patient), dehiscence of intestinal anastomosis or bowel perforation (3 patients), biliary fistula (1 patient), pleuric effusion in 2 cases.
Perioperative mortality was 2,8% (1 patient, that presented hemorrage, then sepsis, then DIC).
Regarding the first 21 patients treated with CDDP and C-mytomicin (Group A), the results where not very satisfactory, with a median survival time of 14,5 months, lower than we expected.
Survival was calculated using the method of Kaplan-Meier. (Tab. 1).
We observed that in this group the median PCI was 17 (70 % of the patients had a PCI higher than 13 and 6 patients had a PCI higher than 20), the CC score for 8 of those patients was 2, meaning an incomplete cytoreduction; the median duration of the operation was 12 hours, meaning a large diffusion of carcinomatosis, requiring aggressive visceral resections, linked with high postoperative complication rate.
We observed, however, that in this group, the patients with a complete cytoreduction and a lower PCI index showed an overall survival of 17,5 months, higher than the median survival of the entire group.
These data, together with the excellent results published by Elias, convinced us to: 1) make a better selection of the patients, including in the protocol patients with a maximum PCI index of 15; 2) introduce Elias’ protocol of treatment based on folinic acid plus 5-FU i.v associated with peritoneal perfusion with oxaliplatinum.
So we selected the last 15 patients with a PCI lower than 15 (Group B), and adopted Elias’ protocol in 11 patients (in 3 cases we could not use oxaliplatinum because of patients’ intolerance, in 1 case there was recurrence after HAPP with Oxaliplatinum). The median PCI was 13,5 and we achieved complete cytoreduction (CC-0) in all patients. In this selected group the median survival is then climb up to 28,3 months. Survival was calculated using the method of Kaplan-Meier. (Tab. 2).
The first patient was operated on 40 months ago and he is AWD (alive with disease), 2 patients are A.W.D. at a F.U. of 8 and 10 months, 9 patients are NED ( no evidence of disease) at a F.U. (follow up) with range 6-36 months, 1 patient DOD (died of disease) with relapse 3 months after the operation, 1 patient died 2 months after operation of heart infarction, 1 patient had a small
relapse in the abdominal wall 12 months after the treatment and underwent node resection and HAPP again with C-Mytomicin alone 7 months ago.
In current surgical practice, peritoneal seeding from colorectal cancer found at the time of surgical exploration is treated by colectomy alone. The patient is given a poor prognosis and is usually referred for systemic chemotherapy. Unfortunately, in these patients, long-term survival is rarely, if ever, achieved. The principal studies dedicated to the natural history of peritoneal carcinomatosis from colorectal cancer confirmed this poor prognosis, with a median survival ranging between 6 and 8 months and no 5-year survivors. (2,11-13)
The carcinomatosis extent was found to be the principal prognostic indicator, but even with a limited extent, median survival of peritoneal carcinomatosis did not exceed 10 months.
In the last decade, results of locoregional treatment giving a hope of cure in selected carcinomatosis patients emerged.
The combination of hyperthermia and loco-regional chemotherapy has antineoplastic effects because the peritoneal cavity can be considered a "pharmacological sanctuary" due to the "peritoneal-plasma barrier". This barrier prevents leakage into systemic circulation of high molecular weight drugs, providing dose intensive therapy. On the other hand, hyperthermia increases drug penetration into tissues, the cytotoxicity of selected drugs, has an anti-tumor effect itself. HAPP has maximal efficacy when all the macroscopic disease has been removed (3-7).
A preliminary results of a phase III study of HAAP combined with C-Mitomycin was reported by the Netherlands Center Institute (10). Patients with known colorectal carcinomatosis were preoperatively randomly assigned to standard treatment with palliative surgery followed by systemic Fluorouracil and Leucovorin or treatment with maximal cytoreductive surgery with HAAP.
After a mean follow-up of 24 months, the 2-year survival rates were 43% in the experimental group and 16% in the standard group (P=.01). The study was stopped for ethical reasons.
A study of Glehen (2) et al including a large population of 506 patients, confirmed the interesting survival results observed in all these single institution studies using the combination of cytoreductive surgery and perioperative intraperitoneal chemotherapy for the treatment of colorectal carcinomatosis. With an overall median survival time of 19.2 months, the 3-year and 5-year survival rates were 39% and 19%, respectively. Thirty-eight 5-year survivors were observed, whereas no patient survived beyond 5 years in the studies dedicated to the natural history of colorectal carcinomatosis. The combination of two aggressive locoregional therapeutic approaches can lead to increased morbidity and mortality rates. This study reported morbidity and mortality rates of 22.9% and 3.7%, respectively, with 8.3% of digestive fistula. These results are comparable to those previously reported by the two most important trials dedicated to the analysis of the complications that occur after cytoreductive surgery and perioperative intraperitoneal chemotherapy and that concluded that morbidity was correlated with the magnitude of surgery (14,15). No evaluation of the magnitude of surgery was recorded in the present study, but we observed that extended carcinomatosis that required extensive cytoreductive surgery had a significant negative influence on the rate of complications.
Elias et al (16), who treated patients with the combined procedures only when complete cytoreductive surgery was possible, previously reported that morbidity rates were correlated with carcinomatosis extent. Surgeons must use their judgment to achieve a balance between the postoperative risk of extensive surgery and potential benefit in survival and quality of life. Extended carcinomatosis was also an independent negative prognostic indicator. Its association with other negative prognostic indicators, such as lymph node involvement, poor differentiation, and liver metastasis, may lead to contraindicate patients for aggressive surgery combined with perioperative intraperitoneal chemotherapy with a curative intent.
The high but acceptable rate of complications emphasizes the necessity for careful patient selection. As age greater than 65 years seemed to be a significant negative prognostic indicator of survival, this aggressive combined procedure should be reserved for younger patients, without cardio-respiratory or renal failure, especially when carcinomatosis is extended and requires an extensive cytoreductive surgery to expect survival benefit. As it was previously reported the completeness of cytoreduction was the principal independent prognostic indicator. For patients treated with complete cytoreduction, the median survival reached 32.4 months, and the 5-year survival rate was 31%.
In our experience, cytoreduction and HAPP in patients with a PCI index higher than 15 and without a complete cytoreduction has shown worse results than we expected (Group A). Regarding Group B our experience based on better selection of patients (maximum PCI index of 15), associated with complete cytoreduction (CC-0) seems to be encouraging, infact, in this group, the median survival reached 28.3 months.
The main morbidities associated with HAPP combined with cytoreductive surgery are caused by complications of surgery: anastomotic leakages, intraperitoneal sepsis or abscesses.
Results of three multivariate analyses (14-15,17) have showed that the independent factors of morbidity were duration of surgery, extent of carcinomatosis, the number of anastomoses done, and sex. Cytoreductive surgery seems to be the major cause of these complications, but HAPP might also be responsible. The extent and stage of the carcinomatosis has also been reported as an important predictive factor of morbidity. The main morbidity from HAPP is haematological toxic effects, which are reported to arise in 8–31% of patients. Renal toxic effects, when HAPP is delivered with cisplatin, have also been reported.
Although this treatment may improve survival, a great number of patients will have recurrent disease within the first 3 years, hence, because locoregional recurrences occurred in 41.9% of patients treated with CCR-0 or CCR-1 resection and because their median disease-free survival time was 13 months, a second-look procedure may be indicated at 1 year for patients who present without any evidence of recurrence on morphologic exams.
Recurrences with limited carcinomatosis, often undetectable on the standard morphologic exams, could be treated with greater efficiency with a second combined procedure. Independent negative prognostic indicators included lymph node involvement and synchronous resection of liver metastasis. Because they seemed to profoundly influence the prognosis, they must be carefully assessed with preoperative computed tomography scan and/or intraoperative ultrasonography for the detection of liver metastasis and multiple intraoperative biopsies for the assessment of lymph node involvement.
They usually indicate systemic dissemination of the disease. An exclusive locoregional therapeutic approach for a disease that is not confined to the peritoneum cannot be sufficient. Additional systemic chemotherapy should be indicated in these cases.
These recurrences, hence, most often occur intra-abdominally, even if the abdomen is assumed to be free of tumor nodules after the initial cytoreduction and HAPP (R-1 and R-2a).
This contrasts with the natural history of colon cancer; in one-half of patients with colon cancer, the first site of recurrence is the liver. The pattern corresponds more to findings in rectal cancer, where local recurrence occurs more often. The tendency for intra-abdominal recurrences instead of hematogenic metastases can be explained in two ways: either a biological mechanism makes cancer cells more adherent to the peritoneum and encourages local seeding rather than hematogenic spread or else intraabdominal recurrence occurs long before systemic metastases develop (18).
In the literature, complete cytoreduction associated with HAPP permits encouraging results both for overall survival and disease free interval in the treatment of peritoneal carcinomatosis from colonic cancer. In our opinion, these results can be achieved if there is a correct selection of the patients associated with a complete cytoreduction with no residual macroscopic disease. The use of new drugs in HAPP, such as Oxaliplatin, may improve these results.
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