Dr. Marcello Deraco
U.O. Melanoma e Sarcoma
Istituto Nazionale Tumori Milano
Via Venezian 1
20133 Milano, Italia
www.marcelloderaco.com info@marcelloderaco.com
Tel/ Fax: +39.02.76008435
Sugarbaker (2001) reported 86% survival on 224 patient with PMP syndrome due to a Mucinous appendiceal tumor We reported in 2004 33 patients with PMP (21 males and 12 females) were loco regionally treated. One patient underwent surgery twice because of disease recurrence. The closed abdomen technique was employed for IPHP with use of cisplatin (25 mg/m2/L) plus mitomycin-C (3.3 mg/m2/L) for 60 minutes under hyperthermic conditions (42.5 degrees C). Thirty-one patients (92%) were optimally cytoreduced. Five-year overall survival, progression-free survival, and locoregional progression-free survival rates were 97%, 43%, and 59%, respectively. Grade II and grade III morbidity was observed in 5 patient (15%) and 6 patients (18%), respectively. There was one treatment-related death (3%), 21 days after treatment. The study with the largest series was published by SITILO in 2003. Seventy patients with PMP (31 males and 39 females) were enrolled onto a Phase II clinical trial and treated with CRS+IPHP One patient was operated on twice because of disease recurrence. CRS was performed with peritonectomy procedures. The closed, opened and semi-closed abdomen techniques were employed for IPHP using cisplatin plus mitomycin-C for 60 minutes under hyperthermic conditions (42.5°C). Sixty two (87%) patients were optimally cytoreduced. Five-year overall survival, progression-free survival and locoregional progression-free survival were 91%, 54% and 69%, respectively. Thirteen Grade III complications occurred in 10 (14%) patients and the most frequent one was gastrointestinal fistula/perforation (11%). There was one case (1.4%) of treatment-related mortality 21 days after treatment. CRS associated with IPHP permitted complete tumour removal with an acceptable morbidity and mortality in patients with PMP. These studies confirmed the efficacy of the combined treatment on long-term survival and local disease control.
Sebbag et al. in 2000 reported on 33 patients with peritoneal mesothelioma treated by CRS with peritonectomy procedures and perioperative intraperitoneal chemotherapy (cisplatin, doxorubicin). Median survival was 31.0 months; overall projected survival at 3 years was 56 per cent. The most significant positive predictive factors of survival were: female sex (P= 0.003), low prior surgical score (P=0.002), completeness of cytoreduction (P=0.0002) and second-look surgery (P=0.019). The morbidity rate for this combined treatment was 33 per cent and the perioperative mortality rate was 3 per cent. The largest series of patients is that published by SITILO in 2003 (41). Sixty one patients with PM (31 males and 30 females) were enrolled onto a Phase II multicentric clinical trial. CRS was performed with peritonectomy procedures. The closed, opened and semi-closed abdomen techniques were employed for IPHP using cisplatin plus mitomycin-C or cisplatin and doxorubicin for 60/90 minutes under hyperthermic conditions (42.5°C). Mean follow-up was 20 months (range: 0.1-76). Forty six (74%) patients were optimally cytoreduced. Five-year overall and 5 yr progression-free survivals were 54% and 37%, respectively. Completeness of cytoreduction was significantly associated with outcome. Twenty Grade III complications occurred in 14 (23%) patients and the most frequent one was digestive fistula/perforation (11%). No treatment-related mortality was recorded. The authors concluded that CRS + IPHP was proven to be acceptable in terms of morbidity and mortality in patients with PM and suggest a positive impact on outcome. Further prospective controlled studies are warranted to confirm these results
Ovarian cancer with an incidence of 44.000 cases a year in 2004 in Europe, remains the most lethal of all gynaecological malignancies, being responsible for about 50% of all deaths for female genital tract cancer Piso et al. published a series of 19 patients; of those, 11 patients had recurrent and 8 primary ovarian cancer. Intraperitoneal chemotherapy consisted of either cisplatin or mitoxantrone. Macroscopically complete cytoreduction to less than 2 mm implants was achieved in 9 patients. A 5-year survival rate of 15% was reported despite a total of 9 patients with concomitant liver metastases. Survival was the same for both primary and recurrent cases. Ryu et al. published the biggest retrospective series on ovarian cancer patients treated by cytoreductive surgery with or without intraperitoneal hyperthermic chemotherapy consisting of carboplatin and interferon-α. All patients had undergone in the past the primary standard staging procedure for ovarian cancer. A total of 117 patients were reviewed and 74 of them had stage III disease. For this subgroup of patients, the median survival was 60.9 months for the 35 patients receiving both CRS and intraperitoneal hyperthermic chemotherapy compared with only 22.3 months for patients in the CRS only group (P = 0.0015). Five-year OS was 53.8% for the former and 33.3% for the latter. This is very meaningful as almost 27% of patients with advanced ovarian cancer undergoing a second surgery became long-term survivors in this study. In 2001 we evaluated 27 patients with advanced/recurrent EOC. Two-year overall survival was 55%. Median time to overall progression and local progression were 21.8 months and 16 months, respectively. Variables that affected the overall survival or time-to-progression were as follows: residual disease (p=.00025), patient age (p=.04), and lag time between diagnosis and CRS+IPHP (p=.04). Treatment-related morbidity, mortality and toxicity were 11%, 4% and 27%, respectively.
In order to confirm these apparently encouraging results, the SITILO (Italian society of integrated locoregional therapy) is conducting a prospective multicentric randomized study to test the effectiveness of secondary CRS associated with IPHP in patients with cisplatin resistant advanced EOC. Patients with EOC stage III/IV, submitted to surgical staging and 6 courses of first-line platinum based chemotherapy, and with persistent but clinically resectable disease, or early relapsing tumors (< 6months after the completion of first line chemotherapy) will be randomly allocated to one of these treatment groups: 1) Study group: secondary CRS and IPHP followed by second line chemotherapy; 2) Control group: second line chemotherapy. The primary endpoint is overall and progression-free survivals. Some secondary endpoints will be the analysis of morbidity, mortality and toxicity related to the procedure.
In 2004 in Europe, colorectal cancer was the second most common form of cancer (381,000 cases) and second most common cause of death due to cancer (203,700 deaths). At initial diagnosis of colon cancer, the peritoneal surface is involved by tumor in 10% to 15% of patients. Peritoneal surfaces is the second most common site for cancer recurrence after so-called curative colorectal cancer resections, occurring in as many 50% of patients. A retrospective multicenter study was performed to evaluate the international experience with CRS+IPHP and to identify the principal prognostic indicators. All patients had cytoreductive surgery and perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy). PC from appendiceal origin was excluded. The study included 506 patients from 28 institutions operated between May 1987 and December 2002. Their median age was 51 years. The median follow-up was 53 months. The morbidity and mortality rates were 22.9% and 4%, respectively. The overall median survival was 19.2 months. Patients in whom cytoreductive surgery was complete had a median survival of 32.4 months, compared with 8.4 months for patients in whom complete cytoreductive surgery was not possible (P <.001). The use of neoadjuvant chemotherapy, lymph node involvement, presence of liver metastasis, and poor histologic differentiation were negative independent prognostic indicators. The authors concluded that the therapeutic approach combining CRS+IPHP achieved long-term survival in a selected group of patients with PC from colorectal origin with acceptable morbidity and mortality. The complete cytoreductive surgery was the most important prognostic indicator. Verwaal et al. in 2003 published a prospective randomized study to confirm the findings from uncontrolled studies that aggressive CRS+IPHP is superior to standard treatment in patients with peritoneal carcinomatosis of colorectal cancer origin. One hundred five patients were randomly assigned to receive either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy consisting of aggressive cytoreduction with IPHP, followed by the same systemic chemotherapy regime. The primary end point was survival. After a median follow-up period of 21.6 months, the median survival was 12.6 months in the standard therapy arm and 22.3 months in the experimental therapy arm (log-rank test, P =.032). The treatment-related mortality in the aggressive therapy group was 8%. Subgroup analysis of the IPHP group showed that patients with 0 to 5 of the 7 regions of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survival than patients with 6 or 7 affected regions (log-rank test, P <.0001). If the cytoreduction was macroscopically complete (R-1), the median survival was also significantly better than in patients with limited (R-2a), or extensive residual disease (R-2b; log-rank test, P <.0001). The authors concluded that CRS+IPHP improves survival in patients with PC of colorectal origin. However, patients with involvement of six or more regions of the abdominal cavity, or grossly incomplete cytoreduction, had still a grave prognosis.
In 2004 in Europe, gastric cancer was the 5th most common form of cancer (171,000 cases) and 3th most common cause of death due to cancer (137,000 deaths). There is no standard treatment for peritoneal dissemination from gastric cancer. Yonemura et al. in the most recent article in this field reported on 107 patients with peritoneal dissemination from gastric cancer treated with surgery (conventional or peritonectomy) and IPHP. Complete cytoreduction was achieved in 47 (43.9%) of the 107 patients: Eighteen of 65 who underwent conventional surgery and 29 of 42 who had peritonectomy. Twenty-three patients (21.5%) suffered from complications. The overall operative mortality rate was 2.8 per cent. The median survival for all patients was 11.5 months, with a 5-year survival rate of 6.7%. Median survival after complete cytoreduction was 15.5 months and that after incomplete cytoreduction was 7.9 months, with 5-year survival rates of 13 and 2% respectively. Completeness of cytoreduction and peritonectomy were independent prognostic factors. The 5-year survival rate after complete cytoreduction by peritonectomy with CHPP was 27 per cent. A brief review of the literature from the other studies published in the last 5 years on this issue presents data in general confirming a survival advantage in the patients who received the combination CRS+IPHP with respect those with only palliative surgery. Moreover, the better survival was observed in the subset of patients submitted to optimal cytoreduction associated with IPHP. Most of these studies are controlled but not randomized which warrants further investigations with further formal trials to confirm these encouraging results.
