Nicolas Tsavaris

Gabapentin monotherapy for the treatment of chemotherapy-induced neuropathic pain: a pilot study.

OBJECTIVE This study was conducted to investigate the efficacy and safety of gabapentin monotherapy in the management of chemotherapy-induced neuropathic pain. PATIENTS Seventy-five cancer patients who had previously received chemotherapy, and had experienced at least one symptom of neuropathic pain were included in the intervention group. They received a fixed low-dose of gabapentin (800 mg/day). The control group consisted of 35 cancer patients with similar treatment history and symptomatology, who refused treatment with gabapentin and, therefore, received a fixed-dose combination of naproxen and codeine/paracetamol. OUTCOME MEASURES Patients were grouped in three categories according to the severity of their neuropathic symptoms at baseline: mild, moderate, and severe. Analgesic efficacy of the study drug was assessed by means of a patient-answered questionnaire. Four stages of analgesic response were established: complete, partial, minor, and no response. RESULTS All patients completed the study and were evaluable. In the intervention arm, gabapentin led to a complete response in 25.3% of patients (19/75), partial response in 44% (33/75), minor response in 25.3% (19/75), and no response in 5.3% (4/75). The response to gabapentin correlated with the severity of the underlying neurotoxicity. Approximately 25% of patients receiving gabapentin experienced mild somnolence, but none discontinued it. In the control group, none experienced complete response (0/35), while partial, minor, and no response were observed in 5.7% (2/35), 45.7% (16/35), and 48.6% (17/35), respectively. Compared with the control group, gabapentin therapy led to a statistically significant better response in patients of each baseline neurotoxicity group. CONCLUSIONS Gabapentin monotherapy seems to be well tolerated and useful for the management of chemotherapy-induced neuropathic pain.

Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO).

Aims and Background The understanding of hormonal therapies in postmenopausal women with metastatic breast cancer has advanced greatly in the past several decades. With the introduction of orally active, potent and selective third-generation aromatase inhibitors (anastrozole, letrozole and exemestane), approaches to the treatment of hormone-sensitive advanced breast cancer are undergoing reevaluation. For treatment of advanced or metastatic disease that has progressed on tamoxifen, all three agents are active. The purpose of the study was to assess the antitumor efficacy and tolerance of exemestane administered as third-line hormonal therapy to postmenopausal women with metastatic breast cancer refractory to letrozole and anastrozole. Study design Sixty postmenopausal women with stage IV hormone receptor-positive carcinoma of the breast were enrolled in the study. All patients had received two prior hormonal manipulations and had measurable or assessable disease. All adverse events were monitored. Results Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-30.4). The overall clinical benefit was 38.3% (95% CI, 21.2-49.3), and the median duration of objective tumor response was 20 months (range, 9-26). The median time to death was 17.4 months (95% CI, 16.14-18.66). Conclusions Exemestane represents an active and well-tolerated treatment option in pretreated patients with advanced breast cancer who have received standard first- and second-line hormonal therapies. By extending the sequence of hormonal therapy, disease progression and the need for chemotherapy may be significantly delayed.

Combination chemotherapy with cisplatin-vinblastine in malignant mesothelioma

From June 1985 to March 1993, 20 consecutive patients with histologically proven malignant mesothelioma were treated with cisplatin 100 mg/m2 i.v. infusion on day 1 and vinblastine 6 mg/m2 i.v. on day 1 and 8. Treatment was repeated every 4 weeks until progression. All patients were evaluated clinically and by CT-scan and were staged (Stage IV), according to Butchards criteria, on entry to the study. None had prior surgical excision. Eighty-one chemotherapy cycles were administered to 20 patients. One complete response, four partial responses, nine stable diseases and six progressions were noted. One partial responder entered complete response following an operation. Toxicity was acceptable and no treatment-related deaths occurred. The median survival for responders was 19.3 months; for patients with stable disease 15.7 months and for non-responders, 5.2 months. The mean duration of response was 13 months. We conclude that for this small group of patients, the combination cisplatin-vinblastine is effective, with acceptable toxicity in malignant mesothelioma. Further study with a larger number of patients is necessary.

Biochemical modulation of fluorouracil: comparison of methotrexate, folinic acid, and fluorouracil versus folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial

Abstract Recent advances in biochemical pharmacology have revealed the basis for the biological modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic acid (FA). Sequential use of MTX given 24 h prior to 5-FU has resulted in enhanced cell kill in vitro and in vivo. In addition, administration of FA prior to 5-FU has led to potentiation of 5-FU action by stabilization of the ternary complex of thymidine synthase. In the present randomized study, two groups of patients with advanced colorectal cancer were treated as follows: 43 patients (pts) in group A received 5-FU + FA, whereas 45 pts in group B received 5-FU + FA + MTX. The dosage was as follows: group A received FA i. v. at 300 mg/m2 per day, prior to i. v. 5-FU at 500 mg/m2 per day on days 1 – 4; group B was given MTX i. v. at 130 mg/m2 per day on day 0, followed 24 h later by FA at 15 mg q6h × 6, and 5-FU + FA was started on day 1 and given at the same doses and schedule described for group A. Objective responses were achieved by 8/43 pts in group A (1 complete response and 7 partial responses) and by 18/45 pts in group B (3 complete and 15 partial responses), all occurring in the liver. There was no significant difference in the median time to progression (group A 6.1 months, group B 6.8 months) or the median survival (group A 9.2 months, group B 10.3 months). Toxicity was significantly greater in group B [grade 2 – 3 mucositis 20% versus only 2% in group A (P <0.0001); grade 3 diarrhea in group B 15% versus 3% in group A (P <0.001)]. According to our results, double biological modulation of 5-FU with MTX + FA led to an enhanced response rate with increased toxicity as compared with the 5-FU + FA regimen given at less than its maximally tolerated dose.

High-dose epirubicin as a single agent in the treatment of patients with advanced breast cancer. A Hellenic Co-operative Oncology Group study.

Fifty-two women with advanced breast cancer were treated with 6 cycles of epirubicin. Even though the study was started with a dose schedule of 110 mg/m2 every 3 weeks, the average treatment interval was 26 days and the median weekly dose 78% of the protocol requirement. Forty-eight patients were evaluable for response; 3 achieved a complete remission which lasted for 17, 24 and 65 weeks, respectively, and 14 a partial remission. Median survival was 32 weeks. Toxicity included nausea/vomiting (68%), anemia (24%), leukopenia (37 %), thrombocytopenia (8 %), alopecia (81 %), stomatitis (24%), diarrhea (14%), fever (19%) and fatigue (14%). Also 1 treatment-related death occurred and 2 cases of arrhythmia. Monotherapy with high doses of epirubicin has definite activity in advanced breast cancer and deserves further study in combination with hematopoietic growth factors which might allow a higher dose Intensity.

Comparison of ondansentron versus ondansentron plus methylprednisolone as antiemetic prophylaxis during cisplatin-containing chemotherapy

We compared the antiemetic efficacy of ondansentron versus ondansentron and corticosteroids in cisplatin-induced emesis. None of our patients had received prior chemotherapy. All patients received chemotherapy including cisplatin 100 mg/m2. Forty patients received ondansentron alone (Group A) and 40 the combination of ondansentron and methylprednisolone (Group B). Ondansentron was given at a dose of 8 mg in 100 mL N/S over 10 min by intravenous infusion. The initial dose was administered before the cisplatin and was followed by 8 mg orally in the afternoon and before sleeping the first day of chemotherapy. During the next 2 days, the patients received 8 mg orally 3 times daily. Methylprednisolone was given as an intravenous bolus of 40 mg before chemotherapy and then together with each dose of ondansentron at a dose of 16 mg orally. Group A had significantly longer duration of nausea after chemotherapy than group B (117 +/- 111 min, 62 +/- 71 min, P < 0.013). The response on emesis was also improved in group B, especially the day of chemotherapy [treatment failure: group A: 13 patients (30%) versus group B: 5 patients (11.6%), P < 0.03] and the next day [complete response: group A: 17 patients (39.5%) versus group B: 30 patients (69.7%), P < 0.005]. Patients in group B presented more sedative effects (P < 0.001) and better appetite (P < 0.02) than patients in group A. There were no other significant differences in side effects (activity, headache, constipation, etc). We conclude that corticosteroids improve the antiemetic efficacy of ondansentron in cisplatin-induced chemotherapy, and should be included in antiemetic regimens.

Pancreatic adenocarcinoma-associated polymyositis treated with corticosteroids along with cancer specific treatment: case report

BackgroundAdenocarcinoma of the pancreas only rarely is associated with inflammatory myopathy. In this setting, polymyositis may be treated with glucocorticoids in combination with cancer specific treatment.Case presentationWe present the case of a 52-year-old man with stage IIA pancreatic tail adenocarcinoma who underwent surgical treatment and six months into therapy with gemcitabine he developed symmetrical, painful, proximal muscle weakness with peripheral oedema. Re-evaluation with imaging modalities, muscle histology and biochemistry conferred the diagnosis of polymyositis associated with pancreatic cancer progression. The patient was treated with glucocorticoids along with gemcitabine and erlotinib which resulted in complete remission within six months. He remained in good health for a further six months on erlotinib maintenance therapy when a new computer tomography scan showed pancreatic cancer relapse and hence prompted 2nd line chemotherapy with gemcitabine.ConclusionsPolymyositis associated with pancreatic cancer may respond to glucocorticoids along with cancer specific treatment.

Leucovorin + 5-fluorouracil plus dipyridamole in leucovorin + 5-fluorouracil-pretreated patients with advanced colorectal cancer: a pilot study of three different dipyridamole regimens.

Dipyridamole, an inhibitor of nucleoside transport, increases the activity of 5-fluorouracil in a dose-dependent manner. The purpose of the present study was to determine whether dipyridamole with 5-fluorouracil and leucovorin gave an improved therapeutic outcome. Sixty patients entered in the present pilot study had previously received 5-fluorouracil (450 mg/m2) and leucovorin (100 mg/m2), every week, and relapsed during this treatment, which ended at least 6 weeks prior to study entry. Dipyridamole was administered at three different dosing schedules (DS) and methods of administration in three groups of patients. DS I: dipyridamole, 30 mg/m2 in normal saline solution, in 90 min iv infusion, followed by leucovorin, 100 mg/m2 iv push, followed by 5-fluorouracil, 450 mg/m2 in normal saline solution, in 60 min iv infusion, dipyridamole tablets (75 mg) every 12 hrs, continuously during the time of chemotherapy. DS II: dipyridamole, 50 mg/m2 in normal saline solution, in 90 min iv infusion, and the rest was the same as DS I. DS III: without oral dipyridamole, patients received dipyridamole (50 mg/m2) iv in the same manner as in DS I and II. Treatment was continued until tumor progression or unacceptable toxicity. All patients (n = 60) entered in the present study were assessable for response and toxicity. No complete response was observed. No patient at DS I responded, whereas 2 patients at DS II and 3 at DS III had a partial response (P <0.1). Stable disease was found with DS I (n = 1), DS II (n = 8) and DS III (n = 9) (P <0.01). More patients progressed at DS I (n = 19) than at DS II (n = 10) and DS III (n = 8) (P <0.0007). The median duration of response was 11 weeks (range, 8-16). Time to progression was 17 weeks for DS I, 15 weeks (range, 10-19) for DS II, and 14 weeks (range, 11-21) for DS III (P = 0.43). Median survival did not differ significantly between DS I (29 weeks; range, 14-48), DS II (31.5 weeks; range, 17-63) and DS III (36 weeks; range, 16-58) (P = 0.2). Neutropenia was most severe with DS I (grade 2, P <0.01) and DS II (grade 1, P <0.05) and nausea/vomiting with DS I (grade 0, P < 0.0005, grade 1, P <0.0002, grade 2, P <0.02) and DS III (grade 3, P <0.0009). Diarrhea was most severe in DS II (grade 3, P <0.005). Mucositis was increased in DS II (grade 0, P <0.008), anorexia in DS II (grade 0, P <0.032) and fatigue in DS I (grade 0, P <0.003). More patients in DS I than with the other two DS experienced headache (P <0.044). According to the response achieved at DS III (15% partial response and 45% stable disease) and the toxicity which was well tolerated mainly in this DS (except for nausea and vomiting grade 3, P <0.009), it can be stated that DS III is the appropriate dose and the simplest schedule of administration (administration of dipyridamole during therapy only). In conclusion, it appears that dipyridamole might still have a role in enhancing the clinical activity of drugs involved in the inhibition of the thymidylate synthetase biochemical pathway and its activity in combination with these agents (5-fluorouracil + leucovorin) as frontline treatment should therefore be explored in future phase II studies.

Efficacy of tropisetron in patients with advanced non-small-cell lung cancer receiving adjuvant chemotherapy with carboplatin and taxanes

Even though significant progress has been made, chemotherapy-induced emesis remains a challenging problem. Few studies focus on emesis in patients treated with carboplatin and the observation period is limited to the initial 24 h following chemotherapy. Thus, we investigated if tropisetron (T) monotherapy can adequately prevent acute and delayed emesis in non-small-cell lung cancer (NSCLC) patients receiving a moderately emetogenic chemotherapy (MEC) (carboplatin-containing) regimen. Furthermore, we explored the merits of adding dexamethasone (D) or alprazolam (A) to T, especially in the setting of a pre-existing high level of stress. We studied 60 patients with advanced NSCLC receiving carboplatin and taxanes in three consecutive cycles. During the first cycle, patients received 5 mg of T intravenously before chemotherapy and the same dose per os on each of the following 3 days. In the second cycle, T was co-administered with 8 mg of D once a day, while, during the third cycle, T was combined with per os A 0.25 mg every 12 h and continued over the following 3 days. Finally, we evaluated the impact of stress on the anti-emetic response achieved with the previously described regimens. The combination of T + A was superior to T monotherapy and the combination of T + D, regarding the prevention of acute and delayed emesis. Both T + A and T + D combinations led to appetite improvement, while patients receiving T + A experienced sedation more frequently. Interestingly, subgroup analysis revealed that patients without underlying stress obtained no further benefit by the addition of A or D, while both T + A and T + D combinations led to a better anti-emetic response in patients with stress. In conclusion, T monotherapy provides a satisfactory result in controlling nausea and emesis caused by a MEC regimen in patients without stress. However, the addition of D and, mainly, A improves its anti-emetic effect in patients with obvious stress.