Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial.

OBJECTIVES: The non-small cell lung cancer (NSCLC) meta-analysis suggested a survival benefit for cisplatin-based chemotherapy when given in addition to surgery, radical radiotherapy or 'best supportive care'. However, it included many small trials and trials with differing eligibility criteria and chemotherapy regimens. The aim of the Big Lung Trial was therefore to run a large pragmatic trial to confirm the survival benefits seen in the meta-analysis. METHODS: In the surgery setting, a total of 381 patients were randomised to chemotherapy (C, 192 patients) or no chemotherapy (NoC, 189 patients). C was three 3-weekly cycles of cisplatin/vindesine, mitomycin/ifosfamide/cisplatin, mitomycin/vinblastine/cisplatin or vinorelbine/cisplatin. RESULTS: Chemotherapy was given before surgery in 3% of patients whilst 97% received adjuvant chemotherapy. Baseline characteristics were: median age 61 years, 69% male, 48% squamous cell, 93% WHO PS 0-1, 27% stage I, 38% stage II, and 34% stage III. Complete resection was achieved in approximately 95% of patients. In the C group, 13% received no chemotherapy, 21% one or two cycles, and 64% all three cycles of their prescribed chemotherapy (60% of the latter with no delays or modification). 30% had grade 3/4 toxicity, mainly haematological, nausea/vomiting and neutropenic fever, and six patients were reported as having a treatment-related death. 198 (52%) of patients have died, but there is currently no evidence of a benefit in overall survival to the C group: HR 1.02 (95% CI 0.77-1.35), P = 0.90). CONCLUSIONS: This trial has failed to observe a survival benefit with adjuvant chemotherapy following complete resection of stage I-III NSCLC. However, the hazard ratio and 95% confidence intervals are consistent with the previously reported meta-analysis and two large recently reported trials, which suggest a small survival benefit with cisplatin-based chemotherapy.     

Estimation of the additional costs of chemotherapy for patients with advanced non-small cell lung cancer

BACKGROUND: A large multicentre randomised trial, the Big Lung Trial, which in part compared supportive care with or without cisplatin-based chemotherapy in patients with advanced non-small cell lung cancer, provided an opportunity to evaluate the impact on the UK National Health Service of the costs incurred with the use of chemotherapy. METHODS: This costing study was based on the retrospective collection of resource use data from hospital records. Case notes from 194 patients (98 chemotherapy + supportive care (C), 96 supportive care alone (NoC)) were inspected in eight centres recruiting the largest numbers of patients into the Big Lung Trial. Quantities were multiplied by fixed unit costs to calculate a total cost for each patient. The main outcome measure was the total cost incurred by the use of secondary care resources (including investigations, chemotherapy, radiotherapy, surgical procedures, inpatient days, outpatient attendances, and hospice inpatient care) in the two groups. RESULTS: Patients randomised to receive cisplatin-based chemotherapy had an average of 3.4 more inpatient bed days than the mean of 11.9 days for patients randomised to supportive care alone, and more outpatient attendances. NoC patients were more likely to have received palliative radiotherapy. The mean total cost for C patients was 5355 sterling pound compared with 3595 sterling pound for the NoC group, difference 760 sterling pound (95% CI 781 sterling pound to 2742 sterling pound ). When split, the cost in the C group associated with the administration of chemotherapy was 1233 sterling pound and non-chemotherapy costs were 4122 sterling pound . CONCLUSION: The additional cost of chemotherapy was not offset by a reduction in subsequent costs (as the non-chemotherapy costs were similar), so the survival benefit of about 10 weeks observed in the C group was achieved with the cost of chemotherapy administration.     

Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration

Objectives:To evaluate the effect of adjuvant chemotherapy in invasive bladder cancer.Methods:We conducted a systematic review and meta-analysis of updated individual patient data from all available randomised controlled trials comparing local treatment plus adjuvant chemotherapy versus the same local treatment alone.Results:Analyses were based on 491 patients from six trials, representing 90% of all patients randomised in cisplatin-based combination chemotherapy trials and 66% of patients from all eligible trials. The power of this meta-analysis is clearly limited. The overall hazard ratio for survival of 0.75 (95% CI 0.60–0.96, p = 0.019) suggests a 25% relative reduction in the risk of death for chemotherapy compared to that on control. Cox regression suggests that small imbalances in patient characteristics do not bias the results in favour of chemotherapy. However, the impact of trials that stopped early, of patients not receiving allocated treatments or not receiving salvage chemotherapy is less clear.Conclusions:This IPD meta-analysis provides the best evidence currently available on the role of adjuvant chemotherapy for invasive bladder cancer. However, at present there is insufficient evidence on which to reliably base treatment decisions. These results highlight the urgent need for further research into the use of adjuvant chemotherapy. The results of appropriately sized randomised trials, such as the ongoing EORTC-30994 trial are needed before any definitive conclusions can be drawn.     

TREATMENT PRINCIPLES IN ADVANCED NON-SMALL-CELL LUNG CANCER

Non-small-cell lung cancer (NSCLC) accounts for more than three-quarters of all lung tumours and is the leading cause of deaths due to cancer in Australia. More than half of the patients with NSCLC present with advanced disease. Radiation therapy has been the mainstay of active treatment for these patients. There is increasing evidence supporting the benefit of chemotherapy as an addition to radiation therapy in locally advanced non-metastatic disease. The use of cisplatin-based chemotherapy prior to radiation therapy would appear to be a new standard of care in patients with stage III B NSCLC. In advanced (metatastic) disease, palliation of symptoms remains the major goal of current treatment programmes. This can be achieved with the best supportive care, radiotherapy, and, in selected patients, platinum-based chemotherapy. Clinical trials to test new treatments, with survival, quality of life and cost-benefit as endpoints, are essential. The present study discusses the current status of conventional and newer treatment methods in locally advanced and metastatic disease.     

Adjuvant chemotherapy for surgically resected non-small cell lung cancer

Despite surgical resection, patients with early-stage (I to IIIA) non-small cell lung cancer (NSCLC) are at considerable risk of recurrence and death from their lung cancer. In recent years, multiple, large, randomized trials assessing the efficacy of adjuvant chemotherapy for resected NSCLC have been reported. Three of 6 trials with 300 or more patients with early-stage NSCLC have demonstrated that adjuvant cisplatin-based chemotherapy can significantly improve 5-year survival in carefully selected patients with resected NSCLC. These benefits have been confirmed in a meta-analysis of modern cisplatin-based adjuvant trials. The most consistent benefit has been reported in patients with resected stage II and IIIA NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. Herein, we review the results of the major adjuvant chemotherapy trials and their implications for the treatment of patients with completely resected NSCLC. A future challenge will be to identify the subsets of patients who will derive the greatest benefit from adjuvant chemotherapy. Current trials are also underway to define the role of novel targeted therapies, such as inhibitors of the epidermal growth factor receptor and monoclonal antibodies, in adjuvant treatment strategies.     

Surgery for non-small cell lung cancer: systematic review and meta-analysis of randomised controlled trials

BACKGROUND: Surgery is considered the treatment of choice for patients with resectable stage I and II (and some patients with stage IIIA) non-small cell lung cancer (NSCLC), but there have been no previously published systematic reviews. METHODS: A systematic review and meta-analysis of randomised controlled trials was conducted to determine whether surgical resection improves disease specific mortality in patients with stages I-IIIA NSCLC compared with non-surgical treatment, and to compare the efficacy of different surgical approaches. RESULTS: Eleven trials were included. No studies had untreated control groups. In a pooled analysis of three trials, 4 year survival was superior in patients undergoing resection with stage I-IIIA NSCLC who had complete mediastinal lymph node dissection compared with lymph node sampling (hazard ratio estimated at 0.78 (95% CI 0.65 to 0.93)). Another trial reported an increased rate of local recurrence in patients with stage I NSCLC treated with limited resection compared with lobectomy. One small study reported a survival advantage among patients with stage IIIA NSCLC treated with chemotherapy followed by surgery compared with chemotherapy followed by radiotherapy. No other trials reported significant improvements in survival after surgery compared with non-surgical treatment. CONCLUSION: It is difficult to draw conclusions about the efficacy of surgery for locoregional NSCLC because of the small number of participants studied and methodological weaknesses of the trials. However, current evidence suggests that complete mediastinal lymph node dissection is associated with improved survival compared with node sampling in patients with stage I-IIIA NSCLC undergoing resection.     

The present status of postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancers, with patients having a poor prognosis. Approximately one third of NSCLC patients present with early-stage disease in which potentially curative resection and multi-modality therapy. Although adjuvant chemotherapy is the standard practice for patients with stages I-III breast and colorectal cancer, the therapeutic efficacy of adjuvant chemotherapy, following complete surgical resection of early stage NSCLC, has not been fully established. Several prospective randomized trials for patients with early stage NSCLC (stages I-IIIA) have confirmed a survival benefit with cisplatin-based adjuvant chemotherapy, as demonstrated in the 1995 meta-analysis performed by the NSCLC Collaborative Group. Studies from Japan have reported that adjuvant therapy with uracil-tegaful (UFT) afforded an improvement of 4% in the 5-year survival rate and a relative risk reduction of 26% in mortality at 5 years among patients with T1-2N0 (stage I) disease. In particular, the Japan Lung Cancer Research Group has demonstrated an improvement in the 5-year survival rate of 11%, favoring chemotherapy with UFT in the subset of patients with T2N0 (stage IB) disease. Two published meta-analyses based on abstracts have estimated a relative risk reduction in mortality of 11-13% at 5 years. The Lung Adjuvant Cisplatin Evaluation (LACE), which was based on a pooled analysis of five randomized trials, has demonstrated that cisplatin-based adjuvant chemotherapy improved survival in patients with completely resected NSCLC. This benefit depended on stage, being greatest in patients with stage II or IIIA disease. This analysis has suggested that platinum-based adjuvant chemotherapy may have no benefit for patients with stage IA and only a marginal benefit for patients with stage IB. Thus, the information available at the current time supports the administration of adjuvant chemotherapy for patients who have undergone complete resection of stages IB-IIIA NSCLC. Further research is needed to define the role of adjuvant platinum-based chemotherapy and its use, in conjunction with chest radiotherapy as the treatment for patients with resected stages IB and IIIA NSCLC.     

Double-blind randomised trial comparing 5-fluorouracil plus leucovorin to placebo for metastatic colorectal carcinoma

OBJECTIVE: Previous randomised trials of chemotherapy for metastatic colorectal cancer have not concealed the allocation of treatment from participants. Most of these unblinded trials showed improved survival with chemotherapy. This trial used a double-blind design to test the hypothesis that there is no difference between the effect of 5-fluorouracil plus leucovorin and the effect of placebo on the survival of subjects with metastatic colorectal cancer. PATIENTS AND METHODS: In one hospital, 147 subjects with metastatic colorectal cancer were studied from 1989 to 2001. 73 were allocated chemotherapy with 5-fluorouracil plus leucovorin. 74 were allocated placebo. The primary end point was survival after randomization. Secondary end points were performance score, quality of life, serum level of carcinoembryonic antigen (CEA) and toxicity of treatment. RESULTS: One hundred and forty-two patients were followed up until death. The median survival time in the chemotherapy group was 8.7 months (95% confidence interval (CI) 6.9-11.0 months) compared to 6.7 months in the placebo group (95% CI 5.3-7.9 months). Chemotherapy did not affect performance status but slowed the rise of CEA and caused appreciable toxicity. CONCLUSIONS: In this double-blind trial, chemotherapy with 5-fluorouracil plus leucovorin did not improve survival, did not impair performance, but caused appreciable toxicity.     

Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review

BACKGROUND: Lung cancer remains a devastating disease with few effective treatment options. Recent developments in chemotherapy have led to cautious optimism. This paper reviews the evidence on the clinical and cost effectiveness of four of the new generation drugs for patients with lung cancer. METHODS: A systematic review of randomised controlled trials (RCTs) identified from 11 electronic databases (including Medline, Cochrane library and Embase), reference lists and contact with experts and industry was performed to assess clinical effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine. Clinical effectiveness was assessed using the outcomes of patient survival, quality of life, and adverse effects. Cost effectiveness was assessed by development of a costing model and presented as incremental cost per life year saved (LYS) compared with best supportive care (BSC). RESULTS: Of the 33 RCTs included, five were judged to be of good quality, 10 of adequate quality, and 18 of poor quality. Gemcitabine, paclitaxel, and vinorelbine as first line treatment and docetaxel as second line treatment appear to be more beneficial for non-small cell lung cancer than BSC and older chemotherapy agents, increasing patient survival by 2-4 months against BSC and some comparator regimes. These gains in survival do not appear to be at the expense of quality of life. Survival gains were delivered at reasonable levels of incremental cost effectiveness for vinorelbine, vinorelbine with cisplatin, gemcitabine, gemcitabine with cisplatin, and paclitaxel with cisplatin regimens compared with BSC. CONCLUSION: Although the clinical benefits of the new drugs appear relatively small, their benefit to patients with lung cancer appears to be worthwhile and cost effective.     

Results of induction chemotherapy followed by surgical resection in patients with stage IIIA (N2) non-small cell lung cancer: the importance of the nodal down-staging after chemotherapy

Objective: Chemotherapy of stage IIIA non-small cell lung cancer (NSCLC) using second generation, cisplatin-based combinations has shown to improve the results; however, the distant relapses remain the major problem. Encouraging results in the treatment of stage IV NSCLC with newer agents (gemcitabine, placlitaxel) has encouraged us to use them in stage III. The aim of this study was to assess feasibility and efficacy of induction chemotherapy with cisplatin and gemcitabine followed by surgery for patients with stage IIIA (N2) NSCLC. Methods: From February 1996 to December 1999, 36 consecutive patients with mediastinoscopically staged N2 NSCLC received three cycles of cisplatin (80 mg/m², day 2) and gemcitabine (1200 mg/m², day 1+8) followed by surgery in responding patients. Patients with stable disease or even local progression received radiotherapy. All patients had clinical N2 disease (mediastinal lymph nodes metastasis) observed on CT scan. Results: No major complications of the chemotherapy occurred. Twenty-five patients (70%) had a clinical partial response and were surgically explored, with 18 complete resections (70%). There were no in-hospital deaths, although four (16%) major complications: bronchopleural fistula (two), respiratory insufficiency (one), oesophagospleural fistula (one). In the total group of 36 patients, 3-year survival was 20%. So far, no patient without surgery has survived longer then 27 months; median survival was 8 months. In the group of the 25 patients who underwent surgery 3-year survival was 30%, with a median survival of 21 months. The difference is significant (P=0.0027). In the surgical group, the survival of patients with down staged disease (56%) was greater than that of patients with persistent N2 disease (44%) after chemotherapy (3-year survival of 59 and 0%, respectively; P=0.0013). Conclusion: induction chemotherapy with cisplatin and gemcitabine resulted in major tumour regression in a large percentage of patients with clinical N2 disease. In responding patients both the complete respectability rate and survival were higher when compared to historical controls. Survival was significantly better in patients down-staged to a mediastinal negative disease.     

Adjuvant Chemotherapy for Invasive Bladder Cancer: A 2013 Updated Systematic Review and Meta-Analysis of Randomized Trials

Context

The role of adjuvant chemotherapy remains poorly defined for the management of muscle-invasive bladder cancer (MIBC). The last meta-analysis evaluating adjuvant chemotherapy, conducted in 2005, had limited power to fully support its use.

Objective

To update the current evidence of the benefit of postoperative adjuvant cisplatin-based chemotherapy compared with control (ie, surgery alone) in patients with MIBC.

Evidence acquisition

A comprehensive literature review was performed to identify all randomized controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy with control for patients with MIBC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to May 2013. An updated systematic review and meta-analysis was performed.

Evidence synthesis

A total of 945 patients included in nine RCTs (five previously analyzed, one updated, and three new) were examined. For overall survival, the pooled hazard ratio (HR) across all nine trials was 0.77 (95% confidence interval [CI], 0.59–0.99; p = 0.049). For disease-free survival, the pooled HR across seven trials reporting this outcome was 0.66 (95% CI, 0.45–0.91; p = 0.014). This disease-free survival benefit was more apparent among those with positive nodal involvement (p = 0.010).

Conclusions

This updated and improved meta-analysis of randomized trials provides further evidence of an overall survival and disease-free survival benefit in patients with MIBC receiving adjuvant cisplatin-based chemotherapy after radical cystectomy.     

Postoperative adjuvant therapy for stage IB non-small-cell lung cancer.

OBJECTIVE: Although surgical resection alone is considered adequate treatment in stage IB non-small-cell lung cancer (NSCLC), long-term survival is not satisfactory and the recurrence rate is quite high. The validity of postoperative chemotherapy at stage IB in terms of disease-free and overall survival was assessed in a randomised trial. METHODS: The trial was designed as a randomised, two-group study with postoperative adjuvant chemotherapy versus surgery alone as control group. All patients had stage IB disease (pT2N0) assessed after a radical surgical procedure. Chemotherapy consisted of treatment with cisplatin (100 mg/m(2) on day 1) and etoposide (120 mg/m(2) on days 1--3) for a total of six cycles. RESULTS: Between January 1988 and December 1994, 66 patients were included in the study. Thirty-three belonged to the adjuvant chemotherapy group and 33 to the control group. Groups were homogeneous for conventional risk factors. There was no clinical significant morbidity associated to chemotherapy. Patients were followed for a minimum period of 5 years. The rates of locoregional recurrence and distant metastases were 18 and 30%, respectively, in the adjuvant chemotherapy group and 24 and 43%, respectively, in the control group. The 5-year disease-free survival rates were 59% in the adjuvant group and 30% in the control group (P = 0.02). The difference in the Kaplan--Meier survival between the groups was significant as assessed using the log-rank test (P = 0.04). CONCLUSIONS: Our results suggest that adjuvant chemotherapy may reduce recurrences and prolong overall survival in patients at stage IB NSCLC deemed radically operated. Despite being difficult to accept, the use of adjuvant chemotherapy might have better long-term results.     

Chemotherapy for muscle-invasive bladder cancer in the perioperative setting: current standards

Radical cystectomy remains the gold standard treatment for muscle-invasive bladder cancer. Although surgery achieves excellent local control, within 5 years, almost 50% of patients have a relapse and, subsequently, progression to systemic disease developing. Randomized trials of cisplatin-based chemotherapy regimens in the neoadjuvant setting have shown the potential to improve survival. Suboptimal trial design, insufficient numbers of patients, and lack of standardization of the chemotherapy regimens used have plagued adjuvant studies. Given the lethality of recurrent transitional cell carcinoma of the bladder, perioperative cisplatin-based chemotherapy should be considered a standard of care.     

Method of Presenting Oncology Treatment Outcomes Influences Patient Treatment Decision-Making in Metastatic Colorectal Cancer

Background The methods used to communicate relevant outcomes in oncology to patients will likely influence treatment decisions. The purpose of this study was to examine the influence of three different methods of describing the efficacy of therapy on treatment decisions regarding management of metastatic colorectal cancer. Methods Participants reviewed a clinical scenario and randomly received one of three ways of describing efficacy of chemotherapy in metastatic colorectal cancer: (1) relative risk reduction, (2) tumor response rate, and (3) median overall survival. They received the same clinical scenario but were presented four treatment options: (1) observation and supportive care, (2) chemotherapy, (3) surgery, and (4) surgery and chemotherapy and the accompanying median overall survival estimate. Results Participants included 102 preclinical medical students. In the first scenario, 85% chose chemotherapy in the relative risk reduction group, as did 88% of the tumor response rate group, but significantly fewer participants did so in the median overall survival group (35%; P < .001). In the second scenario, there was a significant difference in treatment preferences, with 4% of participants choosing observation/supportive care. None chose chemotherapy only, 19% chose surgery only, and 77% chose surgery plus chemotherapy (P < .001). Conclusions This study demonstrated that different methods of describing oncology treatment outcomes associated with therapy for metastatic colorectal cancer to the liver can have a dramatic effect on patient treatment decisions.     

Chemotherapy in gastric cancer: a review and updated meta-analysis.

The five years survival rate for patients with gastric cancer is 15-25%. With the aim of improving survival, chemotherapy has been used in different adjuvant settings. Similarly, but with the aim of improving quality of life and prolonging life, chemotherapy has been used extensively in metastatic disease. In this review we have included studies of systemic and intraperitoneal chemotherapy given before, during or after operation and for advanced disease. A meta-analysis has been made on the 21 randomised studies that used adjuvant systemic chemotherapy postoperatively. A significant survival benefit for the patients treated postoperatively compared with controls was identified (odds ratio (OR) 0.84, 95% confidence interval (CI) 0.74 to 0.96). When western and Asian studies were analysed separately we found no survival benefit for the treated patients in the western groups (OR 0.96 (95 CI 0.83 to 1.12)). Flaws in the conduct of several trials made it difficult to draw firm conclusions, including the exclusion of a small but clinically meaningful survival benefit. Preoperative or neoadjuvant chemotherapy has shown effects in some patients, but no significant benefit was found in the few randomised studies. The few studies that reported intraperitoneal therapy showed no detectable survival benefit either. In patients with advanced disease, four small randomised studies found significantly longer survival in the treated patients. The survival benefit is in the range of 3-9 months, and there were also improvements of the quality of life. Several drug combinations have been tested, however, with no confirmed superiority for a particular regimen. Conclusions: Adjuvant chemotherapy cannot be recommended as a routine because of the lack of confirmed beneficial effects. Some patients with advanced disease will have a clinically important benefit from palliative chemotherapy, so this can be recommended for patients who are otherwise in good health.     

Chemotherapy is associated with improved survival in adult patients with primary extremity synovial sarcoma

PURPOSE: To determine if ifosfamide-based chemotherapy (IF) offers a survival benefit to adult patients with primary extremity synovial sarcoma. PATIENTS AND METHODS: Prospectively collected patient data from 2 institutions was used to identify all adult patients (>or=16 years) with >or=5 cm, deep, primary, extremity, synovial sarcoma that underwent surgical treatment of cure from 1990 to 2002. A total of 101 patients were identified and the median follow-up for survivors was 58 months. Clinical, pathologic, and treatment variables were analyzed for disease-specific survival (DSS), distant recurrence-free survival (DRFS), and local recurrence-free survival (LRFS). RESULTS: Sixty-eight (67%) patients were treated with IF and 33 (33%) patients received no chemotherapy (NoC) for the primary tumor. The characteristics of the IF-treated patients [median tumor size = 7.2 cm; monophasic n = 46 (68%)] were similar to NoC patients [median tumor size = 7 cm; monophasic n = 23 (70%)]. The 4-year DSS of the IF-treated patients was 88% compared with 67% for the NoC patients (P = 0.01). Smaller size (HR = 0.3 per 5-cm decrease, P < 0.0001) and treatment with IF (HR = 0.3 compared with NoC, P = 0.007) were independently associated with an improved DSS. Treatment with IF was independently associated with an improved DRFS (HR = 0.4, P = 0.03) but not associated with an improved LRFS (P = 0.39). CONCLUSION: Ifosfamide-based chemotherapy was associated with an improved DSS in adult patients with high-risk, primary, extremity, synovial sarcoma and should be considered in the treatment of such patients.     

The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma

OBJECTIVE: To determine if chemotherapy offers a survival benefit to patients with large, high-grade, primary extremity liposarcoma. SUMMARY BACKGROUND DATA: The impact of chemotherapy on the survival of patients with primary extremity soft tissue sarcoma is controversial and its effect on individual histologic subtypes is not defined. PATIENT AND METHODS: Two prospectively collected sarcoma databases were used to identify all patients with >5 cm, high-grade, primary extremity liposarcoma that underwent surgical treatment of cure from 1975 to 2003 (n = 245). Clinical, pathologic and treatment variables were analyzed for disease-specific survival (DSS), distant recurrence-free survival (DRFS) and local recurrence-free survival (LRFS). RESULTS: Sixty-three (26%) patients were treated with ifosfamide based chemotherapy (IF), 83 (34%) with doxorubicin based chemotherapy (DOX) and 99 (40%) received no chemotherapy (NoC). To assess the impact of DOX, a contemporary cohort analysis of patients treated from 1975 to 1990 was performed. The 5 year DSS of the DOX treated patients was 64% (53%-74%) compared with 56% (51%-79%) for the NoC patients (log-rank P value = 0.28). To assess the impact of IF, a contemporary cohort analysis of patients treated from 1990 to 2003 was performed. The 5 year DSS of the IF treated patients was 92% (84%-100%) compared with 65% (51%-79%) for the NoC patients (log-rank P value = 0.0003). Independent prognostic factors for improved DSS were smaller size (HR = 0.7, P = 0.01), myxoid/round cell histologic subtype (HR = 0.3, P = 0.03) and treatment with IF (HR = 0.3, P = 0.01). The five-year DRFS of the IF treated patients was 81% (70%-92%) compared with 63% (50%-76%) for the NoC patients (log-rank P value = 0.02). The 5 year LRFS of the IF treated patients was 86% (76%-96%) compared with 87% (77%-97%) for the NoC patients (log-rank P value = 0.99). CONCLUSIONS: In patients with large, high-grade, primary extremity liposarcoma; DOX is not associated with improved DSS and IF is associated with an improved DSS. Treatment with IF should be considered in patients with high-risk primary extremity liposarcoma.     

Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable): a systematic review

OBJECTIVES: To determine the effectiveness of radical radiotherapy in medically inoperable stage I/II non-small cell lung cancer (NSCLC) and the extent of treatment related morbidity. METHODS: Randomised trials were sought by electronically searching the Cochrane Clinical Trials Register, and both randomised and non-randomised trials were sought by searching Medline and Excerpta Medica (Embase). Further studies were identified from references cited in those papers already identified by electronic searching. The studies included were those of patients of any age with stage I/II NSCLC receiving radiotherapy at a dose of >40 Gy in 20 fractions over 4 weeks or its radiobiological equivalent. RESULTS: Two randomised and 35 non-randomised studies were identified. One randomised and nine non-randomised studies did not meet the selection criteria, leaving one randomised and 26 non-randomised studies for analysis. In the randomised trial 2 year survival was higher following continuous hyperfractionated accelerated radiotherapy (CHART; 37%) than following 60 Gy in 30 fractions over 6 weeks (24%). An estimated 2003 patients were included in the 26 non-randomised studies; overall survival was 22-72% at 2 years, 17-55% at 3 years, and 0-42% at 5 years. Following treatment, 11-43% of patients died from causes other than cancer. Cancer specific survival was 54-93% at 2 years, 22-56% at 3 years, and 13-39% at 5 years. Complete response rates were 33-61% and local failure rates were 6-70%. Distant metastases developed in approximately 25% of patients. Better response rates and survival were seen in those with smaller tumours and in those receiving higher doses although the reasons for prescribing higher doses were not clearly stated. The outcome was worse in those with prior weight loss or poor performance status. Assessment of treatment related morbidity and effects on quality of life and symptom control were inconclusive because of the lack of prospective evaluation and paucity of data. CONCLUSIONS: No randomised trials compared a policy of immediate radical radiotherapy with palliative radiotherapy given when patients develop symptoms. In the absence of such trials, radical radiotherapy appears to result in a better survival than might be expected had treatment not been given. A substantial, though variable, proportion of patients died during follow up from causes other than cancer. The optimal radiation dose and treatment technique (particularly with respect to mediastinal irradiation) remain uncertain.     

Chemotherapy in the treatment of cancer of the pancreas

Opinions about the value of chemotherapy in pancreatic cancer vary from the idea that its use should be abandoned because of lack of proven efficacy and considerable toxicity to the idea that it may produce clinically meaningful responses correlated with improved survival. A systematic review of the available literature-based evidence was undertaken. The results are discussed in relation to supportive evidence from recent studies focusing on patient benefit. Six randomized trials of chemotherapy in advanced disease and two in the adjuvant setting with a no-active treatment group were identified. All eight trials were small, and the methodology was not always what is currently desirable. One of four palliative trials reported during the early 1980s, and both trials completed during the 1990s showed a slight survival benefit with chemotherapy. In one of the trials, quality of life (QoL) was also more often improved after 5-fluorouracil-based chemotherapy than after best supportive care. Supportive evidence for a slight prolongation of survival and a clinical benefit also comes from trials comparing different drugs. No standard regimen is defined, although one drug, gemcitabine, has been approved in some countries for the treatment of advanced pancreatic cancer. The two randomized adjuvant trials included a very small number of patients, and, although a survival benefit was seen, conclusive evidence supporting the use of adjuvant chemo (radio) therapy is still lacking. Chemotherapy has low activity in advanced pancreatic cancer, but it can improve survival and well-being in some patients. Received for publication on June 22, 1998; accepted on July 30, 1998     

Liver Resection Improves the Survival of Patients with Multiple Hepatocellular Carcinomas

Background  According to current guidelines of hepatocellular carcinoma (HCC) treatment, multiple HCCs are usually not suitable for surgical resection. However, surgical resection is still possible for patients with multiple HCCs. The role of hepatic resection vs transarterial chemoembolization (TACE) for multiple HCCs should be further clarified. Methods  We retrospectively enrolled 1065 patients with multiple HCCs. Among them, 294 received surgical resection, 367 received transarterial chemoembolization (TACE), and 404 received chemotherapy or supportive care. Three staging systems (TNM, CLIP, and BCLC) were used for comparison of stage-specific survival between different treatment modalities. Results  The median survival of multiple HCC patients who received surgical resection was 37.9 months, while it was 17.3 months in TACE group, and 2.8 months in supportive group (P < .001). The 1-year, 3-year, 5-year survival rates for surgical group were 77.4%, 51.9%, and 36.6%, respectively. Kaplan-Meier survival analysis demonstrated that patients who received surgical resections had the best survival, followed by TACE and supportive care. For patients of the same stage, surgical resection yields better results than TACE. Surgery could offer better survival than TACE for patients either within or beyond Milan’s criteria. Conclusions  Our results indicate that if patients have preserved liver functions, hepatic resection is helpful, even for patients with multiple HCCs.