Departments of 1 Internal Medicine and 2 Radiation Oncology, West German Cancer Centre Essen, University of Duisburg, Essen; 3 Department of Thoracic Endoscopy and Surgery, Ruhrlandklinik, Germany E-mail: wilfried.eberhardt@uni-essen.de
Defining the problem
Has there been any major progress in the combined modality treatment for stage III locally advanced non-small-cell lung cancer (NSCLC) within the last 10 years? The answer is certainly yes, but currently we have to admit that the absolute gain for our patients has been relatively small, when looking from the broader perspective of the general patient population with NSCLC [1]. Differences in 5-year survival rates that have been achieved by complex bi- or tri-modality protocols have generally been observed in the range of between 3% and 7% improvement [2, 3]. Some therapists may be satisfied with these figures, others may not.
This naturally contrasts with the situation in a given individual patient case, in whom optimised approaches have led to definite cure of the disease, whereas years before only palliation could be achieved by local treatment modalities alone [2, 4]. Therefore, from the individual patients perspective, discussions about short-term toxicities during induction treatment (neutropenia, thrombopenia, anaemia and esophagitis) might seem a bit narrow-minded. However, performing aggressive treatments in patients with typically multiple co-morbidities (e.g. pulmonary, cardiovascular) carries a clear and objective risk that cannot be denied. Peri- and postoperative deaths are constantly observed in between 2% and 11% of patients put on clinical trials with induction therapy followed by definitive surgery, even in centres who have developed the logistics and the experience to handle such complex protocols [510]. Objective data analyses of risk factors derived from the co-morbidity profiles of the treated patient populations within this setting are still very rare [8,10]. As a major risk factor, performance of pneumonectomy (especially right-sided) has been identified [6, 8, 10, 11]. Not sufficiently well documented, so far, is a probable learning effect that may lower this risk as the experience gained by the interdisciplinary multimodality team increases over time.
Preoperative concurrent chemoradiotherapy: the paths to tri-modality
The paper by Trodella et al., in this issue of Annals of Oncology, reports on a relatively large group of stage III NSCLC patients put on an induction protocol based on concurrent chemoradiation followed by, if possible, definitive surgery [12]. Altogether, 92 patients over a rather long time period of 8 years were entered on this open feasibility trial in a single institution, that included two different radio-chemotherapy protocols during two subsequent time periods of the investigation. One was based on single-agent carboplatin given simultaneously with conventionally fractionated radiotherapy (qd; 68 of 92 patients), the second was based on cisplatin [plus 5-fluorouracil (5-FU)] and concurrent hyperfractionated radiotherapy (b.i.d., 24 of 92 patients). The two different protocols of preoperative chemoradiotherapy were found to be feasible and the toxicity profile observed in both subgroups was generally acceptable. Of all 92 patients enrolled on the study (stage IIIA, 57 patients; stage IIIB, 35 patients), 61 became eligible for surgery following chemoradiotherapy and 56 patients (61%) could be completely resected at the time of thoracotomy. The actuarial 5-year survival rate for the whole study population was found to be 15%. The overall results of this multimodality treatment strategy were analysed based on the downstaging effect of the induction therapy, and patients with pathological stage 0I disease, found at the time of surgery following the initial therapy, showed a significantly longer disease-free survival (DFS), as well as overall survival (OS) duration (median DFS, 26.2 months; median OS, 32.5 months) than those without any major pathological response (pathological stages IIIII; median DFS, 11.2 months; median OS, 18.3 months). The authors conclude from their data that for short-term evaluation of the efficacy of different induction protocols in stage III NSCLC, pathological downstaging could be proposed as an important surrogate endpoint shown to have a high positive predictive value. They hypothesise that, as a consequence of this, the overall value of any induction protocol should at best be critically judged by the amount of induced downstaging found at the time of definitive surgical resection. Also, this parameter could be more easily used to compare the effectiveness of different induction protocols.
Interpreting the results of this feasibility trial
When trying to interpret the results presented in this study, there are a number of important issues that have to be raised:
(f) Points (b) to (e) are important issues that should not be forgotten when evaluating complex tri-modality protocols. A reduction to point (a) alone may be much too confined in its perspective.
What else can we learn from trials that have been reported within the last 10 years?
One mans pride, another mans burden
While there are no generally accepted standards of care in the treatment of locally advanced NSCLC [8], we will be left with a situation in which the selection of patients to protocols based on permutations of chemotherapy, radiotherapy and surgery will pre-dominantly be based on the experience and logistics of the treatment centre and its participating experts. Since there is a marked heterogeneity of patients as well as doctors in the treatment of stage III disease (patient substages, patient co-morbidity profiles, centre logistics, centre experience), this will lead to a situation in which the treatment protocol will largely remain one mans pride, but may also turn out as another mans burden. The investigation presented by Trodella et al. in this months journal underlines the fact that also in Europe more and more large treatment groups have gathered significant experience with trimodality strategy in phase-II trials. It is definitely time to move forward with large randomised trials with pre-, well-defined, and thus reproducible, patient selections, patient populations and quality standards for multi-modality treatment groups. Certainly, a baseline requirement for high quality treatment decisions in such situations is a functioning multimodality panel at each interdisciplinary treatment centre, typically comprising of pulmonologists, medical and radiation oncologists and thoracic surgeons.
REFERENCES
1. Jemal A, Tiwari R, Murray T et al. Cancer Statistics 2004. CA Cancer J Clin 2004; 54: 829.
2. Dillman RO, Herndon J, Seagren SL et al. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996; 88: 12101215.
3. Furuse K, Fukuoka M, Kawahara M et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999; 17: 26922699.
4. Le Chevalier T, Arriagada R, Quoix E et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma. Lung Cancer 1994; 10 (Suppl 1): S239S244.[Medline]
5. Albain KS, Rusch VW, Crowley JJ et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995; 13: 18801892.[Abstract]
6. Eberhardt W, Wilke H, Stamatis M et al. Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in advanced non-small-cell lung cancer: mature results of a phase II trial. J Clin Oncol 1998; 16: 622634.[Abstract]
7. Eberhardt W, Bildat S, Korfee S. Combined modality therapy in NSCLC. Ann Oncol 2000; 11 (Suppl 3): 8595.[Medline]
8. Eberhardt WE, Albain KS, Pass H et al. Induction treatment before surgery for non-small cell lung cancer. Lung Cancer 2003; 42 (Suppl 1): S9S14.[Medline]
9. Grunenwald DH, Andre F, Le Pechoux C et al. Benefit of surgery after chemoradiotherapy in stage IIIB (T4 and/or N3) non-small cell lung cancer. J Thorac Cardiovasc Surg 2001; 122: 796802.
10. Stamatis G, Djuric, D, Eberhardt W, et al. Postoperative morbidity and mortality after induction chemoradiotherapy for locally advanced lung cancer: an analysis of 350 operated patients. Eur J Cardio-thorac Surg 2002; 22: 292297.
11. Martin J, Ginsberg RJ, Abolhoda A et al. Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. Ann Thorac Surg 2001; 72: 11491154.
12. Trodella L, Granone P, Valente S et al. Neoadjuvant concurrent radiochemotherapy in locally advanced (IIIA-IIIB) non-small cell lung cancer: long-term results according to downstaging. Ann Oncol 2004; 15: 389398.
13. Clamon G, Herndon J, Cooper R et al. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 1999; 17: 411.
14. Schaake-Koning C, van den Bogaert W, Dalesio O et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992; 326: 524530.[Abstract]
15. Turrisi AT III, Kim K, Blum R et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999; 340: 265271.
16. Albain KS, Scott CB, Rush VR et al. Phase II comparison of concurrent chemotherapy plus radiotherapy (CT/RT) and CT/RT followed by surgical resection for stage IIIA (pN2) non-small cell lung cancer: initial results from intergroup 0139. Proc Am Soc Clin Oncol 2003; 22: 621 (Abstr 2497).