Cytoreduction and HIPEC in the treatment of "unconventional" secondary peritoneal carcinomatosis

BACKGROUND: Peritoneal metastasis (PM) is considered a terminal and incurable disease. In the last 30 years, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) radically changed the therapeutic approach for these patients and is regarded as the standard of care for pseudomyxoma peritonei from appendiceal cancer and peritoneal mesotheliomas. Improved survival has also been reported in treating PM from ovarian, gastric, and colorectal cancers. However, PM often seriously complicates the clinical course of patients with other primary digestive and non-digestive cancers. There is increasing literature evidence that helped to identify not only the primary tumors for which CRS and HIPEC showed a survival advantage but also the patients who may benefit form this treatment modality for the potential lethal complications. Our goal is to report our experience with cytoreduction and HIPEC in patients with PM from rare or unusual primary tumors, discussing possible "unconventional" indications, outcome, and the peculiar issues related to each tumor. METHODS: From a series of 253 consecutive patients with a diagnosis of peritoneal carcinomatosis and treated by CRS and HIPEC, we selected only those with secondary peritoneal carcinomatosis from rare or unusual primary tumors, excluding pseudomyxoma peritonei, peritoneal mesotheliomas, ovarian, gastric, and colorectal cancers. Complications and adverse effects were graded from 0 to 5 according to the WHO Common Toxicity Criteria for Adverse Events (CTCAE). Survival was expressed as mean and median. RESULTS: We admitted and treated by CRS and HIPEC 28 patients with secondary peritoneal carcinomatosis from rare or unusual primary tumors. Morbidity and mortality rates were in line with those reported for similar procedures. Median survival for the study group was 56 months, and 5-year overall survival reached 40.3 %, with a difference between patients with no (CC0) and minimal (CC1) residual disease (52.3 vs. 25.7), not reaching statistical significance. Ten patients are alive disease-free, and eight are alive with disease. CONCLUSIONS: Cytoreduction and HIPEC should not be excluded "a priori" for the treatment of peritoneal metastases from unconventional primary tumors. This combined therapeutic approach, performed in an experienced center, is safe and can provide a survival benefit over conventional palliative treatments

Computerized system for staging peritoneal surface malignancies

Background: Peritoneal surface malignancies (PSMs) are usually staged using Sugarbaker's Peritoneal Cancer Index (PCI) and completeness of cytoreduction score (CC-s). Although these staging tools are essential for selecting patients and evaluating outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), both scoring models lack some anatomic information, thus making staging laborious and unreliable. Maintaining Sugarbaker's original concepts, we therefore developed a computerized digital tool, including a new anatomic scheme for calculating PCI and CC-s corresponding closely to patients' real anatomy. Our new anatomic model belongs in a web-based application known as the PSM Staging System, which contains essential clinical and pathological data for the various PSMs currently treated. Methods: The new digital tool for staging PSM runs on a personal computer or tablet and comprises male and female colored anatomic models for the 13 endoabdominal regions, with borders defined according to real anatomic landmarks. A drag-and-drop tool allows users to compute the PCI and CC-s, making it easier to localize and quantify disease at diagnosis and throughout treatment, and residual disease after CRS. Conclusions: Once tested online by registered users, our computerized application should provide a modern, shareable, comprehensive, user-friendly PSM staging system. Its anatomic features, along with the drag-and-drop tool, promise to make it easier to compare preoperative and postoperative PCIs, thus improving the criteria for selecting patients to undergo CRS plus HIPEC. By specifying the size, site, and number of residual lesions after CRS plus HIPEC, our digital tool should help stratify patients into outcome classes

Prevention of Peritoneal Metastases from Colon Cancer in High-Risk Patients: Preliminary Results of Surgery plus Prophylactic HIPEC

The study compared the outcome in patients with advanced colonic cancer at high risk of peritoneal metastases (mucinous or signet-ring cell) without peritoneal or systemic spread, treated with standard colectomy or a more aggressive combined surgical approach. The study included patients with colonic cancer with clinical T3/T4, any N, M0, and mucinous or signet ring cell histology. The 25 patients in the experimental group underwent hemicolectomy, omentectomy, bilateral adnexectomy, hepatic round ligament resection, and appendectomy, followed by HIPEC. The control group comprised 50 patients treated with standard surgical resection during the same period in the same hospital by different surgical teams. Outcome data, morbidity, peritoneal recurrence rate, and overall, and disease-free survival, were compared. Peritoneal recurrence developed in 4% of patients in the experimental group and 22% of controls without increasing morbidity (P < 0.05). Actuarial overall survival curves disclosed no significant differences, whereas actuarial disease-free survival curves showed a significant difference between groups (36.8 versus 21.9 months, P < 0.01). A more aggressive preventive surgical approach combined with HIPEC reduces the incidence of peritoneal recurrence in patients with advanced mucinous colonic cancer and also significantly increases disease-free survival compared with a homogeneous control group treated with a standard surgical approach without increasing morbidity

Peritonectomy Procedures and HIPEC for Peritoneal Metastasis from Ovarian Cancer

Peritoneal carcinomatosis (PC) is the most impressive and frequent evidence of loco-regional spread of epithelial ovarian cancer (EOC). For most of its natural history, PC remains confined to the peritoneal district, thus representing a target for various combinations of surgery and systemic or loco-regional chemotherapy. PC is observed both in primary settings, i.e. in patients first treated for locally advanced EOC, and in recurrent, previously treated, EOC patients at any FIGO stage. Since 2000s, the use of hyperthermic intraperitoneal chemotherapy (HIPEC) combined with maximum cytoreduction (peritonectomy) has gradually spread in the treatment of PC from ovarian cancer, as well as for gastrointestinal carcinomatosis and primary tumours of the peritoneum. Use of combined peritonectomy + HIPEC in the treatment of ovarian carcinomatosis is the most discussed issue among those concerning peritoneal surface malignancy (PSM). The main criticism concerns the use of HIPEC, since the need for maximal cytoreduction is consolidated and does not raise any doubts. Communities of surgeon and oncologic gynaecologists who believes in the role of HIPEC have started controlled clinical trials aimed at clarifying the role of HIPEC associated to peritonectomy, but these studies are difficult to conduct and time-consuming. At present and pending the results of future prospective trials, the role and limits of application of the procedure are drawn from experiences from three basic study groups: collective reviews, multicentre studies, monocentric case studies produced by high-volume HIPEC centers. A comprehensive literature review and an in-depth analysis of our personal experience, based on the largest monocentric case series (130 cases), have helped to provide an assessment on the role of peritonectomy + HIPEC in about 2000 patients treated for initial and recurrent PC from ovarian cancer. Comparison of the overall results drawn from these studies, indicates that peritonectomy + HIPEC is able to guarantee in these patients better overall survival (OS) and higher progression-free survival (PFS) rates than those derived from traditional treatments, with acceptable morbidity and mortality. Notwithstanding, some specific aspects, including the role of chemoresistance and neoadjuvant and adjuvant treatments, should be clarified by further experience and the results of on-going trials

A Small Molecule SMAC Mimic LBW242 Potentiates TRAIL- and Anticancer Drug-Mediated Cell Death of Ovarian Cancer Cells

BACKGROUND: Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (SMAC) has been described to sensitize for apoptosis. We have explored the pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays. PRINCIPAL FINDINGS: LBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis. CONCLUSION: LBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer

Prevention of peritoneal carcinomatosis from colorectal cancer: a critical issue.

[No abstract available

Complications after colorectal resections during peritonectomy and HIPEC in advanced peritoneal carcinomatosis from ovarian cancer.

INTRODUCTION The current options for treating patients with primary or recurrent diffuse ovarian carcinomatosis include peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC). The main role of peritonectomy in this integrated procedure is to achieve maximal cytoreduction by multiple parietal and visceral resections, whereas HIPEC serves to sterilize microscopic or millimetric residual sites of tumor. Among the various visceral resections needed for maximal cytoreduction, colorectal resections account for nearly 50%. Despite consensus on the oncologic appropriateness of colorectal resections to achieve optimal cytoreduction, technical controversies persist and information is lacking on how these procedures influence outcome and survival, AIM: to identify a reasonable surgical strategy for colorectal resections to reach optimal cytoreduction and minimize operative risks. METHODS From a series of 70 patients prospectively enrolled from November 2000 to April 2009 in a single-center phase-II study on the use of peritonectomy and HIPEC (closed technique at the end of surgery) in the treatment of diffuse primary or recurrent peritoneal carcinomatosis from ovarian cancer we selected for this study all 52 consecutive patients who also underwent colorectal resection. • Surgical Technique for Peritonectomy The extent of peritoneal carcinomatosis was classified according to the peritoneal cancer index (PCI). Aggressive surgical cytoreduction to leave the patient with no visible disease then proceeded in three stages: treatment of the parietal peritoneum, visceral resections and lymphadenectomy •Surgical Technique for Colorectal Resection Involvement of the pelvis the and cul-de-sac along as well as the uterus and adnexa or recurrent disease of the pelvis ! en bloc resection of the internal genitalia or pelvic recurrence along with the rectum and sigmoid colon (TME). Right iliac fossa carcinomatosis involving the cecum, appendix, terminal ileum or ascending colon ! standard right hemicolectomy. Involvement of the pelvis and all colonic segments, with nodules penetrating deeply into the colonic wall ! total colectomy, rectal resection and terminal ileostomy. We generally preferred to construct an ostomy and postpone restoring intestinal continuity for a second look. In most patients, before restoring intestinal continuity we waited for at least 6 months after post-peritonectomy systemic chemotherapy. The completeness of cytoreduction (CC) was scored as proposed by Sugarbaker. Statistical Analysis A multiple regression test was used to analyze the influence of morbidity and mortality risk factors on patient’s outcome. The Kaplan-Meier method was used to construct survival curves and the log-rank test was used to assess the significance of differences between curves. The Cox regression model was used to determine the prognostic value of independent variables. P values <0.05 were considered to indicate statistical significance. The NCSS package was used to analyze the data base and perform statistical tests. DISCUSSION At a mean follow-up of 30.2 months (range 4-79), the estimated mean survival was 33.2 months and the mean disease- free survival was 27 months. In 74.3% of the cases (52/70 patients) a colorectal resection was needed to achieve satisfactory cytoreduction levels. Our experience in these patients therefore suggests that rectal resection alone or associated with other colonic resections is the crucial surgical step on which patients’ outcome depends. The major anatomic and pathological prognostic factors reflecting clinical outcome were colorectal wall involvement and CC score. In contrast to most investigators, a technical point we underline is the need for a low rectal resection leaving a rectal stump no longer than 5 cm completely removing the mesorectum. We also used inferior mesenteric artery ligation at its origin from the aorta (high tie) and the inferior mesenteric vein at the inferior pancreatic border including a large amount of the mesocolon and adequate lymphadenectomy. In most patients in our series (75%) the tumor infiltrated the muscular layers up to the mucosa; in 25% the tumor involved only the intraperitoneal rectal or colonic wall serosa, the peritoneal pouch or mesorectum without infiltrating the muscular layers. As many as 22 of the 52 patients (42.3%) undergoing colorectal resection in our series had mesenteric lymph-node metastases alone or in association with typical ovarian node metastases and 20 (41.6%) of patients who underwent rectal resection had mesorectal lymph-node metastases. This pattern of malignant spread shows a direct relationship between infiltration of the colorectal wall and mesenteric lymph-node metastases and suggests that optimal surgical management of these patients must include the resection procedures commonly used for primary large bowel carcinoma. Even though some investigators underline this concept, the appropriate surgical management of large bowel involvement in primary and recurrent diffuse peritoneal ovarian carcinomatosis in practice remains unapplied. In this scenario, for example, some resect a limited rectosigmoid segment (15 cm) constructing the colorectal anastomosis high (9-10 cm from the anal verge) without excising the entire mesorectum. Many also provide poor or no information on mesenteric lymphadenectomy and when they supply information resect a mean 5 lymph nodes, inadequate for oncologic exeresis. Besides, hardly surprisingly, this sleeve fashion resection leads to a high percentage of microscopic residual disease on the colorectal stump (20%). Hence in our opinion, mistakenly, more emphasis is placed on restoring intestinal continuity with a colorectal anastomosis without a colostomy than on observing the necessary oncologic rules. After rectal resection we generally avoided restoring intestinal continuity immediately and according to the entity of colorectal resection construct a colostomy or ileostomy. We postpone restoring intestinal continuity until after systemic postperitonectomy chemotherapy ends and after a further 6 months follow-up for patients who remain disease free. This strategy minimizes the numerous operative risks in critically ill patients, many of whom have intestinal obstruction (30%), all of whom have diffuse carcinomatosis (mean PCI 18), more than 50% of whom also require intestinal anastomoses or local excision of tumor implants from the large and small bowel wall, and who have generally suffered a mean blood loss of 1700 mL, and finally, all of whom have to undergo HIPEC. This strategy also has the distinct therapeutic advantage of allowing second-look surgery, especially in apparently disease-free patients with low tumor markers. Our unpublished experience shows that 7 of the 12 patients who underwent surgery to restore intestinal continuity had minimal recurrent disease that was resected during reconstruction surgery. These 7 patients also underwent a second HIPEC procedure. Of the 12 patients who underwent bowel reconstruction, 2 with a coloanal anastomosis, 7 with a colorectal stapler anastomosis, and 3 patients who underwent total colectomy with ileostomy had an ileorectal anastomosis with a J pouch. Three other patients available for reconstruction refused a new operation. Late reconstruction is particularly safe because the first operation improves the patient’s general conditions and leaves a stiff, healthy rectal stump. All patients who underwent reconstruction except one in whom a rectovaginal fistula developed, had an uncomplicated postoperative course. Comparing patients undergoing cytoreduction with and without HIPEC, Ryu et al. observed higher rates of intraabdominal complications such as intestinal perforation, intestinal obstruction, and sepsis in patients who underwent HIPEC. In our series only two patients, both of whom had only mild pelvic carcinomatosis, had colorectal anastomoses, all the others had colostomy or ileostomy, depending on the extent of colonic resection. In our series the mean PCI was relatively high (mean 18.8) and colorectal resections were invariably needed to achieve optimal cytoreduction. When we investigated the prognostic role of colorectal resection in the outcome of our patients our findings again underline growing evidence on the role of maximal cytoreduction and clearly show that colorectal resections are merely a step in this process similar to the other visceral or parenchymal resections necessary and unavoidable to reach radical cytoreduction. Not with standing the small number of patients studied, our results seem to suggest as a major negative pathologic factor colorectal wall involvement reaching the mucosal layer given that none of these patients in our series survived. This new finding implies that whenever diagnostic procedures identify these high risk patients surgery might usefully be preceded by neoadjuvant chemotherapy. Conclusion Colorectal resection are an unavoidable step in achieving maximal cytoreduction and hence in improving outcome and survival. The high rate of deep infiltration into the colorectal wall along with the pericolic, mesenteric and mesorectal lymphonode metastases suggest that colorectal resections should follow the strict oncologic rules applied for primary cancer. To minimize the operative risks, after rectal resection anastomosis should be postponed for at least 6 months in patients who remain disease-free after systemic post-peritonectomy CHT ends, that allows second-look surgery in appatently disease-free patients