Giuseppe Cannata

Subcutaneous octreotide versus oral loperamide in the treatment of diarrhea following chemotherapy.

Forty patients with chemotherapy-related diarrhea were randomized to receive (i) octreotide 0.5 mg three times per day s.c. or (ii) loperamide 4 mg three times per day p.o. until complete remission of diarrhea was achieved. In the octreotide group 80% of patients showed complete resolution of loose bowel movements within 4 days of therapy, while in the loperamide group this goal was obtained in only 30% of cases (p < 0.001). If after 4 days no benefit was seen, patients were considered to have failed antidiarrheal therapy. Failure was recorded in only one case (5%) treated with s.c. octreotide and in five patients (25%) who received loperamide. The mean duration of antidiarrheal therapy necessary to achieve remission was 3.4 days in the octreotide group and 6.1 days in the lorepamide group (p < 0.001). Treatment with octreotide was very well tolerated with mild abdominal pain in 15% of cases and pain in the injection site in 15% of patients. Subcutaneous octreotide is highly effective in the management of chemotherapy-related diarrhea in cancer patients.

A pilot study of vinorelbine on a weekly schedule in recurrent and/or metastatic squamous cell carcinoma of the head and neck

Vinorelbine (VNR), 5′-nor-anhydrovinblastine, is a new semi-synthetic vinka alkaloid with selective affinity for mitotic microtubules, which has been shown to be active against several non small cell lung cancer lines in vitro [1]. VNR has been reported to yield a 34.7 % and 20 % overall response rate in patients with squamous cell lung carcinoma and bronchial adenocarcinoma respectively [2]. Moreover, VNR has been shown to be active in advanced breast carcinoma where it may induce a 30–50 % response rate depending on the extent of pretreatment [3]. We tested the activity and toxicity of single agent VNR given on a weekly schedule in a series of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCHNC).

Oral granisetron with or without methylprednisolone versus metoclopramide plus methylprednisolone in the management of delayed nausea and vomiting induced by cisplatin‐based chemotherapy. A prospective randomized trial

Background. A single‐institution, randomized open trial was prospectively performed to compare orally administered granisetron with or without intramuscularly administered methylprednisolone to metoclopramide plus methylprednisolone in the prevention of delayed nausea and vomiting induced by cisplatin‐based chemotherapy. The effects of antiemetic treatments were evaluated from days 2 to 5 of the first cycle after cisplatin administration among patients who had never before received chemotherapy.

A prospective evaluation of the activity of human granulocyte-colony stimulating factor on the prevention of chemotherapy-related neutropenia in patients with advanced carcinoma

After informed consent, 86 patients with advanced cancer undergoing potentially myelosuppressive cytotoxic chemotherapy were randomized to receive placebo or subcutaneous granulocyte-colony stimulating factor (G-CSF) 5 micrograms/Kg/day in order to prevent severe neutropenia and its related morbidity. The incidence of neutropenia (absolute neutrophil count < 1,000/mm3) was significantly reduced in patients receiving G-CSF than in controls (18% versus 42%; P < 0.05). The duration of neutropenia was also shortened by the administration of G-CSF (4.8 versus 8.2 days; P < 0.05). Therapy with G-CSF has also a positive impact on the dose-intensity of employed regimens. Patients treated with G-CSF showed oral fungal disease in 9% of cases, while control patients had a 21% incidence (NS). Patients treated with G-CSF received 91% of the programmed dose-intensity as compared to 71% of control patients (P < 0.05). These data strengthen the clinical usefulness of G-CSF in the prevention of chemotherapy-related neutropenia, infections, and reduction in dose-intensity. Further studies are required to establish if the increase in dose-intensity allowed by G-CSF treatment may positively influence the outcome of cancer patients.

A Phase II Study of Levofolinic Acid and 5-Fluorouracil Plus Cisplatin in Patients with Advanced Head and Neck Squamous Cell Carcinoma

Forty patients with advanced squamous cell carcinoma of the head and neck (SCHNC) were treated with a combination of levofolinic acid 100 mg/m2+5-fluorouracil 375 mg/m2 in a 4-hour infusion plus cisplatin 20 mg/m2 in a 2-hour infusion for 5 consecutive days, repeated every 21-28 days. In the group of 20 previously untreated patients, a 90% overall response rate (ORR) with a 30% complete response rate (CRR) was obtained. In the group of 20 pretreated patients with recurrent and/or metastatic SCHNC, a 55% ORR with 15% CRR was achieved. This treatment was given on an outpatient basis and was generally very well tolerated with only 2 patients requiring hospitalization. Grade 1-2 gastrointestinal and hematological side effects were the most frequent toxicities. One patient had grade 4 liver toxicity, 1 had grade 4 anemia, and 1 grade 3 neurotoxicity. This treatment seems very active in both previously untreated and pretreated patients. However, in the latter group the mean duration of complete response (12.2+ months) and of partial response (7.4+ months) are, in our opinion, still unsatisfactory.

Methotrexate, Vinblastine, Epidoxorubicin, and Bleomycin as Second-Line Chemotherapy for Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

Thirty evaluable patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck region previously treated with cisplatin-based chemotherapy were treated with a combination of methotrexate, vinblastine, epidoxorubicin, and bleomycin as second-line chemotherapy. Besides surgery and/or radiotherapy all patients had previously received chemotherapy as induction therapy or as palliation for recurrent disease. Only 20% of patients achieved a partial objective response with a mean duration of 5.6 months (range 3.2-6.2), and 30% of patients had a stabilization of disease with a mean duration of 4.2+ months (range 3.8-6.0). Patients who responded had rhinopharyngeal carcinoma, poorly differentiated histology, or they had not been previously treated with radiotherapy. All remaining patients (50%) progressed. Toxicity was significant with grade 3-4 leukopenia in 30% of cases, grade 2-3 mucositis in 40% of patients, and grade 2-3 vomiting in 43% of cases. In consideration of the dismal clinical results and of the significant toxicity recorded, we do not recommend to use this combination as second-line therapy in recurrent head and neck cancer. Further chemotherapy should be reserved to carefully selected cases with a reasonably high chance of response.

TREATMENT OF CISPLATIN-RELATED NAUSEA AND VOMITING WITH A COMBINATION OF ONDANSETRON AND METOCLOPRAMIDE : A PILOT STUDY

Forty chemotherapy-naive patients receiving high-dose cisplatin were included in a pilot study of a combination of ondansetron plus metoclopramide as antiemetic therapy. Patients received ondansetron 16 mg plus metoclopramide 0.5 mg/kg in 250 cm3 of normal saline i.v. 15 min before cisplatin administration on day 1; then ondansetron 8 mg was given orally b.i.d. and metoclopramide 0.5 mg/kg was given intramuscularly t.i.d. for 4 days. This combination was given to all patients receiving the first cycle of chemotherapy. At the second cycle of chemotherapy all patients received the same antiemetic treatment as above plus methylprednisolone 125 mg i.v. on day 1 and then intramuscularly once a day for 4 days. There were 20 females and 20 males with a mean performance status of 1 (range 0–2) and a mean age of 58 years (range 36–68). Ten patients had ovarian carcinoma, eight patients had uterine adenocarcinoma and 22 had non-small cell lung carcinoma. The mean cisplatin dose was 96 mg/m2. All patients denied significant alcohol consumption. At cycle 1, complete protection against acute emesis was achieved in 22 patients (55%), major protection in 12 cases (30%), minor protection in four patients (10%) and failure in two cases (5%). On the other hand, the efficacy of this combination on delayed vomiting was not striking. For delayed vomiting, complete protection was observed in nine patients (23%), major protection in 13 cases (33%), minor protection in 10 patients (25%) and failure in eight cases (20%). At cycle 2, patients also received methylprednisolone showing complete protection from vomiting in 19 cases (47%) and major protection in 12 cases (30%). Results achieved with ondansetron plus metoclopramide are in the range reported for ondansetron alone in the medical literature. Although this study was not prospectively carried out in a randomized fashion, the results are not suggestive of a possible positive effect of metoclopramide addition to ondansetron. On the other hand, these results stress the role that corticosteroids may play in the control of delayed emesis. Toxicity was predictable and the frequency of side-effects was in the range reported in other studies with ondansetron.

Subcutaneous low-dose interleukin-2 and intravenous 5-fluorouracil plus high-dose levofolinic acid as salvage treatment for metastatic colorectal carcinoma

Thirty-three consecutive patients with recurrent and/or metastatic colorectal carcinoma (CRC) refractory to previous chemotherapy have been treated with levofolinic acid (1-FA) 100 mg/m2 i.v. over 1 h infusion followed by 5-fluorouracil (5-FU) 600 mg/m2 i.v. bolus every week for 6 weeks followed by a 2 week interval. Patients also received rIL-2 s.c. at 3 MU daily from day 1 to day 5 of each week for at least four consecutive weeks per cycle. Enrolled patients were divided in two groups: (i) group 1 including patients with progressive tumor refractory to chemotherapy with 1-FA + 5-FU given for metastatic disease and (ii) group 2 consisting of patients with diagnosis of metastatic disease within 3 months from the completion of adjuvant chemotherapy with 5-FU + levamisole (LEV) after primary surgery. No objective response was observed in the group of 11 patients with CRC resistant to previous 1-FA + 5-FU, thus no further patient with progressive disease after 1-FA + 5-FU was included in the trial. In the group of patients pretreated with 5-FU + LEV, four patients experienced a PR with a mean duration of 7.3 months (range ≥4.0–8.6) for an overall response rate of 18% (95% CI 12–26%). A stabilization of disease was observed in five cases (23%) with a mean duration of ≥5.6 months (range ≥2.0–7.0). The remaining 13 patients progressed. No complete responses were achieved. The mean overall survival was ≥9.5 months (range ≥2.0–14.0). Toxicity was generally mild. This study demonstrates that the combination of s.c. rIL-2 and intravenous 5-FU + 1-FA on a weekly schedule may be safely given to patients with metastatic CRC on an outpatients basis. The addition of low-dose rIL-2 does not modify the toxicity profile of 5-FU + 1-FA, even if IL-2-related side-effects such as systemic symptoms or cardiac abnormalities are to be expected. The clinical activity of the combination is not good, at least in terms of response rate, even if the duration of partial responses may suggest to test rIL-2 in a prospective study with response duration and overall survival as the final endpoints

Weekly 5-fluorouracil and folinic acid plus escalating doses of cisplatin with gluthatione protection in patients with advanced head and neck cancer

Twenty-two patients with advanced head and neck carcinoma were treated with 5FU 400 mg-2 m{-1} week and folinic acid 500 mg m-2 week-1 plus CDDP in escalating doses from 20 to 40 mg m-2 week-1 without forced diuresis. Reduced gluthatione at the dose of 1.5 g m-2 was employed to protect patients from CDDP-related nephrotoxicity. The aims of the study were: a) to evaluate the therapeutic efficacy of this schedule, and b) to evaluate reduced gluthatione as uroprotector. Out of 20 evaluable patients 14 (70 %) had a major objective response. A CR with a mean duration of 9.0+ months was achieved in 15% of the patients, a PR of 5.8+ months in 55 % of the patients, while 3 patients had stable disease and 4 progressed. It was possible to escalate CDDP up to 35 mg m-2 week{-1}, but at the dose of CDDP 40 mg m-2 week-1 the occurrence of grade 2 renal toxicity provoked a severe reduction of dose-intensity. Overall, this treatment has been very well tolerated by most patients with few cases of grade 3 gastrointestinal or hematological toxicity. In conclusion, the schedule seems effective and may be safely given to patients with advanced head and neck cancer on outpatient basis. Reduced gluthatione seems to be able to reduce, at least partially, CDDP-related nephrotoxicity permitting the delivery of higher CDDP doses.

Combination chemotherapy of 5-fluorouracil, epidoxorubicin and mitomycin C in the palliative treatment of locally advanced and/or metastatic adenocarcinoma of the stomach.

Thirty-seven consecutive patients with advanced and/or metastatic gastric adenocarcinoma received a combination of 5-fluorouracil 600 mg/m2 on days 1, 8, 29, 36; epidoxorubicin 75 mg/m2 i.v. on days 1, 29; mitomycin C 10 mg/m2 i.v. on day 1. This cycle was repeated every 8 weeks. Out of a total of 34 evaluable patients, 2 (5.8%) had a complete response and 7 (20.6%) had a partial response with an overall median duration of 40 weeks (range 20-128). The median survival of responding patients was not reached after a mean follow-up of 76 weeks, while that of patients with no change and progressive disease was reached at 36 and 13 weeks respectively. Treatment was generally well tolerated with hematological and gastrointestinal toxicities being the major side-effects. Despite the use of epidoxorubicin 75 mg/m2, the 26.4% (95% confidence limits 16-36%) objective response rate is not satisfactory. Evaluation of more aggressive protocols is strongly recommended within the limits of controlled trials.