Rami Younan

Sentinel Node Biopsy After Neoadjuvant Chemotherapy in Biopsy-Proven Node-Positive Breast Cancer: The SN FNAC Study

PURPOSE An increasing proportion of patients (> 30%) with node-positive breast cancer will obtain an axillary pathologic complete response after neoadjuvant chemotherapy (NAC). If sentinel node (SN) biopsy (SNB) is accurate in this setting, completion node dissection (CND) morbidity could be avoided. PATIENTS AND METHODS In the prospective multicentric SN FNAC study, patients with biopsy-proven node-positive breast cancer (T0-3, N1-2) underwent both SNB and CND. Immunohistochemistry (IHC) use was mandatory, and SN metastases of any size, including isolated tumor cells (ypN0[i+], ≤ 0.2 mm), were considered positive. The optimal SNB identification rate (IR) ≥ 90% and false-negative rate (FNR) ≤ 10% were predetermined. RESULTS From March 2009 to December 2012, 153 patients were accrued to the study. The SNB IR was 87.6% (127 of 145; 95% CI, 82.2% to 93.0%), and the FNR was 8.4% (seven of 83; 95% CI, 2.4% to 14.4%). If SN ypN0(i+)s had been considered negative, the FNR would have increased to 13.3% (11 of 83; 95% CI, 6.0% to 20.6%). There was no correlation between size of SN metastases and rate of positive non-SNs. Using this method, 30.3% of patients could potentially avoid CND. CONCLUSION In biopsy-proven node-positive breast cancer after NAC, a low SNB FNR (8.4%) can be achieved with mandatory use of IHC. SN metastases of any size should be considered positive. The SNB IR was 87.6%, and in the presence of a technical failure, axillary node dissection should be performed. We recommend that SN evaluation with IHC be further evaluated before being included in future guidelines on the use of SNB after NAC in this setting.

Morbidity, toxicity, and mortality classification systems in the local regional treatment of peritoneal surface malignancy

To reach a consensus for reporting complications related to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Reporting the adverse events related to CRS + HIPEC is not standardized yet. Post‐operative complications can be divided in two categories: the effects of surgical manipulation per se and the toxic effects of the heated intraoperative chemotherapy. Additive and/or synergistic effects also exist. Different centers have published their experience with regard to the complications associated with the procedure. Various classification systems have been used which makes a temptative comparison of the different techniques and results almost impossible. An effort was made here to review the existing major classification systems: The Bozzetti classification, the Clavien classification (and two proposed modifications from Feldman et al. and Elias et al.) and the Common terminology criteria for adverse events (CTCAE) version 3.0 of the National Institute of Health (NIH) criteria. A related document was sent to an international panel of experts. The CTCAE was adopted by the panel of experts as the unique classification system to be used for reporting complications related to CRS + HIPEC. J. Surg. Oncol. 2008;98:253–257.

Drugs, carrier solutions and temperature in hyperthermic intraperitoneal chemotherapy

At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on technical aspects of cytoreductive surgery (CRS) for peritoneal surface malignancy was obtained through the Delphi process. Conflicting points concerning drugs, carrier solution and optimal temperature for hyperthermic intraperitoneal chemotherapy (HIPEC) were discussed. J. Surg. Oncol. 2008;98:247–252.

Impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on systemic toxicity.

IntroductionThe purpose of this study was to analyze the postoperative systemic toxicity and procedure-related mortality (PRM) of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal surface malignancies (PSMs).Patients and methodsA total of 242 (84 males/158 females) patients with PSM underwent 247 consecutive procedures. The mean age was 52 years (range 22–79). CRS was performed using peritonectomy procedures. The HIPEC technique through the closed abdomen was conducted with cisplatin (CDDP 25 mg/m2/l of perfusate)+mitomycin C (MMC 3.3 mg/m2/l perfusate) or CDDP (43 mg/l perfusate)+doxorubicin (Dx 15.25 mg/l perfusate) at 42.5°C. These dosages were reduced by 30% when the patient had received systemic chemotherapy before the CRS+HIPEC. Systemic toxicities were graded according to the NCI CTCAE v3 criteria.ResultsG3-5 systemic toxicity rate was 11.7 % and adverse events were bone marrow suppression, 13; nephrotoxicity, 14; neutropenic infection, 2 and pulmonary toxicity, 1. Independent risk factors for G3-5 systemic toxicity after multivariate analysis were a dose of CDDP for HIPEC of 240 mg or more (OR 2.78, CI 95% 1.20–6.45) and CDDP+Dx schedule for HIPEC (OR 2.36, CI 95% 1.02–5.45). PRM was 1.2%.ConclusionsCRS+HIPEC presented acceptable systemic toxicity and PRM rates. Independent risk factors for systemic toxicity were the CDDP+Dx schedule and CDDP dose for HIPEC.

Bowel Complications in 203 Cases of Peritoneal Surface Malignancies Treated With Peritonectomy and Closed-Technique Intraperitoneal Hyperthermic Perfusion

BackgroundPeritonectomy and intraperitoneal hyperthermic perfusion (IPHP) are increasingly used in the management of carcinomatosis of various sites of origin. We analyzed the risk factors for bowel complications with primary anastomoses and the closed technique for IPHP.MethodsFrom 1995 to 2004, 203 consecutive procedures were performed at the National Cancer Institute of Milan. We retrospectively analyzed this series of patients. Treated pathologies included peritoneal mesothelioma; pseudomyxoma peritonei; colorectal, ovarian, or gastric carcinomatosis; and abdominal sarcomatosis. All digestive anastomoses were performed before the IPHP. Only one defunctioning stoma was used.ResultsWe found a bowel complication rate of 10.8%. The bowel complications:anastomoses ratio was 11.3%. On univariate analysis we found a statistically significant association between bowel complications and the following variables: sex, previous systemic chemotherapy status, number of anastomoses ( fewer than two vs. two or more), duration of the procedure (<8.7 vs. ≥8.7 hours), and extent of cytoreduction. After multivariate analysis, male sex (odds ratio [OR], 4.2), no previous systemic chemotherapy (OR, 3.5), and duration of the procedure ≥8.7 hours (OR, 6.3) were considered independent risk factors for bowel complications.ConclusionsBowel complications are not increased when primary unprotected anastomoses are performed during peritonectomy and IPHP when the closed technique is used. Male sex, duration of the procedure, and no previous systemic chemotherapy are independent unfavorable risk factors.

A Phase II Neoadjuvant Trial of Sequential Nanoparticle Albumin-Bound Paclitaxel Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide in Locally Advanced Breast Cancer

BACKGROUND Neoadjuvant chemotherapy has become standard treatment for women with locally advanced breast cancer (LABC). Various regimens have explored the addition of newer agents to determine safety and efficacy. The aim of this phase II study was to incorporate albumin-bound paclitaxel with sequential anthracycline-based therapy. PATIENTS AND METHODS Sixty-six women with LABC but without prior treatment and regardless of hormone receptor or HER2 status were enrolled. All patients were to receive albumin-bound paclitaxel weekly for 12 weeks followed by 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) every 3 weeks for 4 cycles. Trastuzumab was allowed in HER2-positive (HER2+) patients. Primary endpoint was pathologic complete response (pCR; CR) in breast. Secondary endpoints included pCR in breast and nodes, clinical CR, 2-year progression-free survival, and overall survival. RESULTS Sixty-five patients received at least 1 dose of chemotherapy and were included in this analysis. Sixty-three patients completed 4 cycles of albumin-bound paclitaxel. Sixty-two patients received at least 1 dose of FEC, and 58 completed 4 cycles. Seventeen of 19 HER2+ women received trastuzumab. The pCR in breast was 29% (19 of 65). For the HER2+ subset, the pCR was 58% (11 of 19). Both albumin-bound paclitaxel and FEC were well tolerated. The most significant toxicities were grade 2/3 neuropathy (16%) with albumin-bound paclitaxel and grade 3/4 febrile neutropenia (7%) with FEC. CONCLUSION Albumin-bound paclitaxel given over 12 weeks is well tolerated. Albumin-bound paclitaxel should be further evaluated in a randomized setting in both adjuvant and neoadjuvant trials.

Incidence of Postoperative Pancreatic Fistula and Hyperamylasemia after Cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy

IntroductionThe purpose of this study was to analyze the postoperative pancreatic morbidity of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal surface malignancies (PSM).Patients and methodsTwo hundred and sixty five patients (87M/178F) with PSM underwent 270 consecutive procedures. The mean age was 52 years (range: 22–79 years). CRS was performed using peritonectomy procedures. HIPEC through the closed abdomen technique was conducted using cisplatin (CDDP 25mg/m2/L of perfusate)+mitomycin C (MMC 3.3 mg/m2/L of perfusate) or CDDP (43mg/L of perfusate)+doxorubicin (Dx 15.25 mg/L of perfusate), at 42.5°C. Diagnosis and classification of postoperative pancreatic fistula (POPF) were performed according to the international study group on pancreatic fistula criteria. Serum amylase alterations were graded according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) v3.ResultsPOPF was observed in 13 (4.8%) cases. Three cases were classified as major (grade C). Two cases presented postoperative pancreatitis. G3-4 alteration of amylase was observed in 12.3% of the cases. Performing splenectomy and CDDP dosage for HIPEC >240mg were proven to be independent risk factors for both G3-4 hyperamylasemia and POPF.ConclusionsCRS+HIPEC presented an acceptable rate of pancreatic morbidity which did not contribute to the mortality related to the procedure. Most of the POPF were mild and/or easily controlled by conservative measures. Although not specific a normal amylasemia could be a useful marker of pancreatic integrity after CRS+HIPEC.

Technical aspects of cytoreductive surgery.

At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on technical aspects of cytoreductive surgery (CRS) for peritoneal surface malignancy was obtained through the Delphi process. Five conflicting points were discussed: radicality of the peritonectomy procedure, cytoreduction of neoplastic nodules <2.5 mm, the timing of bowel anastomoses in relation to hyperthermic intraperitoneal chemotherapy (HIPEC) and indications of protective ostomies. According to the panel of experts a partial parietal peritonectomy restricted to the macroscopically involved regions could be indicated in all listed clinical conditions with the exception of peritoneal mesothelioma. No expert was of the opinion that a radical parietal peritonectomy is advisable irrespective of the disease being treated. All the experts agreed that electrovaporization of small (<2.5 mm) non‐infiltrating metastatic nodules in the mesentery would be appropriate, even if theoretically the HIPEC affords microscopic cytoreduction. The panel also agreed that in the closed technique for HIPEC administration the intestinal anastomoses should be fashioned after completion of the perfusion. Finally when considering the place for protective ostomies the experts voted for a flexible approach allowing the surgeon to exercise discretion for individual patients. J. Surg. Oncol. 2008;98:232–236.

The Delphi approach to Attain consensus in methodology of local regional therapy for peritoneal surface malignancy.

At the Fifth International Workshop on Peritoneal Surface Malignancy (PSM), held in Milan, December 2006, the consensus on technical aspects of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was obtained through the Delphi process. The following topics were discussed: pre‐operative workup; eligibility to CRS + HIPEC; intra‐operative staging system; technical aspects of surgery; residual disease classification systems; HIPEC: nomenclature and modalities; drugs, carrier solution and optimal temperature; morbidity grading systems. Conflicting points regarding above‐mentioned topics were elaborated and voted in two rounds by a panel of international experts in local‐regional therapy. The purpose of this manuscript is to describe the organization and the methodology of the consensus statements and to interpret and discuss the implications of the most striking results. J. Surg. Oncol. 2008;98:217–219.

Pharmacokinetics of intraperitoneal irinotecan in a pig model

Complete surgical cytoreduction of peritoneal implants and immediate intraperitoneal (lP) chemotherapy offers the greatest survival in selected patients with peritoneal carcinomatosis. This study was undertaken to describe the metabolism and pharmacokinetics of normothermic intraperitoneal CPT‐11, free and glucuronized SN‐38, in a pig model. Thirteen pigs were used for experimentation. Animals were grouped for IV and IP CPT‐1 1 administration. Eleven pigs underwent laparotomy through a midline incision and instillation of 100, 200, and 400mg IP CPT‐11. Systemic venous blood, portal blood and peritoneal fluid samples were taken at 5, 10, 20, 30, and 45 min, then every hour up to 8 hr for the 100 mg. For the three groups, peritoneal CPT‐11 exposition was on average 4.9 times greater in the peritoneum than in the systemic venous or portal circulations and the systemic CPT‐11 fraction absorbed from the peritoneum linearly increased with time. Free SN‐38 was measurable in the earliest peritoneal samples taken. The initial instillation dose of CPT‐11 did not impact on the SN‐38 converted fraction, which remained stable at approximately 0.04% during the first 4 hour. Mean peritoneal SN‐38: CPT‐11 AUC ratio was 0.043. OPT‐11 peritoneal conversion into SN‐38 appeared slightly Inferior to the systemic conversion ratio. This norrnothermic IP OPT‐11 pharmacokinetic study performed in a pig model confirms the possibility to achieve at least a 30 times higher peritoneal than systemic exposure. Peritoneal exposure to active SN‐38 begins at the moment of CPT‐11 peritoneal instillation. A fixed and small traction of less than 0.1% of CPT‐11 is converted into SN‐38, underlying the importance of a sufficient initial IP dose of CPT‐11. J. Surg. Oncol. 2010; 101:637–642.