Michael Alfred Ströhlein

Peritoneal Carcinomatosis: Cytoreductive Surgery and HIPEC--Overview and Basics

Tumor involvement of the peritoneum—peritoneal carcinomatosis—is a heterogeneous form of cancer that had been generally regarded as a sign of systemic tumor disease and as a terminal condition. The multimodal treatment approach for patients with peritoneal carcinomatosis, which had been conceived and developed, consists of what is known as cytoreductive surgery, followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Depending on the tumor mass as assessed intraoperatively and the histopathological differentiation, patients who undergo cytoreductive surgery and HIPEC have a significant survival benefit. Mean increases in the survival period ranging from six months to up to four years have now been reported. In view of the substantial logistic effort and the extent of the surgery involved, this treatment approach represents a major challenge both for patients and for surgical oncologists, as well as for the members of the overall interdisciplinary structure required, which includes oncology, anesthesiology and intensive care, psycho-oncology, and patient management. The surgical procedures alone may take 8–14 hr. The present paper provides an overview of the basis for the approach and the use of specialized classifications and quantitative prognostic indicators.

Clinical efficacy of cytoreductive surgery and hyperthermic chemotherapy in peritoneal carcinomatosis from gastric cancer.

Evaluation of: Yang XJ, Huang CQ, Suo T et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a Phase III randomized clinical trial. Ann. Surg. Oncol. 18(6), 1575–15781 (2011). Peritoneal carcinomatosis (PC) is the most common pattern of metastasis and recurrence in patients with gastric cancer and is associated with poor clinical outcome and survival. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) was recently established as a new treatment option for PC of gastrointestinal cancer. However, the role of cytoreductive surgery in gastric cancer and the intrinsic role of HIPEC remains unclear. The evaluated article presented a single center Phase III study, randomizing 68 patients with PC from gastric cancer to surgical cytoreduction only (CRS; n = 34) versus cytoreduction plus HIPEC with cisplatin and mitomycin (CRS+HIPEC; n = 34). Median overall was 6.5 months in the CRS group and 11.0 months in the CRS+HIPEC group (p = 0.046). Serious adverse events were acceptable in both groups. Multivariate analysis found CRS+HIPEC, synchronous PC, complete cytoreduction, systemic chemotherapy >6 cycles and no incidence of severe adverse events independent predictive factors for survival. This was the first study to show the positive effects of HIPEC in addition to CRS in PC independently of the tumor entity. In patients with gastric cancer, multimodal treatment concepts combining surgical cytoreduction and HIPEC may provide a new option in carefully selected patients.

The Role of Relative Lymphocyte Count as a Biomarker for the Effect of Catumaxomab on Survival in Malignant Ascites Patients: Results from a Phase II/III Study

Purpose: We report the role of relative lymphocyte count (RLC) as a potential biomarker with prognostic impact for catumaxomab efficacy and overall survival (OS) based on a post hoc analysis of the pivotal phase II/III study of intraperitoneal catumaxomab treatment of malignant ascites. Experimental Design: The impact of treatment and RLC on OS was evaluated using multivariate Cox models. Kaplan–Meier and log-rank tests were used for group comparisons. Survival analyses were performed on the safety population [patients with paracentesis plus ≥1 dose of catumaxomab (n = 157) and paracentesis alone (n = 88)]. Determination of the optimal cutoff value for RLC was based on five optimality criteria. Results: OS was significantly longer with catumaxomab versus paracentesis alone (P = 0.0219). The 6-month OS rate with catumaxomab was 28.9% versus 6.7% with paracentesis alone. RLC had a positive impact on OS and was an independent prognostic factor (P < 0.0001). In patients with RLC > 13% (n = 159: catumaxomab, 100 and control, 59), catumaxomab was associated with a favorable effect on OS versus paracentesis alone (P = 0.0072), with a median/mean OS benefit of 41/131 days and an increased 6-month survival rate of 37.0% versus 5.2%, respectively. In patients with RLC ≤ 13% at screening (n = 74: catumaxomab, 50 and control, 24), the median (mean) OS difference between the catumaxomab and the control group was 3 (16) days, respectively (P = 0.2561). Conclusions: OS was significantly improved after catumaxomab treatment in patients with malignant ascites. An RLC > 13% at baseline was a significant prognostic biomarker. Clin Cancer Res; 20(12); 3348–57. ©2014 AACR.

Extended pancreas donor program - the EXPAND study rationale and study protocol.

AbstractBackgroundSimultaneous pancreas kidney transplantation (SPK), pancreas transplantation alone (PTA) or pancreas transplantation after kidney (PAK) are the only curative treatment options for patients with type 1 (juvenile) diabetes mellitus with or without impaired renal function. Unfortunately, transplant waiting lists for this indication are increasing because the current organ acceptability criteria are restrictive; morbidity and mortality significantly increase with time on the waitlist. Currently, only pancreas organs from donors younger than 50 years of age and with a body mass index (BMI) less than 30 are allocated for transplantation in the Eurotransplant (ET) area. To address this issue we designed a study to increase the available donor pool for these patients.Methods/DesignThis study is a prospective, multicenter (20 German centers), single blinded, non-randomized, two armed trial comparing outcome after SPK, PTA or PAK between organs with the currently allowed donor criteria versus selected organs from donors with extended criteria. Extended donor criteria are defined as organs procured from donors with a BMI of 30 to 34 or a donor age between 50 and 60 years. Immunosuppression is generally standardized using induction therapy with Myfortic, tacrolimus and low dose steroids. In principle, all patients on the waitlist for primary SPK, PTA or PAK are eligible for the clinical trial when they consent to possibly receiving an extended donor criteria organ. Patients receiving an organ meeting the current standard criteria for pancreas allocation (control arm) are compared to those receiving extended criteria organ (study arm); patients are blinded for a follow-up period of one year. The combined primary endpoint is survival of the pancreas allograft and pancreas allograft function after three months, as an early relevant outcome parameter for pancreas transplantation.DiscussionThe EXPAND Study has been initiated to investigate the hypothesis that locally allocated extended criteria organs can be transplanted with similar results compared to the currently allowed standard ET organ allocation. If our study shows a favorable comparison to standard organ allocation criteria, the morbidity and mortality for patients waiting for transplantation could be reduced in the future.Trial registrationTrial registered at: NCT01384006

Relative lymphocyte count is a prognostic parameter in cancer patients with catumaxomab immunotherapy

BACKGROUND Catumaxomab (anti-EpCAM × anti-CD3) treatment in peritoneal carcinomatosis (PC) of EpCAM-positive cancers was effective in phase I and II studies. Recently, it was approved in the EU for treatment of peritoneal carcinomatosis and malignant ascites. Aim of this hypothesis-generating study was to identify predictive or prognostic biomarkers with relevance for overall survival. METHODS 34 patients with PC in phase I/II studies with catumaxomab treatment were assessed for age, Karnofsky Index (KI), relative (RLC) and absolute lymphocyte count, relative and absolute granulocyte count, T-cell subsets, NK cells, and monocytes before catumaxomab therapy. Disease control (responder) was defined by stable disease, partial response or complete response (RECIST v1.0) >3 months or survival >6 months. Correlation analysis, Kaplan-Meier curves, ROC calculation, and multivariate regression were used for statistical analysis. RESULTS Mean RC values significantly differed between the non-responder (14.0%) and the responder group (23.9%; p=0.001). RLC was correlated with overall survival (p=0.03). RLC of >12% defined by ROC calculation was associated with prolonged survival (p=0.035; hazard ratio of 2.775 for patients with RLC <12%). Patients with RLC >12% showed a mean survival of 15.6 versus 5.6 months in patients with RLC ≥ 12% (p=0.001). Multivariate analysis found the individual RLC before therapy (p=0.039) and the KI performance status (p=0.002) to be independent prognostic parameters. Increasing KI by 1% resulted in a risk decrease of 10.1%. Increasing RLC by 1% resulted in a risk decrease of 4.6%. Age and the extent of PC did not significantly influence survival. CONCLUSIONS RLC and KI were identified as potential prognostic parameters for superior disease control and overall survival after catumaxomab treatment. RLC may be used as a biomarker to indicate a suitable immune status for catumaxomab therapy. The predictive impact has to be confirmed in further studies.

The current status of immunotherapy in peritoneal carcinomatosis

ABSTRACT Introduction: Peritoneal carcinomatosis (PC) is a cancer disease with an urgent need for effective treatment. Conventional chemotherapy failed to show acceptable results. Cytoreductive surgery and hyperthermic chemoperfusion (HIPEC) are only beneficial in few patients with resectable peritoneal metastasis. Immunotherapy could be attractive against PC, as all requirements for immunotherapy are available in the peritoneal cavity. Areas covered: This review analyzes the present literature for immunotherapy of PC. Advances from immune stimulators, radionucleotide-conjugated- and bispecific antibodies to future developments like adoptive engineered T-cells with chimeric receptors are discussed. The clinical development of catumaxomab, which was the first intraperitoneal immunotherapy to be approved for clinical treatment, is discussed. The requirements for future developments are illustrated. Expert commentary: Immunotherapy of peritoneal carcinomatosis is manageable, showing striking cancer cell killing. Improved profiles of adverse events by therapy-induced cytokine release, enhanced specific killing and optimal treatment schedules within multimodal treatment will be key factors.

Perioperative Systemic Chemotherapy, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: Results of the Prospective Multicenter Phase 2 COMBATAC Trial

Micro‐Abstract The prospective phase 2 COMBATAC (COMBined Anticancer Treatment of Advanced Colorectal cancer) trial evaluated perioperative systemic chemotherapy + cetuximab combined with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in 26 patients with peritoneal metastatic colorectal cancer. The combined treatment regimen is safe and feasible, and is associated with acceptable morbidity and mortality rates. The survival rates are comparable to published data after CRS/HIPEC. Background Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as parts of an interdisciplinary treatment concept including systemic chemotherapy can improve survival of selected patients with peritoneal metastatic colorectal cancer (pmCRC). Nevertheless, the sequence of the therapeutic options is still a matter of debate. Thus, the COMBATAC (COMBined Anticancer Treatment of Advanced Colorectal cancer) trial was conducted to evaluate a combined treatment regimen consisting of preoperative systemic polychemotherapy + cetuximab followed by CRS + HIPEC and postoperative systemic polychemotherapy + cetuximab. Patients and Methods The COMBATAC trial is a prospective, multicenter, open‐label, single‐arm, single‐stage phase 2 trial. Twenty‐six patients with synchronous or metachronous colorectal or appendiceal peritoneal carcinomatosis were included. Enrollment was terminated prematurely by the sponsor because of slow recruitment. Progression‐free survival as primary end point and overall survival were estimated by the Kaplan‐Meier method. Also evaluated were morbidity according to Common Terminology Criteria for Adverse Events v4.0 and feasibility of the combined treatment concept. Results Median progression‐free survival for the intention‐to‐treat population (n = 25) was 14.9 months. Median overall survival was not reached during the study duration. Ninety‐two adverse events were documented in 16 patients, including 14 serious adverse events in 9 patients. The overall morbidity rate was 64%, and the grade 3/4 morbidity rate was 44%. Of all grade 3/4 morbidity events, 36.4% were related to systemic chemotherapy and 22.7% to surgery, whereas 40.9% were not directly related. There was no treatment‐related mortality. Conclusion The results of the COMBATAC trial show that the multimodal treatment concept consisting of perioperative systemic chemotherapy and CRS + HIPEC is safe and feasible. Progression‐free survival in selected patients with colorectal or appendiceal peritoneal metastasis might be improved.

Erratum to: Transvaginal hybrid NOTES cholecystectomy—results of a randomized clinical trial after 6 months

1 Department of Abdominal, Vascular and Transplant Surgery, Cologne-Merheim Medical Center, Witten/Herdecke University, Ostmerheimer Strasse 200, 51109 Cologne, Germany 2 Department of General, Visceral, Vascular and Thoracic Surgery, Clinic of Kempten, Robert-Weixler-Strasse 50, 87439 Kempten, Germany 3 Department for Obstetrics and Gynecology, Holweide Hospital, Neufelder Strasse 32, 51067 Cologne, Germany Langenbecks Arch Surg DOI 10.1007/s00423-016-1472-6 (2019) 404 (Suppl 1):S25

Erratum to: Appendectomy in Germany—an analysis of a nationwide survey 2011/2012

Stapling device/endo-GIA 3.6 66.6 Endoloop only n.a. 24.2 Endoloop with purse string/Z-suture n.a. 2.6 Resorbable clips 2.2 3.8 Nonresorbable clips 0.3 1.2 Mesoappendix Ligation 91.5 n.a. Bipolar coagulation 6.1 45.5 Stapling device 1.2 12.5 Resorbable clips 0.9 15.1 Nonresorbable clips 0.3 9.2 Monopolar coagulation n.a. 6.4 Lavage routinely Yes 48.1 49.9 No 51.9 50.1 Abdominal drain Always/mostly 9.5 8.3 Rarely/never 21.4 34.5 Depending on intraoperative finding 69.1 57.2 Subcutaneous Redon drain Always/mostly 4.5 n.a. Rarely/never 75.6 n.a. Depending on intraoperative finding 19.9 n.a. Subcutaneous suture Always/mostly 42.6 n.a. Rarely/never 42.4 n.a. Depending on intraoperative finding 15 n.a. Skin closing Intracutaneous and resorbable 36.5 48.3 Interrupted sutures 35.2 44.8 Staples 14.1 3.1 Intracutaneous and non resorbable 10.3 3.8