Iterative Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Peritoneal Metastases.

BACKGROUND: Our aim was to analyze the safety and efficacy of iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (iCRS-HIPEC) in patients with peritoneal recurrence from different tumor types. PATIENTS AND METHODS: Data on indications, intraoperative findings and postoperative outcome of all patients treated with iCRS-HIPEC at our Institution were reviewed. RESULTS: Between 2010-2018, 10 iCRS-HIPEC procedures for peritoneal recurrence in eight patients were performed. The median peritoneal cancer index was 14.5 (range=2-33). Completeness of cytoreduction was CC0-1 in most cases (9/10). Three grade III-IV complications (two intestinal fistulas, one bleeding) were recorded and there was no operative mortality. After a median follow-up of 19.5 months, six patients experienced recurrence after a median of 12.5 months. CONCLUSION: iCRS-HIPEC is a safe procedure in selected patients with recurrent peritoneal surface malignancies. Selection criteria still remain questionable and need to be further evaluated in large cooperative multi-institution studies.

Diagnostic value of contrast-enhanced CT combined with 18-FDG PET in patients selected for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

PURPOSE: Aim of the study is to assess the reliability and correlation with surgical peritoneal cancer index (PCI) of combined PET/CT and ceCT scans (PET/ceCT) performed in a session in patients with peritoneal carcinomatosis candidates for cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: We retrospectively analyzed data collected from 27 patients with different types of peritoneal carcinomatosis candidates to CS + HIPEC who underwent FDG PET/ceCT in a single session. Two nuclear medicine physicians and two radiologists independently and blindly evaluated PET/CT and ceCT imaging, respectively. In the case of discordance, the consensus was reached by a discussion between the specialists. Moreover, the combined images were evaluated by all the specialists in consensus. The PCIs obtained from surgical look, PET/CT, ceCT, and PET/ceCT were compared with each other. The coefficients of correlation (r) were calculated. The study was conducted after approval of local ethics committee. RESULTS: Surgical PCI was available in 21 patients. The coefficient of correlation between PCI of PET/CT and surgery was 0.528, while it resulted higher between PET/ceCT and surgery (r = 0.878), very similar to ceCT and surgery (r = 0.876). The r coefficient between surgical PCI and PET/CT was higher in patients with a non-mucinous cancer (n = 12) than the counterpart (0.601 vs. 0.303) and the addition of ceCT significantly increases the correlation (r = 0.863), which is anyway similar to ceCT alone (r = 0.856). CONCLUSIONS: PET/ceCT as single examination is more accurate than PET/CT but not than ceCT alone for the definition of PCI in a selected group of patients candidates to CS + HIPEC.

Hyperthermic isolated limb perfusion in locally advanced limb soft tissue sarcoma: A 24-year single-centre experience.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) is a locoregional treatment aimed at avoiding amputation in patients with advanced extremity soft tissue sarcomas (STS). Over the last 25 years, HILP procedure has been implemented to maximise its therapeutic ratio. METHODS: A retrospective analysis including 117 patients who underwent HILP from 1989 to 2013 was performed. Three different drug schedules were applied: 1) doxorubicin (n = 47), 2) high dose (3-4 mg) tumour necrosis factor-alpha (TNF-α) plus doxorubicin (n = 30), 3) low dose (1 mg) TNF-α plus melphalan (L-PAM) (n = 40). Tumour response was evaluated by MRI or CT and surgical specimens. Toxicity and local progression-free survival (LPFS) were also evaluated. RESULTS: In total 92 (78.6%) patients had primary, 25 (21.4%) had recurrent and 17 (14.5%) had metastatic disease. The subjects in the three groups were homogeneous for clinical-pathological features. Pathological response was complete in 55 patients (47%), partial in 35 (29.9%), regardless of drug schedule (p = 0.501) and tumour presentation (p = 0.094). Wieberdink III-V toxicity was registered in 19.1%, 20% and 2.5% of patients, respectively (p < 0.051). Twenty-eight patients (23.9%) received adjuvant radiotherapy with no relevant toxicity. Five-year LPFS was 81.6% and 74.2% in patients with primary or recurrent disease, respectively (p = 0.652). After a median follow-up of 36.5 months, the limb sparing rate was 77.8%. CONCLUSIONS: HILP performed with different drugs was equally active, either in primary, recurrent or metastatic STS, providing effective limb sparing and durable local control. Low dose TNF-α plus L-PAM had the most favourable toxicity profile. Adjuvant radiotherapy was not associated with relevant toxicity.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal sarcomatosis: long-term outcome from a single institution experience.

AIM: We assessed the long-term local disease-free survival (LDFS) and overall survival (OS) of patients with peritoneal sarcomatosis (PS) uniformly-treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CS plus HIPEC). PATIENTS AND METHODS: Retrospective data of 15 patients who underwent CS plus HIPEC for PS were extracted from a prospectively collected database. DFS and OS were calculated from the date of CS plus HIPEC to local relapse and death, respectively. RESULTS: After a median follow-up of 28 months (range=4-144 months), median LDFS was 15 months (95% Confidence Interval CI=1-40 months). Median OS was 27 (95% CI=24.7-29.3) months. Long-term OS was achieved in three patients (20%) and ranged between 93 and 144 months. Female sex was the only factor significantly correlated with a greater LDFS (p=0.018). Patients with PS of visceral origin seem at lower risk of recurrence and death but the difference did not prove significant. CONCLUSION: In our series, long-term survival was achieved in 20% of patients after CS plus HIPEC, with a benefit in female patients with PS of visceral origin. The impact of HIPEC after radical surgery for PS remains questionable and still has to be further evaluated in large cooperative multi-institutional studies.

The role of laparoscopy in peritoneal surface malignancies selected for hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: Cytoreductive surgery (CS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was developed as locoregional treatment for primary or secondary peritoneal tumors. The role of laparoscopy over several stages of diagnosis and the treatment of the patients affected by peritoneal carcinomatosis and selected for CS + HIPEC shows some peculiarities, and their potential application in this field is not fully known. Our aim was to review and summarize the applications, the results, and the future directions of laparoscopy in the management of the patients affected by carcinomatosis and scheduled for CS + HIPEC. METHODS: Appropriate keywords were adopted to identify the relevant studies on this topic in PubMed/Medline electronic databases. RESULTS: The role of laparoscopy in diagnosis and staging of patients selected for CS + HIPEC seems to have a great but probably underestimated potential. Laparoscopic CS + HIPEC is technically feasible with an acceptable morbidity profile, especially in patients with low tumor load. In selected patients with malignant ascites, laparoscopic HIPEC achieves a good palliative effect, with a low morbidity profile. CONCLUSIONS: Laparoscopy plays a partially explored role in diagnosis and staging of patients selected for CS + HIPEC. The use of laparoscopic HIPEC with an adjuvant, curative, or palliative intent seems feasible, but further studies are required in order to explore and validate all potential indications. For all these reasons, it would be advisable to provide every HIPEC center with specific laparoscopic skills.

Cyto-reductive Surgery combined with Hyperthermic Intra-peritoneal Chemotherapy for Peritoneal Surface Malignancies: current treatment and results.

Cyto-reductive Surgery (CS) combined with Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) as loco-regional treatment of Peritoneal Surface Malignancies (PSM) has increasingly gained acceptance in clinical practice. This review summarizes the more relevant studies on this topic. Indications, pre-operative work-up, technical aspects, outcome and future directions of this combined approach in the treatment of Peritoneal Surface Malignancies are discussed here and proposed in an informative and didactic manner.

The consensus statement on the locoregional treatment of abdominal sarcomatosis.

Abdominal sarcomatosis (AS) is a rare condition characterized by soft tissue sarcoma spreading throughout the abdomen, in the absence of extra-abdominal dissemination. Retroperitoneal sarcomas, pelvic sarcomas, particularly uterine leiomyosarcoma, and gastrointestinal stromal tumors (GISTs) most frequently give rise to AS. Systemic chemotherapy is the standard of care for AS from non-GIST sarcomas, but with an essentially palliative aim and major limitations. Innovative targeted therapies has deeply affected the natural history of GIST, at least in prolonging significantly survival in responsive patients. In this context, the notion that abdominal spread in the lack of extra-peritoneal lesions may typically occur in a number of patients, along with the dismal prognosis generally carried by AS, has prompted a few centers to perform cytoreductive surgery and perioperative intraperitoneal chemotherapy. To date, the rarity of these presentations makes it difficult to evaluate the clinical results and the role of combined local-regional treatment is still a matter of debate. This article presents the results of a group of experts from around the World trying to achieve a consensus statement in AS comprehensive management. A questionnaire was placed on the website of the 5th International Workshop on Peritoneal Surface Malignancy and the experts voted via internet.

Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease.

BACKGROUND: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement

Hyperthermic isolation limb perfusion with TNFalpha in the treatment of in-transit melanoma metastasis.

BACKGROUND: Hyperthermic isolation limb perfusion (HILP) with tumor necrosis factor alpha (TNFalpha) and IFNgamma was pioneered by Liénard and Lejeune in 1988. The TNFalpha was empirically employed at a dosage of 3-4 mg, that is ten times the systemic maximum tolerated dose (MTD). After eighteen years from its first clinical application, more than 300 patients have been treated. The aim of this study is to clarify two major arguments: the TNFalpha dose and eligibility criteria for patient selection. PATIENTS AND METHODS: A phase I-II study has previously been conducted in 20 patients with in-transit melanoma metastases using a combination of melphalan and TNFalpha at dosages ranging from 0.5 to 3.3 mg. Twenty patients were treated and a complete pathological response of 70% was recorded, with no correlation between tumor response and TNFalpha. The dose of 1 mg of TNFalpha provided the best results regarding efficacy and toxicity. On the basis of this results a large phase II SITILO study was undertaken. Patients with stage IIIA - IIIAB (presence of in transit metastases and/or regional node involvement) were considered eligible; a total of 113 patients were enrolled in the study. The disease was bulky (> 10 nodules or fewer nodules with a diameter > or = 3 cm) in 42.5% of the patients and unresectable in 33%. Forty patients were treated with a TNFalpha dosage > 1 mg and 73 with 1 mg. All the patients were submitted to HILP via axillary and iliac vessels for tumor of upper and lower limb, respectively. TNFalpha was injected in the extracorporal circuit at the pre-established dose, followed after 30 minutes by melphalan (13 and 10 mg/L of limb volume for upper and lower limbs, respectively). RESULTS: A grade 1 and 2 limb toxicity was found in 52.9% and 30.1% of the patients, respectively, 5.5% of patients exhibited a grade 3 and 4, whereas grade 5 limb toxicity was not found. The complete and partial responses were 63% and 24.5%, respectively, with an objective response of 87.5%. We tried to correlate the typed tumor response (CR or not CR) and the TNFalpha dosage < or = 1 mg or > 1 mg, but no statistically significant difference was found between the two groups. The bulky disease was the only prognostic factor able to influence the tumor response. CONCLUSION: Only patients with bulky melanoma disease can benefit from HILP with TNFalpha at a low dose of 1 mg.

Hyperthermic isolated perfusion with low-dose tumor necrosis factor alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcomas.

BACKGROUND: Tumor necrosis factor (TNF)-alpha-based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-alpha. METHODS: HILP with low-dose TNF-alpha (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF-alpha concentrations in plasma and perfusate were measured throughout perfusion. RESULTS: A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF-alpha was 56. CONCLUSIONS: HILP with low-dose TNF-alpha and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity.

Hyperthermic intraperitoneal intraoperative chemotherapy after cytoreductive surgery for the treatment of abdominal sarcomatosis: clinical outcome and prognostic factors in 60 consecutive patients.

BACKGROUND: Abdominal sarcomatosis is a rare nosologic entity with a poor prognosis. After a Phase I study on cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy (HIIC), the authors reported the results of the treatment of 60 patients using this novel multimodal approach. METHODS: Twenty-nine patients had multifocal primary disease and 31 patients had recurrent abdominal sarcoma. Tumor histology was represented by visceral (n = 26 [43%]) and retroperitoneal (n = 34 [57%]) sarcoma. All patients underwent cytoreductive surgery (with no or minimal residual disease) and 90-minute HIIC with doxorubicin (15.25 mg/L of perfusate) and cisplatin (43 mg/L). The clinical outcome and the prognostic value of 11 clinicopathologic variables were analyzed. RESULTS: No postoperative deaths occurred. The morbidity rate was 33% and the moderate to severe locoregional toxicity rate was 15%. The median time to local disease progression and the median overall survival were 22 months and 34 months, respectively. Using multivariate analysis, histologic grading and completeness of surgical cytoreduction predicted patient prognosis, indicating that both local progression-free and overall survival were affected significantly by tumor aggressiveness and local disease control. CONCLUSIONS: Although these results were encouraging, there was no definitive conclusion reached regarding the therapeutic activity of this locoregional treatment. In addition, the toxicity rate was substantial. In the absence of effective systemic agents, the therapeutic potential of cytoreductive surgery plus HIIC should be explored further in comparative trials.

Hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-alpha and melphalan for bulky in-transit melanoma metastases.

BACKGROUND: Melphalan (L-PAM) hyperthermic isolated limb perfusion (HILP) is currently considered the standard treatment for patients with in-transit metastases from cutaneous melanoma. We here report on the results of L-PAM and low-dose tumor necrosis factor (TNF)alpha HILP in patients with bulky disease. METHODS: Twenty patients underwent TNFalpha (1 mg) and L-PAM (10 mg/L) HILP. Perfusion was performed for 90 minutes, and systemic leakage was strictly monitored. Locoregional toxicity was evaluated according to Wieberdink's criteria, whereas tumor response was evaluated with physical examination and ultrasound scan with or without fine-needle aspiration of any suspected recurrence. RESULTS: In all cases, systemic leakage was <5%. No postoperative deaths occurred, and locoregional toxicity was mild (grade 1 or 2) in 95% of patients. A complete tumor response was obtained in 14 patients (70%), and partial responses were obtained in 5 patients (25%). After a median follow-up of 18 months, six patients are alive and disease free, seven are alive with local or distant recurrence or both, and seven have died of disease. CONCLUSIONS: Low-dose TNFalpha HILP can achieve tumor responses comparable with those reported with higher doses of cytokine. Moreover, this drug regimen is associated with acceptable local toxicity, carries a smaller risk of systemic toxicity, and incurs lower costs.

Hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from gastric adenocarcinoma.

BACKGROUND: Patients with peritoneal carcinomatosis from gastric carcinoma have a dismal prognosis. Hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) has been proposed to treat residual disease after cytoreductive surgery. PATIENTS AND METHODS: From January 1998 through July 2002, 13 patients with peritoneal carcinomatosis from gastric cancer underwent complete cytoreductive surgery followed by HIIC. Chemo-hyperthermia was performed using mitomicin C (3.3 mg/m2) and cisplatin (25 mg m2) for 90 minutes, at a mean intraperitoneal temperature of 41.7 degrees C. RESULTS: No postoperative death was observed. Moderate locoregional toxicity (ileus) was observed in eight cases (42%), while two patients (10%) experienced mild systemic toxicity (myelosuppression or fever). Postoperative complication rate was 26% (pleural effusion, n = 4; septicemia = 1). Median overall survival was 15 months, and the median local progression free survival was 10 months. CONCLUSIONS: Cytoreductive surgery followed by HIIC resulted a feasible procedure, the overall morbidity rate being acceptable. Although the study was conducted in a subset of patients with peritoneal carcinomatosis from gastric cancer (resectable disease), survival results are encouraging.

TNFalpha-based isolated perfusion for limb-threatening soft tissue sarcomas: state of the art and future trends.

The management of limb-threatening soft tissue sarcomas has not yet been standardized. Although local disease control does not affect overall survival, amputation or highly mutilating surgery may be required, which impairs the patient's quality of life. Various neoadjuvant approaches have been proposed to allow limb-sparing surgery for these locally advanced tumors. With TNFalpha-based hyperthermic isolated limb perfusion, the majority of patients can be spared amputation, with acceptable rates of locoregional and systemic complications. As yet, no other available treatment seems to give comparable results when applied to limb-threatening soft tissue sarcomas. Nevertheless, several issues remain to be addressed, such as the type and dose of drugs, repeatability of the procedure, association with radiotherapy, further indications, and evaluation of response. The authors describe the principles underlying TNFalpha-based hyperthermic isolated limb perfusion, review the worldwide experience so far published, and discuss the above issues. The potential future developments of this locoregional therapeutic approach will also be reported.

Cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from colon adenocarcinoma.

BACKGROUND: Hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) has been recently proposed to treat peritoneal carcinomatosis arising from colon adenocarcinoma, which is usually regarded as a lethal clinical entity. The purpose of this study was to evaluate the clinical outcome of this combined treatment. METHODS: A retrospective study of 46 patients treated for peritoneal carcinomatosis from colon adenocarcinoma was performed. Thirty-four patients were treated with complete cytoreductive surgery immediately followed by intraoperative HIIC with mitomycin C and cisplatin. The clinical outcome of these 34 patients was analyzed; the median follow-up period was 14.5 months. RESULTS: No postoperative deaths were reported. The postoperative morbidity rate was 35%. No severe locoregional or systemic toxicity was observed. The 2-year overall survival was 31%, and the median survival time and the median time to local disease progression were 18 and 13 months, respectively. Survival and local disease control in patients with well- and moderately differentiated colon adenocarcinoma were significantly better than in those with poorly differentiated tumors. CONCLUSIONS: Considering the dismal prognosis of this condition, HIIC seems to achieve encouraging results in a selected group of patients affected with resectable peritoneal carcinomatosis arising from colon adenocarcinoma. These findings support the conduction of formal phase III randomized trials.