Phase II study of neo-adjuvant chemotherapy for locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy improves survival of locally advanced gastric cancer patients. However, benefit is limited and the best regimen remains controversial. OBJECTIVES: Our primary objective of this prospective, multicenter phase 2 study was to evaluate the pathological complete response rate (PCR) with 2 cycles of docetaxel and capecitabine. METHODS: To be eligible, patients had to have histologically documented gastric cancer, a ECOG performance status 0 or 1, T3or4 Nany M0 staging after oesophagogastroduodenoscopy (OGD), endoscopic ultrasound (EUS), CT scan of thorax and abdomen, and negative laparoscopic examination and peritoneal washing. Eligible patients received two cycles of intravenous docetaxel 60 mg/m(2) on day 1 and oral capecitabine 900 mg/m(2) two times per day from day 1 to day 14 every 3 weeks. We evaluated the response by CT scan and EUS. The patients underwent curative resection with D2 lymphadenectomy subsequently. RESULTS: 18 patients were enrolled in the study: 66% were male and the median age was 60 years. 17 patients had T3 disease at diagnosis. There was no pCR noted. 4 patients had a partial response of 22% (95% CI: 7-42%), 8 patients had stable disease and 3 patients had disease progression. The median survival was 17.1 months with 3 long-term survivors after at least 3 years of follow-up. The treatment was well tolerated with neutropenia being the most common toxicity. We observed 22% grade III and 33% grade IV neutropenia, but no neutropenic fever or death was observed from chemotherapy. CONCLUSION: Neo-adjuvant chemotherapy with docetaxel and capecitabine has limited activity against GC. More effective treatment regimens are needed urgently. TRIAL REGISTRATION NUMBER: NCT00414271.

The Singapore Liver Cancer Recurrence (SLICER) Score for relapse prediction in patients with surgically resected hepatocellular carcinoma.

BACKGROUND AND AIMS: Surgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection. METHODS: Records for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992-2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis. RESULTS: A nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log-likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities. CONCLUSION: The SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling.

Localized gastrointestinal stromal tumor of the rectum: An uncommon primary site with prominent disease and treatment-related morbidities.

Well-established clinicopathological variables used in the risk stratification of gastrointestinal stromal tumor (GIST) may not completely predict rectal GIST, an uncommon and poorly studied GIST subset. The aim of the present study was to determine the patterns of relapse and morbidities associated with recurrence in rectal GIST. A single-institution retrospective study between 2002 and 2011 was conducted, identifying 9 patients (8%) with localized rectal GIST, while comparing small intestinal (n=37) and gastric (n=63) GIST (median age, 60 years). Rectal GIST tumors were smaller compared to small intestinal/gastric GIST (P=0.044). The number of mitoses per 50 high-power field (HPF) did not differ by primary site. In general, 73% of patients were high-risk, as defined by the National Institutes of Health (NIH) consensus criteria, however, only 25% received adjuvant imatinib. Fewer rectal GIST patients achieved negative surgical margins compared to small intestinal/gastric GIST (67 vs. 92%; P=0.054). Of the 9 patients with localized rectal GIST 6 had peri-operative tumor rupture, anastomotic breakdown or required anal sphincter-compromising surgery. At the time of the first relapse, 83% of the recurrences were local failures for rectal GIST, compared to 21% for small intestinal/gastric GIST (P=0.005). The median relapse-free survival was 51 months for the entire cohort, and 54, 36 and 56 months for rectal, small intestinal and gastric GIST, respectively (P=0.468). Rectal GIST was found to be associated with high rates of local relapse and significant morbidity, despite being significantly smaller compared to GIST of other sites. A multimodality peri-operative therapeutic approach may be required to improve outcomes.

Activity of thalidomide and capecitabine in patients with advanced hepatocellular carcinoma.

BACKGROUND: Thalidomide has shown modest activity in advanced hepatocellular carcinomas (HCCs). Single-agent capecitabine has also been used in patients with HCC, with objective responses being reported. In our study, we review the use of thalidomide and capecitabine combination in advanced HCC. METHODS: From November 2003 and September 2008, 42 patients with advanced HCC who were not eligible for clinical trial or conventional chemotherapy were treated with oral capecitabine (2000 mg/m/d) for 14 days every 3 weeks and oral thalidomide at the doses of 50 to 200 mg/d. RESULTS: Almost 50% of patients had Child-Pugh B or C liver cirrhosis and a history of regional or systemic therapy. Three patients achieved complete responses lasting more than 52 weeks, including 1 patient who achieved pathological complete response and underwent curative resection. There were 3 patients with partial responses and 13 with stable disease. Median overall survival of all 42 patients was 9.9 months. The median progression-free survival was 5.1 months. The presence of ascites, portal vein thrombosis, and poorer Child-Pugh liver cirrhosis status also resulted in significantly poorer survival outcome. Treatment was well tolerated. Fatigue was the most common side effect occurring in 16 (38%) patients, but only 1 patient had grade 3 toxicity and had to stop treatment. Two other patients developed grade 3 palmar-plantar erythrodysesthesia from capecitabine. CONCLUSIONS: The combination of thalidomide and capecitabine has activity in advanced HCC and can result in complete pathological response. Treatment is well tolerated even in less-fit patients who have been pretreated and deserve further study.

Capecitabine with radiation is an effective adjuvant therapy in gastric cancers.

AIM: To analyze the outcome of patients who received concurrent capecitabine (Xeloda) and radiation (XRT) compared to the established concurrent 5-fluorouracil (5-FU) with radiation (5FU-RT) and fluoropyrimidine-based chemotherapy alone as adjuvant treatment in gastric cancers. METHODS: All patients with gastric cancers who received adjuvant treatment at the National Cancer Centre Singapore between 1996 and 2006 were reviewed. Treatment outcomes of patients who received XRT were compared with those who had 5FU-RT or chemotherapy alone as adjuvant therapy for gastric cancers. RESULTS: A total of 108 patients were reviewed. Median age at diagnosis was 60. The majority of the patients (64.8%) had advanced stage III and IV disease (with no distant metastasis). All except 4 patients had D2 gastrectomy. Twenty one patients (19.4%) had positive surgical resection margins. Thirty three patients received XRT compared with 52 who had 5FU-RT and 23 who received chemotherapy alone. For the patients in the chemotherapy-only group, all had fluoropyrimidine-based therapy, with added cisplatin in 7 patients and epirubicin in 2 patients. Median recurrence-free survival was longer for the XRT group (52 mo) compared to the 5FU-RT (35 mo) and chemotherapy-only groups (25 mo) (P = 0.48). The patients in the XRT group achieved similar median overall survival (53 mo) as the 5FU-RT (54 mo) and the chemotherapy-only groups (44 mo) (P = 0.5). CONCLUSION: Capecitabine with concurrent radiation was as effective as concurrent 5FU with radiation or fluoropyrimidine-based chemotherapy alone when used as adjuvant treatment in patients with gastric cancers.

Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients.

PURPOSE: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)-pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. EXPERIMENTAL DESIGN: DCs were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 x 10(6) cells per dose) at biweekly intervals. RESULTS: Twenty patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved late tumor regression, yielding a clinical benefit response rate of 40% (95% CI, 22-61%). Although overall median progression-free survival was 2.4 months (95% CI, 1.9-4.1 months), five patients (25%) experienced prolonged progression-free survival (>6 months), two of whom (10%) remain progression-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding patients that may correlate with vaccine activity and report a prevaccination protein signature distinguishing responders from nonresponders. CONCLUSION: This phase II vaccine study using mature, MCL-pulsed DCs has shown promising results and warrants further evaluation in a prospective randomized setting. (Clin Cancer Res 2009;15(24):7726-36).

Gastrointestinal stromal tumour in the elderly.

AIM: To analyze the outcome of elderly patients compared with the younger age group patients who were diagnosed with gastrointestinal stromal tumours (GIST) at our institution. METHODS: Patients diagnosed with GISTs were analyzed according to two age groups, those who were at least age 65 and less than age 65. RESULTS: A total of 49 patients were reviewed. Median age at diagnosis was 59. 18 patients (36.7%) were of age at least 65 or above. Of these 11 patients presented with localized disease. Five patients subsequently developed recurrence with metastatic disease. The median recurrence free survival was 18.5 months. This was not significantly different compared to the younger age group patient (P=0.598). On univariate analysis, the presence of co-morbidities was found to be significantly associated with decrease recurrence-free survival (P=0.046). 13 patients (72.2.%) of the elderly age group had metastatic disease. 8 of these patients had metastasis at diagnosis and 5 developed metastasis at recurrence. The median progression-free survival for these patients was 33 months and there was no significant difference compared to the younger age group patient (P=0.887). On univariate analysis, low albumin was associated with low progression survival (P=0.047). The median overall survival for the elderly patients was 37.6 months. There was no significant difference compared to the younger age group patient (P=0.119). Presence of co-morbidity was associated with lower overall survival in the elderly age group in the multivariate analysis (P=0.037). CONCLUSION: The elderly with GIST can achieve a similar outcome as younger patients. Presence of co-morbidity was found to affect the survival of elderly patients with GIST.

RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and highly resistant to available chemotherapies. Mammalian target of rapamycin (mTOR) functions to regulate protein translation, angiogenesis and cell cycle progression in many cancers including HCC. In the present study, subcutaneous patient-derived HCC xenografts were used to study the effects of an mTOR inhibitor, RAD001 (everolimus), on tumour growth, apoptosis and angiogenesis. We report that oral administration of RAD001 to mice bearing patient-derived HCC xenografts resulted in a dose-dependent inhibition of tumour growth. RAD001-induced growth suppression was associated with inactivation of downstream targets of mTOR, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, up-regulation of p27(Kip1) and down-regulation of p21(Cip1/Waf1), Cdk-6, Cdk-2, Cdk-4, cdc-25C, cyclin B1 and c-Myc. Our data indicate that the mTOR pathway plays an important role in angiogenesis, cell cycle progression and proliferation of liver cancer cells. Our study provides a strong rationale for clinical investigation of mTOR inhibitor RAD001 in patients with HCC.

Phase II trial of gemcitabine in combination with cisplatin in inoperable or advanced hepatocellular carcinoma.

INTRODUCTION: Advanced hepatocellular carcinoma (HCC) has a dismal prognosis and is notoriously chemo-resistant. We conducted a Phase II prospective study to evaluate the activity and tolerability of gemcitabine and cisplatin in chemo-naïve advanced hepatocellular carcinoma. The trial considered a "no further interest" response rate of 10% and a target response rate of 30%. Utilising a Simon's minimax two-stage design with a type I error of 0.05 and power of 80%, 25 subjects would be required. Fifteen patients would be needed in stage 1 and if fewer than 2 responses were observed, the trial would be stopped and lack of efficacy claimed. MATERIALS AND METHODS: Patients with advanced HCC, diagnosed based on histology or by World Health Organization (WHO) criteria, were administered gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on day 1 and day 8 of a 21-day schedule. Assessment of response based on computer tomography was performed after every 2 cycles of chemotherapy. RESULTS: The trial was stopped early due to a lack of efficacy. A total of 15 patients were accrued. Twelve patients were hepatitis B positive and the other 3 patients were negative for both hepatitis B and C. Only 1 patient had a history of prior heavy alcohol use. Two patients had Child C liver cirrhosis, 5 patients had Child B cirrhosis, and the remaining 8 patients had Child A cirrhosis. This regime was well tolerated and there was only 1 patient who experienced grade IV toxicities. Only 5 of 15 patients experienced grade III toxicities (nausea and emesis, 1 patient; anemia, 1 patient; thrombocytopenia, 1 patient; and neutropaenia, 2 patients). Only 1 patient experienced a partial response to the combination of gemcitabine and cisplatin. A further 3 patients experienced stable disease and 11 patients progressed on chemotherapy. The median time to progression was 6 weeks. The progression-free curve showed a sharp descent in the initial part of the study, suggesting that many patients had disease progression after enrollment. The median overall survival was 18 weeks. CONCLUSION: The progression-free survival and overall survival in our study were extremely short. Based on the results of our phase 2 study, we are unable to recommend further studies utilising gemcitabine and cisplatin combination in patients with advanced HCC.

Induction concurrent chemoradiotherapy using Paclitaxel and Carboplatin combination followed by surgery in locoregionally advanced non-small cell lung cancer--Asian experience.

INTRODUCTION: It has been established that combined chemoradiotherapy treatment benefits selected patients with stage III Non Small Cell Lung Cancer (NSCLC). However, locoregional recurrence still poses a problem. The addition of surgery as the third modality may provide a possible solution. We report our experience of using the triple-modality approach in this group of patients. MATERIALS AND METHODS: This is a retrospective review of 33 patients with stage III NSCLC treated between 1997 and 2005. Patients have good performance status and no significant weight loss. There were 26 males (79 %) with median age of 63 years (range, 43 to 74) and median follow-up of 49 months. Seventy-six percent had Stage IIIA disease. Chemotherapy consisted of paclitaxel at 175 mg/m2 over 3 hours followed by carboplatin at AUC of 5 over 1 hour. Thoracic radiotherapy was given concurrently with the second and third cycles of chemotherapy. All patients received 50 Gray in 25 fractions over 5 weeks. RESULTS: The main toxicities were grade 3/4 neutropenia (30%), grade 3 infection (15 %) and grade 3 oesophagitis (9%). Twenty-five patients (76%) underwent surgery. Of the 8 who did not undergo surgery, 1 was deemed medically unfit after induction chemoradiotherapy and 4 had progressive disease; 3 declined surgery. Nineteen patients (58 %) had lobectomy and 6 had pneumonectomy. The median overall survival was 29.9 months and 12 patients are still in remission. CONCLUSION: The use of the triplemodality approach is feasible, with an acceptable tolerability and resectability rate in this group of patients.

A new chemoimmunotherapy regimen (OXAFI) for advanced hepatocellular carcinoma.

BACKGROUND: Chemotherapeutic treatment options for advanced unresectable and/or metastatic hepatocellular carcinoma (HCC) are limited. Currently available treatments are associated with low response rates and little evidence of improved survival, so we evaluated a new chemoimmunotherapy regimen. METHODS: Seven patients with unresectable and/or metastatic HCC were treated with intravenous oxaliplatin (30mg/m2) and doxorubicin (20mg/m2) given on days 1, 8 and 15 in a 28-day cycle, a daily continuous infusion of fluorouracil (200mg/m2) and subcutaneous interferon alfa-2b 5 MU administered thrice weekly (OXAFI). Treatment was administered to a maximum of six cycles. Data on the response to treatment, toxicity, surgical procedures and survival outcome was reviewed. RESULTS: The best response was three partial responses, three stable disease responses and one progressive disease response. Two patients underwent interval hepatic resection, and histological analysis in one patient showed a complete pathological response. Another patient underwent a liver transplant after four cycles of treatment. These three patients were alive with no evidence of disease at 23, 21 and 18 months follow-up, respectively. At a median follow-up of 14 months (range 2-23 months), one patient died 2 months after diagnosis due to progressive disease, while all six other patients were alive. Neutropenia was the predominant toxicity, but there were no episodes of febrile neutropenia, hospital admissions or deaths. There were no cases of hepatitis B virus re-activation. CONCLUSIONS: OXAFI shows activity in HCC and has manageable toxicity. Complete pathological remission is possible with this regimen.

Phase II trial of 5-fluorouracil/leucovorin/gemcitabine/cisplatin as second-line treatment in patients with metastatic or recurrent colorectal carcinoma: a cancer therapeutics research group study.

BACKGROUND: Second-line treatment of relapsed or metastatic colorectal cancer (CRC) after failure of treatment with a fluoropyrimidine is composed of oxaliplatin in combination with a fluoropyrimidine or an irinotecan-containing regimen. Cisplatin and gemcitabine are synergistic in preclinical studies, as is 5-fluorouracil (5-FU) combined with either agent. Fixed-rate infusional gemcitabine is more effective than bolus administration in animal models. PATIENTS AND METHODS: A 2-stage phase II trial was conducted to assess the efficacy (the primary endpoint was response rate) and safety of a regimen consisting of 5-FU 400 mg/m(2) as an intravenous bolus at the middle of a 60-minute infusion of leucovorin 100 mg/m(2), followed by gemcitabine 800 mg/m(2) over 80 minutes, and cisplatin 20 mg/m(2) over 15 minutes. Treatment was repeated weekly for 3 weeks followed by a 1-week rest. Patients with advanced CRC were eligible if they had experienced treatment failure with fluoropyrimidine-based therapy. RESULTS: Nineteen patients were enrolled. The median age was 60 years; 15 patients were men and 4 were women. Twelve patients had colon cancer and 7 had rectal cancer. Sites of metastasis were as follows: liver (n = 10), lung (n = 8), skin (n = 1), and non-regional lymph nodes (n = 1). All patients had an Eastern Cooperative Oncology Group performance status of 0/1. A total of 44 cycles of chemotherapy were delivered (median, 2 cycles; range, 1-5 cycles). One patient exhibited a partial response (5%), 8 had stable disease (42%), and 5 experienced disease progression (26%); another 5 patients were nonevaluable (26%). The median time to progression was 8 weeks and median survival was 36 weeks. Grade 3/4 toxicities were as follows: diarrhea (n = 1), dyspnea (n = 1), pneumonia (n = 1), neutropenia (n = 2), and thrombocytopenia (n = 1). CONCLUSION: Despite acceptable toxicity and a reasonable overall survival, the combination of 5-FU/leucovorin/gemcitabine/cisplatin does not seem to improve current standard therapy in the second-line treatment of patients with CRC in whom a first-line fluoropyrimidine-containing regimen has failed.

A randomized phase II trial of single-agent gemcitabine, vinorelbine, or docetaxel in patients with advanced non-small cell lung cancer who have poor performance status and/or are elderly.

BACKGROUND: Patients with poor performance status and/or are elderly are frequently considered a compromised group at high risk of chemotherapy-related morbidities and less likely to benefit from treatment. We aimed to evaluate tolerability and efficacy of three single-agent regimens in these patients. PATIENTS AND METHODS: Patients with advanced non-small cell lung cancer who had performance status 2/3 and/or were aged 70 and older were randomly assigned to receive gemcitabine, vinorelbine, or docetaxel. Objective response, toxicities, and quality of life were evaluated. RESULTS: One hundred thirty-five patients were registered, of whom one was ineligible. Of the 134 patients, 43 received gemcitabine, 45 vinorelbine, and 46 docetaxel. The response rate was 16%, 20%, 22% for gemcitabine, vinorelbine, and docetaxel, respectively. The main grade 3/4 toxicities were fatigue (18%) and neutropenia (16%). There was improvement in global health scores, cough, and dyspnea for all treatment groups. The improvement in dyspnea was most marked in patients with performance status 3. CONCLUSION: There was no significant advantage of any of the treatment arms over the rest. There was benefit seen with improvement of quality of life in patients who were able to receive more cycles of chemotherapy.

Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination.

PURPOSE: The marked variability of irinotecan (Ir) clearance warrants individualized dosing based on hepatic drug handling. The aims of this trial were to identify parameters from functional hepatic nuclear imaging (HNI) that correlate with (1) Ir pharmacology, and (2) single-nucleotide polymorphisms (SNPs) for the ABCB1 (P-glycoprotein) and UGT-1A1 genes, known to influence Ir handling. METHODS: Patients underwent genotyping for ABCB1 SNPs and UTUGT-1A1*28 carriage and HNI with 99mTc-DIDA (acetanilidoiminodiacetic acid)/99mTc-DISIDA (disofenin) and MIBI (99mTc-sestamibi) scans, probes for biliary transport proteins ABCC1 and -2, and ABCB1 function. HNI data were analyzed by noncompartmental and deconvolutional analysis to provide hepatic extraction and biliary excretion parameters. Patients received Ir, fluorouracil, and folinic acid using a weekly x2, every-3-weeks schedule. Plasma was taken for Ir and SN-38 analysis on day 1, cycle 1. RESULTS: Of the 21 patients accrued, Ir pharmacokinetics data were obtained from 16 patients. 99mTc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both 99mTc-DIDA/DISIDA and MIBI 1-hour RET correlated with SN-38 area under the curve (AUC; P < .01). On multiple regression analysis, SN-38 AUC = -215 + 18.68 x bilirubin + 4.27 x MIBI 1-hour RET (P = .009, R2 = 44.2%). HNI parameters did not correlate with Ir toxicity or UGT1A1*28 carriage. MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to wild-type (P = .015). CONCLUSION: Functional imaging of hepatic uptake and excretory pathways may have potential to predict Ir pharmacokinetics. Evaluation of a larger cohort as well as polymorphisms in other biliary transporters and UGT1A1 alleles is warranted.

Paclitaxel, carboplatin, and gemcitabine in metastatic nasopharyngeal carcinoma: a Phase II trial using a triplet combination.

BACKGROUND: Patients with nasopharyngeal carcinoma (NPC) are treated primarily with radiotherapy. In the disseminated state, platinum-based, 2-drug combination regimens yielded response rates of 55-75%, achieving a median survival of 10-12 months. With the proven efficacy of second-generation cytotoxics like paclitaxel and gemcitabine in patients with metastatic NPC, the authors hypothesized that a triplet combination incorporating these newer cytotoxics may improve treatment results. METHODS: Thirty-two patients with metastatic NPC were treated with combination chemotherapy that included paclitaxel 70 mg/m(2) on Days 1 and 8, carboplatin dosed to area under curve of 5 on Day 1, and gemcitabine 1000 mg/m(2) on Days 1 and 8 every 21 days for a maximum of 8 cycles. RESULTS: Two patients achieved a complete response, and 23 patients achieved a partial response, for an overall response rate of 78%. The main toxicities were hematologic, with 41% of patients experiencing Grade 3 or 4 anemia, 41% of patients experiencing Grade 3 or 4 thrombocytopenia, and 78% of patients experiencing Grade 3 or 4 neutropenia. The median time to disease progression was 8.1 months, and the median overall survival was 18.6 months. CONCLUSIONS: The combination of paclitaxel, carboplatin, and gemcitabine showed promising efficacy against metastatic NPC but at the expense of considerable toxicity.

Chemo-radiotherapy for stage III unresectable non-small cell lung cancer long-term results of a prospective study.

INTRODUCTION: Combined-modality treatment is considered standard of care in the treatment of stage III non-small-cell lung cancer (NSCLC). This study was designed to assess the efficacy and tolerability of induction paclitaxel/carboplatin followed by concurrent thoracic radiotherapy and weekly paclitaxel. MATERIALS AND METHODS: Patients with unresectable stage III NSCLC were treated prospectively with two cycles of paclitaxel (175 mg/m2) and carboplatin (area under the curve of 6) followed by radiotherapy (60-66 Gy) concurrent with 6 weekly doses of paclitaxel (60 mg/m2). Response was determined 8 weeks after the completion of treatment and treatment-related toxicities were assessed at each visit during treatment and follow-up. RESULTS: Sixty-three patients were treated, 5 had complete response and 33 had partial response, giving a response rate of 60%. Thirty-seven percent of patients developed grade 3 or 4 neutropenia; 48% had significant esophagitis requiring the use of narcotic analgesics. Two patients developed esophageal stricture subsequently. The median survival was 51 months and 12 months for stage IIIA and IIIB patients, respectively. Progression-free survival was 16 months and 11 months respectively. CONCLUSIONS: The response rate was encouraging. Esophagitis was a significant morbidity and should prompt modification of treatment regimen, either in the chemotherapy schedule or by adjusting the radiotherapy treatment planning.

Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer.

PURPOSE: Greater toxicities have been recognized to be a consequence of combined chemotherapy and radiotherapy in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This study was designed to determine if the use of amifostine could reduce treatment-related toxicities associated with the use of paclitaxel plus carboplatin and thoracic radiotherapy. PATIENTS AND METHODS: Sixty patients with unresectable stage III NSCLC were treated with two cycles of paclitaxel 175 mg/m2 and carboplatin (area under the time-concentration curve = 6), followed by thoracic radiotherapy (64 Gy) with concurrent weekly paclitaxel 60 mg/m2. Patients were randomly assigned to receive 740 mg/m2 of amifostine (arm A) or placebo (arm B) before each dose of paclitaxel and carboplatin. Treatment-related toxicities were evaluated at each visit and nerve conduction tests were performed before and after treatment for the objective assessment of neurotoxicity. RESULTS: There was no significant difference between arms A and B in grade 3 to 4 neutropenia. In all 72 neurophysiological parameters measured, there was no significant difference between the two treatment arms, although there was a trend toward fewer patients showing deterioration in arm A for six of the parameters. Grade 2 to 3 esophagitis occurred in 43% of patients in arm A and in 70% of patients in arm B. The difference of -27% (95% confidence limit = -50%, 0.4%) was not statistically significant. Response rates and survival were also not significantly different between the two arms. CONCLUSION: Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.