Validation of a Nomogram to Predict Recurrence in Patients with Mucinous Neoplasms of the Appendix with Peritoneal Dissemination After Cytoreductive Surgery and HIPEC.

BACKGROUND: Survival of patients affected by mucinous appendiceal neoplasms with peritoneal dissemination (PD) is mainly related to histopathological features. However, prognostic stratification is still a concern, as the clinical course of the disease is often unpredictable. The aim of this study is to construct and externally validate a nomogram predicting disease-free survival (DFS) in mucinous appendiceal neoplasms with PD treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). PATIENTS AND METHODS: Patients treated in two referral centers were included: Hospital General Universitario Gregorio Marañón, Madrid, Spain (derivation cohort) and Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy (validation cohort). Cox regression analysis identified factors associated with shorter DFS in the derivation cohort. The nomogram performance was externally evaluated in the validation cohort using concordance index and calibration plots. Histology was classified according to the Peritoneal Surface Oncology Group International (PSOGI). RESULTS: The derivation cohort included 95 patients, and the validation cohort 348. Five-year DFS rates were 51.5 and 62%, respectively. Cox regression analysis (derivation cohort) identified PSOGI histology of the peritoneal components, number of preoperative elevated tumor marker, and peritoneal disease extent, as assessed by peritoneal carcinomatosis index, to be predictors of DFS. The model's predictive capacity was higher than that of PSOGI classification alone, with respective concordance indexes of 0.702 ± 0.023 and 0.610 ± 0.018 (validation cohort). The nomogram approximated the perfect model in the calibration plots at 3- and 5-year DFS. CONCLUSIONS: An easy-to-use model that provides better prognostic stratification than histopathological features has been constructed. This nomogram may help clinicians in individualized survival predictions and informed clinical decision-making.

Toward the molecular dissection of peritoneal pseudomyxoma.

BACKGROUND: Outcome of pseudomyxoma peritonei (PMP) after cytoreductive surgery (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC) is heterogeneous even after adjusting for clinico-pathological prognostic variables. The identification of additional prognostic or even predictive biomarkers is an unmet clinical need. PATIENTS AND METHODS: Forty patients with mucinous appendiceal tumors and PMP were clinically eligible and had evaluable tumor samples obtained after CRS and HIPEC. We carried out next-generations sequencing (NGS) of 50 gene's hotspot regions contained in the Hotspot Cancer Panel v2 using the Ion Torrent Personal Genome Machine platform (Life Technologies). RESULTS: KRAS and GNAS mutations were found in 72% and 52%, and their allelic frequency was below 10% in 55% and 43% of samples, respectively. KRAS and GNAS mutations were associated with worse progression-free survival (PFS) at univariate analysis (P = 0.006 and 0.011, respectively). At multivariate analysis, only KRAS mutations were independently associated with PFS (P = 0.012); GNAS mutations were not-being significantly associated with other poor prognostic features such as incomplete cytoreduction or KRAS mutations. Validation of results was carried out in an independent bi-institutional cohort of 25 patients and the prognostic effect of KRAS mutations was again confirmed in the multivariate model (P = 0.029). NGS approach allowed the discovery of other potentially druggable mutations such as those in PI3K, AKT, LKB1, FGFR3 and PDGFRA. CONCLUSIONS: Given the homogeneity of this series and the sensitivity of NGS in this low-cellularity tumor, we demonstrated for the first time a poor prognostic role of KRAS mutations.

Peritoneal metastases: challenges for the surgeon.

Peritoneal surface malignancies (PSM) include peritoneal metastases from gastrointestinal and gynecological tumor and rare primary peritoneal malignancies. PSM have been historically considered as end-stage metastatic conditions only amenable to palliative options. Only in recent years, better knowledge of their natural history and pattern of disease-progression has evolved into the concept that PSM represent a local-regional disease stage. A novel treatment approach aiming at definitive disease eradication combines aggressive cytoreductive surgery (CRS) and perioperative local-regional chemotherapy, either in the form of hyperthermic intraperitoneal chemotherapy (HIPEC), or normothermic early postoperative chemotherapy. Such a combined treatment approach has reportedly resulted in a survival improvement over historical controls, and it is gaining an increasing acceptance as standard of care for selected patients with PSM. This article reviews the most recent literature data on the surgical and comprehensive management of PSM. Epidemiology and natural history of the different disease entities are briefly discussed. Cytoreductive surgical procedures and intraperitoneal chemotherapy administration techniques are described, focusing on the technical variants adopted in our institution. Indications for combined treatment, and outcomes following CRS/HIPEC, are addressed, including peritoneal metastases from appendiceal tumors (pseudomyxoma peritonei), colorectal cancer, gastric cancer, epithelial ovarian cancer, and rare primary peritoneum based neoplasms, such as diffuse malignant peritoneal mesothelioma, and primary peritoneal (extra-ovarian) serous papillary carcinoma.

Multicentre study of the learning curve and surgical performance of cytoreductive surgery with intraperitoneal chemotherapy for pseudomyxoma peritonei.

BACKGROUND: The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. METHODS: Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. RESULTS: Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84·4, 25·7 and 29·0 per cent respectively. The median annual centre volume was 17 (range 6-66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78-284) and 96 (86-284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. CONCLUSION: The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10-15 million inhabitants would be ideal.

Postoperative complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy affect long-term outcome of patients with peritoneal metastases from colorectal cancer: a two-center study of 101 patients.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is an effective but potentially morbid treatment for colorectal cancer peritoneal metastases. The impact of treatment-related morbidity on long-term survival has been reported in various malignancies, but it has never been assessed in this clinical setting. OBJECTIVE: The aim of this study was to assess the impact of major postoperative complications on oncological outcomes after cytoreduction and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases. DESIGN: Two prospective databases were reviewed. Major complications were defined as grade 3 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The extent of peritoneal involvement was scored by the use of the Peritoneal Cancer Index. SETTINGS: This study was conducted in 2 high-volume peritoneal malignancy management centers. PATIENTS: One hundred one consecutive patients with peritoneal metastases potentially amenable to macroscopically complete cytoreduction were selected. INTERVENTIONS: Peritonectomy procedures and multivisceral resections were used to remove all macroscopic tumor, and mitomycin-C plus cisplatin-based hyperthermic intraperitoneal chemotherapy was used to control microscopic residual disease. MAIN OUTCOME MEASURES: The primary outcomes measured were overall and disease-specific survival. RESULTS: Mortality and major morbidity were 3.0%, and 23.8%. Median follow-up was 44.9 months (95% CI, 24.1-65.7). Five-year disease-specific survival was 14.3% for patients who experienced major complications and 52.3% for those who did not (p = 0.001). Five-year overall survival was 11.7% for patients who experienced major complications, and 58.8% for those who did not (p = 0.003). At multivariate analysis, major morbidity correlated to both worse overall and disease-specific survival, along with a Peritoneal Cancer Index >19, and suboptimal cytoreduction. Poor performance status correlated only to worse disease-specific survival, and liver metastases correlated to worse overall survival. Longer operative time (OR, 4.1; 95% CI, 1.3-12.6; p = 0.01) and Peritoneal Cancer Index >19 (OR, 2.6; 95% CI, 1.1-6.0; p = 0.02) were independent risk factors for major morbidity. LIMITATIONS: This study is limited by its observational design. CONCLUSIONS: The prevention of major complications, by refining surgical technique and patient selection, is crucial because it affects oncologic outcome.

Sulfatide imaging identifies tumor cells in colorectal cancer peritoneal metastases.

Even with systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC), peritoneal metastases (PM) remain a common site of disease progression for colorectal cancer (CRC) and are frequently associated with a poor prognosis. The mass spectrometry (MS) method known as Matrix-Assisted Laser Desorption/Ionization - Time of Flight (MALDI-TOF) is frequently used in medicine to identify structural compounds and biomarkers. It has been demonstrated that lipids are crucial in mediating the aggressive growth of tumors. In order to investigate the lipid profiles, particularly with regard to histological distribution, we used MALDI-TOF MS (MALDI-MS) and MALDI-TOF imaging MS (MALDI-IMS) on patient-derived tumor organoids (PDOs) and PM clinical samples. According to the MALDI-IMS research shown here, the predominant lipid signature of PDOs in PM tissues, glycosphingolipid (GSL) sulfates or sulfatides, or STs, is unique to the areas containing tumor cells and absent from the surrounding stromal compartments. Bioactive lipids are derived from arachidonic acid (AA), and AA-containing phosphatidylinositol (PI), or PI (18:0-20:4), is shown to be highly expressed in the stromal components. On the other hand, the tumor components contained a higher abundance of PI species with shorter and more saturated acyl chains (C34 and C36 carbons). The cellular subversion of PI and ST species may alter in ways that promote the growth, aggressiveness, and metastasis of tumor cells. Together, these findings suggest that the GSL/ST metabolic programming of PM may contain novel therapeutic targets to impede or halt PM progression.

Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases.

BACKGROUND: There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)]. RESULTS: KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRASMUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRASMUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRASMUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRASMUT1 and KRASMUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRASMUT1 showed a similar survival rate to KRASWT patients, whereas KRASMUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001). CONCLUSIONS: In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

External multicentre validation of pseudomyxoma peritonei PSOGI-Ki67 classification.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease. Adding of the Ki67 proliferation index to the PSOGI PMP classification provided two different subcategories of the extensive HG-PMP group (HG-PMP ≤15% and HG-PMP >15%) with different survival in a previous unicentric study. This study aims to carry out an external and multicentre validation of this new proposed classification. METHOD: It was a prospective analysis of samples from a historical and international cohort of patients. A representative area with higher cellular density was used to determine the Ki67%. The Ki67 proliferation index (%) was determined in all the HG-PMP patients. A Cox proportional hazard models and multivariable COX models were used. The Kaplan-Meier method and the two-tailed log-rank test were used to analyse the effect of different PSOGI-Ki67 categories on OS and DFS. Its predictive accuracy was analysed using Harrel's C-index and the ROC curve. The calibration was performed using the calibration plots matching. RESULTS: After exclusions, 349 patients were available for analysis. The 5-years OS were 86% for LG-PMP, 59% for HG-PMP≤15, 38% for HG-PMP>15 and 42% for SRC-PMP (p = 0.0001). The 5-years DFS were 49% for LG-PMP, 35% for HG-PMP≤15, 16% for HG-PMP>15 and 18% SRC-PMP (p = 0.0001). The discrimination capability of PSOGI-Ki67 was validated. CONCLUSION: the PSOGI-Ki67 classification discriminates and predicts the OS and DFS in patients with PMP dividing the HG-PMP category into two well-defined sub-categories. The Ki67 proliferation index should be incorporated routinely in the pathology report for these patients.

Importance of gender in diffuse malignant peritoneal mesothelioma.

BACKGROUND: Combined therapy involving cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has been shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). The present study aims to investigate gender as a potential prognostic factor on overall survival. PATIENTS AND METHODS: Over a period of two decades, 294 patients who underwent CRS and perioperative intraperitoneal chemotherapy were selected from a large multi-institutional registry to assess the prognostic significance of gender on overall survival. RESULTS: Female patients were shown to have a significantly improved survival outcome than male patients (P < 0.001). Staging according to a recently proposed tumor-node-metastasis categorization system was significant in both genders. Older female patients had significantly worse survival than younger female patients (P = 0.019), a finding that was absent in male patients. Female patients with low-stage disease were found to have a very favorable long-term outcome after combined treatment. CONCLUSIONS: Gender has demonstrated a significant impact on overall survival for patients with DMPM after CRS and perioperative intraperitoneal chemotherapy. An improved understanding of the role of estrogen in the pathogenesis of DMPM may improve the prognostication of patients and determine the role of adjuvant hormonal treatment in the future.

Secondary cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent epithelial ovarian cancer: a multi-institutional study.

OBJECTIVE: To assess the efficacy and morbidity and mortality of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent epithelial ovarian cancer (EOC). DESIGN: A retrospective study conducted using information extracted from a multi-institutional prospective database on peritoneal surface malignancies (PSMs). Setting Four Italian centres specializing in locoregional treatment of PSM. POPULATION: Patients with recurrent EOC. METHODS: Fifty-six patients underwent 57 combined procedures. CRS was performed using peritonectomy procedures and HIPEC using the closed-abdomen technique with cisplatin and doxorubicin or cisplatin and mitomycin-C. MAIN OUTCOME MEASURES: Overall survival (OS), progression-free survival (PFS), morbidity and mortality rates. RESULTS: The median age of the patients was 55.2 years (range 30-75 years). The median peritoneal cancer index was 15.2 (range 4-30). Forty-seven patients had microscopic residual disease (completeness of cytoreduction, CC-0), seven had residual disease ≤2.5 mm (CC-1) and one had residual disease >2.5 mm (CC>2). Major complications occurred in 15 patients (26.3%), and procedure-related mortality occurred in three patients (5.3%). The median follow-up time was 23.1 months. The median OS and PFS were 25.7 (95% CI 20.3-31.0) and 10.8 (95% CI 5.4-16.2) months, respectively. The 5-year OS and PFS were 23% and 7%, respectively. Independent prognostic factors affecting OS according to the multivariate analysis were Eastern Cooperative Oncology Group performance status, preoperative serum albumin, and completeness of cytoreduction. CONCLUSIONS: Patients with recurrent EOC treated with CRS and HIPEC showed promising results in terms of outcome. The combined treatment strategy could benefit subsets of patients wider than that defined for conventional secondary debulking surgery without HIPEC. These data warrant further evaluation in randomised clinical trials.

Preliminary results of a program for the implementation of laparoscopic colorectal surgery in an Italian comprehensive cancer center during the COVID-19 pandemic.

Despite operative benefit and oncological non-inferiority, videolaparoscopic (VLS) colorectal surgery is still relatively underutilized. This study analyzes the results of a program for the implementation of VLS colorectal surgery started in an Italian comprehensive cancer center shortly before COVID-19 outbreak. A prospective database was reviewed. The study period was divided in four phases: Phase-1 (Open surgery), Phase-2 (Discretional phase), Phase-3 (VLS implementation phase), and Phase-4 (VLS consolidation phase). Formal surgical and perioperative protocols were adopted from Phase-3. Postoperative complications were scored by the Clavien-Dindo classification. 414 surgical procedures were performed during Phase-1, 348 during Phase-2, 360 during Phase-3, and 325 during Phase-4. In the four phases, VLS primary colorectal resections increased from 11/214 (5.1%), to 55/163 (33.7%), 85/151 (57.0%), and 109/147 (74.1%), respectively. The difference was statistically significant (P < 0.001). All-type VLS procedures were 16 (3.5%), 61 (16.2%), 103 (27.0%), and 126 (38.6%) (P < 0.001). Conversions to open surgery of attempted laparoscopic colorectal resections were 17/278 in the overall series (6.1%), and 12/207 during Phase-3 and Phase-4 (4.3%). Severe (grades IIIb-to-V) postoperative complications of VLS colorectal resections were 9.1% in Phase-1, 12.7% in Phase-2, 12.8% in Phase-3, and 5.3% in Phase-4 (P = 0.677), with no significant differences with open resections in each of the four phases: 9.4% (P = 0.976), 11.1% (P = 0.799), 13.8% (P = 1.000), and 8.3% (P = 0.729). Despite the difficulties deriving from the COVID-19 outbreak, our experience suggests that volume of laparoscopic colorectal surgery can be significantly and safely increased in a specialized surgical unit by means of strict operative protocols.

Multi-institutional experience of diffuse intra-abdominal multicystic peritoneal mesothelioma.

BACKGROUND: This study was undertaken to measure survival of patients with multicystic peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy through a multi-institutional collaboration. METHODS: A multi-institutional data registry, established by the Peritoneal Surface Oncology Group, was used to identify patients with peritoneal mesothelioma and the subgroup with multicystic tumours, treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Outcomes for this subgroup are reported. The primary endpoint was overall survival. A secondary endpoint was the incidence of treatment-related complications. RESULTS: Of 405 patients with peritoneal mesothelioma, 26 (6·4 per cent) had multicystic tumours. There were 20 women and six men with a mean(s.d.) age of 42(12) years. The median peritoneal carcinomatosis index (PCI) was 14 (range 6-39). There was no perioperative mortality. Six patients developed grade III or IV complications. After a median follow-up of 54 (range 5-129) months, all 26 patients were still alive. CONCLUSION: Multicystic peritoneal mesothelioma appears to be a distinct subtype of peritoneal mesothelioma, where long-term survival may be achieved through cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma.

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%-100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future.

Appendiceal tumours and pseudomyxoma peritonei: Literature review with PSOGI/EURACAN clinical practice guidelines for diagnosis and treatment.

Pseudomyxoma Peritonei (PMP) is a rare peritoneal malignancy, most commonly originating from a perforated epithelial tumour of the appendix. Given its rarity, randomized controlled trials on treatment strategies are lacking, nor likely to be performed in the foreseeable future. However, many questions regarding the management of appendiceal tumours, especially when accompanied by PMP, remain unanswered. This consensus statement was initiated by members of the Peritoneal Surface Oncology Group International (PSOGI) Executive Committee as part of a global advisory role in the management of uncommon peritoneal malignancies. The manuscript concerns an overview and analysis of the literature on mucinous appendiceal tumours with, or without, PMP. Recommendations are provided based on three Delphi voting rounds with GRADE-based questions amongst a panel of 80 worldwide PMP experts.

Diffuse malignant peritoneal mesothelioma: Failure analysis following cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC).

Improved survival has been reported for diffuse malignant peritoneal mesothelioma (DMPM) treated by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). The issue of treatment failure has never been extensively addressed. The present study assessed the failure pattern, management, and outcome of progressive DMPM following comprehensive treatment. Clinical data on 70 patients with DMPM undergoing cytoreduction and HIPEC were prospectively collected; after a median follow-up of 43 months, disease progression occurred in 38 patients. Progressive disease distribution in 13 abdominopelvic regions was analyzed. In 28 patients undergoing adequate cytoreduction (residual tumor < or =2.5 mm), clinicopathological factors correlating to disease progression in each region were investigated. Median time to progression was 9 months [95% confidence interval (CI) 1.6-35.9]. Median survival from progression was 8 months (95% CI 4-16.2). The failure pattern was categorized as peritoneal progression (n = 31), liver metastases (n = 1), abdominal lymph-node involvement (n = 2), pleural seeding (n = 4). Small bowel was the single site most commonly involved (n = 27). Residual tumor < or =2.5 mm (versus no visible) was the only independent risk factor for disease progression in epigastric region (P = 0.047), upper ileum (P = 0.029), upper jejunum (P = 0.034), and lower jejunum (P = 0.002). Progressive disease was treated with second HIPEC in 3 patients, debulking in 4, systemic chemotherapy in 16, and supportive care in 15. At multivariate analysis, time to progression <9 months (P = 0.009), poor performance status (P = 0.005), and supportive care (P = 0.003) correlated to reduced survival from progression. We conclude that minimal residual disease, compared with macroscopically complete cytoreduction, correlated to failure in critical anatomical areas, suggesting the need for maximal cytoreductive surgical efforts. In selected patients, aggressive management of progressive disease seems worthwhile.

Hyperthermic isolated perfusion with tumor necrosis factor-alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcoma: the experience of the Italian Society of Integrated Locoregional Treatment in Oncology (SITILO).

BACKGROUND: Tumor necrosis factor-alpha (TNFalpha)-based hyperthermic isolated limb perfusion (HILP) is routinely carried out at most oncological institutions in the treatment of locally advanced soft tissue limb sarcoma (STS), employing high TNFalpha dosages. After a phase I-II study, the SITILO (Italian Society of Integrated Locoregional Therapies in Oncology) centers began to employ the lower dose of 1 mg of TNFalpha. The aim of this paper is to report on the results obtained in 75 patients with limb-threatening STS treated with a low TNFalpha dose and doxorubicin (Dx). PATIENTS AND METHODS: HILP with TNFalpha (at a dosage of either 1 mg) and Dx was administered to 75 patients with limb-threatening STS: 37 males and 38 females; median age 50 years; tumor in the lower and upper limbs in 58 and 17 patients, respectively; primary and recurrent tumors in 45 and 30 patients, respectively. Most tumors (77%) were high grade. Tumor resection was carried out 6 to 8 weeks after HILP. RESULTS: The grade of limb toxicity was mild to moderate in the vast majority of patients (76%). Grades IV and V were observed, but only when high muscle temperatures were recorded and high TNFalpha dosages were employed. Systemic toxicity was also mild to moderate and there were no postoperative deaths. Complete and partial tumor responses were 34% and 48%, respectively, with an overall response of 82% . Limb sparing surgery was carried out in 85.3% of patients. At a median follow-up of 28 months, 16 recurrences (21.3%) were recorded, with a 5-year locoregional disease-free survival of 63% . The 5-year disease-free survival and overall survival were 36.7% and 61.6%, respectively. CONCLUSION: HILP with 1 mg of TNFalpha is an effective neoadjuvant therapy resulting in a high rate of limb sparing in limb-threatening STS, with acceptable local reactions and negligible systemic toxicity.

Multicystic peritoneal mesothelioma treated by surgical cytoreduction and hyperthermic intra-peritoneal chemotherapy (HIPEC).

BACKGROUND: Multicystic peritoneal mesothelioma (MPM) is an extremely uncommon lesion with uncertain malignant potential. Multiple recurrences after surgical interventions and transition to aggressive malignancies have been reported. Here, we review our experience with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of MPM. PATIENTS AND METHODS: Five women with MPM underwent 6 procedures of cytoreduction and close-abdomen HIPEC with cisplatin and doxorubicin. Three patients had recurrent disease after 1, 2 and 4 previous debulkings, respectively. RESULTS: Optimal cytoreduction (residual tumor nodules < or =2.5 mm) was performed in all the procedures. One grade 4 postoperative complication (NCI/CTCAE v.3.0) and no operative mortality occurred. Median follow-up was 31 months (range 3-102). MPM recurred in two patients: one is presently disease-free after a second cytoreduction with HIPEC and the other is alive with minimal stable disease. CONCLUSION: Definitive eradication by means of cytoreduction and HIPEC seems a safe and effective therapeutic option for MPM.

Cytoreductive surgery and HIPEC improve survival compared to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups.

BACKGROUND: Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. OBJECTIVE: To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. MATERIAL AND METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. RESULTS: Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3-26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively. CONCLUSION: Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.