| HOME | HELP | CONTACT US | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Multidisciplinary Thoracic Oncology Program, Divisions of Hematology/Oncology and Thoracic Surgery, Departments of Medicine, Surgery and Biostatistics, School of Medicine and Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Correspondence: Mark A. Socinski, M.D., CB# 7305, University of North Carolina, Chapel Hill, NC 27599-7305, USA. Telephone: 919-966-4431; Fax: 919-966-6735; e-mail: socinski{at}med.unc.edu
 |
ABSTRACT |
|---|
 Top Abstract IntroductionMethodsConclusionsReferences |
|---|
Key Words. Non-small cell lung cancer • Adjuvant chemotherapy
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsConclusionsReferences |
|---|
Although postoperative adjuvant chemotherapy improves survival in several solid tumors, its role in NSCLC remains controversial [8]. A recent meta-analysis suggests that early trials which employed alkylating agents in the postoperative setting have a detrimental effect on survival [9]. In the cisplatin era, 11 randomized trials have been reported [10-20]. The patient populations studied in these trials have varied from Stage I to Stage III, and many of the trials were designed and carried out in the early to mid-1980s, employing chemotherapy regimens and supportive care measures reflective of that time period. The recent meta-analysis [9] has suggested a reduction in the odds ratio for death in those trials employing postoperative cisplatin-based adjuvant chemotherapy. However, it is generally believed in the oncologic community that adjuvant chemotherapy has no role in the management of curatively resected NSCLC [21]. We believe that a lack of sufficient data exists to fully resolve this question rather than that the existing data sufficiently exclude a positive role of adjuvant chemotherapy in curatively resected NSCLC. After all, absence of proof is not proof of absence. The purpose of this review is to describe and critically analyze the published and ongoing trials of adjuvant cisplatin-based chemotherapy in resected NSCLC.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsConclusionsReferences |
|---|
Eleven studies were identified. Each study was examined for the number of patients enrolled, balance of control and chemotherapy arms with respect to prognostic factors, statistical methods, statistical significance, chemotherapy regimen employed, compliance with treatment regimens, reasons for lack of compliance, toxicity and overall survival.
A methodologic scoring system was developed to evaluate the quality of the design and to report the results of the trials. The criteria used were adapted from the CONSORT statement, which applies to randomized clinical trials focusing on survival data [22]. The 13 criteria selected by the four authors (Table 1
) were felt to be the essential criteria with which a study group should design, execute, and report a clinical trial addressing the role of adjuvant chemotherapy in NSCLC. Furthermore, these criteria were felt to be essential to providing sufficient information to enable a reader to draw meaningful conclusions from the data. The authors independently scored each criterion using a scale of 0, 0.5, and 1.0: 0 if the criterion was clearly not met by the study, 0.5 if the criterion was partially met by the study, or 1.0 if the criterion was clearly met by the study. The authors include a medical oncologist (MAS), a surgical oncologist (FCD), a biostatistician (MJS), and an internal medicine resident (SG). Average scores were determined by averaging the individual scores of the four reviewers with thirteen, indicating a perfect score.
|
60% node-negative patients entered into the trial) and those that included predominantly node-positive patients (defined as 60% node-positive patients entered into the trial).
Completeness and Quality of Reporting
Many of the trials did not include sufficient data from which to draw meaningful clinical conclusions. As noted above, a scale (Table 1
) modified from the CONSORT statement [22] was used to objectify the completeness and quality of reporting in each of the 11 trials. Table 2 shows the average score for each of the 11 studies reviewed. Overall, there was good agreement among the authors regarding study reporting quality. Correlations between authors ranged from .55 to .95, the latter representing the strong agreement between MAS and FCD. The correlation between each author and the average score ranged from .80 to .98. For 68% of the individual criteria, three of the four authors issued the same score. The remaining cases primarily represent more lenient versus tougher scoring by the reviewer, which was consistent for an individual criterion. Overall, the studies adequately addressed criteria 1, 2, 4, and 12 with average scores of .86, .93, .75, and .78, respectively. No prospectively defined stopping rules were used for any of the studies, so all authors gave zero scores for criterion 5. The average scores for the remaining eight criteria ranged from .38 to .56. Although there were some gaps in methods and reporting, an attempt was made to combine the study results to determine if a trend exists for the effect of chemotherapy for either predominantly node-negative or node-positive patients.
|
Predominantly Node-Negative Trials
Overall, 1,084 evaluable patients were studied in the five predominantly node-negative trials (Table 3). The composite five-year survival rate of the chemotherapy arm patients (n = 598) was 61%. The composite five-year survival rate of the control arm patients (n = 486) was 55%. When examined individually, the treatment effects at five years for the five predominantly node-negative trials ranged from a 13% benefit for chemotherapy [10] to a 1% benefit for surgery alone [14]. There was no evidence of heterogeneity of effect between the trials (Qw =1.68, p = .79). Overall, a 5.6% marginally significant five-year survival advantage for chemotherapy was obtained, with the standard error being 3.0% (p = .06). Each of these five trials is summarized briefly below.
|
for dosing schedule). Three hundred ten patients were eligible for analysis. Follow-up was 100% at five years. The three groups were well matched in terms of sex, age, histological classification, pathologic T and N status, and pathologic stages. The Uft group experienced a significant survival advantage compared to the control group (p = .02). A multivariate analysis with Cox's proportional hazards model identified postoperative adjuvant chemotherapy as a significant prognostic factor for survival, with hazards ratios (against the control group) of 0.64 (95% CI, 0.42 to 0.97) in the CVUft group and 0.55 (95% CI, 0.36 to 0.86) in the Uft group. Specific data regarding the need for dose reduction or discontinuation of treatment secondary to toxicity were not presented. In 1995, the Study Group of Adjuvant Chemotherapy for Lung Cancer in Japan published a trial [11] with a similar chemotherapy arm as in the Wada trial [10]. This study compared cisplatin, adriamycin, and Uft (CAUft) versus observation alone following curative resection in 309 patients. Compliance in this study was not well reported. It was noted that 14.9% of patients had chemotherapy "interrupted" at some point, although specific data regarding the reasons for interruption and mean total dose received were not reported. The trial did not find a statistically significant survival difference in the chemotherapy group versus control (p = 0.35). However, patients enrolled in this trial were not stratified for prognostic factors and the CAUft arm had significantly more advanced pathological lymph node stage than the control group. When the authors adjusted for this variable, CAUft did confer a significant survival advantage at five years when compared to controls (p = 0.044).
In 1993 Feld et al. [12] reported a trial comparing cyclophosphamide, adriamycin, and cisplatin (CAP) versus observation alone following complete resection of T1N1 or T2 N0 disease (Table 3). No difference in survival between the CAP and observation arms was observed. Compliance in this study was poor, with only 53% of patients receiving all four planned cycles of chemotherapy and only 57% of this subgroup receiving chemotherapy on time. A full 20% of patients in the chemotherapy arm received no treatment at all. Reasons for the poor compliance were not directly discussed, although it was reported that 88% of patients had mild to severe nausea and vomiting and 65% had hematologic toxicity. Overall, no survival difference was found (p = .92). However, recurrence and death rates in the squamous cell population both favored the chemotherapy arm (p = 0.05), while the non-squamous cell group fared less well than the control group (p = 0.06).
In 1992, Niiranen et al. [13] published results on 110 patients randomized to receive either adjuvant CAP or observation following surgery. Fifty-seven percent of the patients on the CAP arm received the planned therapy, with 70% of patients receiving at least three cycles. The timing of the chemotherapy received relative to the planned schedule was not reported. Thirty percent of patients in the CAP arm refused treatment at some point and 13% received no chemotherapy at all (22% of patients refused because of nausea and vomiting). The CAP arm had a better survival (p = 0.05) with a five-year survival rate of 67% in the CAP arm versus 56% in the control arm. The groups were well balanced in terms of prognostic factors, including pathological T and N stage, gender, and histological subtype. However, more patients underwent pneumonectomy in the control population (22 versus 11 patients). Patients who underwent pneumonectomy had a significantly worse outcome than patients undergoing lobectomy (p = 0.002), representing a possible bias against the control group. The five-year survival rate for those patients undergoing lobectomy was 74% in the CAP group and 64% in the control group (p = 0.24).
Ichinose et al. [14] published a trial in 1991 comparing three cisplatin-based chemotherapy arms with observation following curative resection. The chemotherapy arms included CAP with mitomycin, cisplatin-vindesine, and cisplatin-adriamycin-pepleomycin (Table 3). The authors' goal was to deliver "at least two cycles" of treatment. Compliance was reported as "good" for all patients. The only specific compliance data reported was that 30% of patients refused treatment beyond two cycles, and an average of only 2.3 cycles was delivered (range 1-6). No significant survival difference between the arms was seen.
Predominantly Node-Positive Trials
Overall, 880 evaluable patients were studied on one of six predominantly node-positive trials (Table 4). The composite two-year survival rates of the chemotherapy and control arm patients were 48% (n = 437) and 40% (n = 443), respectively. Ohta et al. [15] and Kimura et al. [16] both had notably higher survival rates in the chemotherapy arms, while Ohta et al. [15] also had an unusually high survival rate in the control arm compared with the other trials. Excluding those two trials, the two-year survival rates drop to 39% and 33%, and the remaining trials appeared statistically homogeneous. The treatment effects for the six predominantly node-positive trials ranged from a 31% advantage for chemotherapy [16] to a 13% benefit for surgery alone [17]. A marginal lack of homogeneity of treatment effect was found (Qw = 12.03, p = .13). Besides the two extreme treatment effects (which also had the smallest sample sizes), the effects of the four other trials clustered between a 4% and 11% benefit for chemotherapy. Overall, an 8.2% two-year survival advantage for chemotherapy was obtained, which is marginally significant (p = .06), since the standard error is 4.3%. In general, these trials were small, had poor compliance with treatment and heterogeneous patient populations and often did not reach their accrual goal. It is therefore difficult to interpret these studies, each of which is briefly summarized below.
|
). Compliance with treatment was reportedly good, with 70% of patients in the radiotherapy arm receiving greater than 50 Gy, 88% of chemotherapy patients receiving greater than two-thirds of the planned drugs, and 67% of these patients receiving at least 50 Gy. Specific reasons for noncompliance were not addressed, although 8% of patients reportedly had grade 3-4 toxicity, 6% with grade 3-4 hematologic toxicity, and three patients reportedly died from the complications of chemotherapy. This study found no significant difference in survival (p = 0.63). In a subset analysis, patients with N2 disease treated with chemotherapy plus radiotherapy had a significantly better survival than the radiotherapy-alone group (p = 0.003) with five-year rates of 19% and 6%, respectively. This survival advantage appeared to be due to a reduction in distant metastases in the N2 patients receiving chemotherapy (44% versus 18% at five years, p = 0.002). There was no difference in local relapse. In the N0/N1 group, however, a reverse trend was observed, with poorer survival in those patients treated with chemotherapy (p = 0.03). The authors postulate that the reason for this discrepancy may be that N2 patients have higher metastatic potential and therefore may gain more from systemic treatment. This trial did not meet its accrual goal. The study was designed to show a 10% survival increase in the chemotherapy group at one year with a type I error of 0.05 and 90% power. Given these assumptions, 362 deaths were required using a one-sided test. Although a four-year accrual time was planned, the study was closed after five years with only 233 deaths. A study by Pisters et al. [17] in 1994 reported a randomized trial of radiotherapy plus or minus vindesine and cisplatin in 72 N2 patients having undergone surgical resection. Sixty-one percent of the patients had a complete resection, while 39% were incompletely resected. (No definition for an "incomplete resection" was given). All patients received mediastinal radiation (40 Gy), and patients with incomplete resections received intraoperative brachytherapy (125I implants). The groups were well balanced for T stage, histology, performance status, and extent of resection. Thirty-six patients were randomized to receive chemotherapy. Only 13 patients (36%) received all four doses of cisplatin. Ninety-two percent of the patients received the planned dose of external beam radiation, and 71% of eligible incompletely resected patients received implants. Reasons for noncompliance were not reported in detail. No significant survival advantage was found for either arm. This trial was initially designed to enroll 50 patients per arm; however, it was stopped early because of "noncompliance with the randomization process." The study had little power to identify either a benefit or a detriment to chemotherapy in this setting.
Ohta et al. [15] in 1993 reported a randomized trial of 209 Stage III patients receiving either postoperative cisplatin and vindesine or observation alone, 181 of whom were analyzed. All patients underwent a complete surgical resection. The patients were well balanced between treatment arms except for age, with significantly older patients in the control arm (56 versus 59 years, p = 0.05). There were fewer patients with N2 disease and more patients with T3N0/1 in the control arm than in the chemotherapy arm. Although this tended to benefit the control arm, these differences did not achieve statistical significance. Only 41% of patients received all three cycles of chemotherapy as planned. The average cumulative dose was reported to be 68% of the planned dose. The most frequent reason for patients not receiving the second cycle was patient refusal (occurring in 43% of cases). Survival did not significantly differ between the two groups (p = 0.86). A multivariate analysis showed that advanced pathologic N stage was associated with a poor outcome. Survival for pN0 was 62%, pN1 44% and pN2 29% (p = 0.01). Given this finding, it is somewhat disconcerting that there were more patients with N2 disease in the chemotherapy arm. Also, this trial was designed to detect a 20% increase in the three-year disease-free survival in patients receiving postoperative chemotherapy but was stopped slightly short of the planned accrual of 100 evaluable patients in each group.
Lad et al. [19] published a trial of 172 patients with locally advanced, incompletely resected NSCLC randomized to receive radiation therapy (40 Gy) plus or minus six cycles of CAP. One hundred sixty-four patients were eligible for analysis. There were significantly more N1 patients in the chemotherapy arm than in the control (20 versus 10, p = 0.03). Only 51% of patients received all six cycles. Reasons for noncompliance were not provided. The survival rate at one year was 68% for the chemotherapy arm versus 54% for the radiation arm (p = 0.02); however, the death rates did not differ after the first year. The study examined both recurrence and death rates on a rate per person per year and found that the chemotherapy group had significantly lower recurrence and death rates per person than the radiation alone arm during the first year.
Holmes et al. [20] randomized 141 patients with either Stage II or III adenocarcinoma or large-cell undifferentiated carcinoma to either four cycles of CAP chemotherapy or intrapleural BCG/levamisole/isoniazid. One hundred thirty patients were eligible for analysis. The survival at two years was 41% for the chemotherapy arm versus 30% in the immunotherapy arm (p = 0.08). Compliance in the chemotherapy arm was poor, with 24% of patients receiving no chemotherapy at all. The reported average cumulative dose was 58% of the planned dose. Reasons for noncompliance were not specified, although 87% of patients suffered gastrointestinal toxicity and 48% hematologic toxicity. The two groups were reportedly well balanced for prognostic factors; however, the control arm had significantly more T3 disease than the treatment arm (p = 0.024). Adjustment for T status as well as stage and performance status did not significantly alter their results.
Kimura et al. [16] reported a small series of adjuvant immunochemotherapy following complete resection of Stage II and III patients with NSCLC. A total of 82 patients were enrolled according to the treatment arms in Table 4. The study was originally designed as a three-arm study: observation, chemotherapy alone, and immunochemotherapy. In the first three years of the study, the authors stated that the results in the chemotherapy alone arm were so "poor" that this arm was subsequently discontinued, and randomization continued only between observation and immunochemotherapy. Over the course of the study, 33 patients were randomized to immunochemotherapy, 13 patients to chemotherapy alone, and 36 patients were in the observation arm. Overall survival was reported to be significantly better in the immunochemotherapy arm than in the controls, (p = 0.004). Patients who died without a recurrence were to be censored cases. Specific data concerning the number of censored cases were not given. All patients in the immunochemotherapy group received at least two cycles of chemotherapy and two cycles of LAK, IL- 2.
Why We Still Don't Know
The role of adjuvant cisplatin-based chemotherapy in resected NSCLC remains uncertain despite the trials discussed above that were designed to address the issue. In general, all the trials have similar problems: A) small numbers of patients limiting the statistical power of the study; B) heterogenous patient populations; C) substandard chemotherapy regimens by current-day standards; D) inadequate delivery of chemotherapy, likely secondary to the difficulty in delivering postoperative chemotherapy in this population and substandard supportive care by current-day standards, and E) less than optimally executed clinical trials. Most of the trials enrolled heterogenous patient populations ranging from Stage I to IIIA. This combines groups of patients with dramatically different survival outcomes [24]. Although this results in more rapid accrual, it yields subpopulations among which overall prognosis varies dramatically. Despite these problems, our analysis suggests a trend reaching marginal significance toward improved survival in those patients receiving adjuvant chemotherapy after resection for NSCLC.
In the recent meta-analysis [9], trials were divided between those that included either of the following:
| surgery versus surgery + chemotherapy surgery + radiotherapy versus surgery + radiotherapy + chemotherapy
|
In the former group, 1,394 patients were analyzed and the overall hazard ratio favored chemotherapy (0.87), resulting in a reduction in the risk of death of 13%. The absolute benefit, which was 3% at two years and 5% at five years, was not statistically significant. In the latter group, 668 patients were analyzed and the overall hazard ratio again favored the chemotherapy group (0.94), resulting in a reduction in the risk of death of 6%. Again, the absolute benefit, which was 2% at two years and 5% at five years, was not statistically significant.
The small number of patients (2,062) included in the NSCLC meta-analysis limits the statistical power of that analysis. In contrast, the meta-analysis examining the effect of adjuvant chemotherapy in breast cancer had approximately 75,000 patients involving 31,000 recurrences and 24,000 deaths [25]. In the breast cancer meta-analysis, a 6% improvement in 10-year survival was demonstrated for chemotherapy. Individually, most of the trials in either breast or colon cancer that have shown a benefit to adjuvant chemotherapy have included substantially more patients than the trials in NSCLC summarized here. As noted in Tables 3 and 4, the largest trial randomized 323 patients to one of three different treatment arms [10]. Small but clinically meaningful survival benefits in the NSCLC population were unlikely to be detected by the existing studies, given the inadequate numbers of patients. Also, several of the trials [15, 17, 18] did not reach the accrual goal dictated by the statistical assumption made in the design of the trial. The existing trials, therefore, should not be regarded as conclusive for a lack of benefit to adjuvant therapy and do not provide a definitive answer to the question.
Drug delivery, including both dose and dose intensity, was also inadequate in the majority of studies. The dose of cisplatin in five of the 11 studies was 
50 mg/m2. Table 5 lists the percentages of patients in each of the trials who received no therapy at all (but were randomized to receive it) and the percentage of patients who received all of the planned cycles. In certain studies [20], up to 24% of patients randomized to receive postoperative adjuvant chemotherapy never received it. In those studies that had a defined duration of adjuvant chemotherapy, typically only 50% (range 36%-76%) of patients received the full course of treatment. Given compliance to treatment figures like this, the existing trials hardly seem a fair test of adjuvant chemotherapy in resected NSCLC. In addition, the regimen studied most frequently (CAP) contained agents such as doxorubicin and cyclophosphamide that have inferior single-agent activity compared with a number of newer agents now available. Some of these newer agents, such as vinorelbine [26], paclitaxel [27], and gemcitabine [28], have been shown, in combination with cisplatin, to provide superior survival results or less toxicity in advanced NSCLC. The incorporation of these more active combination regimens into earlier stages of the disease could very well provide enhanced survival. Advances in the outpatient delivery and supportive care of patients utilizing new and more effective antiemetic agents (5HT3 inhibitors), growth factors (filgrastim), and appropriate hydration schedules may allow more effective delivery of more active drugs than was possible during the era that the majority of these studies were carried out. Also, advances in the field of thoracic surgery have led to shorter recovery times and hospitalization and less morbidity, thereby allowing patients to perhaps be better "chemotherapy candidates" in the postoperative setting.
|
Current Ongoing Trials of Adjuvant Chemotherapy in NSCLC
The role of adjuvant chemotherapy with or without thoracic radiation therapy (TRT) is continuing to be studied in curatively resected patients with NSCLC (Table 6). A North American Intergroup trial has recently completed accrual. In that trial, approximately 462 patients were enrolled after complete resections for pathological Stage II (T1-2N1M0) and IIIA (T1-2N2M0;T3N1-2M0) disease. Patients were randomly allocated to either TRT alone or concurrent cisplatin/etoposide and TRT. The primary objectives of the study are to determine if chemotherapy plus TRT is superior to TRT alone in improving survival and preventing local recurrences. The trial was designed to detect a 40% increase in median survival for the combination arm with a sensitivity of 0.852. As noted, this trial recently completed accrual and awaits analysis.
|
The Montreal Multicenter Trial enrolled completely resected patients from 1984 to 1992, accruing 430 patients. Patients without lymph node invasion were randomized to observation alone versus vindesine/cisplatin, while patients with lymph node involvement received post-operative TRT with or without vindesine/cisplatin. This study has been published in abstract form only and no survival data were given. The investigators also examined predictors of relapse such as lymph node metastases, vascular invasion, chemotherapy dose intensity, and the presence of p53 abnormalities.
The Adjuvant Lung Project Italy (ALPI) trial is a randomized trial for Stages I, II, and IIIA patients who have undergone a curative resection. Patients are randomized to postoperative mitomycin, vindesine, and cisplatin (MVP) versus observation with TRT at the discretion of the treating physician. The study is designed to detect a 20% reduction in mortality following adjuvant MVP with 80% power at the 5% level of significance. It is estimated by the investigators that 1,500 patients will be required, and approximately 550 patients were enrolled onto the study as of May 1997. The European Organization for the Research and Treatment of Cancer (EORTC) is also participating in this study.
The International Adjuvant Lung Cancer Trial (IALT) is a large multicenter randomized trial currently being conducted worldwide. This trial will assess the impact of three or four cycles of cisplatin-based chemotherapy on the survival in curatively resected Stages I, II and IIIA NSCLC. The trial will accrue approximately 3,000 patients. A reduction in mortality of 5%-10% in curatively resected NSCLC is the assumption used in the design of this trial. Given the planned number of patients to be accrued, this trial will have substantially more statistical power than currently published trials of adjuvant therapy in NSCLC.
The British Thoracic Society is conducting The Big Lung Trial (BLT) examining the impact of three cycles of cisplatin-based chemotherapy on the survival of curatively resected NSCLC. Patients may also receive postoperative radiation therapy. In patients undergoing surgery alone, 4,000 will be randomized to receive cisplatin-based chemotherapy or observation. This will be sufficient to detect a 5% improvement in five-year survival (50% to 55%) with at least 90% power. In patients undergoing surgery plus radiotherapy, 2,500 patients will be randomized to receive cisplatin-based chemotherapy or observation. This will be sufficient to detect a 5% improvement in five-year survival (20% to 25%) with at least 90% power. The total number of 6,500 patients to be included in this trial will make it the largest trial to date examining the role of cisplatin-based chemotherapy in adjuvant therapy of NSCLC.
The CALGB has recently activated a trial in Stage I NSCLC including only T2N0 patients. The randomization in this study is between adjuvant carboplatin/paclitaxel (four cycles) and observation. The primary objective of the study is to determine a survival benefit of the chemotherapy. The study is designed with an 80% power to detect a 13% increase in the five-year survival and will require 500 patients. It is anticipated that accrual will be completed in approximately three years.
|
Conclusions |
|---|
|
TopAbstractIntroductionMethodsConclusionsReferences |
|---|
|
References |
|---|
|
TopAbstractIntroductionMethodsConclusionsReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  K. M.W. Pisters, W. K. Evans, C. G. Azzoli, M. G. Kris, C. A. Smith, C. E. Desch, M. R. Somerfield, M. C. Brouwers, G. Darling, P. M. Ellis, et al. Cancer Care Ontario and American Society of Clinical Oncology Adjuvant Chemotherapy and Adjuvant Radiation Therapy for Stages I-IIIA Resectable Non Small-Cell Lung Cancer Guideline J. Clin. Oncol., December 1, 2007; 25(34): 5506 - 5518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Alam, G. Darling, F. A. Shepherd, J. A. Mackay, W. K. Evans, and Lung Cancer Disease Site Group of Cancer Care Onta Postoperative Chemotherapy in Nonsmall Cell Lung Cancer: A Systematic Review. Ann. Thorac. Surg., May 1, 2006; 81(5): 1926 - 1936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Park, C.-T. Lee, H. W. Lee, H. J. Baek, J. I. Zo, and Y. M. Shim Postoperative adjuvant chemotherapy for stage I non-small cell lung cancer Eur. J. Cardiothorac. Surg., June 1, 2005; 27(6): 1086 - 1091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Diasio Adjuvant Chemotherapy for Adenocarcinoma of the Lung -- Is the Standard of Care Ready for Change? N. Engl. J. Med., April 22, 2004; 350(17): 1777 - 1779. [Full Text] [PDF]
|
|
|
|
 |
|
 G. V. Scagliotti, R. Fossati, V. Torri, L. Crino, G. Giaccone, G. Silvano, M. Martelli, M. Clerici, F. Cognetti, and M. Tonato Randomized Study of Adjuvant Chemotherapy for Completely Resected Stage I, II, or IIIA Non-Small-Cell Lung Cancer J Natl Cancer Inst, October 1, 2003; 95(19): 1453 - 1461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Schroen, F. C. Detterbeck, R. Crawford, M. P. Rivera, and M. A. Socinski Beliefs Among Pulmonologists and Thoracic Surgeons in the Therapeutic Approach to Non-small Cell Lung Cancer Chest, July 1, 2000; 118(1): 129 - 137. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | CONTACT US | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| THE ONCOLOGIST | STEM CELLS | CME | ALPHAMED PRESS JOURNALS |
