Syndrome of inappropriate anti-diuretic hormone secretion in cancer patients: results of the first multicenter Italian study.

BACKGROUND: Hyponatremia in cancer patients is often caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The aim of this observational multicenter study was to analyze the medical and economic implications of SIADH in this setting. METHODS: This study included 90 oncological patients from 28 Italian institutions that developed SIADH between January 2010 and September 2015. Data on clinical-pathological characteristics, anticancer therapies, hyponatremia, and related treatments were statistically analyzed. RESULTS: The majority were lung cancer patients (73%) with metastatic disease at the onset of hyponatremia (83%). A total of 76 patients (84%) were hospitalized because of SIADH and less than half (41%) received tolvaptan for SIADH treatment. The duration of hospitalization was significantly longer in patients who did not receive tolvaptan and in those who do not reach sodium normalization during hospitalization. Patients who experienced a second episode of hyponatremia following tolvaptan dose modification/discontinuation presented a significantly lower serum sodium value at the time of hospitalization and minimum sodium value during hospitalization compared with patients who had not experienced another episode. The severity of hyponatremia, defined as minimum sodium value during hospitalization with a cut-off value of 110 mmol/l, and not obtaining sodium correction during hospitalization significantly correlated with overall survival rate. CONCLUSIONS: Hyponatremia due to SIADH could result in longer hospitalization and in a decreased overall survival when not adequately treated, and tolvaptan represents an effective treatment with a potential effect of both improving overall survival and decreasing duration of hospitalization.

Epirubicin and gemcitabine as first-line treatment in malignant pleural mesothelioma.

Malignant pleural mesothelioma represents a rare disease, for which chemotherapy actually remains unsatisfactory. From August 1998 to November 2001, 28 chemo-radio-immunonaive patients were consecutively enrolled in the trial: 22/6 males/females; median age 63 years (range, 45-79); median ECOG PS 1 (range, 0-2). They were treated with epirubicin (100 mg/m2 iv on day 1) plus gemcitabine (1000 mg/m2 iv on days 1 and 8) every 4 weeks for 6 cycles. Patients who responded to chemotherapy (n = 6) were subsequently treated with interleukin-2 (4,500,000 IU) subcutaneously every other day, until progression. A total of 124 epirubicin-gemcitabine cycles were administered (median, 6/patient; range, 2-6). Twenty-six patients were evaluated for toxicity. According to WHO criteria, we observed grade III-IV hematological and gastrointestinal toxicity respectively in 3 patients (11%) and 1 patient (3%). No red cell transfusions were required and no toxic deaths occurred. Two patients (8%) could not be evaluated for response (no therapy performed). According to WHO criteria, the final responses were: partial in 4 patients (14%), stable disease in 19 patients (69%), and progression in 3 patients (10%). In 26 patients, the median survival was 55 weeks (range, 7-222) and median time to progression 30 weeks (range, 4-156). At the time of this writing, no patient is alive. The 1-year survival was 32%, 2-year survival 11%, and 4% at 3 and 4 years. All patients were at stage III, and time to progression was 58 weeks and survival 63.5 weeks, without any toxicity. This multi-center phase II clinical trial showed that epirubicin plus gemcitabine, as a first-line treatment in malignant pleural mesothelioma, has promising activity with a good tolerability profile and symptom palliation. The role of interleukin-2 in maintenance therapy for malignant pleural mesothelioma is encouraging and requires further study.

Phase I/II trial of gemcitabine plus cisplatin and etoposide in patients with small-cell lung cancer.

OBJECTIVE: The objectives of this phase I/II study were to define the maximum tolerated dose (MTD), safety, and activity of cisplatin, etoposide, and gemcitabine (PEG) in the treatment of previously untreated patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Chemonaive patients received fixed doses of gemcitabine (1000 mg/m(2) on days 1 and 8) and cisplatin (70 mg/m(2) on day 2) and escalating doses of etoposide (starting dose of 50 mg/m(2) on days 3, 4, and 5) every 3 weeks. No prophylactic granulocyte colony-stimulating factors were used. RESULTS: From September 1998 to April 2000, 56 patients with limited- or extensive-stage SCLC were enrolled and received a total of 235 cycles. Two different etoposide doses were tested in eight patients. At the second level (75 mg/m(2)), two out of two patients experienced dose-limiting toxicities (neutropenia and thrombocytopenia) and no further dose-escalation was attempted, thus an etoposide dose of 50 mg/m(2) was defined as the MTD. In the subsequent phase II evaluation, 48 additional patients were enrolled, for a total of 54 patients treated at the MTD. Grade 3/4 neutropenia and thrombocytopenia occurred in 66.7 and 53.7% of patients, respectively. Non-hematologic toxicity was mild, with grade 3 diarrhea and fatigue as the main side effects. Two patients died of neutropenic sepsis (one at 75 mg/m(2) and the other at 50 mg/m(2) etoposide). Ten complete and 29 partial responses were reported, for an overall response rate of 72.2% (95% confidence interval, 56.6-85.0%). The median duration of response and median survival were 8.0 and 10 months, respectively, with a 1-year survival probability of 37.5%. CONCLUSIONS: The combination of PEG is feasible and well tolerated as front-line chemotherapy in SCLC. A randomized comparison of this triplet is underway.

Phase II study of Taxol combined With ifosfamide and carboplatin in the treatment of stage IIIb-IV non-small-cell lung cancer.

The objective of the present study was to evaluate the activity and the toxicity of an original combination of paclitaxel (Taxol), ifosfamide, and carboplatin in patients with stage IIIB-IV non-small-cell lung cancer (NSCLC). Sixty-one patients with previously untreated stage IIIB-IV NSCLC were enrolled by five institutions. Paclitaxel was given at the dose of 200 mg/m iv in 3 hours, ifosfamide (with mesna) at the dose of 3 g/m and carboplatin at an area under the curve 5, on day 1, every 21 days for a total of six cycles in responding or stabilized patients. Among the 59 patients evaluable for response, 2 complete remissions and 25 partial remissions were achieved for an overall response rate of 45.7% (95% CI = 32.7-59.2). According to an intention-to-treat analysis, the response rate was 44.2%. Thirteen patients had a stable disease, whereas 19 progressed. The median time to progression was 7.7 months (range: 1-18), whereas the median overall survival was 10 months (range: 1-30+). The 1-year survival rate was 43%. Hematologic toxicity was exceptionally mild, and peripheral neurologic toxicity of grade III was experienced by only three patients. There was one toxic death. This original triplet regimen based on paclitaxel, ifosfamide, and carboplatin has proved active, safe, and easy to deliver on an outpatient basis for patients with advanced NSCLC. Randomized studies both versus carboplatin-paclitaxel and other triplets are clearly warranted.

Gemcitabine, paclitaxel, and cisplatin as induction chemotherapy for patients with biopsy-proven Stage IIIA(N2) nonsmall cell lung carcinoma: a Phase II multicenter study.

BACKGROUND: The objective of the current study was to define the activity and tolerability, as well as the influence on resectability, of the combination of gemcitabine, paclitaxel, and cisplatin (GTP) as induction chemotherapy for patients with Stage IIIA(N2) nonsmall cell lung carcinoma (NSCLC). METHODS: Forty-nine chemotherapy-naïve patients (median age, 61 years; World Health Organization performance status, 0-1) with biopsy-proven Stage IIIA(N2) disease received 1000 mg/m(2) gemcitabine, 125 mg/m(2) paclitaxel, and 50 mg/m(2) cisplatin on Days 1 and 8 of every 3 weeks until reevaluation for surgery or definitive radiotherapy. RESULTS: Grade 3-4 neutropenia was the most common hematologic toxicity, occurring in 32.7% of patients; however, only 1 case of febrile neutropenia was reported. Grade 3-4 thrombocytopenia occurred in 12.2% of patients but was not associated with bleeding. Severe nonhematologic toxicities were uncommon; the only Grade 4 nonhematologic toxicity was diarrhea, which occurred in 4% of patients. One patient died after the first course of therapy, but this event was found to be unrelated to treatment. Thirty-six patients (73.5%) achieved an objective response, and an additional 4 patients had stable disease with clearance of mediastinal lymph nodes. Overall, 29 patients underwent thoracotomy and 27 (55%) underwent complete resection. Mediastinal nodes were free of tumor in 35% of all cases, and 8 pathologic complete responses (16%) were reported. Median survival was 23 months, with a 1-year survival rate of 85%. CONCLUSIONS: GTP is highly active as an induction chemotherapy regimen for Stage IIIA(N2) NSCLC and yields good toxicity results. The use of GTP in combination with radiotherapy and new biologic drugs should be explored.

Is delayed chemotherapy-induced emesis well managed in oncological clinical practice? An observational study.

Nausea and vomiting have a negative influence on the quality of life of patients receiving chemotherapy. The Consensus Conference held in 1997 outlined the therapeutic procedure to prevent delayed emesis that might otherwise be induced by chemotherapy. So far, no study has evaluated the correct management of delayed emesis in clinical practice. This study was performed in an attempt to verify the conformity of the delayed emesis therapy administered in some oncological centres with the Consensus Conference guidelines. A total of 149 patients were observed for a minimum of one up to a maximum of four chemotherapy cycles; analysis of the data took account of whether the chemotherapy had a high (HEC), moderate (MEC) or low (LEC) emetogenic potential. Among 42 patients who received HEC, 18 (43%) received antiemetic prophylaxis conforming to standards; 23 (54.7%) of these 42 had delayed emesis, only 8 (34.7%) of whom were treated with adequate antiemetic protection. MEC was administered to 72 patients, 46 (64%) of whom received adequate prophylaxis; delayed emesis was observed in 31 (43%) of the 72 patients, 20 (64.5%) of whom received antiemetic prophylaxis according to established guidelines. Of 35 patients treated with LEC, 22.8% manifested delayed emesis; a high percentage of these patients, 68.5%, received prophylaxis, even though it was unnecessary. Of all patients observed, only 50.3% received correct antiemetic protection. We deduce from the study that antiemetic treatment for delayed emesis in clinical practice needs more attention. Correct prophylaxis is necessary when HEC is given, and antiemetic protection for patients receiving MEC must be improved; among patients treated with LEC those at high risk must be identified so that overtreatment can be avoided.