A phase II study of gemcitabine in combination with oxaliplatin as first-line chemotherapy in patients with inoperable biliary tract cancer

Purpose   The aim of this study is to investigate the efficacy and safety of gemcitabine and oxaliplatin combination chemotherapy as first-line therapy in patients with inoperable biliary tract cancer (BTC). Methods   The treatment of this non-randomized phase II study consisted of gemcitabine 1,000 mg/m² intravenously (i.v.) on day 1 and oxaliplatin 85 mg/m² i.v. on day 2 every 2 weeks until disease progression, unaccep toxicity or patients’ refusal. Results   From Sept 2006 to Oct 2007, 40 patients were enrolled. In the ITT analysis, the objective response rate was 15.0% and the disease control rate was 52.5%. The median overall survival (95% CI) was 8.5 months (6.4–10.7) and the time to progression was 4.2 months (0.5–7.9). For the 305 cycles, observed grade 3/4 toxicity was uncommon. Conclusions  Gemcitabine and dose adjusted oxaliplatin combination chemotherapy had moderate anti-tumor activity and was well tolerated as a first-line treatment for patients with inoperable BTC.     

Phase II study of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer

Purpose To evaluate the efficacy and safety of gemcitabine in combination with carboplatin at standard rate or fixed dose rate infusion in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods In this prospective study, patients with chemonaive advanced NSCLC were randomized to receive gemcitabine at a standard rate (gemcitabine 1,200 mg/m² over 30 min, the standard arm) or a fixed dose rate (gemcitabine 1,200 mg/m² over 120 min, the FDR arm) on days 1 and 8 every 3 week cycle. In both treatment arms, carboplatin at AUC of 5 was administered over 4 h following gemcitabine on day 1 of each cycle. Results From November 2003 to June 2005, a total of 42 patients, in which 7 (17%) patients had stage III_B disease and 35 (83%) had stage IV disease, were enrolled into this study. All patients were included in efficacy and toxicity assessment. No patient had a complete response. Seven (33%) patients in the standard arm and 10 (48%) in the FDR arm had a partial response. The median time to progression and median overall survival time in the standard arm was 5.4 months (95% CI, 3.8–7 months) and 11.5 months (95% CI, 8.2–14.8 months), respectively, while in the FDR arm was 6.5 (95% CI, 4.4–8.6 months) months, 12.0 months (95% CI, 11.3–12.7 months), respectively. The most frequently reported grade 3 or 4 hematological toxicities were thrombocytopenia (38% patients in the standard arm and 43% in the FDR arm) and neutropenia (24% in the standard arm and 33% in the FDR arm). Although hematological toxicity occurred in a little higher percent of patients in the FDR arm than in the standard arm, there were no discernible differences by statistical analysis in both treatment arms (P > 0.05). And significant nonhematologic toxicities were infrequent and tolerable in both arms. No significant difference existed also (P > 0.05). Conclusion In this phase II study, gemcitabine in combination with carboplatin either at standard rate or fixed dose rate infusion was clinically effective and well tolerated in patients with advanced NSCLC.     

A Phase II study of cisplatin preceded by a 12-h continuous infusion of concurrent hydroxyurea and cytosine arabinoside (Ara-C) for adult patients with malignant gliomas (Southwest Oncology Group S9149)

Inhibition of DNA excision repair can modulate resistance to cisplatin. Cytosine arabinoside (Ara-C) and hydroxyurea (HU), in combination, inhibit the excision-repair system and removal of platinum-DNA adducts. Marked cytotoxic synergy had been demonstrated in vitro at clinically achievable levels. The three-drug regimen was found to be feasible in clinical pilot studies. A Phase II study in patients with relapsed or progressive anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) was performed in the Southwest Oncology Group. The primary end point was 6 month survival, historically about 42%. A loading dose of HU 1,260 mg/m² IV over 1 h was followed by Ara-C 1,200 mg/m² plus HU 5,040 mg/m² IV over 12 h, followed by cisplatin 100 mg/m² IV over 1 h. A total of 76 patients were registered. The GBM stratum registered 56 patients in a two-stage accrual. Among 51 eligible GBM patients, the 6-month survival probability was 41% (95% CI 28–55%), and median overall survival was 5 months (95% CI 4–6 months). The 6-month progression-free survival probability was 25% (95% CI 14–37%), and median progression-free survival was 2 months (95% CI 2–4 months). One patient achieved a partial response (2%, 95% CI 0–10%), 13 patients had stable disease (25%, 95% CI 14–39%). Twenty-two patients progressed, and 14 were not assessable for response. The AA stratum was closed early after 20 patients due to slow accrual. Among 19 eligible patients, the 6-month survival probability was 58% (95% CI 36–80%), and median overall survival was 7 months (95% CI 7–14 months). The 6-month progression-free survival probability was 26% (95% CI 6–46%), and median progression-free survival was 3 months (95% CI 2–5 months). No responses were seen. Six patients (32%) had stable disease (95% CI 13–57%), 11 progressed, and 2 were not assessable for response. Of the 70 patients evaluable for toxicity, two died of infection. Twenty-three patients (33%) experienced Grade 4 toxicities, primarily hematological. Cisplatin combined with HU and Ara-C did not improve the 6 month survival rate in patients with relapsed or progressive AA or GBM. Significantly more hematological toxicity was seen than expected from cisplatin alone. Although benefit might be possible in a more platinum-sensitive tumor type, further clinical trials with this regimen for patients with glioblastoma multiforme or anaplastic astrocytoma are not justified.     

Gemcitabine and cisplatin combination regimen in patients with anthracycline- and taxane-pretreated metastatic breast cancer

This study was conducted to evaluate the response rate of gemcitabine and cisplatin as second-line combination chemotherapy in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Thirty-eight eligible women with measurable disease and anthracycline- and taxane-pretreated MBC were enrolled. The chemotherapy treatment consisted of gemcitabine (1,250 mg/m² by intravenous infusion over 30 min on days 1 and 8) and cisplatin (75 mg/m² by intravenous infusion over 1 h on day 1), which were administered every 21 days. Thirty-seven of 38 (97.4%) of patients were assessable for response. The objective response rate was 42.1% (95% CI, 26.4–57.8%) with 16 partial responses. The median time to progression (TTP) and overall survival (OS) for all patients were 5.4 months (95% CI, 2.7–8.1 months) and 13.9 months (95% CI, 9.4–18.4 months), respectively. The most frequent hematologic-related adverse events were grade 3/4 leucopenia and thrombocytopenia, observed in 10 patients (27.0%) and 11 (29.7%), respectively. Grade 3 stomatitis was observed in 3 (8.1%) patients. No grade 4 nonhematologic toxicity was observed in this study. No treatment-related deaths occurred during the study. In conclusion, the combination of gemcitabine and cisplatin is a safe and tolerable regimen as second-line combination for patients with anthracycline- and taxane-pretreated MBC.     

Fixed dose-rate infusion of gemcitabine in combination with cisplatin and UFT in advanced carcinoma of the pancreas

Background: Gemcitabine is currently considered the standard treatment for advanced pancreatic cancer (APC). Cisplatin and a fluoropyrimidine have some activity in the treatment of this cancer. The aim of this trial is to evaluate the efficacy and toxicity of a fixed dose-rate infusion of gemcitabine associated with cisplatin and UFT in patients with APC. Patients and methods: Forty-six chemotherapy-naïve patients with APC that was either unresectable or metastatic were included in this phase II study. All of them had Karnofsky performance status ≥50 and unidimensionally measurable disease. Treatment consisted of gemcitabine 1,200 mg/m² given as a 120-min infusion weekly for three consecutive weeks, cisplatin 50 mg/m² on day 1 and oral UFT 400 mg/m²/day (in two to three daily doses) on days 1 to 21; cycles of treatment were given every 28 days. Results: A total of 208 cycles of chemotherapy were given with a median of 4 per patient. Fourteen patients (30%) achieved partial responses (95% CI 19–48%) and 17 (37%) had stable disease. The median time to progression was 5 months, and the median overall survival 9 months. Nineteen patients (49%; 95% CI 32–64%) had a clinical benefit response. Grade 3–4 WHO toxicities were as follows: neutropaenia in 26 patients (57%), with 5 cases of febrile neutropaenia (11%), thrombocytopaenia in 15 (33%), anaemia in six (13%), diarrhoea in 5 (11%), asthenia in 2 (4%) and mucositis in 1 (2%). Seven patients required hospitalisation for treatment-related complications. Conclusion: A fixed dose-rate infusion of gemcitabine associated with cisplatin and UFT is active in patients with APC, though at the cost of considerable toxicity.     

Gemcitabine and paclitaxel chemotherapy for advanced urothelial carcinoma in patients who have received prior cisplatin-based chemotherapy

Background  The objective of this study was to evaluate the efficacy and toxicity of combination chemotherapy with gemcitabine and paclitaxel as a second-line regimen in patients with advanced urothelial carcinoma. Methods  Twenty patients with advanced urothelial carcinoma who were resistant to an M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy regimen were administered chemotherapy consisting of intravenous gemcitabine 2500 mg/m² and paclitaxel 150 mg/m² (GP) every 2 or 3 weeks. Results  The patients received a median of 7.7 cycles of treatment (range, 2–20 cycles). Six of the 20 patients (30%; 95% confidence interval [CI], 10%–50%) had a major response to treatment (a complete response [CR] in 5% and a partial response [PR] in 25%). Seven patients (35%) had stable disease (SD). The median duration of response was 4.5 months (range, 1–9 months) and the disease control rate (CR + PR + SD) was 65%. The median survival was 11.5 months (range, 2–22 months) and the 1-year survival rate was 35%. The patients tolerated this regimen well, with only grade 3–4 neutropenia being observed in 6 patients (30%), anemia in 3 (15%), and thrombocytopenia in 1 (5%). The response rate to M-VAC in the first-line chemotherapy was significantly associated with the response to GP as the second-line chemotherapy. Conclusion  The combination of gemcitabine and paclitaxel is active and well tolerated as a second-line treatment in patients with advanced urothelial carcinoma.     

Low dose Gemcitabine plus cisplatin in a weekly-based regimen as salvage therapy for relapsed breast cancer after taxane-anthracycline-containing regimens

Purpose Cisplain-gemcitabine is a synergistic chemotherapy (CT) combination highly proven in a broad spectrum of epithelial neoplasms and shows a non-cross-resistance profile with the most active drugs in metastatic breast cancer (MBC). We have conducted an exploratory study to determine if treatment with low doses of a combination of fixed-rate gemcitabine infusion and cisplatin was clinically meaningful in women relapsing after a minimum of 2 prior lines of CT for advanced disease (range 2–6), which had to have necessarily included both anthracyclines and taxanes. Another goal was to find the optimal individual schedule by adjusting frequency and dosage according to patient tolerability. Patients and methods From May 2002 to November 2003, 22 patients with relapsed advanced BC and a minimum of two prior CT lines were offered treatment with gemcitabine (G) (initial dose 750 mg/m², or 600 mg/m2 if the patient had received more than two previous CT lines) plus cisplatin (P) (initial dose 30 mg/m², or 20 mg/m² in case of ≥3 prior CT lines) on days 1 and 8 of a 21-day cycle. Treatment was postponed to day 15 if it could not be given on day 8, without dose reduction. If treatment could not be given on day 15, a 20% dose reduction was allowed and treatment given the next week. Further dose reductions were allowed as needed up to a maximum of three. Treatment continued until disease progression or intolerable toxicity. Median age was 54.5 years (35–75). Median Karnofsky was 90 (range 80–90). Median number of prior CT lines was 3 (2–6). 90.9% of patients had received adjuvant CT. All had prior anthracyclines and taxanes. Other agents used included 5-FU/eniluracil, MTA, RPR 109881A, trastuzumab, cisplatin, VP16, vinorelbine, capecitabine and irinotecan. 72.7% had received radio-therapy and 68.1% hormonal therapy (median 2 lines, range 1–4). Results Partial responses (PR) were seen in 9.1% of patients and stable disease (SD) in 36.4%. Clinical Benefit Rate (PR+SD) was derived in 45.5% of patients. Median time to progression was 4 months (95% CI, 3–5) in general and 6 months (95% CI, 4–8) in patients with clinical benefit. Median survival for the entire group was 8 months (95% CI, 5–11) and 19 months when clinical benefit was obtained (95% CI, 11–25). Patients received a median of 8.5 CT administrations (range, 2–45). Forty-three percent of doses were delayed. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Cisplatin and gemcitabine doses were reduced in 75% and 62% of all cycles, respectively. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Toxicities grade >3 were neutropenia 35% and thrombocytopenia 15%. All other toxicities were grade 2 or less, including sensorial neuropathy (30%), asthenia (34%), nausea/vomiting (20%) and oral mucositis (15%). There were no treatment-related deaths. Reasons for discontinuation were progression (18 patients), death (3 patients) and patient decision (1 patient). Conclusion Weekly cisplatin-gemcitabine with flexible downwards individual tailoring is a safe and effective salvage treatment in heavily pretreated MBC patients with good PS.     

Weekly gemcitabine and cisplatin combination therapy in patients with transitional cell carcinoma of the urothelium: A phase II clinical trial

Purpose: To determine the efficacy of gemcitabine and cisplatin combination therapy in patients with advanced and/or metastatic transitional cell urothelial carcinoma.Patients and methods: Forty-two chemonaïve patients with Karnofsky performance status (KPS) 70 were treated with cisplatin 35 mg/m² followed by gemcitabine 1000 mg/m² (30 min i.v. infusion) on days 1, 8, and 15 every twenty-eight days.Results: Thirty-eight patients were evaluable for efficacy. Half had visceral disease. There were seven complete (18%) and nine partial responses (24%), for a response rate of 42% (95% confidence interval (95% CI): 26%–59%). Responses were independently reviewed. Median response duration was 13.5 months (95% CI: 8.5–18.1 months), median time to progressive disease 7.2 months (95% CI: 4.0–9.1 months) and median survival 12.5 months (95% CI: 8.1–18.7 months); one-year survival was 52%. Laboratory toxicities included leucopenia (44% grade 3; 17% grade 4), neutropenia (25% grade 3; 33% grade 4) and thrombocytopenia (29% grade 3; 49% grade 4). Four patients had grade 4 symptomatic toxicity (three nausea and vomiting, one diarrhoea). There were no grade 4 infections and no toxic deaths.Conclusions: The combination of gemcitabine and cisplatin is active in patients with locally advanced and/or metastatic urothelial carcinoma. The weekly schedule of cisplatin is considered inappropriate.     

The role of palliative chemotherapy for advanced pulmonary pleomorphic carcinoma

Pulmonary pleomorphic carcinoma is an uncommon malignant tumor of the lung, which has the dual cell components of spindle or giant cells and epithelial cells. The objective of this study was to investigate the clinical course and efficacy of palliative chemotherapy in patients with advanced pulmonary pleomorphic carcinoma. Twelve patients were diagnosed with advanced pulmonary pleomorphic carcinoma and received palliative chemotherapy from February 2000 to December 2007. Among the 12 patients, five patients received gemcitabine/cisplatin, three patients received gemcitabine/carboplatin, two patients received paclitaxel/carboplatin, one patient received paclitaxel/cisplatin, and one patient received docetaxel/cisplatin as first-line chemotherapy. The median patient's age was 62 (range, 32–72 years). Among the 12 patients, nine patients had relapsed disease after curative resection and three patients had metastatic disease at the initial presentation. After treatment with first-line palliative chemotherapy, seven patients (58%) had progressive disease, three patients (25%) had stable disease, and only two patients (17%) had a partial response. The median overall survival from the day of initiation of first-line chemotherapy was only 8 months (95% CI, 6–10) with median follow-up of 26 months. These results showed the dismal prognosis and the poor response to chemotherapy of advanced pulmonary pleomorphic carcinoma. Further studies are needed to investigate whether the current strategy of palliative chemotherapy for the treatment of advanced pulmonary pleomorphic carcinoma can be justified or not. Moreover, additional novel treatment approaches are required.     

Simplified FOLFIRI in pre-treated patients with metastatic gastric cancer

Purpose  Second-line chemotherapy in patients with metastatic gastric cancer (MGC) pre-treated with cisplatin is not a standard option. We studied a combination of irinotecan, fluorouracil and folates. Methods  Patients progressive to cisplatin-based chemotherapy were enrolled. Irinotecan 180 mg/m², folinic acid 200 mg/m², and fluorouracil 400 mg/m² were given on day 1, immediately followed by fluorouracil 2,400 mg/m² 46 h continuous infusion (simplified FOLFIRI), every 2 weeks. Results  Between June 2002 and May 2003, 28 patients were treated. Median age was 57 years (range 38–68). Most patients had a distal primary (90%), and metastatic disease (71%). Partial response was obtained in six patients (21%, 95% CI 8–41) and stable disease in eight (21%, 95% CI 13–41). Among the six responsive patients three were refractory to docetaxel. At a median follow-up of 2.9 years median time to progression was 4 months (95% CI: 2–5), and median overall survival was 5 months (95% CI 4–9). Toxicity was mild, without treatment-related deaths or life-treating adverse events. Conclusions  Simplified FOLFIRI was moderately active and well tolerated in unselected patients with MGC pre-treated with cisplatin-based chemotherapy. Its role in patients refractory to taxanes is promising and warrants further investigation.     

Fixed-dose rate infusion of gemcitabine and weekly cisplatin in elderly or poor performance status patients with unresectable non-small cell lung cancer

Purpose  We investigated the efficacy and toxicity of a 4-week schedule of a fixed dose rate infusion of gemcitabine and weekly cisplatin in elderly or poor performance status patients with unresectable non-small cell lung cancer (NSCLC). Methods  In this study, 48 patients with previously untreated NSCLC were given combination chemotherapy that consisted of gemcitabine 1,000 mg/m² (10 mg/m²/min fixed dose rate infusion) and cisplatin 25 mg/m², and both drugs were given weekly on days 1, 8 and 15. Results  A partial response and stable disease were observed in 20 patients (41.7%, 95% CI; 27.8–55.6%) and 12 patients (25.0%), respectively. The overall median survival was 10.30 months (range: 7.85–12.74 months). Major toxicities included neutropenia (grade 3 to 4, 29.2%) and infection (grade 3 to 4, 27.1%). Conclusions  Our results indicate that this regimen is a feasible treatment for elderly or poor performance status patients with unresectable NSCLC. Nevertheless, the morbidity due to myelosuppression and infection following this treatment should be carefully considered. G.-W. Lee and M.-H. Kang contributed equally to this work.     

Phase II study of docetaxel and cisplatin combination chemotherapy in metastatic gastric cancer

Purpose: Docetaxel, as a single agent, has demonstrated activity in patients with advanced gastric cancer and cisplatin has shown lack of overlapping toxicities with docetaxel. Therefore, we conducted a phase II study to assess the efficacy and the toxicity of a combination regimen of docetaxel plus cisplatin in patients with advanced gastric cancer who have never been treated with palliative chemotherapy. Methods: Ninety-two patients with metastatic gastric cancer were enrolled from April 2000 to March 2004. Patients with histologically confirmed gastric adenocarcinoma, at least one bi-dimensionally measurable lesion, no prior palliative chemotherapy and at least 6 months from the end of adjuvant chemotherapy were eligible for study entry. Docetaxel 75 mg/m² and cisplatin 75 mg/m² were given on day 1. The cycle was repeated every 3 weeks. The objective response was evaluated after three cycles of chemotherapy. Toxicity was assessed according to the National Cancer Institute common toxicity criteria scale version 2.0. Results: In total, 401 cycles were administered, with a median of 5 cycles per patient (range 1–9 cycles). The median age was 56 years (range 31–76). Eighty-six patients were evaluable for treatment response. The objective response rate was 43.5% (95% CI, 33.4–53.6) with one complete response and 39 partial responses. Twenty patients (21.7%) had stable disease and 26 patients (28.3%) had a progression. The median time to progression was 7.0 months (95% CI, 5.0–9.0) and the median overall survival was 11.5 months (95% CI, 9.5–13.4). The chemotherapy was generally well tolerated and the most common grade 3–4 toxicities were neutropenia (17.4%), nausea/vomiting (13.0%) and diarrhea (7.6%). Conclusion: The combination chemotherapy of docetaxel with cisplatin in advanced gastric cancer was tolerable for most patients and showed a promising antitumor activity as a first-line therapy.Keon Woo Park and Jin Seok Ahn contributed equally to this work.     

Phase II study of a gemcitabine and cisplatin combination regimen in taxane resistant metastatic breast cancer

Purpose: To determine the safety and efficacy of gemcitabine and cisplatin in patients with taxane resistant metastatic breast cancer. Patients and methods: Thirty-three taxane resistant metastatic breast cancer patients were treated with gemcitabine 1,250 mg/m² IV infusion over 30 min on days 1 and 8, and with cisplatin 75 mg/m² by IV infusion over 1 h on day 1 in 21 day cycles. Results: Of the 30 evaluable patients, there were 9 (30%) partial responses and no complete response, an overall objective response rate of 30%. Median time to progression and median survival duration for all study subjects were 7 (95% CI 5.1–8.9 months) and 15 months (95% CI 10.5–19.5 months), respectively. Toxicities included grade 3 and 4 leucopenia in 10 (30%), thrombocytopenia in 6 (18%), anemia in 2 (6%) and oral mucositis in 2 (6%). No grade 3 or 4 peripheral neuropathy, renal dysfunction, hepatic dysfunction, or nausea/vomiting was observed, and no treatment-related deaths occurred. Conclusion: The described gemcitabine plus cisplatin combination was found to be an active and tolerable salvage regimen in patients with taxane resistant metastatic breast cancer.     

Gemcitabine plus docetaxel as first-line chemotherapy in patients with advanced non-small cell lung cancer: a lung cancer Galician group phase II study

Background Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer (NSCLC) than that of both agents in monotherapy. Methods This phase II study evaluated a 3-week based schedule of docetaxel 85 mg/m² (1-h i.v. infusion, d8) combined with gemcitabine 1,000 mg/m² (30-min i.v. infusion; d1,8) as first-line chemotherapy for patients with advanced NSCLC. Results Forty-one patients with non-resectable, stage IIIB/IV, and bidimensionally measurable disease were enrolled. A total of 182 chemotherapy cycles (median 6, range 1–6) was administered to 40 patients during the study; one patient did not receive chemotherapy due to a protocol deviation. Two patients were not evaluable for treatment efficacy. The overall response rate found was 44% (95% CI, 29–59%): three patients (7%) had a complete response and 15 patients (37%) had a partial response (median duration of response = 4.0 months). With a median follow-up of 8.7 months, the median time to disease progression was 4.4 months and the median overall survival was 7.3 months. The combined gemcitabine plus docetaxel chemotherapy was well tolerated except for pulmonary toxicity. The main grade 3–4 hematological toxicity was neutropenia (28% of patients, 9% of cycles). Two cases of febrile neutropenia were reported. The main grade 3–4 non-hematological toxicity was pulmonary toxicity (23% of patients, 6% of cycles). Conclusion Gemcitabine 1,000 mg/m² on days 1 and 8 in combination with docetaxel 85 mg/m² on day 8 given in 3-week cycles is an active and well-tolerated first-line chemotherapeutic regimen for advanced NSCLC.     

A phase II study of capecitabine and cisplatin (XP) as first-line chemotherapy in patients with advanced esophageal squamous cell carcinoma

Purpose The combination of 5-fluorouracil (5-FU) and cisplatin (FP) remains the mostly used regimen for metastatic esophageal squamous carcinoma. This phase II study assessed the efficacy and safety of capecitabine/cisplatin (XP) as a first-line chemotherapy in a homogenous cohort of patients with metastatic or recurrent esophageal squamous cell carcinoma. Materials and methods Patients received 60 mg/m² of cisplatin intravenously (IV) on day 1 and capecitabine 1,250 mg/m²/dose orally twice a day on days 1–14. Treatment cycles were repeated every 3 weeks until the documented disease progression, unacceptable toxicity, or patient’s refusal. Immunohistochemical studies against thymidylate synthase (TS) and thymidine phosphorylase (TP) were performed to seek predictive markers for treatment response. Results Between December 2003 and March 2006, 45 patients entered the study. All patients had histologically proven squamous cell carcinoma of the esophagus. The overall response rate (ORR) was 57.8% (95% CI, 43.3–72.2) with 0 CR and 26 PRs. The median duration of response in responders was 4.6 months (1.0–15.6 months). With a median follow-up duration of 25.7 months (10.8–42.6 months), the median time to progression was 4.7 months (95% CI, 2.5–7.0) and the median survival time was 11.2 months (95% CI, 8.5–13.9). Common grade 3 or 4 non-hematological adverse events were anorexia (18/191, 9.4%), fatigue (9/191, 4.7%), constipation (6/191, 3.1%), hand-foot syndrome (6/191, 3.1%) and diarrhea (4/191, 2.1%). The most common grade 3 or 4 hematological adverse events were neutropenia (33/191, 17.3%), followed by leucopenia (11/191, 5.8%), anemia (2/191, 1.0%) and thrombocytopenia (1/191, 0.5%). There was no treatment-related death. Neither TS nor TP showed predictive value for treatment response. Conclusion The XP regimen demonstrated a promising antitumor activity in metastatic esophageal squamous cell carcinoma, which may potentially replace the FP regimen.     

Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized,multicenter, open-label,phase III study of gemcitabine–cisplatin plus necitumumab versus gemcitabine–cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer

BackgroundSQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression.Patients and methodsPatients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m² i.v., days 1 and 8) and cisplatin (75 mg/m² i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors.ResultsA total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine–cisplatin group than in the gemcitabine–cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade ≥3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%).ConclusionsIn line with SQUIRE ITT, addition of necitumumab to gemcitabine–cisplatin significantly prolonged OS and was generally well tolerated in the subpopulation of patients with EGFR-expressing advanced sq-NSCLC. The benefit from addition of necitumumab to chemotherapy was not apparent in this analysis for the small subgroup of patients with non-EGFR-expressing tumors.Clinical TrialNCT00981058.     

Phase II trial of a 2-h infusion of gemcitabine plus carboplatin as first-line chemotherapy for advanced non-small-cell lung cancer

Purpose: To evaluate the efficacy and safety of the combination of using gemcitabine as a rate infusion of 10 mg/m² per min with carboplatin in front-line chemonaive patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Fifty-four chemonaive patients with stage IIIB or IV NSCLC have been included, 44 males and 10 females, with a median age 63 years (range 19–75). Thirty-two (59%) patients had adenocarcinoma, 13 (24%) squamous cell, 1 (2%) large cell carcinoma and 8 (15%) others. Eight (15%) had stage IIIB and 46 (85%) stage IV. Treatment was consisted of 1,200 mg/m² gemcitabine given as a 2-h continuous infusion (10 mg/m² per min) on days 1 and 8 of each cycle an AUC 5 carboplatin as on day 1, repeating each cycle for every 21 days. A total of 223 chemotherapy cycles were administered, with a median of four cycles per patient (range 1–6), and 15 (28%) patients received all six cycles. Results: Of the 54 patients enrolled, all were evaluated for toxicity and 51 assessed for response. The overall response rate was 41% (95% confidence interval, 28–57%) with complete and partial responses of 4 and 37%, respectively. The median time to disease progression was 5.0 months (95% CI, 3.7–6.3 months), and median overall survival time was 11.5 months (95% CI, 9.9–13.1 months). One-year survival was 42%. The main grade 3–4 toxicity (according to the WHO scale) consisted of neutropenia (56%) and thrombocytopenia (57%). Patients were required platelet transfusion in 27 cycles (12%) and hematopoietic growth factors support care in 56 (25%) cycles. No bleeding episodes were recorded. Grade 3 nausea/vomiting occurred in 6% and grade 1–2 skin rash occurred in 43%. Conclusions: Prolonged gemcitabine infusion combined with carboplatin is manageable and tolerated, and its efficacy is similar to that of other chemotherapeutic schemes used for NSCLC treatment.     

S-1 and Gemcitabine as an Outpatient-based Regimen in Patients with Advanced or Metastatic Pancreatic Cancer

Objective: The standard beneficial chemotherapy proved for patients withpancreatic cancer is a regimen containing gemcitabine. Noveloral fluoropyrimidine, S-1, can be added to gemcitabine to improvethe efficacy of chemotherapy and to provide better conveniencefor patients. We aimed to evaluate the efficacy and safety ofS-1 plus gemcitabine combination chemotherapy as a first-linetreatment in patients with locally advanced or metastatic pancreaticcancer. Methods: Patients with histologically confirmed, bidimensionally measurableadvanced/metastatic pancreatic cancer were eligible for thestudy. Chemotherapy consisted of S-1 (30 mg/m² p.o. bid fromDay 1 to 14) and gemcitabine (1000 mg/m² on Days 8 and 15) every3 weeks based on the results of a previously reported PhaseI trial. Treatment was repeated until disease progression orunacceptable toxicity occurred. Results: From January 2005 to August 2007, 22 patients were enrolled.Median age was 62 years (range, 50–73). Nineteen patients(86.3%) had metastases and of these, 11 patients (57.9%) hadmultiple liver metastases. The overall response rate was 27.3%(95% CI, 8.7–45.9), with a partial response in six patients,stable disease in nine (40.9%) and progressive disease in seven(31.8%). With a median follow-up of 25.4 months, the mediantime to progression and overall survival were 4.6 (95% CI, 2–7.2months) and 8.5 months (95% CI, 6.8–10.1 months), respectively,and 1-year survival rate was 27.3%. S-1 plus gemcitabine waswell tolerated. Grade 3/4 hematological adverse events wereneutropenia (9.1/9.1%) and anemia (4.5/0%). Non-hematologicaladverse events were mainly gastrointestinal events. Twenty patients(91%) received chemotherapy on an outpatient basis. Conclusions: Combination chemotherapy of S-1 plus gemcitabine appears tobe active and well tolerated as first-line treatment in patientswith advanced/metastatic pancreatic cancer.     

Phase II trial of gemcitabine and irinotecan in previously treated patients with small-cell lung cancer

Purpose To investigate the activity of gemcitabine combined with irinotecan in patients with relapsed small cell lung cancer (SCLC). Patients and methods SCLC patients who had experienced treatment failure with one prior chemotherapy were eligible. Patients were required to have a performance status of 0–2 and adequate organ function. Treatment consisted of gemcitabine (1,000 mg/m²) and irinotecan (150 mg/m²) on days 1 and 15 of a 28 day cycle. Results Thirty-one patients were enrolled and 30 patients received protocol treatment (10 had refractory disease and 20 had sensitive disease). The median age was 64 years, and the median performance status was one. An objective response was obtained in 36.7% (95% CI: 17.3.1–56.0%) of the patients. The median overall survival time was 14.4 months, and the 1 year survival rate was 51%. The chief grade 3/4 toxicities included neutropenia (42%), thrombocytopenia (3%), diarrhea (9%), and liver dysfunction (3%). The only grade 4 toxicities were one case of grade 4 neutropenia (3.3%) and one case of grade 4 thrombocytopenia (3.3%). Conclusion Gemcitabine plus irinotecan is an active regimen that seems to be well-tolerated by patients with previously treated SCLC.     

The combination of capecitabine and irinotecan in treating 5-Fluorouracil- and Oxaliplatin-pretreated metastatic colorectal cancer

Purpose Since the combination of capecitabine and irinotecan has successfully been used as a first-line treatment in metastatic colorectal cancer (MCRC), we expected promising results when given as a second-line treatment to metastatic colorectal patients who had been pretreated with 5-Fluorouracil and Oxaliplatin. Methods Thirty-three MCRC patients participated in this study and received an oral dose of 1,000 mg/m² capecitabine twice daily on days 1–14 and a dose of 100 mg/m² irinotecan infused over 90 min on days 1 and 8, every 3 weeks. Results The overall response rate in intent-to-treat was 33.3% (95% CI, 21.5–58.3%), including one complete response (3.0%) and ten partial responses (30.3%); 12 patients (36.4%) had disease stabilization and only 9 (27.3%) progressed. The median time to progression was 6.7 months (95% CI, 4.8–8.6 months). After a median follow-up time of 12 months, nine patients (27.3%) were still alive with metastatic disease. The median response duration for all patients was 6.7 months (95% CI, 3.9–9.5 months) and the median overall survival was 13.4 months (95% CI, 11.0–15.8 months) with a 1-year survival rate of 55.4%. Myelosuppression was commonly observed; NCI-CTC (v 2.0) grade 3/4 neutropenia, however, occurred in eight (24%) patients and grade 3 anemia was seen in one patient (3%). The most common (grade 3/4) non-hematological toxicity was diarrhea (15%) and the other severe grade 3/4 toxicities included nausea/vomiting in one patient (3%), stomatitis in one patient (3%), hand-foot syndrome in one patient (3%). Conclusions The combination of capecitabine and irinotecan is an effective and well-tolerated regimen for second-line treatment of metastatic colorectal cancer. However, further phase III trials are required to clarify its use in the treatment of metastastic colorectal cancer patients who have been pretreated with 5-fluorouracil and oxaliplatin.