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Three Part Question

In patients with [fully resected non-small-cell lung cancer], does [chemotherapy] improve [5 year survival]?

Clinical Scenario

You are seeing a 60 year old patient 5 days after a left lower lobectomy for a 4cm squamous cell carcinoma. There were no obvious nodular involvement at operation. He is diabetic and an ex-smoker but otherwise relatively well and ready to go home. You tell him that he is ready to go, but that he will probably need chemotherapy in a few weeks time. He is alarmed at this and worried that the operation has therefore not been a success, and you enter into a long discussion about chemotherapy, the operation , and his likely prognosis. After this lengthy discussion you wonder whether it is really worth referring these early stage patients for chemotherapy and thus resolve to look up the evidence.

Search Strategy

Medline 1966-April 2006, using the Ovid interface.
[exp antineoplastic agents] AND [lung resection.mp OR exp thoracic surgery, video assisted OR exp thoracic surgery OR exp video-assisted surgery OR lobectomy.mp OR resect$.mp] AND [exp lung neoplasms OR exp carcinoma, non-small-cell lung] Limit results to human studies.

Search Outcome

The search produced 1081 potentially relevant abstracts. The UK MRC meta-analysis reported in 1995which used an individual patient data methodology, was regarded as a definitive review of pre-1995 work. Studies published prior to this date were therefore not individually included. This left 681 studies published after 1995.
Fourteen published studies identified as being the best evidence are tabulated in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Winton et al, 2005, Canada/USA	482 patients randomized, pathological stage 1B (45%), stage 2 (55%), all ECOG 0-1	PRCT (Level 1b)	Primary endpoint overall survival.	5 year survival improved by 15% (69% vs. 54%, p=0.03) Subgroups: significant benefit stage II (hazard ratio 0.59(0.42, 0.85), not stage IB.	Cisplatin and Vinorelbine 4 cycles. 58% received 3 or more cycles. No radiotherapy. Modern regime, no potential confounding by radiotherapy.
Arrigada et al, 2004, France	1867 patients randomized, pathological stage 1 (36.5%, 2 (24.2%, 3 (39.3%). WHO performance status 0(54.2%), 1(38.1%), 2(7.7%).	PRCT (level 1b)	Primary endpoint overall survival.	Improved survival with chemotherapy, hazard ratio 0.86(0.76, 0.98). 5-year disease-free survival 39.4% (chemo) vs. 34.3%.	Cisplatin with Etoposide (56.5%) or Vinblastine (11%) or Vinorelbine (26.8%) or Vindesine (5.8%) Radiotherapy planned in 30.6%, delivered to 24%).
Scagliotti et al, 2003, Italy	1209 patients randomized, pathological stage 1 (4%), 2 (47%) or 3A (49%).	PRCT (level 1b)	Primary endpoint overall survival.	No significant difference in survival. Secondary outcome disease free survival not significant (hazard ratio 0.89 (0.76, 1.03).	Mitomycin C, Vindesine and Cisplatin, 3 planned cycles. (69% received all three). 39% scheduled to receive radiotherapy.
Waller et al, 2003, UK	381 patients randomized (within larger trial). Pathological stage 1 (29%), 2 (37%), 3A (27%) or 3B/4 (6%) WHO PS 0(35%), 1(57%), 2(8%).	PRCT (level 1b)	Primary endpoint overall survival.	No significant difference in survival (Hazard ratio 1.02 (0.77, 1.35) favouring observation). No significant difference on subgroup analysis.	3 cycles of 4 possible cisplatin-based regimes (64% received 3 cycles). 14% received radiotherapy. Broad inclusion criteria and therapy options. Relatively underpowered. Some incompletely-resected patients included.
Keller et al, 2000, USA	488 patients randomized, pathological stage 2 (42%), 3A (58%). ECOG 0(40%) or 1 (60%)	PRCT (level 1b)	Primary endpoint overall survival.	No significant difference in survival (hazard ratio 0.93 (0.74, 1.18).	Cisplatin and Etoposide, 4 cycles (69% actually received all or part of 4 cycles). Radiotherapy to all patients. Large number of institutions and surgeons (192 surgeons operated on only 1 patient).
Kato et al, 2004, Japan	999 patients randomized (20 excluded before analysis), all stage 1 adenocarcinoma. ECOG 0,1 or 2	PRCT (level 1b)	Primary endpoint overall survival.	5 year survival 88% (chemo) vs 85% (observation) p=0.04. Subgroups; UFT significantly better in T2 disease, not significantly different in T1.	Oral Uracil/Tegafur twice daily 2 years, 74% completed 1 year, 61% 2 years. No radiotherapy.
Nakagawa et al, 2005, Japan	332 patients randomized, all stage 1. ECOG 0,1 or 2	PRCT (level 1b)	Primary endpoint overall survival.	5-year survival not significantly different (UFT 82.2% vs 75.9%, p=0.105). Subgroup analysis; pT1 significantly better survival with UFT vs observation, adenocarcinoma especially so.UFT compliance 50.9% at 1 year.	Failed to recruit target numbers, higher than expected control arm survival made study underpowered for stated endpoint.
Endo et al, 2003, Japan	221 patients randomized, stage 1 (87%) and stage 2 (13%). ECOG 0 (84%), 1 or 2	PRCT (level 1b)	Primary endpoint overall survival.	No significant difference in overall outcome, subgroup stage or pathological type outcomes.	2 year UFT course. 63% completed treatment as prescribed. Powered for a 20% difference in 5 year survival, therefore underpowered.
Wada et al, 1999, Japan	229 patients randomized, 86% stage 1, 14% stage 2.	PRCT (level 1b)	Primary endpoint overall survival.	No overall survival difference. Subgroups-pT1N0 better with chemo (5 year survival 90.7% vs 75.3%, p 0.03)	Two courses Cisplatin then 1 year UFT treatment arm. Designed to detect a 10% survival benefit with 80% power, therefore underpowered given small benefits detected by other trials. 67.9% completed both cycles of Cisplatin, 78.8% received UFT for 1 year.
Wada et al, 1996, Japan	323 patients randomized into 3 arms (surgery alone, surgery/cisplatin/UFT, surgery UFT). Pathological stages 1-3.	PRCT (level 1b)	Primary endpoint overall survival.	5 year survival; -49% surgery alone. -60.6% surgery, cisplatin and UFT. -64.1% surgery and UFT. 1. and 2. Both significantly different from surgery alone	Did not show significant difference between UFT/Cisplatin and UFT alone arms (although not powered to do so).
MRC meta-analysis, 1995, UK	Trials recruiting between 1965 and 1991. 52 studies, 9387 patients (including all arms), divided as follows; -4357 patients surgery vs. surgery/ chemotherapy -807 patients surgery/radiotherapy vs. surgery/radio/chemotherapy	Meta-analysis (level 1a)	Endpoint survival.	Alkylating agent therapy arm favoured observation only.	High quality study. The observed trend towards improved survival, although non-significant, stimulated many later randomized trials. Alkylating agent regimes identified as detrimental.
Sedrakyan et al, 2004, UK	Trials included in MRC analysis plus those reported from 1995-2004. 19 trials, 7200 patients	Meta-analysis (level 1a)	Endpoint survival.	In favour of chemotherapy when all trials included. Hazard ratio 0.89 (0.82, 0.96). UFT arm in favour of chemotherapy with hazard ratio 0.83(0.73, 0.95). 13% relative reduction in 5 year mortality ( 7%-19%) 4% absolute risk reduction. NNT 25 to save a life after 5 years.	UFT trials and Platinum-based trials analyzed separately.
Hamada et al, 2005, Japan	2003 patients in 6 trials. Tumours T1 (65.3%), T2 (33.6%), N0 (96%)	Meta-analysis (level 1a)	Endpoint survival.	Favoured surgery plus UFT (hazard ratio 0.74 (0.61, 0.88). Over surgery alone. 5 year survival 81.5% vs 77.2% p=0.011.	Analysis of UFT trials. Majority of patients with early disease (96% N0), high proportion adenocarcinoma.
Hotta et al, 2004, Japan	11 trials containing 5716 patients, completed between 1992-2004. Random-effects model.	Meta-analysis (level 1a)	Endpoint survival.	Favoured platinum-based chemotherapy- Hazard ratio 0.891 (0.815, 0.975) p = 0.012 Favoured UFT-based chemotherapy, Hazard ratio 0.799 (0.668, 0.957) p = 0.015	Analysis of trials since the 1995 MRC meta-analysis. Well conducted study of modern-era trials.

Comment(s)

Platinum-Based Chemotherapy Trials The UK MRC meta-analysis of 1995 showed a trend towards improved survival with both platinum and UFT based adjuvant chemotherapy following complete resection compared with surgery alone (Non-small Cell Lung Cancer Collaborative Group). Although this trend did not reach statistical significance the findings stimulated large new randomized trials. These trials differed in the pathological stages they recruited, and in the use of radiotherapy. The JBR-10 study and IALT studies demonstrated an overall benefit with chemotherapy. Both utilized a modern chemotherapy regime, although IALT recruited stage III and allowed radiotherapy, whereas JBR-10 did not. The three negative trials all allowed radiotherapy and later stage patients. Two meta-analyses(Hamada, Hotter) have shown moderate benefit with chemotherapy over surgery alone, with identical and significant hazard ratios of 0.89. Uracil/Tegafur (UFT) Trials Uracil-Tegafur or UFT (Taino Pharmaceuticals, Tokyo) has been studied in Japan. Tegafur is a prodrug of flourouracil, given with Uracil, which inhibits the breakdown of flourouracil. It is given orally, providing stable plasma levels over long periods. A heterogeneous study including stage I-III (Wada) showed an overall survival benefit, but this was not confirmed in further studies (Kato, Nakagawa, Endo, Wada). However, subgroup analyses of some of these trials found a survival benefit in early-stage disease (Nakagawa, Wada), and the JLCRG stage I adenocarcinoma-only study showed an overall survival benefit. In the one study with both a platinum and a UFT arm there was no significant difference between the regimes (Wada). 3 recent meta-analyses have now confirmed a significant overall survival benefit for UFT over surgery alone, with Hazard ratios of 0.74 to 0.82(Hamada, Hotta). Currently, UFT is not available in the EU or US. United Kingdom Clinical Guidelines The UK National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN) issued joint clinical guidelines on the management of lung cancer in February 2005( www.nice.org.uk and www.sign.ac.uk ). NICE concluded, "Adjuvant chemotherapy should be offered to NSCLC patients who have had a complete resection, with discussion of the risks and benefits". However, NICE further described surgery and chemotherapy as "suitable for some patients" in stage I, II and IIIA, although surgery alone remained "first choice for eligible patients" in stage I and II. Similarly, the SIGN guideline states "adjuvant chemotherapy should be considered for resected NSCLC, but discussed fully given the small margin of benefit, risks of toxicity and uncertainty as to which group of patients are likely to benefit". Conclusions Recent randomized trials of both platinum and UFT-based adjuvant chemotherapy have shown a survival benefit for both regimes compared to surgery alone. These findings have been confirmed in meta-analyses of several randomized controlled trials, and can be considered level 1 evidence for both regimes. No benefit of one regime over another has been demonstrated, and compliance rates for both are moderate. The overall survival benefits are relatively small- single figures changes in five-year survival. Many trials have not reported quality of life analysis, which is particularly significant when the survival benefit is modest. For these reasons, some fully informed patients may not wish chemotherapy, and the decision merits careful discussion, tailored to an individual patient's circumstances. Whether the benefits seen apply to all pathological stages needs further clarification. The role, if any, of adjuvant radiotherapy and the use of biomarkers predicting response to chemotherapy remain subjects of active study. An updated individual patient data meta-analysis of recent trials is currently in preparation. The role of neo-adjuvant chemotherapy is the subject of ongoing clinical trials, including the Bimodality Lung Oncology Trial (BLOT) and the UK MRC Lu-22 Trial.

Editor Comment

WHO PS- World Health Organisation Performance Status. ECOG- Eastern Cooperative Oncology Group performance status score Platinum-Based Regimes: Winton, Arriagada, Scagliotti, Waller, Kelly. UFT Regimes: Kato, Nakagawa, Endo, Wada (1996, 1999). Meta-Analyses: MRC (1995), Sedrakyan, Hamada, Hotta.

Clinical Bottom Line

Post-operative adjuvant chemotherapy carries a small survival benefit in those patients with complete resection of their lung cancer. This survival benefit is in the region of a 4% absolute survival advantage at 5 years. Thus 25 patients require chemotherapy to save one life at 5 years. This should be discussed with all patients following complete resection of non-small-cell lung cancer.

References

1. Winton T, Livingston R, Johnson D et al. for the JBR-10 Investigators. Vinorelbine plus Cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352:2589-2597.
2. Arriagada R. Bergman B. Dunant A et al. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy inpatients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350:351-360.
3. Scagliotti GV. Fossati R. Torri V et al. Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer-Lung Cancer Cooperative Group Investigators. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. Journal of the National Cancer Institute 2003;95(19):1453-61.
4. Waller D, Peake MD, Stephens RJ, Gower NH et al. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the big lung trial. Eur J Cardiothorac Surg 2004; 26(1):173-182.
5. Keller SM, Adak S, Wagner H, Herskovic H et al. for the Eastern Cooperative Oncology Group. A randomised trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small cell lung cancer. N Engl J Med 2000; 343: 1217-1222.
6. Kato H, Ichinose Y, Ohta M et al. for the Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomised trial of adjuvant chemotherapy with Uracil-Tegafur for adenocarcinoma of the lung. N Engl J Med 2004; 350: 1713-1721.
7. Nakagawa M, Tanaka F, Tsubota N et al. A randomised phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery. Ann Oncol. 2005; 16(1): 75-80.
8. Endo C, Saito Y, Iwanami H et al. A randomized trial of postoperative UFT therapy in p stage I, II non-small cell lung cancer: North-east Japan Study Group for Lung Cancer Surgery. Lung Cancer 2003; 40(2): 181-186.
9. Wada H, Miyahara R, Tanaka F et al. Postoperative adjuvant chemotherapy with PVM (Cisplatin + Vindesine + Mitomycin C) and UFT (Uracil + Tegafur) in resected stage I-II NSCLC (non-small cell lung cancer). Eur J Cardiothorac Surg 1999; 15(4): 438-43.
10. Wada H, Hitomi S, Teramatsu T. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. West Japan Study Group for Lung Cancer Surgery. J Clin Oncol 1996; 14(4): 1048-54.
11. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311(7010):899-909.
12. Sedrakyan A, Van Der Meulen J, O'Byrne K et al. Postoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis. J Thorac Cardiovasc Surg 2004; 128(3):414-419.
13. Hamada C, Tanaka F, Ohta M et al. Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol 2005; 23(22): 4999-5006.
14. Hotta K, Matsuo K, Ueoka H et al. Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomised controlled trials. J Clin Oncol 2004; 22(19):3860-3867.