Preoperative chemoradiation approaches to locally advanced non-small-cell lung cancer: one man’s pride, another man’s burden?

W. Eberhardt1, M. Stuschke2 and G. Stamatis3

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 patient’s 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 0–I 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 II–III; 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:

1 When evaluating the data of the whole study population, we have to keep in mind that there is marked heterogeneity based on the two clearly different treatment protocols. Protocol A is based on single-agent carboplatin and once daily radiotherapy. Protocol B is based on cisplatin and 5-FU and hyperfractionated twice-daily radiotherapy. Data on single-agent carboplatin in chemoradiation protocols are not clearly convincing within the literature [13]. Even single-agent cisplatin may be a much better partner for concurrent chemoradiotherapy approaches [14]. Hyperfractionated twice-daily radiation—especially when given simultaneously to chemotherapy—may be more effective when looking at the analogue model of small-cell lung cancer [15]. However, radiotherapy fraction doses of 1.2 Gy (b.i.d.) are generally thought to be slightly inferior to the more frequently used 1.5 Gy doses twice daily. Interestingly, even in this trial, pathological downstaging was observed more frequently in the protocol B part of the study (pathological stage 0–I in 11 of 15 patients) in comparison to the protocol A part (pathological stage 0–I in 15 of 41 patients). There also seems to be a difference in the rate of pneumonectomy between the two study periods and the two induction protocols and this may also point to a better pathological downstaging with protocol B based on cisplatin, 5-FU and concurrent twice-daily radiation.
2 The perioperative mortality rate observed in this study was found to be rather high at 11.4% (7 of 61 patients). However, again there seems to be a much lower rate during the second time period (protocol B, 1/18 patients; 5.5%) in comparison to the first period (protocol A, 6/43 patients; 13.9%). Although there may also be a learning effect behind this data set, these results clearly favour the cisplatin-based protocol. However, this study again points to the problem of perioperative mortality within these aggressive tri-modality approaches. In the future, it will be necessary to clearly define risk factors for patients taken onto these complex protocols.
3 Comparisons of OS and DFS results between the two protocols in this study are not yet justified as the follow-up periods for both groups are rather different.
4 The overall 5-year survival result of this study (rate of 15%) again raises the question about the overall role of surgery within this setting. Five-year survival rates of ≥15% have been reported for bi-modality treatment protocols based on definitive radio-chemotherapy alone [3, 7]. Therefore, radio-chemotherapy has a clearly curative potential on its own. The most important question for the future will be to better define those patient groups that benefit most from the inclusion of surgery, or on the other hand, to identify those patient groups that may be cured following chemoradiation alone. These prognostic and predictive factors have to be defined preferably within large prospectively randomised trials—the Intergroup trial 0139 being the most recent one presented at the American Society of Clinical Oncology meeting and the International Association for the Study of Lung Cancer (IASLC) conference [16].
5 The investigators’ proposal to use pathological downstaging as a surrogate end point for the evaluation of the efficacy of preoperative, induction protocols deserves to be looked at in detail:
(a) Pathological response is clearly one important surrogate (and therefore short-term) parameter when evaluating different induction protocols. However, there seems to be a difference between downstaging of the primary tumor (T4, T3, T2ÆT1,T0) in comparison to downstaging of nodal disease (N3, N2ÆN1, N0).
(b) Induced peri- and postoperative mortality is another major parameter that has to be taken into account when interpreting the value of a given induction protocol.
(c) Five-year survival is probably the most definite end point that should always be critically analysed for any therapeutic strategy.
(d) Any clinical trial in stage III based on complex multimodality treatment will always have difficulties in taking into account the remarkable heterogeneity of patients populations in stage III, including the individual co-morbidity profiles of the included patients.
(e) Parameters such as compliance to a given protocol and achieved cumulative cisplatin doses may have further impact and should be documented carefully.

(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?

1 Stage III disease subsummizes a rather heterogeneous patient group concerning the overall prognosis including patients with more loco-regional risks (e.g. ‘T4’) or either distant risks (‘N2/N3’ or ‘large tumour burden’) [7, 8]. Any comprehensive judgement of treatment strategies has to acknowledge this marked heterogeneity.
2 Patients with proven stage III disease represent a rather heterogeneous patient population concerning co-morbidity risks including pulmonary function limitations, cardio-vascular or cerebro-vascular co-morbidities, or other major co-morbidities with evident organ dysfunctions. Similar to any ‘patients selection for medical operability’, these patients should be carefully investigated and pre-defined selection procedures are a pre-requisite if patients are put on complex or intensive protocols. These are important points that have to be discussed openly with patients when putting them on protocols or trials with aggressive bi- or tri-modality approaches.
3 There may be subsets of patients that may profit from definitive surgery, but these subsets have not yet been clearly defined. There is some evidence that selected T4N0–1 patients should be taken to definitive thoracotomy [5, 8]. Other patients groups, including those with important co-morbidities, may have the best chance of cure and long-term survival with bi-modality protocols of concurrent chemoradiotherapy. It will be very important in the future to define these patients groups within controlled and preferably randomised clinical trials.

One man’s pride, another man’s 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 man’s pride’, but may also turn out as ‘another man’s burden’. The investigation presented by Trodella et al. in this month’s 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.

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