Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project.

BACKGROUND: The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) aimed to investigate whether a 3 months (3M) of oxaliplatin/fluoropyrimidine-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) administration in 3-year disease-free survival (3yDFS) in high-risk (HR) stage II or stage III colon cancer (CC). METHODS: Hellenic Oncology Research Group (HORG)-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX. RESULTS: In total 1115 patients, 413 with HR stage II and 702 with stage III CC, were randomized. The median follow-up was 67.0 (38.3-126.0) months. Overall, 394 DFS events (202 in 3M arm and 192 in 6M arm) where recorded. The 3yDFS rate was 77.2% [95% confidence interval (CI) 72.1% to 82.3%] for 3M and 77.9% (72.6% to 82.5%) for 6M of treatment [hazard ratio (HR) 1.05 (95% CI 0.61-1.55); P = 0.647]. Eighty DFS events (3M N = 41; 6M N = 39) were observed in HR stage II patients for a 3yDFS rate of 82.7% and 83.4%, respectively (HR 1.05; 95% CI 0.68-1.63, P = 0.829). For stage III patients, 314 DFS events (3M N = 161 and 6M N = 153) were observed, for a 3yDFS rate of 72.9% for 3M versus 74.1% for 6M (HR 1.06; 95% CI 0.81-1.42, P = 0.622). For HR stage II patients receiving FOLFOX4, 3yDFS rate was 76.7% for 3M and 79.3% for 6M (HR 1.21; 95% CI 0.54-2.70). For HR stage II patients receiving CAPOX the 3yDFS rate was 85.4% for 3M and 83.8% for 6M (HR 0.99; 95% CI 0.59-1.67). For stage III patients receiving FOLFOX4, the 3yDFS rate was 71.5% for 3M and 77.3% for 6M (HR 1.18; 95% CI 0.74-1.86). For stage III patients receiving CAPOX, the 3yDFS rate was 74.5% for 3M and 74.7% for 6M (HR 0.99; 95% CI 0.70-1.44). CONCLUSIONS: The results of the HORG-IDEA study are in line with those of the global IDEA project, indicating that the 3yDFS is dependent on the administered adjuvant regimen and the choice and duration of regimen should be personalized. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01308086.

Smoking effects on quality of life of allergic rhinitis patients after sublingual immunotherapy.

BACKGROUND: Although tobacco smoking is of great concern, there is no evidence for the effects of smoking on quality of life (QoL) results after sublingual immunotherapy (SLIT). OBJECTIVE: This study aims tο explore any association between smoking habits (duration and quantity) and QoL results after SLIT in allergic rhinitis (AR). METHODOLOGY: One hundred and sixty three patients following SLIT for AR were participated. SLIT efficacy related to smoking was prospectively evaluated by means of validated widely used QoL questionnaires, either for assessing psychology (Zung Anxiety Scale, State-Trait Anxiety Inventory, Zung Depression Scale and Beck Depression Inventory) or generic (Short Form-36) ones, pre- and immediately upon cessation of SLIT. Smoking habits were expressed in pack-years. RESULTS: Significant improvement of total symptoms score (T5SS) and of all QoL questionnaires' results were observed in our patients' group, both for smokers and non smokers. The comparison of changes between smokers and non smokers, controlling for the effect of all patients' characteristics, showed that there was no significant differences on improvement values. Additionally multivariate linear regression analysis revealed that the effect of pack-years on the QoL scales was not significant. CONCLUSIONS: Our results suggest that smoking habits (quantity of daily smoking and duration) do not influence the success of SLIT with regards to QoL outcomes.

Presence of hyaluronidase isoforms in nasal polyps.

BACKGROUND: Nasal polyps are benign lesions originating from the nasal mucosa or paranasal sinuses. The most important etiological factor seems to be increased hydration of epithelium and hyperplasia of the extracellular matrix, which may involve hyaluronan, a high molecular mass extracellular glycosaminoglycan. Degradation of hyaluronan proceeds through the action of specific hyaluronidases. OBJECTIVE: The aim of the present study was to investigate the hydrodynamic size of hyaluronan and the presence of the various hyaluronidase isoforms in nasal polyps. METHODS: Samples of polypoid mucosal tissue and normal nasal mucosa were obtained from twenty patients suffering from nasal polyposis. Zymographic analysis and western blotting were used to detect hyaluronidase activity. RESULTS: The results indicated the presence of hyaluronan of small molecular mass in all samples examined. About one third of it has a mean molecular mass of 240 kDa, exactly that required for the expression of inflammatory response. Laboratory analysis suggested that degradation of hyaluronan occurred through the action of three hyaluronidase isoforms: Hyal-1, Hyal-2 and PH-20. CONCLUSIONS: Since hyaluronan fragments of 200-250 kDa induce the expression of inflammatory cytokines, a specific role of hyaluronidases in the development or progression of nasal polyps may be concluded. Therefore, new treatment protocols may be proposed.

Irinotecan plus weekly 5-fluorouracil and leucovorin as salvage treatment for patients with metastatic colorectal cancer: a phase II trial.

BACKGROUND: A phase II study was conducted to evaluate the toxicity and efficacy of irinotecan/5-fluorouracil/leucovorin (CPT-11/5-FU/LV (AIO schedule)) as salvage treatment in patients with metastatic colorectal cancer. PATIENTS AND METHODS: 33 patients relapsing after oxaliplatin (L-OHP)-based first-line chemotherapy were enrolled. Their median age was 69 years, 20 (61%) patients were male, and performance status (WHO) was 0, 1, and 2 in 15, 16 and 2 patients respectively; prior surgery 20 (61%) patients; adjuvant chemotherapy 11 (33%) patients, and adjuvant radiotherapy 6 (18%) patients. The number of metastatic sites was 1, 2, and > or =3 in 11, 11, and 11 patients, respectively. CPT-11 was administered on day 1 at the dose of 80 mg/m(2) in 30-90 min infusion and LV (500 mg/m(2)) on the same day as a 2-hour infusion followed by 5-FU (2,600 mg/m(2)/day) as a 22-hour infusion on day 1 for 6 subsequent weeks. The regimen was repeated every 7 weeks. RESULTS: All patients were evaluable for toxicity and for response. Complete response was achieved in 2 patients (6%) and partial response in 4 patients (12%) (RR 18%, CI 5.95-35.43%); 13 patients (40%) had stable disease, and 14 (42%) progressive disease. After a median follow-up period of 9 months, the median duration of response was 5 months, the median time to progression 7.5 months, and OS 14 months. Grade 3-4 neutropenia occurred in 13 patients (39%), febrile neutropenia in 3 (9%), grade 2 anemia in 11 (33%), grade 4 thrombocytopenia in 1 (3%). Grade 3-4 diarrhea occurred in 12 patients (36%), grade 3-4 neurotoxicity in 3 (9%), and grade 3 asthenia in 4 (12%). No treatment-related deaths occurred. The median dose intensity was 85% for CPT-11, and 88% for 5-FU and LV. CONCLUSIONS: The combination of weekly CPT-11 and infusional 5-FU/LV is an active and relatively well-tolerated regimen as salvage treatment in MCC.

Major hepatectomy and right hemicolectomy at the time of primary cytoreductive surgery for advanced ovarian cancer: report of a case.

Major liver involvement at the time of diagnosis is a rare event in patients with ovarian cancer, and the issue of major hepatectomy at the time of primary cytoreductive surgery is controversial. A 61-year-old woman was admitted to our hospital with nonspecific abdominal pain of 2-month duration and weight loss of 5 kg during the last semester. A computed tomography scan demonstrated bilateral ovarian masses, extending to the right iliac fossa, pressing the cecum-ascending colon. In the liver parenchyma, three cystic lesions were found of about 6-cm maximum diameter each, along with pelvic lymphadenopathy. There was no ascites. The diagnosis of advanced ovarian cancer was clinically suspected; the patient underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy, right hemicolectomy, omentectomy, left lobectomy, deroofing, and draining of the cystic formation of the right liver lobe along with systematic pelvic and para-aortic lymphadenectomy. Systemic chemotherapy (six cycles of paclitaxel/carboplatin) was subsequently administered, and after 15 months of follow-up period, the patient is still in first remission and alive. Ovarian cancer with concomitant extensive right colon infiltration and hematogenous liver metastases can be successfully managed with aggressive surgical resection and postoperative chemotherapy in carefully selected patients.

Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.

PURPOSE: The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC. PATIENTS AND METHODS: Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status < or = 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support. RESULT: Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P =.017), median time to progression (TTP; 9.4 v 6.1 months; P =.003) and median survival (14.2 v 9.3 months; P =.026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P =.005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P =.089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P =.006), thrombocytopenia (5.7% v 0.9%; P =.046), and neutropenic sepsis (11.6% v 3.8%; P =.001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. CONCLUSION: MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma.

Docetaxel versus docetaxel/cisplatin in patients with advanced non-small-cell lung cancer: preliminary analysis of a multicenter, randomized phase III study.

The purpose of this study was to compare the efficacy and safety profile of docetaxel versus the combination of docetaxel/cisplatin as frontline treatment of patients with advanced or metastatic non-small-cell lung cancer (NSCLC) in a multicenter, randomized, prospective phase III trial. Patients with unresectable stage IIIB or metastatic stage IV NSCLC who had previously undergone no chemotherapy were allocated to receive either docetaxel (100 mg/m2 in a 1-hour intravenous infusion; group A) or the combination of docetaxel (100 mg/m2 day 1) and cisplatin (80 mg/m2 day 2) after adequate hydration (group B). Appropriate premedication was given before docetaxel infusion. All patients in group B received granulocyte colony-stimulating factor (150 microg/m2 subcutaneously) support from days 3 to 9 after treatment. Response and toxicity were assessed by World Health Organization criteria. From March 1999 to November 2001, 302 patients were randomly assigned to receive docetaxel (group A, n = 146) or docetaxel/cisplatin (group B, n = 156). The overall response rate was significantly higher in the combination arm (18% vs. 36%; P < 0.001). However, the 2 groups did not differ in median duration of response, time to progression (TTP), median overall survival (OS), or 1-year survival rate. Drug combination was associated with higher toxicity than single-agent therapy. Both regimens had comparable activity in terms of TTP and OS in chemotherapy-naive patients with advanced NSCLC; however, single-agent therapy had a more favorable toxicity profile.

Frontline treatment of advanced gastric cancer with docetaxel and granulocyte colony-stimulating factor (G-CSF): a phase II trial.

We conducted a phase II study to evaluate the efficacy and tolerance of docetaxel monotherapy with granulocyte colony-stimulating factor (G-CSF) support in patients with advanced gastric cancer. Thirty patients with measurable advanced gastric cancer were enrolled. Twenty-four patients were chemotherapy-naive and six patients had previously received adjuvant chemotherapy after complete surgical resection. Docetaxel was administered at 100 mg/m2 IV during 1 hour every 3 weeks. G-CSF 5 microg/kg SC was also given on days 2 through 8 prophylactically to all patients. All patients were evaluable for response and toxicity. We observed one complete and five partial responses for an overall response rate of 20% (95% confidence interval: 6-34%). In addition, seven patients (23%) had stable disease. After a median follow-up time of 7 months, the median duration of response was 4.5 months, the median time of tumor progression was 6 months, and the median survival was 7 months. The estimated probability of 1-year survival was 28%. Toxicity was generally mild. Grade III/IV neutropenia occurred in 11 (36%) patients. Neutropenia with fever developed in three patients (10%). There were no toxic deaths. Docetaxel with G-CSF support is an active drug and well tolerated by patients with advanced gastric cancer. Docetaxel merits further investigation in combination with other active agents as frontline treatment in patients with advanced gastric cancer.

Phase I study of the gemcitabine/oxaliplatin combination in patients with advanced solid tumors: a preliminary report.

The purpose of this study was to determine the maximum tolerated dose and evaluate the dose-limiting toxicities of the gemcitabine/oxaliplatin combination in patients with advanced-stage solid tumors. Of the 48 enrolled patients, 35% had first-line, 23% had second-line, and 42% had third-line therapy. Patients received escalating doses of 1,000 to 1,600 mg/m2 gemcitabine on days I and 8 plus 60 to 120 mg/m2 oxaliplatin on day 8, every 21 days. The dose-limiting toxicities (first nine dose levels) were grade 4 neutropenia, grade 3 asthenia, and grade I to 3 neutropenia or thrombocytopenia. One hundred fifty-three cycles have been administered without any febrile neutropenia or toxic death. Grade 3-4 neutropenia and grade 3 thrombocytopenia were noted in 13 (9%) and seven (5%) cycles, respectively. Nonhematologic toxicity has been mild; the most common was grade 2 to 3 asthenia occurring in 29% of cycles. Among 30 evaluable patients, four partial responses have been observed (response rate, 13%). In this phase I study, the maximum tolerated dose of this drug combination has not yet been reached, although gemcitabine up to 1,600 mg/m2 (days I and 8) plus oxaliplatin up to 120 mg/m2 (day 8) was active and well tolerated, warranting further evaluation in phase II studies.

A dose-escalation study of irinotecan (CPT-11) in combination with cisplatin in patients with advanced non-small cell lung cancer previously treated with a docetaxel-based front line chemotherapy.

PURPOSE: A phase I study was conducted to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a CPT-11 plus cisplatin combination as salvage treatment in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-two patients with histologically confirmed NSCLC, who had failed taxotere-based front-line chemotherapy, were enrolled. The patients' median age was 61 years, 19 (86%) were male, and 17 (77%) had a performance status (World Health Organization (WHO)) 0-1. CPT-11 was administered as a 60-min i.v. infusion at a fixed dose of 100 mg/m2 on day 1 and at escalating doses on day 8, starting from 100 mg/m2 with increments of 10 mg/m2; cisplatin was administered at a fixed dose of 80 mg/m2 on day 8, 2 h after CPT-11 administration. Treatment was repeated every 3 weeks. RESULTS: At the dose of CPT-11 120 mg/m2, three out of four enrolled patients presented DLTs (grade 4 neutropenia, febrile neutropenia and delayed diarrhea); the addition of G-CSF at this level did not permit further dose-escalation. Grade 3/4 neutropenia was observed in 12 (18%) cycles, febrile neutropenia in four (6%), and grade 3/4 thrombocytopenia in four (6%). Grade 3/4 diarrhea was seen in six (29%) patients, and grade 2/3 nausea and vomiting in 12 (57%). Neurotoxicity grade 2 was observed in six (29%) patients and grade 3 in one (5%). Other toxicities were mild. The MTD was CPT-11 100 mg/m2 on day 1 and 110 mg/m2 on day 8 in combination with CDDP 80 mg/m2 on day 8. Among 12 patients evaluable for response, partial response was achieved in two (16.7%) patients and stable disease in five (41.7%). CONCLUSION: The combination of CPT-11 and cisplatin has substantial but manageable toxicity and marginal activity as salvage treatment of patients with NSCLC who have failed taxotere-based front-line chemotherapy: further investigation is warranted to define its precise role in the second-line setting.

First-line treatment of metastatic breast cancer with mitoxantrone, vinorelbine, and carboplatin.

A phase II trial was conducted with mitoxantrone (12 mg/m2, day 1), vinorelbine (30 mg/m2, day 1), and carboplatin (250 mg/m2, day 2) every 21 days. Fifty eligible women who had not received prior chemotherapy for metastatic breast cancer (MBC) entered the study. Objective responses were observed in 28 patients (56%; 95% confidence interval: 42.4-69.74%), with 4 complete (8%) and 24 partial responses (48%). Stable disease was observed in 12 patients (24%) and disease progression in 10 (20%). Responses were documented in all involved sites. The median duration of response was 6 months and the median time to tumor progression 8 months. The median survival was 26 months and the estimated 2-year survival was 52%. Grade 3/4 neutropenia was observed in 29 patients (58%) with four neutropenic episodes. Grade 3/4 anemia and thrombocytopenia was observed in 7 (14%) and 11 (22%) patients, respectively. Other toxicities included grade 2/3 nausea and vomiting in 26 patients (52%) and grade 1/2 alopecia in 38 (76%). Grade 1/2 neurosensory toxicity occurred in four patients (8%). In conclusion, this three-drug regimen is effective and well tolerated for the treatment of MBC.

Treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor: a multicenter phase II study.

PURPOSE: To determine the efficacy and tolerance of single-agent docetaxel and granulocyte colony-stimulating factor in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Thirty-three chemotherapy-naive patients (median age, 65 years) with histologically confirmed pancreatic cancer were treated, after appropriate premedication, with docetaxel (100 mg/m(2)) and granulocyte colony-stimulating factor (150 microg/m(2)/d subcutaneously days 2 through 10) every 3 weeks. World Health Organization performance status was 0 to 1 in 28 patients (85%) and 2 in 5 patients (15%). Twenty-nine patients had stage III and IV disease. RESULTS: One complete response (3%) and one partial response (3%) were observed for an overall response rate of 6% (95% confidence interval, 2.1% to 14.2%). Nineteen patients (58%) had stable disease and 12 (36%) had progressive disease. The duration of the two objective responses was 10 and 28 weeks, and the median time to tumor progression was 20 weeks. The median overall survival was 36 weeks. The actuarial 1-year survival was 36.4%. The performance status improved in seven of 21 assessable patients (24%) and pain improved in 14 of 21 (67%) assessable patients; five patients (29%) experienced weight gain during treatment. Disease-related asthenia, anorexia, vomiting, and diarrhea improved in 29%, 15%, 67%, and 47% of the assessable patients, respectively. Serum concentrations of CA 19-9 were decreased by more than 50% in seven patients (35%). Grade 3 and 4 neutropenia occurred in four patients (12%) and eight patients (24%), respectively, with two episodes of febrile neutropenia. There were no treatment-related deaths. Grade 3/4 asthenia occurred in three patients. CONCLUSION: Although docetaxel has a marginal objective activity in pancreatic cancer, it seems to have an important effect on tumor growth control, conferring a clinical benefit.

Post-chemotherapy lymphopoiesis in patients with solid tumors is characterized by CD4+ cell proliferation.

PURPOSE: A phenolypic analysis of peripheral blood lymphocytes was carried out in order to investigate the lymphopenia developed in some patients with solid tumors treated with systemic chemotherapy. PATIENTS AND METHODS: Peripheral blood was obtained from 53 cancer patients receiving chemotherapy with more than grade 2 neutropenia, before treatment, during the nadir of neutrophils and after bone marrow recovery. Cell phenotype was performed using monoclonal antibodies while cell proliferation, using 3HTdR uptake, was evaluated after cell stimulation with PHA-P and anti-CD3 moAb. RESULTS: Post-chemotherapy myelosuppression and rhG-CSF-induced bone marrow recovery were associated with lymphopenia and lymphocytosis reaching pre-treatment values, respectively; both lymphopenia and lymphocytosis concerned all lymphocyte subpopulations. Lymphocytosis was positively correlated with the absolute number of CD3+, CD4+ and CD20+ cells; in addition, the absolute number of HLA-DR+ and CD25+ cells was also increased. During bone marrow recovery, the absolute number of CD25+ cells was correlated with the increased number of both CD3+/CD25+ and CD4+/CD25+ but not of CD8+/CD25+ or CD20+/CD25+ cells. CD4+ lymphopenia (less than 400 cells/dL) was detected in 58% and 21% of the patients during myelosuppression and bone marrow recovery, respectively. PHA-P and anti-CD3 moAb failed to enhance lymphocyte proliferation in 60% and 44% of the patients during bone marrow recovery, respectively. CONCLUSIONS: Post-chemotherapy CD4+ cell repopulation is an active phenomenon. However, in several patients CD4 lymphopenia, which could be associated with functional cell abnormalities, may persist during bone marrow recovery leading to impaired cell-mediated immunity.

Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: a multicenter phase II trial. Greek Breast Cancer Cooperative Group.

PURPOSE: The activity of the docetaxel-gemcitabine combination in women with disease progression after initial chemotherapy for metastatic breast cancer (MBC) was investigated in a multicenter phase II study. PATIENTS AND METHODS: Fifty-two patients with metastatic breast cancer who had disease relapse or progression after completion of an anthracycline-based front-line regimen were treated with gemcitabine 900 mg/m2 on day 1 and day 8 and docetaxel 100 mg/m2 on day 8. G-CSF 150 mucg/m2/d s.c. was given from day 9 to day 16 and the treatment was repeated every three weeks. The patients' median age was 57 years and the performance status (WHO) was 0 for 26, 1 for 20 and 2 for 6 patients. The treatment was second-line for 27 (52%) and > or = third-line for 25 (48%) patients. All patients were evaluable for response and toxicity. RESULTS: Complete response occurred in seven (14%) patients and partial response in 21 (40%) for an overall response rate of 54% (95% confidence interval (95% CI): 40%-67%). Fifteen (29%) patients had stable disease and nine (17%) progressive disease. Of 25 patients previously treated with taxanes. 11 (44%) responded (1 CR, 10 PR). Interestingly, in four patients with disease progression while receiving docetaxel or paclitaxel monotherapy, the docetaxel + gemcitabine combination achieved partial responses. Responses were observed at all metastatic sites (local disease 62%, lymph nodes 58%, skin 44%, lung 47% and liver 36%) with a median duration of response of 3.6 months (range 1-16) and a median time to disease progression of eight months (range 2-18.5). Grade 3 neutropenia developed in 10 (19%) and grade 4 in five (10%) patients. Neutropenia was associated with infection in four patients without toxic deaths. Grade 3 thrombocytopenia developed in nine (17%) patients and grade 4 in two (4%). Non-hematologic toxicity was usually mild. CONCLUSION: The docetaxel-gemcitabine combination is an active and well tolerated salvage treatment in patients with MBC. Previous treatment with taxanes does not preclude a good clinical response to this regimen.

Weekly docetaxel and concomitant boost radiotherapy for non-small cell lung cancer. A phase I/II dose escalation trial.

In this phase I/II study, we investigated the radiosensitising effects of docetaxel in non-small cell lung cancer (NSCLC). 30 patients with stage IIIb (18 patients) and IV (12 patients) NSCLC were treated with 64 Gy of accelerated chest radiotherapy (5-week schedule using a concomitant boost technique) and docetaxel on a weekly basis. The docetaxel starting dose level was 20 mg/m2/week and was escalated by 10 mg/m2 increments in cohorts of 10 patients. Dose-limiting toxicity (grade 3 asthenia) was observed in 6 of 10 patients treated at the 40 mg/m2/week dose level, enforcing a 50% dose reduction in 4 patients. Grade 3 neutropenia was observed in 5 of 30 patients (17%), 3 of which were treated at the high dose level. Peripheral neuropathy occurred in 3 (10%) patients. A significant decrease in the absolute lymphocyte count was observed in all patients; the nadir was reached on day 28 (mean +/- standard deviation (S.D.) = 539 +/- 363/ml) compared with pretreatment values (mean +/- S.D. = 1842 +/- 863/ml; P = 0.002). 6 out of 30 patients (20%) experienced grade 3 oesophagitis, resulting in a 1-2 week delay in overall treatment time. Complete response of the primary tumour was observed in 8 (27%) patients assessed 2 months after treatment. 4 of these patients had disease resistant to previous docetaxel-containing chemotherapy. A partial response occurred in 15 of 30 patients (50%) for an overall response rate of 77% (95% confidence interval (CI) 60-92%). Radiosensitisation with docetaxel is feasible and the recommended dose for further phase II studies is 30 mg/m2/week. Further phase II studies are required to confirm the remarkably high response rate observed in the present trial.

First-line treatment of advanced nonsmall cell lung carcinoma with docetaxel and vinorelbine.

BACKGROUND: Docetaxel and vinorelbine are active agents in the treatment of nonsmall cell lung carcinoma (NSCLC). The efficacy and toxicity of this combination was evaluated in a Phase II study in patients with advanced NSCLC. METHODS: Forty-six chemotherapy-naive patients (44 men and 2 women with a median age of 64 years) with NSCLC (11 with Stage IIIB and 35 with Stage IV disease) were entered into the study; the World Health Organization (WHO) performance status was 0, 1, and 2 in 32, 11, and 3 patients, respectively. Patients received vinorelbine (25 mg/m2) on Day 1 and docetaxel (100 mg/m2) on Day 2 in cycles repeated every 3 weeks. Granulocyte-colony stimulating factor was given to all patients from Day 3 to Day 10. RESULTS: One hundred and seventy-seven courses of chemotherapy were administered. Adverse events included WHO Grade 4 neutropenia (15 patients), Grade 3/4 thrombocytopenia (3 patients), Grade 3 anemia (2 patients), Grade 2 and 3 neurotoxicity (7 patients and 1 patient, respectively), and Grade 3 fatigue (2 patients). Twenty patients (43%) required hospitalization: 11 (24%) for neutropenic fever (2 deaths from sepsis), and 9 (20%) for nonneutropenic pulmonary infections (2 deaths from cardiopulmonary insufficiency). The median overall survival was 5 months and the 1-year survival was 24%. Four complete responses (9.8%) and 11 partial responses (26.8%) (overall response rate of 36.6%; 95% confidence interval, 21.8-51.3%) were documented in 41 evaluable patients (intent-to-treat: 32.6%). Stable and progressive disease occurred in 13 patients each (31.7%). The median duration of response was 5 months and the median time to progression was 3 months (6 months for the responders). CONCLUSIONS: This schedule of docetaxel and vinorelbine combination is effective but its relatively high incidence of complicated neutropenia precludes its general use in patients with advanced NSCLC.

Salvage chemotherapy with paclitaxel, vinorelbine, and cisplatin (PVC) in anthracycline-resistant advanced breast cancer.

The tolerance and the efficacy of the paclitaxel-vinorelbine-cisplatin combination (PVC regimen) was evaluated in 33 patients with anthracycline-resistant stage IV breast cancer, who had disease progression under anthracycline- or mitoxantrone-based chemotherapy. Fourteen (42%) and 19 (58%) patients had primary and secondary resistance to anthracyclines, respectively; 70% had visceral metastases. Patients received vinorelbine (25 mg/m2) followed by paclitaxel (135 mg/m2) in a 3-hour infusion on day 1, and cisplatin (CDDP; 80 mg/m2) on day 2, in a 3-week schedule. A total of 208 chemotherapy courses were administered (median six courses per patient). Grade 3/4 neutropenia occurred in 13 patients (39%), seven of whom were hospitalized for neutropenic fever (5% of the courses). There was no toxic death. Grade 4 thrombocytopenia occurred in two patients (6%) and grade 3 anemia in three patients (9%). Grade 2 and 3 neurosensory toxicity occurred in 11 patients (32%) and two patients (6%), respectively, and grade 3/4 fatigue was observed in four patients (12%). Two (6%) complete and 17 partial responses (52%) (total, 58%; 95% confidence interval, 42%-75%) were documented. Stable disease was observed in eight patients (24%) and progression in six patients (18%). The median duration of response was 6.5+ months. The median survival was 15+ months, and the 1-year survival was 67%. In conclusion, PVC regimen is an active and well-tolerated salvage chemotherapy in patients resistant to anthracycline.

First-line treatment of advanced non-small-cell lung cancer with docetaxel and cisplatin: a multicenter phase II study.

PURPOSE: To evaluate the efficacy and safety of the docetaxel-cisplatin combination in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naïve patients with histologically confirmed, measurable stage IIIB or IV NSCLC, a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow, renal, hepatic and cardiac function were eligible for the study. Patients received docetaxel (100 mg/m2) as an one-hour infusion on day 1 and cisplatin (80 mg/m2) as a 30-min infusion with appropriate hydration on day 2. Granulocyte colony-stimulating factor (G-CSF; 150 micrograms/m2, SC) was given on days 3 to 13. Treatment was repeated every three weeks. RESULTS: Fifty-three patients were enrolled (28 with stage IIIB and 25 with stage IV). One complete and 23 partial responses were observed (overall response rate (OR): 45%; 95% CI: 34.1%-61.8%). The response rate was 57% and 32% in patients with stages IIIB and IV disease (P = NS). The median time to progression was 36 weeks and the median survival 48 weeks; the one-year survival was 48%. Grade 3-4 neutropenia occurred in 23 patients, 15 of whom were hospitalized for neutropenic fever; two patients died of sepsis. Grade 2 neurotoxicity was observed in six patients and grade 3 in five patients; grade 3 fatigue occurred in seven patients, grade 3-4 mucositis in four patients and grade 3-4 diarrhea in six patients. Mild allergic reactions and oedema were observed in five and four patients, respectively. The median dose intensity was 30 mg/m2/week for docetaxel and 24 mg/m2/week for cisplatin, corresponding to 91% and 89% of the specified protocol doses, respectively. CONCLUSIONS: The docetaxel-cisplatin combination is an active regimen in advanced NSCLC, but hematologic toxicity remains high despite the prophylactic use of G-CSF.

Second-line treatment of advanced non-small cell lung cancer with paclitaxel and gemcitabine: a preliminary report on an active regimen.

A phase II study of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/gemcitabine was conducted in patients with non-small cell lung cancer (NSCLC) who had failed first-line docetaxel- or cisplatin-based chemotherapy. Eligibility criteria included histologically confirmed measurable stage IIIB or IV NSCLC and previous exposure to docetaxel- or cisplatin-based regimens, World Health Organization performance status between 0 and 2, adequate hematologic parameters, and adequate hepatic, renal, and cardiac function. Gemcitabine (900 mg/m2) was given on days 1 and 8 as a 30-minute infusion; paclitaxel (175 mg/m2) was administered on day 8 as a 3-hour infusion after appropriate premedication. Granulocyte colony-stimulating factor (150 microg/m2 subcutaneously) was given on days 9 to 15. Treatment was repeated every 3 weeks until patients experienced disease progression. From October 1995 to December 1996, 26 patients with advanced NSCLC were enrolled (three stage IIIB, 23 stage IV). All 26 patients were assessable for toxicity, and 24 were evaluable for response. Two complete (8%) and five partial (21%) responses were observed, for an overall response rate of 29% (95% confidence interval, 11% to 47%). The median duration of response was 2.5 months and the median survival was 8 months. A median of three courses per patient was administered, and the median interval between courses was 21 days. The median delivered dose was 579 mg/m2/wk gemcitabine and 54.5 mg/m2/wk paclitaxel, corresponding to a relative dose intensity of 0.97 and 0.96, respectively. Grade 3/4 neutropenia occurred in two patients (8%). Grade 3 conjunctivitis occurred in one (4%) patient and grade 2/3 neurotoxicity in eight (31%) patients. Grade 3/4 and grade 2 fatigue occurred in four (15%) and eight (31%) patients, respectively. Other toxicities were mild to moderate. These preliminary results suggest that the paclitaxel/gemcitabine combination is an active and well-tolerated salvage regimen in patients with NSCLC previously treated with docetaxel- or cisplatin-based chemotherapy. The paclitaxel/gemcitabine combination merits further evaluation as first-line treatment.

Docetaxel (Taxotere) and vinorelbine in the treatment of non-small cell lung cancer.

The efficacy and safety of a combination of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and vinorelbine were evaluated in two phase II studies including 46 and 39 chemotherapy-naive patients with non-small cell lung cancer, respectively. In the first study, vinorelbine 25 mg/m2 was given on day 1 and docetaxel 100 mg/m2 on day 2, with recombinant human granulocyte colony-stimulating factor support from day 5 until day 12, every 3 weeks. In the second study, docetaxel 75 mg/m2 was given on day 1 and vinorelbine 20 to 25 mg/m2 on days 1 and 5 in a 3-week schedule. Grade 3/4 neutropenia was the most severe toxicity, occurring in 46% to 85% of patients, while febrile neutropenia was observed in 25% to 41% of patients. Two treatment-related deaths occurred in each study. Patients with a poor performance status were at an increased risk of infection. The objective response rates were 36.6% and 27%, respectively (mean, 32%). In two subsequent studies, the efficacy and safety of a triple-drug combination of docetaxel, vinorelbine, and cisplatin was evaluated. In the first study, 14 patients were treated with vinorelbine 25 mg/m2 and cisplatin 80 mg/m2 on day 1 and docetaxel 100 mg/m2 and vinorelbine 20 mg/m2 on day 8, every 3 weeks. In the second study, 46 patients received docetaxel 100 mg/m2 on day 1, cisplatin 100 mg/m2 and vinorelbine 30 mg/m2 on day 21, and vinorelbine 30 mg/m2 on days 28 and 35, every 6 weeks. The main toxicity was also grade 3/4 neutropenia (57% and 80% of patients, respectively). Febrile neutropenia developed in 50% and 15% of the patients in the first and second study, respectively. The overall response rates were 33% and 39%, respectively. It is concluded that combination therapy with docetaxel/ vinorelbine or with docetaxel/vinorelbine/cisplatin has antitumor activity in the treatment of non-small cell lung cancer. Granulocytopenia and febrile neutropenia are the most severe toxicities that limit the usefulness of these regimens.