Daniele Biacchi

Cytoreductive surgery (peritonectomy procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer

Because of scarce data from larger series and nonhomogeneous selection criteria, further information is needed on peritonectomy with hyperthermic intraperitoneal chemotherapy (HIPEC) in managing patients with ovarian peritoneal carcinomatosis.

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.

Proactive Management for Gastric, Colorectal and Appendiceal Malignancies: Preventing Peritoneal Metastases with Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

An integrated treatment strategy using peritonectomy procedures plus hyperthermic intraperitoneal chemotherapy (HIPEC) is now a clinical standard of care in selected patients with peritoneal metastases and primary peritoneal tumors. This comprehensive approach can offer many patients, who hitherto had no hope of cure, a good quality of life and survival despite limited morbidity. The increasingly successful results and chance of interfering in the natural history of disease has prompted research to develop for some clinical conditions a therapeutic strategy designed to prevent malignant peritoneal dissemination before it becomes clinically evident and treat it microscopically (tertiary prevention). The main factor governing successful cytoreductive surgery and predicting outcome is the extent of peritoneal spread assessed with the peritoneal cancer index (PCI). In peritoneal metastases from colorectal and gastric cancer the PCI score acquires a specific role acting as the cut-off between patients who can undergo curative surgery or palliation. Long-term results show that the only group enjoying favorable results are patients with limited disease (a statistical minority). By applying to appropriately selected patients with primary malignancies a proactive management strategy including HIPEC we can treat patients with microscopic peritoneal dissemination and therefore at PCI 0. Among treated conditions pseudomyxoma peritonei enjoys the best results. But a major future advance comes from identifying among lesions at major risk of pseudomyxoma.

Depth of colorectal-wall invasion and lymph-node involvement as major outcome factors influencing surgical strategy in patients with advanced and recurrent ovarian cancer with diffuse peritoneal metastases

BackgroundMore information is needed on the anatomopathological outcome variables indicating the appropriate surgical strategy for the colorectal resections often needed during cytoreduction for ovarian cancer.MethodsFrom a phase-II study cohort including 70 patients with primary advanced or recurrent ovarian cancer with diffuse peritoneal metastases treated from November 2000 to April 2009, we selected for this study the 52 consecutive patients who needed colorectal resection. Data collected included type of colorectal resection, peritoneal cancer index (PCI), histopathology (depth of bowel-wall invasion and lymph-node spread), cytoreduction rate and outcome. Correlations were tested between possible prognostic factors and Kaplan-Meier five-year overall and disease-free survival. A Cox multivariate regression model was used to identify independent variables associated with outcome.ResultsIn the 52 patients, the optimal cytoreduction rate was 86.5% (CC0/1). In all patients, implants infiltrated deeply into the bowel wall, in 75% of the cases up to the muscular and mucosal layer. Lymph-node metastases were detected in 50% of the cases; mesenteric nodes were involved in 42.3%. Most patients (52%) had an uneventful postoperative course. Operative mortality was 3.8%. The five-year survival rate was 49.9% and five-year disease-free survival was 36.7%. Cox regression analysis identified as the main prognostic factors completeness of cytoreduction and depth of bowel wall invasion.ConclusionsOur findings suggest that the major independent prognostic factors in patients with advanced ovarian cancer needing colorectal resections are completeness of cytoreduction and depth of bowel wall invasion. Surgical management and pathological assessment should be aware of and deal with dual locoregional and mesenteric lymphatic spread.

Two synchronous adenocarcinomas of the small bowel in a patient with undiagnosed Crohn's disease of the terminal ileum

A small but significant excess of deaths for tumors of the digestive system has been described in Crohns disease. In a study analyzing all cancers of the small intestine within a defined population, Crohns disease was the major underlying factor for cancer of the small intestine. Areas of the small intestine containing strictures are unusually prone to malignant transformation. We report the rare case of a patient in whom surgery for intestinal occlusion disclosed Crohns disease of the distal ileum complicated by two adenocarcinomas arising within distinct areas of the inflamed bowel.

Neoadjuvant chemotherapy fails to improve survival in advanced ovarian cancer: but is it the real culprit?

To the Editor: T study by Milam et al 1 and other recently published articles on advanced epithelial ovarian cancer all report higher rates of optimal cytoreduction in patients who receive neoadjuvant chemotherapy than in those who undergo primary surgery. Although these studies again confirm the essential prognostic role of cytoreductive surgery in advanced ovarian cancer, none of them succeed in explaining why increasing the rate of optimal cytoreduction leaves survival almost unchanged. One explanation is that regardless of neoadjuvant chemotherapy, optimal cytoreduction, leaving 1 cm or less of residual tumor, rather than complete cytoreductive surgery, is not enough to improve survival. Management of patients with advanced epithelial ovarian cancer (stages IIIC and IV), such as those treated by Millam et al, comprises 2 basic treatment strategiesVchemotherapy and surgery. Whereas neoadjuvant or adjuvant chemotherapy is a fully standardized procedure, surgery remains open to wide patient-related and surgeon-related variability. Standard debulking surgery envisages bilateral hysteroadnexectomy, appendectomy, omentectomy, iliacobturator, and peri-aortocaval lymphadenectomy, associated with less standardized procedures to resect other organs and structures frequently involved by the malignant spread. Given the wide variability in the severity and location of malignant spread within the abdominal cavity, the type of resection needed for debulking surgery therefore varies equally widely. The extent and quality of multiorgan resections depend closely on the individual surgeon’s skill and cytoreductive aim. One of the recently published multicenter studies enrolling a large study sample clearly depicts the wide variability in surgical approaches used for debulking and cytoreduction many often failing to meet the standard requirements for treating ovarian cancer. Insofar as all investigators agree that the most reliable prognostic factor in advanced epithelial ovarian cancer is the degree of cytoreduction, the most pressing problems to face are identifying the best surgical strategies for multiorgan resection, finding reliable criteria for assessing endoperitoneal malignant spread, and, most importantly, improving the surgical skills and procedures needed to achieve complete cytoreduction. We should focus our interest on peritonectomy procedures to obtain complete cytoreduction combined with intraperitoneal hyperthermic chemotherapy to treat microscopic residual disease. Current evidence suggests that this complex strategy does much to benefit outcome. Angelo Di Giorgio, MD Paolo Sammartino, MD, PhD Daniele Biacchi, MD, PhD Department of Surgery ‘‘Pietro Valdoni’’ Sapienza University of Rome Rome, Italy angelo.digiorgio@uniroma1.it

Totally Implantable Venous Access Devices: Efforts Are Needed to Standardize Procedures to Avoid Complication: Reply

We read with interest the article by Biacchi and colleagues published in the 2016 February issue of the Journal [1]. Their retrospective study compared the causes of longterm explantation in cancer patients who had totally implantable venous access devices (TIVADs) inserted using two techniques. The study was well conducted and analyzed the approaches to implanting a TIVAD as the cause of longterm failure. To date, this aspect of such implantation has not been clarified. We have undertaken the surgical technique using the cephalic vein and have demonstrated that in patients who are not at risk do not need prophylactic antibiotic administration [2]. Currently, any cost that could be avoided is welcome because health systems have become more and more expensive worldwide. As Biacchi et al. described, they used a 6.5-Fr silicone catheter in adults. Usually, this size is used in children, although it may also be used in adults. Silicone catheters are more flexible than polyurethane catheters, but the lumen is smaller (Fig. 1). This difference is important when an 8-Fr catheter is placed, but it becomes fundamental when a 6.5-Fr catheter is used because the catheter’s small lumen poses a risk of occlusion and, consequently, thrombosis of the vessel. In effect, their Table 2 showed that there were venous thromboses/ occlusions in 22 of 38 cases using the surgical technique and in 6 of 29 cases using percutaneous puncture. If the authors had used 8 Fr (especially polyurethane) catheters, there may have been fewer complications. Also, although not significant (0.03), their results in the surgical technique group could be considered as a bias of the study. When the cephalic vein is not available, the external jugular vein or the axillary vein could be used for the approach—depending on the anatomy and the situation of the patient—before choosing the subclavian vein [3]. These techniques are less risky than the percutaneous approach, especially if done without ultrasonography guidance. A blind technique to cannulate the subclavian or jugular vein should not be accepted in 2016.

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.MethodsThe 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.ConclusionsOnce 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.

Patient Selection for Treatment

Appropriate patient selection is of primary importance to successful cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC). Given the high morbidity rate associated with these combined procedures, we need to select patients who will derive maximum benefits from treatment and who carry lower risks of postoperative complications and mortality. The high morbidity and mortality rates, especially in treatment groups approaching this type of surgery for the first time, have raised concern and often criticism [1, 2]. At the same time, besides problems linked to postoperative complications, criteria for selecting patients to undergo integrated treatment must take into account preoperative factors predicting a favorable oncologic outcome. Hence, we need to know which tumors causing peritoneal spread this combined treatments should target and to define the extent of peritoneal spread to use as a cutoff beyond which these procedures are contraindicated. To rationalize this topic, even though schematizing has its limitations, we divided selection criteria according to whether they most directly address patients’ characteristics, the site and histology underlying peritoneal spread, and the extent of peritoneal and extraperitoneal malignant spread.

Secondary Cytoreduction Versus Chemotherapy Alone in the Treatment of Patients with Recurrent Ovarian Cancer: Is a Randomized Trial Worthwhile?

The review by Harter et al. [1] entitled “Surgery for relapsed ovarian cancer: when should it be offered?” appropriately analyzes major concerns related to surgery for recurrent ovarian cancer. Despite underlining published reports from various series on secondary cytoreduction in platinum-sensitive patients, seeking a satisfactory answer to the question what should be considered standard care in these patients, they present two ongoing randomized trials (AGO-OVAR DESKTOP III and GOG 213) evaluating cytoreductive surgery versus chemotherapy alone in patients with platinum-sensitive recurrent ovarian cancer. Even though we agree that these studies are needed to obtain level 1 evidence for choosing the optimal treatment in similar clinical scenarios, we feel obliged to express and draw to the scientific community’s attention certain doubts. From currently available data, no one can deny that in selected cases such as the categories identified by the inclusion criteria for the AGO-OVARDESKTOP III trial, the results obtained after secondary surgical cytoreduction in patients with recurrent ovarian cancer are better than those after chemotherapy alone [2, 3]. This consideration raises ethical and practical concerns. As physicians engaged in scientific research, it is our duty to suggest to our patients the therapeutic option likely to guarantee the best outcome. Equally important, when asking patients to take part in a randomized trial, we have the duty to inform them about the reasons for the trial and the results that the two alternative procedures proposed can guarantee. Giving correct information could presumably lead to an accrual dropout. No less important in this context are the latest developments from cytogenetic studies on ovarian carcinoma. In their critical review published on the pathogenesis of ovarian cancer, Kurman and Shih [4] divide epithelial ovarian carcinoma into two groups designated type I and type II that distinctly differ in phenotype, genotype, and clinical behavior. These new concepts on ovarian carcinogenesis inescapably imply that a “blanket approach” to the treatment of ovarian carcinoma no longer suffices. The overriding need now is to develop targeted therapies adapted to the molecular and genetic features shown by the two main tumor types. Randomized trials that fail to take these differences into account can hardly provide reliable results.