Tommaso Cioppa

Treatment of Peritoneal Carcinomatosis by Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemoperfusion (IHCP): Postoperative Outcome and Risk Factors for Morbidity

BackgroundCytoreductive surgery with limited or extended peritonectomy associated with intraperitoneal hyperthermic chemoperfusion (IHCP) has been proposed for treatment of peritoneal carcinomatosis (PC) from abdominal neoplasms.MethodsFifty-nine patients with PC from abdominal neoplasms underwent 61 treatments using this technique from January 2000 to August 2005. Surgical debulking, completed by partial or total peritonectomy, was performed in most cases. In 16 patients with positive peritoneal cytology without macroscopic peritoneal disease, IHCP was performed in order to prevent peritoneal recurrence. IHCP was carried out throughout the abdominopelvic cavity for 60 minutes using a closed abdomen technique. Intra-abdominal temperature ranged between 41°C and 43°C; mitomycin C (25 mg/mq) and cisplatin (100 mg/mq) were the anticancer drugs generally used, and they were administered with a flow rate of 700–800 ml/minute.ResultsMean hospital stay was 13 ± 7 (range 7–49) days. Postoperative complications occurred in 27 patients (44.3%); of these, major morbidity was observed in 17 (27.9%). The most frequent complications were wound infection (9 cases), grade 2 or greater hematological toxicity (5 cases), intestinal fistula (5 cases), and pleural effusion requiring drainage (5 cases). Reoperation was necessary in 5 patients (8.2%). One patient with multiorgan failure died in the postoperative period (mortality rate: 1.6%). Multivariate analysis of several variables identified completeness of cancer resection (CCR-2/3 vs. CCR-0/1, relative risk: 9.27) and age (relative risk: 1.06 per year) as independent predictors of postoperative morbidity. Preliminary follow-up data indicate that survival probability may be high in patients with ovarian or colorectal cancer and low in patients with gastric cancer.ConclusionsIHCP combined with cytoreductive surgery involves a high risk of morbidity, but postoperative complications could be resolved favorably in most cases with correct patient selection and adequate postoperative care. Tumor residual and advanced age significantly increase the risk of morbidity after this procedure.

Multicystic peritoneal mesothelioma: outcomes and patho-biological features in a multi-institutional series treated by cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

AIM This retrospective multi-institutional study addresses the role of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of multicystic peritoneal mesothelioma (MCPM). MCPM is an uncommon tumour with uncertain malignant potential and no current standard therapy. Additionally, poorly defined pathological and biological features of this disease were investigated. METHODS Twelve patients with MCPM underwent 14 procedures of cytoreduction and HIPEC in two Italian referral centres. Nine patients had recurrent disease after previous debulking (one operation in six patients, two in two, four in one). Biological markers related to mesothelioma origin and clinical features were assessed by immunohistochemical studies. RESULTS Median follow-up was 64 months (range 5-148). Optimal cytoreduction (residual tumour nodules ≤2.5 mm) was performed in all the procedures. One grade IV postoperative complication (NCI/CTCAE v.3.0) and no operative death occurred. All the patients are presently alive with no evidence of disease, including two patients who underwent the procedure twice, due to locoregional disease recurrence. Five- and ten-year progression-free survival was 90% and 72%, accounting for a. statistically significant difference (P = 0.0001) with progression-free survival following previous debulking surgery (median 11 months; range 2-31). All cases showed low proliferative activity assessed by mitotic rate and Ki-67 expression. CONCLUSIONS MCPM is a borderline tumour with a high propensity to local-regional recurrence. Definitive tumour eradication by means of cytoreduction and HIPEC seems more effective than debulking surgery in preventing disease relapse. Low mitotic rate and poor Ki-67 expression might be related to the peculiar behaviour of MCMP.

Breast Cancer Local Recurrence: Risk Factors and Prognostic Relevance of Early Time to Recurrence

BackgroundLocal recurrence occurs in 10%–20% of patients treated with breast-conserving surgery for stage I–II breast cancer. The aim of the present study was to investigate breast cancer local recurrence, potential risk factors, and prognostic impact.MethodsA total of 503 patients treated with breast-conserving surgery were included in the study. All patients underwent axillary dissection and postoperative radiotherapy, and all patients had negative margins at pathological examination. Median follow-up was 82 months. Local recurrence was classified as early when it occurred within 2 years from surgery. The risk factors for local recurrence and overall survival were estimated by univariate and multivariate analyses.ResultsForty-six cases (9.1%) of local recurrence were observed, 11 of which occurred within 24 months of surgery; the other 35, sometime later. Statistically significant risk factors for local recurrence were premenopausal status, peritumoral vascular invasion, multifocality, and absence of estrogen receptors. Independent negative prognostic factors for overall survival at 5 and 10 years were N stage, absence of estrogen receptors, and early time to recurrence. Overall survival at 10 years was 10.0% for patients with early recurrence, 87.5% for patients with late recurrence, and 87.9% for patients without recurrence.ConclusionsNone of the studied clinicopathological characteristics alone is a determinant for the choice of surgical treatment. Younger patients treated with breast-conserving surgery should receive aggressive postsurgical treatment and should be followed with an intensive follow-up program when metastatic axillary lymph nodes, negative estrogen receptors, or peritumoral vascular invasion are present.

FOLFOX-4 Stop and Go and Capecitabine Maintenance Chemotherapy in the Treatment of Metastatic Colorectal Cancer

Objective: Patients with metastatic colorectal cancer (MCC) usually receive FOLFOX-4, or other oxaliplatin (L-HOP)-based regimens, until the occurrence of progressive disease, with an increase in the incidence of neurotoxicity which is correlated to the cumulative dose of L-HOP. The aim of this study was to evaluate if FOLFOX-4 stop and go and capecitabine maintenance chemotherapy is associated with a low incidence of severe neurotoxicity in the treatment of MCC patients. Methods: Thirty-three patients were treated with FOLFOX-4 (L-HOP 85 mg/m2 day 1, leucovorin 200 mg/m2, 5-fluorouracil bolus 400 mg/m2 and 22 h 600 mg/m2 days 1 and 2, every 2 weeks). Patients who achieved objective response (OR) or stable disease (SD) then received oral capecitabine 2,500 mg/m2 days 1–14 every 3 weeks; L-HOP was reintroduced as soon as progression occurred. Results: Twenty-eight of the 29 patients who achieved OR or SD then received capecitabine. FOLFOX-4 was reintroduced in 18 patients (56.2%). The median response duration (RD) was 9.2 months and median progression-free survival (PFS) was 8.6 months. Twenty-eight patients (87.5%) had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 1 patient (3.1%). Conclusions: FOLFOX-4 stop and go and capecitabine maintenance chemotherapy was associated with a very low incidence of grade 3 neurotoxicity. Although the number of patients enrolled was far too low for a definite conclusion, RD and PFS were comparable to those usually reported in the treatment of MCC patients.

PRIMARY OSTEOSARCOMA OF THE KIDNEY WITH RETROPERITONEAL HEMORRHAGE. CASE REPORT AND REVIEW OF THE LITERATURE

Primary osteosarcoma of the kidney is a very rare neoplasm with a very poor prognosis and unclear histogenesis. Only 20 cases have been reported in the literature. It has a strong tendency to recur locally and spread to distant sites. We present the clinical case of a 79-year-old man affected by a primary osteosarcoma of the kidney presenting with substantial retroperitoneal tumor hemorrhage. Laparotomy revealed a massive retroperitoneal hematoma due to a bleeding large stony renal mass with multiple bizarre calcifications. The diagnosis of primary renal osteosarcoma was made on the basis of hematoxylin-eosin staining and confirmed by electron microscopy. Hematoma drainage and radical nephrectomy were performed. To our knowledge this is the first case of bleeding renal osteosarcoma reported in the literature. The most important clinical findings, the pathogenesis and the treatment modalities of this rare neoplasm are discussed.

Pharmacokinetics of mitomycin C after resection of peritoneal carcinomatosis and intraperitoneal chemohyperthermic perfusion.

Abstract Over the last few years surgery on patients with abdominal malignancies has become more aggressive but the majority of patients present locoregional recurrence as peritoneal dissemination. Cytoreductive surgery followed by intraperitoneal chemohyperthermic perfusion (ICHP) has been described for treatment and prevention of locoregional cancer spread from various origins. This paper reports our study of the pharmacokinetics of mitomycin C (MMC) administered by intraperitoneal chemohyperthermic perfusion (ICHP) in patients with peritoneal carcinomatosis. 28 patients received MMC 20 mg/m2 intraperitoneally as a perfusion over 60 min. MMC was determined in perfusate, plasma and urine samples with a UVHPLC method. A compartmental model was used to fit the drug concentrations in plasma and perfusate. Our results showed a mean maximum plasma concentration (Cmax) of 0.14±0.086 μg/ml with a peak time (Tmax) of 48..7 ± 5.61 min. The mean area under the curve (AUC) and terminal half-life (t1/2 ) were 15.8 ± 9.8 mg x min / L and 83.7 ± 31.74 min respectively. Clearance (CL) was estimated by fitting the data by a compartmental model and the mean value was 72 ± 66 L/h. The percent of the dose absorbed was very variable and ranged between 14 and 57% (mean 37 ± 14%). The mean percentage of dose recovered unchanged in the urine during 24 hours was 7.21 ± 3.73%. We conclude that ICHP in patients with peritoneal surface malignancies seems to have clinical value since it gives high peritoneal and tumor MMC concentrations with limited systemic exposure and toxicity.

Peritoneal Carcinomatosis from Gastric Cancer

Gastric cancer (GC) is the fourth most common cancer worldwide and the second leading cause of cancer-related mortality [1, 2]. In addition to hematogenous spread, GC may disseminate along the inside surface of the peritoneal cavity, leading to a condition of peritoneal carcinomatosis (PC). In patients undergoing a potentially curative resection of GC, PC may occur in 5–20% [3]. PC of gastric origin has an extremely poor prognosis, with a median survival estimated to be 1–3 months. Systemic chemotherapy has limited effects on this condition, with a median survival of 7–10 months [4–9]. Since 1990, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been used to treat PC from gastrointestinal and ovarian malignancies [10, 11]. CRS is used primarily to treat gross and macroscopic disease, as experimental studies suggest that local chemotherapy may penetrate to a maximal depth of 3 mm [12]. Additionally, CRS also removes intra-abdominal adhesions, allowing greater distribution of cytotoxic agents [13]. The ultimate intent of CRS plus HIPEC is to excise all macroscopic disease and, upon completion, treat the residual tumor or microscopic disease of the peritoneal cavity with chemotherapy agents delivered directly to the site of disease. This higher local concentration of cytotoxic chemotherapy reaches residual microscopic tumor cells [12], and the combination of hyperthermia and chemotherapy has a synergistic effect, thus augmenting the cytotoxicity of chemotherapeutics [13].

Treatment of Peritoneal Carcinomatosis from Colonic Cancer by Cytoreduction, Peritonectomy and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Experience of 12 Years

INTRODUCTION Peritoneal carcinomatosis (PC) is one of the routes of dissemination of abdominal neoplasms and is generally considered a lethal disease, with a poor prognosis by conventional chemotherapeutic treatments. While systemic chemotherapy has little impact on the treatment of peritoneal disease, some centers have reported encouraging results with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). This approach is based on surgical cytoreduction of the primary tumour, peritonectomy (stripping of implants on the peritoneal surface) and HIPEC. The rationale of this treatment, after macroscopic disease removal, is to obtain an elevated and persistent drug concentration in the peritoneal cavity, with limited systemic effects. Many studies have reported encouraging results on overall survival (OS) and the disease-free interval in patients affected by PC. PATIENTS AND METHODS From October 1997 to November 2008, 411 operations for PC were performed in our institution; in 232 cases, cytoreduction plus HIPEC was carried out. Out of 72 operations for colonic cancer: 40 cytoreductions plus HIPEC, 12 cytoreductions+ EPIC (early postoperative intraperitoneal chemotherapy) and 16 debulking or explorative laparoscopies/laparotomies were performed. For the present study, the 40 patients who had undergone cytoreduction plus HIPEC for PC of colorectal cancer (CRC) were considered. RESULTS The complication rate was 55% (22/40) and mortality rate 2.5% (1/40). The specific features of both groups were considered for the survival curves and complication rates, with special reference to the peritoneal carcinomatosis index (PCI; range 0, absence of disease to 39) and completeness of cytoreduction score (CCR; 0, no residual tumor, to CCR 3, residual nodules greater than 25 mm). In Group A, patients operated on prior to 2002, the median survival time was 16.7 months compared to 24.6 months for Group B, those operated on after 2002. The poor survival of Group A seemed to be related to higher PCI and CCR scores. CONCLUSION Correct patient selection based on a maximum PCI of 16, associated with complete cytoreduction (CCR-0), produced encouraging results in our experience. To improve this encouraging survival outcome, it is very important to unify the surgical experience of expertise centres. Our results also suggest the need for an integrated approach to this condition to identify the correct aspect of the surgical domain and results that may be influencing the prognosis and the evolution of this patients.

31 ORAL Treatment of peritoneal carcinomatosis by cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion (IHCP). Postoperative complications and preliminary survival data

CS is high and the efficacy of HIPEC is questionable. In order to improve the results of treatment of PC with regard to perioperative morbidity and survival, new treatment stategies are required. RIT has shown be an effective treatment modality for hematological neoplasms and shows promising results in the treatment of small volume disease, and therefore holds a promise as adjuvant therapy after CS of PC. Materials and methods: PC was induced in male Wag/Rij rats by intraperitoneal injection of 2× 106 the syngeneic CC531coloncarcinoma. Seven days after tumour induction, the animals underwent surgical cytoreduction. The rats were then randomized into three groups. CS alone, CS+HIPEC or CS+RIT. Both HIPEC and RIT were applied immediately following surgery. RIT consisted of the intraperitoneal injection of 2 mCi 177Lu-labeled antiCC531 monoclonal antibody. HIPEC was performed by a closed abdomen perfusion technique using mitomycin C in a concentration of 16 mg/l during 60 minutes. Survival was the primary outcome parameter. Results: CS and CS+RIT were well tolerated. In contrast, animals that received postoperative HIPEC showed significantly more weight loss than the CS group or the group treated with CS+RIT (P<0.001 for both comparisons). The intra-abdominal temperature during the HIPEC procedure ranged between 40.4 41.6°C, median 41.0°C. Median survival of the rats in the CS, and CS+HIPEC and CS+RIT groups was 57, 76 and 93 days respectively. Survival in the CS+RIT group was significantly better than in the CS alone group (P<0.03), whereas no significant difference was found between CS en CS+HIPEC (P=0.2) or between CS+RIT and CS+HIPEC (P=0.5). Conclusion: The application of adjuvant RIT after CS for the treatment of PC of colonic origin is at least as effective as adjuvant HIPEC whereas RIT results in lower toxicity than HIPEC.