Secondary cytoreductive surgery, hyperthermic intraperitoneal intraoperative chemotherapy, and chemotherapy alone: a retrospective comparison of alternative approaches in relapsed platinum sensitive ovarian cancer.

INTRODUCTION: The best treatment for relapsed platinum sensitive epithelial ovarian cancer (EOC) is controversial. The aim of the study was to compare progression-free survival (PFS) and overall survival (OS) in platinum-sensitive EOC patients treated with chemotherapy alone (CTA), secondary cytoreductive surgery (SCR) or SCR plus hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC). MATERIALS AND METHODS: Retrospective analysis of the clinical outcome of 46 EOC patients with at least 30 months of follow-up. RESULTS: Median follow-up time was 32 months for the CTA group, 30 months for the SCR group, and 45 months for the SCR + HIPEC group. Fifteen recurrences were observed in the CTA group, seven in the SCR group, and 16 in the SCR + HIPEC group. The median time elapsed between first and second recurrence (PFI-2) was significantly higher among patients treated with SCR + HIPEC, in comparison with patients treated with CTA (p = 0.012 andp = 0.017, respectively). On the contrary, PFI-2 did not significantly differ between the SCR and SCR + HIPEC groups (p = 0.877). A statistically significant difference in OS favouring SCR + HIPEC in comparison with CTA (p = 0.04) was observed. CONCLUSIONS: SCR HIPEC compared with CTA improves PFI-2 in patients with platinum-sensitive EOC recurrence. SCR + HIPEC might also improve OS in comparison with CTA. No improvement in favor of SCR + HIPEC vs SCR was observed,. These results further support the need of a randomized trial comparing chemotherapy with SCR ± HIPEC in this setting.

Contamination risk for operators performing semi-closed HIPEC procedure using cisplatin.

AIMS: Aim of this study was to assess operators' safety while performing a semi-closed HIPEC procedure for peritoneal carcinomatosis using cisplatin drugs. METHODS: Environmental air, theater personnel urine, operators' gloves and hand skin contamination were assessed during two non-consecutive working days. Six operating surgeons, two anesthesiologists and two theater nurses were included in the study. Glove samples were collected from the inner surface of the external glove and from the external surface of the inner glove from operating surgeons wearing a double pair of gloves. Personnel urine samples were collected before, after and 24 h from the procedure. RESULTS: Air and urine samples permanently resulted below detectable levels for cisplatin presence on all the tested sources and sessions. Cisplatin contamination was detected on the inner surface of the external gloves and on the outer surface of the inner gloves, but in a lower concentration for the latter. Skin wipe samples were below detectable levels for platinum presence. CONCLUSION: The results suggest that two pairs of gloves are adequate to protect the skin from antiblastic drugs. No sign of direct contact or systemic absorption of drugs was ever detected from the inspected samples. Semi-closed HIPEC technique appears to be a safe procedure for operators.

Treatment of diffuse malignant peritoneal mesothelioma (DMPM) by cytoreductive surgery and HIPEC.

AIM: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and locally aggressive tumor with poor prognosis, related in most cases to asbestos exposure. It is increasing in frequency, but currently no standard therapy is available. The biology of this disease is still poorly understood. Several highly specialized centers have recently reported improved survival by means of an innovative local-regional approach. The purpose of this article is to evaluate the survival benefit and the morbidity rate of patients affected by DMPM treated at our institution by cytoreductive surgery (CRS) associated with hyperthermic intraperitoneal perioperative chemotherapy (HIPEC). METHODS: This study includes 42 patients affected by DMPM treated by an uniform approach consisting of cytoreductive surgery associated with HIPEC using cisplatin and doxorubicin. The primary end point was overall survival and morbidity rate. The secondary end point was evaluation of prognostic variables for overall survival. RESULTS: The median follow-up period was 72 months (range 1-235 months). Thirty-five patients (83.3%) presented epithelial tumors and 7 were affected by multicystic mesothelioma. The mean peritoneal cancer index (PCI) was 13. Thirty-eight patients (90.4%) had complete cytoreduction (CC-0/1). The overall morbidity rate was 35.7% associated to a perioperative mortality of 7.1%. Median overall survival rate was 65 months with a 1- and 5-year survival rates of 63% and 44%, respectively. CONCLUSION: The treatment of DMPM by CRS+HIPEC in selected patients is a feasible technique that allows to achieve encouraging results in terms of overall survival rate, with an acceptable morbidity rate. Further investigations are needed to clarify the role and the timing of this promising technique.

Treatment of peritoneal carcinomatosis from ovarian cancer by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC).

AIM: Ovarian cancer may be considered as an "intraperitoneal disease" by itself. When surgical removal associated with systemic chemotherapy fails, usually, the history of the patients is characterized by poor prognosis. Some encouraging results have been reported by the treatment of peritoneal carcinomatosis (PC) from ovarian cancer by complete surgical cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC). The purpose of this article was to evaluate the survival benefit and the morbidity of patients with ovarian cancer treated at our institution by cytoreductive surgery associated with hyperthermic intraperitoneal perioperative chemotherapy (HIPEC). METHODS: Between October 1995 and December 2012 more than 600 operations for PC were performed; in 308 cases surgical cytoreduction associated with HIPEC was carried out. Eighty-five patients treated by cytoreduction associated with HIPEC were affected by recurrent epithelial ovarian cancer (EOC). Statistical analysis was performed on 70 patients (last 15 patients were too recent for evaluation). Two trials were applied: 1) patients presenting first peritoneal relapse after surgery and systemic chemotherapy (CT), 6 months later from last CT administration; 2) multiple relapse patients. RESULTS: On 70 patients, morbidity and mortality rates were 35.7% and 7.1%, respectively. Overall median survival was 42.0 months, but in primary EOC was 48.0 months and in recurrent EOC was 28 months (P=0.12). Statistical analysis revealed that the completeness of cytoreduction was the most statistically significant factor related to survival: in completely citoreduced patients, overall survival was 48 months. CONCLUSION: Citoreductive surgery associated to platinum compounds HIPEC is feasible and relatively safe in recurrent and primary PC from ovarian cancer. Better selection of patients and second-look surgery in high risk-patients have to be investigated to improve those encouraging results.

Treatment of peritoneal carcinomatosis from colonic cancer by cytoreduction, peritonectomy and HIPEC: preliminary results in highly selected patients.

AIM: Peritoneal carcinomatosis (PC) is one of the routes of spread of abdominal neoplasms and is generally considered a lethal disease, with a poor prognosis by conventional chemotherapeutic treatments. While systemic chemotherapy has little impact on the treatment of peritoneal disease, some centers have reported encouraging results on overall survival (OS) and disease-free survival (DFS) with surgical cytoreduction associated with hyperthermic intraperitoneal chemotherapy (HIPEC). The purpose of this article is to evaluate the survival benefit and the morbidity in patients affected by colorectal PC treated at our institution by cytoreductive surgery associated with HIPEC. METHODS: In our institution, from October 1995 to June 2012, about 550 operations for PC were performed; in 300 cases cytoreduction plus HIPEC was carried out. Out of 90 operations for colonic cancer: 50 cytoreduction plus HIPEC, 12 cytoreduction and EPIC (early postoperative intraperitoneal chemotherapy) and 28 debulking or explorative laparoscopies/laparotomies were performed. For the present study, 50 patients who had undergone cytoreduction and HIPEC for PC of colorectal cancer origin (CRC) were considered. RESULTS: The morbidity and mortality rates were 34% (17/50) and 2% (1/50), respectively. The patients were divided in two groups according to PCI (peritoneal cancer index, range 0-39) and CC score (completeness of cytoreduction): in Group A (23 patients, PCI>16, CC-2) the median survival time was 15 months compared to 48.1 months for Group B (27 patients, PCI≤16, CC-0/1). The poor survival of Group A seemed to be related to higher PCI and CC score. CONCLUSION: Patient selection based on a maximum PCI of 16 associated with a complete cytoreduction (CC-0) produced encouraging results.

Treatment of pseudomyxoma peritonei with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC): a single center experience.

AIM: Pseudomyxoma peritonei (PMP) is a rare form of peritoneal carcinomatosis characterized by abnormal quantity of extracellular mucinous material. It almost originates from a primary appendiceal tumor with different malignancy degrees. The purpose of this study was to evaluate outcome and long-term survival on 80 patients affected by PMP after cytoreductive surgery (CRS) associated with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: From October 1995 to June 2012, about 550 operations for PC were performed; in 300 cases surgical cytoreduction in association with HIPEC was carried out. Regarding PMP, 80 procedures of CRS and HIPEC were performed. This approach is based on surgical removal of the primitive cancer, peritonectomy (stripping of implants on the peritoneal surface) and HIPEC performed with cisplatinum and C mytomicin. The rationale of this treatment is to obtain, after macroscopic disease removal, an elevated and persistent drug concentration in the peritoneal cavity, with limited systemic effects. RESULTS: The complication rate was 52.5% (42/80) with no postoperative deaths. The median overall and progression-free survival were 144 and 88 months, respectively. Not complete cytoreductive surgery (P<0.001), tumor histology (P=0.02) and previous systemic chemotherapy (p = 0.03) were identified in the univariate analysis as independent predictors for a poorer long-term survival. In the multivariate analysis, the completeness of cytoreduction was the only significant variable influencing the outcome. Incomplete cytoreduction (P<0.01) resulted the only statistically significant variable associated with a higher incidence of postoperative complications. CONCLUSION: PMP can be treated with curative intent in a large percentage of cases by cytoreductive surgery associated with HIPEC. This new approach could be performed safely with acceptable morbidity and mortality in selected patients treated in specialized centers. Completeness of cytoreduction allows to achieve the best results.

Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer.

BACKGROUND: Interleukin-2 (IL-2) has shown antitumor activity in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is significant, particularly at the cardiorespiratory level. METHODS: To test feasibility, antitumor activity, pulmonary and systemic immunologic effects, and pulmonary function changes of continuous-infusion recombinant IL-2 given to patients with non-small cell lung cancer, eleven subjects with Stage III-IV disease were treated in a standard pulmonary medicine unit with a dose of 18 million IU/m2/day from day 1 to day 13 with 1-day rest on day 7. A second induction course was given after a 3-week rest. In patients with nonprogressive disease, four maintenance courses of 6 days' duration at the same dose were planned. Immunologic tests, including lymphocyte phenotype analysis and assays for the detection of tumor necrosis factor (TNF) and of anti-IL-2 antibodies, were performed before and after treatment in serum and bronchoalveolar lavage fluid (BAL). Cardiopulmonary function tests, including spirometry, arterial blood gas analysis, diffusion capacity, and echocardiography, were obtained before, during, and after treatment. RESULTS: Twenty-one cycles (15 induction courses plus 6 maintenance courses) were administered. No patient was able to complete the six planned courses, and only 3 patients entered the maintenance phase. Reasons for discontinuation included progressive disease in five cases, toxicity in three cases, and patient request in three cases. The most common side effects were fever, hypotension, oliguria, and elevated serum creatinine and liver enzyme levels. No patient required intubation or intensive care. No objective response was seen, and the median survival time was 10 months. Lymphocytosis and eosinophilia were observed in all patients. Surface marker analysis revealed a statistically significant increase in the percentage of CD3+, CD4+, CD25+ and DR+ cells in peripheral blood. Lymphoid cells derived from BAL disclosed an increased natural killer activity after IL-2 treatment, and TNF was increased in BAL fluid. Pulmonary function tests evidenced an increased alveolar-arterial difference for oxygen allied with a decrease of forced expiratory volume in 1 second, forced vital capacity, and carbon monoxide transfer coefficient consistent with a significant, albeit not clinically relevant, interstitial lung defect. CONCLUSION: Continuous-infusion IL-2 is feasible in patients with advanced lung cancer even outside an intensive care unit, but overall compliance is poor. Although clinical pulmonary toxicity is negligible, small but statistically significant alterations of the pulmonary function are evident. In addition, this regimen produces a significant activation of the immune system at the pulmonary level.

Recombinant interferon alpha-2b in the treatment of diffuse malignant pleural mesothelioma.

Fourteen patients with diffuse malignant pleural mesothelioma (DMPM) were enrolled in a Phase II study to assess activity and toxicity of the systemic administration of recombinant (r)-alpha-interferon (IFN)-2b. The IFN schedule was: 3 x 10(6) IU i.m. days 1-4, 6 x 10(6) IU days 5-8, 10 x 10(6) IU days 9-12; then IFN was administered at 10 x 10(6) IU 3 days/week. If grades II-III toxicity occurred, IFN dose was reduced and drug continued at the previous dose level. All patients were evaluated by CT scan. Only one patient was not evaluable for response and toxicity because of inadequate follow-up. Of 13 evaluable patients, we observed 1 objective response, 6 stable disease, and 6 failures (3 progressive disease and 3 early interruptions due to subjective toxicity). The median time to progression was 19 weeks, and the median overall survival was 62 weeks. Toxicity was mild: of 13 patients evaluable for toxicity we observed fever (9 patients), flu-like syndrome (3 patients), fatigue (4 patients), anorexia (2 patients), myelosuppression (3 patients), and muscle pain (1 patient). The results of this study indicate only marginal activity of r-alpha-IFN in the treatment of DMPM.

Malignant pleural mesothelioma. Multivariate analysis of prognostic factors on 113 patients.

We report on clinical features of 113 cases of pathologically confirmed Malignant Pleural Mesothelioma, observed in Genoa (Italy) between 1979 and 1985. Overall median survival was 10 months. Among the pretreatment variables studied (age, sex, asbestos exposure, pathological type, chest pain and dyspnea at the time of diagnosis), the only one of prognostic value in the univariate analysis was the histological subtype: median survivals were 12, 7 and 4 months for the patients in the epithelial, mixed, and fibrosarcomatous groups, respectively (p = 0.0012). A multivariate analysis confirmed the independent predictive power of the histotype (p = 0.0022). A review of literature data concerning prognostic factors in Malignant Pleural Mesothelioma is presented.

Activity of doxorubicin and cisplatin combination chemotherapy in patients with diffuse malignant pleural mesothelioma. An Italian Lung Cancer Task Force (FONICAP) Phase II study.

Twenty-six symptomatic patients with diffuse malignant pleural mesothelioma (DMPM) were enrolled in a Phase II Italian Lung Cancer Task Force (FONICAP) study to assess the activity and toxicity of doxorubicin and cisplatin combination chemotherapy. The drug schedule was as follows; 60 mg/m2 of doxorubicin and 60 mg/m2 of cisplatin both given intravenously (IV) on day 1 every 3 to 4 weeks. Of the 24 evaluable patients, 6 objective partial responses (25%; 95% confidence limits, 9.77% to 46.71%) were observed. Twelve of 24 patients (50%), including 6 with no radiologic evidence of response, had a clinical improvement as demonstrated by an objective reduction of symptom or performance status scores along treatment. The overall median survival time was 10 months. Toxicity was mild and dose reductions or suspensions were not required. The combination of doxorubicin and cisplatin is effective and well tolerated. It might be considered for palliation of symptomatic patients with DMPM.

Intrapleural natural beta interferon in the treatment of malignant pleural effusions.

Effusion recurrence is a major problem in the palliative care of patients with disseminated cancer. Thirty-two patients with recurrent malignant pleural effusions were treated with intracavitary natural beta-interferon at increasing doses (5-20 million units) for a maximum of three administrations. Among 29 evaluable patients, 11 showed complete (27.6%) or partial (10.3%) remission. No difference in response rate was observed according to sex, age, and histological type. All the responses were observed in patients with an effusion volume less than 1,000 ml (11/16; 68.8%). No side effect was observed. In conclusion, intrapleural beta-interferon is promising as a palliative in the treatment of recurrent malignant effusions.

Autonomic nervous system control of heart rate in essential hypertension.

In order to evaluate the role of the autonomic nervous system in controlling heart rate (HR) in essential hypertensive patients (EH), we studied 13 untreated EH, WHO I-II, aged 21-68 years, and 10 normotensive subjects (N), aged 20-68 years. The average variation of heart period (VHP) during regular breathing was used as an index of parasympathetic control of HR. Measurements were carried out supine and during tilting, before and after propranolol (0.15 mg/kg intravenously). A sympathetic control index of HR was derived from the ratio HR before/HR after propranolol. A parasympathetic control index of HR was also obtained from the ratio HR before/HR after atropine (0.03 mg/kg intravenously). The VHP was constantly lower in EH than N (P < 0.001) before and after propranolol, supine and standing. The parasympathetic control index of HR was significantly higher in EH (P < 0.001). A significant negative correlation was found between VHP and the parasympathetic control index (r = -0.73) plotting together all values found in EH and N. The sympathetic control index of HR did not differ between EH and N. These results indicate a lower parasympathetic influence on HR in this group of EH compared with N, while sympathetic control was similar in the two groups. This difference in vagal control of HR persists in the presence of increased sympathetic activity (tilting) and after beta-blockade.

Phase II study of ifosfamide combined with Mesna uroprotection in advanced non-small-cell lung carcinoma and other solid tumors.

Thirty six patients with advanced solid tumors (24 lung: 3 oat-cell, 14 squamous, 7 adenocarcinomas, 3 soft tissue sarcomas, 6 breast carcinomas; 1 seminoma; 2 ovarian adenocarcinomas) entered a phase II study of high-dose ifosfamide (IF) administered in combination with the uroprotective agent sodium 2-mercapto-ethane-sulfonate (Mesna). Fourteen patients had prior treatment; most patients with lung cancer (22/24) were previously untreated; all had measurable disease. The patients median age was 59 (range 31-74). IF was given at 1.8 g/m2 days 1-5 q 4 weeks. Mesna was given after each IF injection at 0, 4 and 8 h randomly, either i.v. (0.36 g/m2) or orally (0.72 g/m2). Twenty-four patients had greater than or equal to 3 courses of therapy, 9 had 2 courses, and 3 had only 1 course; 129 courses were evaluated for toxicity. Mesna was given orally (17 patients, 57 courses) or i.v. (19 patients, 72 courses). The following side-effect were observed: no gross hematuria, microhematuria (14 courses), transitory mild proteinuria (34 courses), leukopenia grade I-II ECOG (26 courses), anemia grade I ECOG (31 courses), 1 case of pancytopenia, alopecia (31 patients), nausea (moderate, 33 courses; severe, 6 courses), vomiting (moderate, 17 courses; severe, 1 course). Five patients showed a partial response (1 oat-cell carcinoma, 2 with squamous lung cancer, 1 with ovarian carcinoma, 1 with breast carcinoma), 14 showed a minor response (2 patients with oat-cell carcinoma, 2 with lung adenocarcinoma, 5 with squamous lung cancer, 1 with seminoma, 1 with sarcoma, 1 with ovarian carcinoma), and 14 showed progression of disease (7 patients with squamous cell lung cancer, 4 with lung adenocarcinoma, 1 with sarcoma, 2 with breast carcinoma). Considering partial plus minor responses, ifosfamide produced some degree of tumor reduction (PR + MR) in 12/23 (52.1%) lung cancer patients. The data reported support the conclusions that Mesna can prevent high-dose IF bladder toxicity, that IF is active in advanced solid tumors, including lung cancer, and that the IF + Mesna combination is a generally safe treatment procedure.

Efficacy of low-dose captopril given twice daily to patients with essential hypertension uncontrolled by a beta blocker plus thiazide diuretic.

Thirty-two patients with moderate to severe essential hypertension whose supine diastolic blood pressure (SDBP) was greater than or equal to 95 mm Hg following 2 weeks' treatment with the optimal dosage of beta blocker-diuretic combination were randomly assigned to the addition of either captopril 25 mg or 50 mg b.i.d. After 6 weeks' treatment, if patients were not normalized (SDBP less than 95 mm Hg), the dose of captopril was doubled for a further 6 weeks. The addition of captopril led to a significant fall in standing and supine diastolic and systolic blood pressure at the end of the sixth and twelfth week of treatment. There was no difference in the change in blood pressure between the two groups. At the end of the study SDBP was normalized in 66% of patients and a further 12.5% had their SDBP reduced by greater than 10%. Captopril 25 or 50 mg administered twice daily proved to be a very effective antihypertensive agent when added to a beta blocker-diuretic combination in patients resistant to optimal doses of these drugs.

Randomized trial of chemoimmunotherapy in advanced non-oat-cell lung cancer.

Thirty patients without any prior chemotherapy and histologically proved non-oat-cell advanced lung cancer entered a randomized trial comparing a combination chemotherapeutic regimen (cyclophosphamide, methotrexate, BCNU) and the same combination plus intradermic BCG. Twenty-nine patients were evaluable for survival. Mean survival was 11 and 3.5 months for chemotherapy and chemoimmunotherapy group, respectively. The difference was statistically significant (P less than 0.025). A tumor enhancement can be postulated. Skin tests before treatment (PPD, Candida, Varidase) seem to be prognostic for survival.