Arend G. J. Aalbers

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer

BACKGROUND Treatment of newly diagnosed advanced‐stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer. METHODS In a multicenter, open‐label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body‐surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence‐free survival. Overall survival and the side‐effect profile were key secondary end points. RESULTS In the intention‐to‐treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery‐plus‐HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence‐free survival was 10.7 months in the surgery group and 14.2 months in the surgery‐plus‐HIPEC group. At a median follow‐up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery‐plus‐HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery‐plus‐HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery‐plus‐HIPEC group, P=0.76). CONCLUSIONS Among patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence‐free survival and overall survival than surgery alone and did not result in higher rates of side effects. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257; EudraCT number, 2006‐003466‐34.)

Perioperative systemic chemotherapy in peritoneal carcinomatosis of lymph node positive colorectal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

BACKGROUND Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the preferred treatment of peritoneal carcinomatosis (PC) of colorectal carcinoma. Patients with positive lymph node status have worse survival after CRS-HIPEC, which is probably due to higher rates of systemic failure. In this study, we analysed the effect of administration and timing of systemic chemotherapy on the outcome of lymph node positive colorectal carcinoma patients treated with CRS-HIPEC. PATIENTS AND METHODS A prospective database was reviewed to identify lymph node positive patients with PC treated with CRS-HIPEC within 1 year after primary tumour diagnosis between 2004 and 2012. Medical history of the patients was studied for the administration of perioperative systemic chemotherapy and follow-up. Outcome parameters were progression-free survival (PFS), overall survival (OS) and pattern of recurrence. RESULTS Seventy-three patients treated with CRS-HIPEC for PC from lymph node positive colorectal carcinoma were identified. Fourteen patients received pre-CRS-HIPEC chemotherapy only, 32 patients underwent post-CRS-HIPEC chemotherapy only, 9 patients received chemotherapy both pre- and post-CRS-HIPEC and 16 patients did not receive any systemic chemotherapy. Of the 47 patients who did not receive pre-CRS-HIPEC chemotherapy, 11 (23%) did not receive any chemotherapy due to major postoperative complications. PFS and OS were significantly higher in patients who received systemic chemotherapy (PFS: median 15 versus 4 months, P = 0.024; OS: median 30 versus 14 months, P = 0.015), although this difference was attenuated after adjustment for major complications. Different chemotherapy timings did not differ significantly in either survival or recurrence patterns. CONCLUSIONS In patients with PC from lymph node positive colorectal carcinoma, perioperative systemic chemotherapy is associated with increased OS and PFS, although this difference may be partly explained by the occurrence of major postoperative complication; with no evidence of difference in PFS, OS and systemic recurrence rate by timing of systemic chemotherapy.BACKGROUND Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the preferred treatment of peritoneal carcinomatosis (PC) of colorectal carcinoma. Patients with positive lymph node status have worse survival after CRS-HIPEC, which is probably due to higher rates of systemic failure. In this study, we analysed the effect of administration and timing of systemic chemotherapy on the outcome of lymph node positive colorectal carcinoma patients treated with CRS-HIPEC. PATIENTS AND METHODS A prospective database was reviewed to identify lymph node positive patients with PC treated with CRS-HIPEC within 1 year after primary tumour diagnosis between 2004 and 2012. Medical history of the patients was studied for the administration of perioperative systemic chemotherapy and follow-up. Outcome parameters were progression-free survival (PFS), overall survival (OS) and pattern of recurrence. RESULTS Seventy-three patients treated with CRS-HIPEC for PC from lymph node positive colorectal carcinoma were identified. Fourteen patients received pre-CRS-HIPEC chemotherapy only, 32 patients underwent post-CRS-HIPEC chemotherapy only, 9 patients received chemotherapy both pre- and post-CRS-HIPEC and 16 patients did not receive any systemic chemotherapy. Of the 47 patients who did not receive pre-CRS-HIPEC chemotherapy, 11 (23%) did not receive any chemotherapy due to major postoperative complications. PFS and OS were significantly higher in patients who received systemic chemotherapy (PFS: median 15 versus 4 months, P = 0.024; OS: median 30 versus 14 months, P = 0.015), although this difference was attenuated after adjustment for major complications. Different chemotherapy timings did not differ significantly in either survival or recurrence patterns. CONCLUSIONS In patients with PC from lymph node positive colorectal carcinoma, perioperative systemic chemotherapy is associated with increased OS and PFS, although this difference may be partly explained by the occurrence of major postoperative complication; with no evidence of difference in PFS, OS and systemic recurrence rate by timing of systemic chemotherapy.

Peritoneal carcinomatosis is less frequently diagnosed during laparoscopic surgery compared to open surgery in patients with colorectal cancer

BACKGROUND During resection of a colorectal tumor a careful inspection of the abdomen should be performed to detect metastases. The aim of the current study was to compare the proportions of patients diagnosed with peritoneal carcinomatosis (PC) during laparoscopic resection (LR) and open resection (OR). METHODS All patients who underwent resection for colorectal cancer in the Eindhoven Cancer Registry area between 2008 and 2012 were included. Proportions of patients with PC were compared between surgical techniques. Multivariate logistic regression analysis was performed. RESULTS 6687 Patients underwent resection for colorectal cancer, of whom 1631 patients (24%) underwent LR, 4665 patients (70%) underwent OR. Conversion took place in 391 patients (19% of laparoscopic treated patients). PC was diagnosed in 1.4% of patients undergoing LR, in 5.0% of patients undergoing OR, and in 3.3% of patients in whom LR was converted to OR (p < 0.001). After adjustment for patient and tumor characteristics (e.g., T- and N-stage), patients who were treated by LR had a lower chance to be diagnosed with PC during surgery than patients undergoing OR (odds ratio = 0.42, p < 0.001). CONCLUSIONS Patients undergoing surgery for colorectal cancer are less frequently diagnosed with PC during LR in comparison to OR. Since effective treatment is currently available for selected patients with PC, a thorough inspection of the peritoneum during surgery is of paramount importance to offer these patients a chance for long-term survival and even cure.

Differentiation of healthy and malignant tissue in colon cancer patients using optical spectroscopy: A tool for image-guided surgery

Surgery for colorectal cancer aims for complete tumor resection. Optical‐based techniques can identify tumor and surrounding tissue through the tissue specific optical properties, absorption and scattering, which are both influenced by the biochemical and morphological composition of the tissue.

A prospective pilot study to assess neoadjuvant chemotherapy for unresectable peritoneal carcinomatosis from colorectal cancer

Twelve to 13% of patients with colorectal cancer (CRC) develop peritoneal carcinomatosis (PC), the majority of whom present with unresectable disease. This study aimed to document the actual response rate to and response characteristics of preoperative modern systemic chemotherapy in this patient group.

Diffuse reflectance spectroscopy as a tool for real-time tissue assessment during colorectal cancer surgery

Abstract. Colorectal surgery is the standard treatment for patients with colorectal cancer. To overcome two of the main challenges, the circumferential resection margin and postoperative complications, real-time tissue assessment could be of great benefit during surgery. In this ex vivo study, diffuse reflectance spectroscopy (DRS) was used to differentiate tumor tissue from healthy surrounding tissues in patients with colorectal neoplasia. DRS spectra were obtained from tumor tissue, healthy colon, or rectal wall and fat tissue, for every patient. Data were randomly divided into training (80%) and test (20%) sets. After spectral band selection, the spectra were classified using a quadratic classifier and a linear support vector machine. Of the 38 included patients, 36 had colorectal cancer and 2 had an adenoma. When the classifiers were applied to the test set, colorectal cancer could be discriminated from healthy tissue with an overall accuracy of 0.95 (±0.03). This study demonstrates the possibility to separate colorectal cancer from healthy surrounding tissue by applying DRS. High classification accuracies were obtained both in homogeneous and inhomogeneous tissues. This is a fundamental step toward the development of a tool for real-time in vivo tissue assessment during colorectal surgery.

Histopathological and molecular classification of colorectal cancer and corresponding peritoneal metastases

Patients with colorectal peritoneal carcinomatosis have a very poor prognosis. The recently developed consensus molecular subtype (CMS) classification of primary colorectal cancer categorizes tumours into four robust subtypes, which could guide subtype‐targeted therapy. CMS4, also known as the mesenchymal subtype, has the greatest propensity to form distant metastases. CMS4 status and histopathological features of colorectal peritoneal carcinomatosis were investigated in this study.

Timing of Systemic Chemotherapy in Patients With Colorectal Peritoneal Carcinomatosis Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

BACKGROUND: Timing of systemic chemotherapy in patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is controversial. Preoperative systemic chemotherapy may offer benefits. OBJECTIVE: The purpose of this study was to evaluate the effect of timing of systemic chemotherapy on survival. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at a tertiary referral center. PATIENTS: Patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy from January 2004 until June 2015 were included. MAIN OUTCOME MEASURES: The influence of patient-related, tumor-related, and treatment-related factors on survival were investigated using Cox regression models. Main outcome was overall survival. RESULTS: A total of 280 consecutive patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. In group A, 78 patients (28%) were treated with preoperative or perioperative chemotherapy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. In group B, 169 patients (60%) were intentionally treated with cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and adjuvant chemotherapy. In group C, 33 patients (12%) had received their chemotherapy before peritoneal carcinomatosis was diagnosed. Median overall survival was 36.9 months (interquartile range, 20.6–79.7 mo) in group A, 43.1 months (interquartile range, 25.7–95.9 mo) in group B, and 34.0 months (interquartile range, 20.0–53.7 mo) in group C (p = 0.19). The extent of peritoneal carcinomatosis (region count of 3–5, HR = 1.58 (95% CI, 1.02–2.45), and 6–7, HR = 3.34 (95% CI, 1.66–6.72) vs 1–2 regions), a higher lymph node ratio (HR = 7.96 (95% CI, 2.16–29.31)), and cycles of systemic chemotherapy (0 cycles, HR = 2.52 (95% CI, 1.48–4.29)) and partial chemotherapy (HR = 2.15 (95% CI, 1.27–3.65) vs complete chemotherapy) were associated with poorer overall survival. LIMITATIONS: Selection bias is present because of the retrospective design of this study. CONCLUSIONS: Timing of systemic chemotherapy does not appear to have impact on survival in patients with colorectal peritoneal carcinomatosis undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Diffusion-weighted MRI assessment of the peritoneal cancer index before cytoreductive surgery: MRI assessment of peritoneal cancer index before cytoreductive surgery

Patients with limited peritoneal metastases from colorectal cancer may be candidates for an aggressive surgical approach including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC). Selection is based on surgical inspection during laparoscopy or laparotomy. The aim of this study was to investigate whether diffusion‐weighted MRI (DW‐MRI) can be used to select patients for CRS–HIPEC.

605PCOLORECTAL CANCER IDENTIFIED USING OPTICAL SPECTROSCOPY

ABSTRACT Aim: Complete tumor resection is essential to improve the outcome and quality of life after surgery for colorectal cancer. The identification of tumor and healthy surrounding tissue could facilitate complete tumor resection. Optical based techniques can identify tumor and surrounding tissue through a tissue specific “optical fingerprint”. Dual-modality Diffuse Reflectance Spectroscopy–Fluorescence Spectroscopy (DRS-FS) was evaluated for discrimination between healthy and malignant tissue in colon surgery with ultimate application implementation into surgical instruments. Methods: Differences in tissue composition and structure were measured through a fiber-optic needle using dual-modality DRS-FS. Resection specimens of colon cancer patients were investigated immediately after resection. Multiple optical parameters were derived from the measurements, including volume concentration of familiar optical absorbers like hemoglobin, b-carotene, water and lipids. Furthermore, scattering- and absorption coefficients were assessed, as well as sources of intrinsic fluorescence. The optical based parameters were cross-validated with the results of histopathological analysis using a classification and regression tree (CART) algorithm. Results: A total of 1273 measurements was performed on 21 specimens. Spectral characteristics of b-carotene, hemoglobin, lipids and water could be identified in the measured spectra. Differentiation of tumor from surrounding tissue was possible with a sensitivity and specificity of 95% and 88%, respectively. In 10 specimens optical data were collected along a needle path towards the tumor. Both DRS and FS spectra showed significant spectral changes when the needle tip was guided from healthy tissue into tumor. Conclusions: This study demonstrates that dual-modality DRS-FS allows accurate identification of colon cancer based on optical detection of differences in tissue composition and structure. The technique, here demonstrated in a needle like probe, may be incorporated into surgical instruments for optical guided surgery or combined in other devices. Disclosure: B.H.W. Hendriks: The author who is affiliated with Philips Research (B.H.) is an employee of Philips. The prototype system described in this article is a research prototype, not a commercial product. All other authors have declared no conflicts of interest.