Lessons to learn from EORTC study 08981: A feasibility study of induction chemoradiotherapy followed by surgical resection for stage IIIB non-small cell lung cancer

1. Introduction 

The overall prognosis of locally advanced non-small cell lung cancer (NSCLC) stage IIIB (any T4 or N3) is poor, and primary surgery is rarely possible. Standard treatment for clearly unresectable disease is sequential or concurrent chemoradiotherapy with full dose chemotherapy [1]. Several studies have demonstrated that locally advanced, potentially resectable and unresectable stage IIIA NSCLC may become operable after induction chemo- or chemoradiotherapy [2], [3]. The strongest predictor of long-term survival after such an induction treatment appears to be the absence of residual tumor in the mediastinal lymph nodes at surgery, the so-called downstaged patients [4], [5], [6].

Based on the promising results of induction therapy for stage IIIA [2], [7], [8], [9], the SWOG investigated if a tri-modality treatment was also feasible for stage IIIB NSCLC (study 8805) [2]. A 3-year survival rate of about 25% was found, without survival difference between stage IIIA and IIIB. Again, the prognosis with persistent N2 or N3 disease after induction therapy was poor, with 5-year survival rates of about 15%. Although the induction treatment was different in subsequent trials (number of chemotherapy cycles, different drugs, standard or hyperfractionated radiotherapy), the resectability rate was similar at about 60%, with a pathologic complete remission rate of about 20% [10], [11], [12], [13], [14]. It is evident now, that persistent N2 or N3 disease after induction treatment is a contra-indication for further surgery [3], [4], [15], and that only those who are downstaged benefit from induction therapy followed by resection Despite these promising results, the potential role of a surgical resection following chemotherapy (with or without radiation) is still controversial. The series published so far are usually limited to single institutional experiences and are listed in Table 1 [2], [16], [17], [18]. Proper and reliable restaging after induction therapy is crucial in order to prove downstaging. Except for the study by Stamatis et al., restaging has been based on CT evaluation, known to be inappropriate for mediastinal staging and restaging with a low accuracy [19]. Therefore, the Lung Cancer Group of the European Organisation for Research and Treatment of Cancer (EORTC) decided, to investigate by study 08981 the feasibility of a tri-modality approach of chemoradiotherapy followed by restaging, with the re-mediastinoscopy and resection in a multicenter setting and this before the publication of the study by Stamatis et al. [16]

Table 1. Differences in the selection criteria and restaging methods in trimodality trials for stage III non-small cell lung cancer

		Stamatis [16]	Grunewald [17]	SWOG 8805 [2]	INT 0139 [18]	EORTC 08981
	Number of patients	174 IIIB, 218 IIIA	40 IIIB	51 IIIB, 75 IIIA	429 IIIA	5 IIIB
	Recruitment period	10 years	3 years	4 years	7 years	2 years
	Participating institutes	Single	Single	Multiple	Multiple	Multiple
	Supraclavicular LN's	No	Yes	Yes	No	No
	T4 esophagus, aorta, vertebrae	No	No	Yes	Not applicable	No
	Sattelite nodule	No	No	Not mentioned		No
	Myocardium	No	No	Not mentioned		No
	Malignant pleural/pericardial effusion	No	No	No		No
	Lower lobe tumors with contralateral upper mediastinal LN's	Yes	Yes	Yes	Not applicable	No
	N2 and N3 confirmation method	Histology	Histology	Histology	Histology	Histology
	T4 confirmation method	CT or MRI	Histology	Histology	Not applicable	Histology
	Restaging method	Mediastinoscopy	CT scan	CT scan	CT scan	Mediastinoscopy

2. EORTC 08981 study design, methods and results 

The EORTC 08981 study was designed as a prospective, non-randomised phase II feasibility study to determine the incidence of radically resected stage IIIB NSCLC following induction chemoradiotherapy. The secondary end-points were the toxicity of the induction regimen, the toxicity of the surgical procedure, the clinical response rate after the induction therapy and pathological response after surgery. Based on the Simon one sample two stage testing procedure [20], considering an unacceptable and an acceptable success rate of, respectively, 40% and 60%, the total sample size was estimated to be 62 eligible patients with an alpha error of 0.10 and a power of 0.95. In this multicenter study only patients with clinical stage IIIB NSCLC (any T4 or N3) could be enrolled. Important selection criterion for the participating centers was, however, that the thoracic surgeon was capable to perform a re-mediastinoscopy in case of N3 disease. If that particular expertise was not present, only patients with T4N0M0 NSCLC were enrolled. The T4 status had to be histologically confirmed. Patients with pleuritis carcinomatosis or N3 due to scalene or supraclavicular lymph node involvement were excluded. Induction chemotherapy treatment consisted of three cycles of cisplatin 80mg/m2 on day 1 and etoposide 100mg/m2 on day 1–3 intravenously. Involved field radiotherapy consisted of 45Gy in 1.8Gy per fraction, for 5 days a week over a period of 5 weeks starting from day 2 of chemotherapy cycle 2. Patients with T4 N0-1M0 disease without progression during induction therapy proceeded directly to surgery without restaging. If a FDG-PET facility was available, a PET scan was performed at baseline. If initial PET positive mediastinal lymph nodes became PET negative at restaging, patients were allowed to proceed directly to thoracotomy without re-mediastinoscopy. When the PET scan remained positive, however, a re-mediastinoscopy had to be performed to exclude persistent N2/3 disease. If there was no PET facility available, patients with N2 or N3 disease without progression during induction therapy had to undergo a re-mediastinoscopy.

Of the initial 10 European thoracic oncological centers expressing their interest in this trial, only five centers were eventually activated. Between May 2001 and August 2002, five male patients were enrolled in two centers. Median age was 67 years (range 60–74 years), all of them with WHO performance score 0 or 1. One patient progressed during induction treatment, and did not undergo restaging or surgery. One patient was restaged by endoesophageal ultrasound (EUS) instead of a re-mediastinoscopy. Grade 3/4 neutropenia or trombocytopenia occurred in four (80%) and two patients (40%), respectively. Half of them relapsed loco-regionally, the others on distant sites. Both patients who underwent a right-sided pneumonectomy developed a bronchopleural fistula.

3. Discussion 

Although it is evident that EORTC study 08981 is a negative study, several other investigators have demonstrated that a tri-modality approach is feasible with acceptable toxicity. Examples of this are the large Intergroup trial of North America, the German Lung Cancer Cooperative Group Study, the studies performed by the West German Cancer Center Consortium, the Italian and French tri-modality experiences and several phase-II studies performed in North America [11], [16], [17], [18].

The participating centers in EORTC study 08981 were large institutions, experienced in chemo-radiation, where multidisciplinairy tumor board meetings take place weekly. Therefore, other reasons may underlie the discrepancy found with the studies published before. One of them is that we used more stringent selection criteria (Table 1). In our trial the T4 status had to be confirmed histologically and patients with supraclavicular lymph node involvement or lower lobe tumors with contralateral upper higher mediastinal lymph node involvement were excluded. In contrast, in the SWOG 8805 trial, 35% of the IIIB patients had N3 disease based on supraclavicular lymph node involvement. With the current available data, IIIB patients with supraclavicular lymph node involvement should, to our opinion, not be enrolled in tri-modality protocols. Although Machtay et al. reported a prolonged survival in a non-randomised study in patients with supraclavicular node metastases treated with chemoradiotherapy [21], Lee et al. demonstrated that patients with supraclavicular lymph node involvement treated with chemoradiotherapy had a median survival of only 12 months while it was 28 months for patients without supraclavicular lymph node involvement, which was statistically significant [22].

A second major reason for the slow accrual is that our restaging method was different from those in the other studies (Table 1). CT evaluation is known to be inappropriate for the staging and restaging of the mediastinum [19], and only patients with cytological or histological confirmed downstaging [2], [4] benefit from resection. Therefore, re-mediastinoscopy received a central role in the restaging of our patients. Even though two centers with surgeons experienced in performing re-mediastinoscopy participated, it appeared to be a major threshold for patient enrollement. Due to extensive fibrosis and difficult access, re-mediastinoscopy leads to more complications and often-incomplete sampling of the mediastinum [23], [24]. Only few studies addressed the role of re-mediastinoscopy in the restaging of lung cancer [25], [26], [27], [28], [29], [30]. Although Van Schil et al. demonstrated that a re-mediastinoscopy has an accuracy of 85% and a negative predictive value of 75% [25], only a small number of patients had undergone radiotherapy, so that no final conclusions can be drawn for the role of the re-mediastinoscopy after chemoradiotherapy [29]. De Leyn et al. showed in a prospective trial that re-mediastinoscopy is technically feasible, but the sensitivity and negative predictive value are low due to fibrosis [30]. Although mediastinoscopy is still regarded the gold standard for mediastinal staging, minimally invasive staging procedures such as EUS [31], [32], [33], [34], [35], [36], [37] and EBUS [36] are attractive alternatives, available in an increasing number of institutions. A combined approach of EUS- and EBUS-fine needle aspiration even allows the investigation of both sides of the mediastinum [36]. This evolution might lead in an increasing number of institutions to a shift in the sequence of mediastinal staging procedures. Upfront staging could be done by minimally invasive procedures such as EUS and EBUS, while surgical procedures could be reserved for playing a role in restaging after induction therapy [29]. In this way, a technically more difficult re-mediastinoscopy is avoided. FDG-PET has not yet proven to be enough accurate in mediastinal restaging. Initial promising data for the assessment of downstaging of mediastinal lymph nodes could not be confirmed [37], [38]. Changes in the microenvironment of the tumor, such as altered perfusion after chemo- or chemoradiotherapy, may impair the presentation of FDG to the metastatic mediastinal node sites. Thus, PET-imaging is not performant enough to detect persistent N2/3 disease. Induction chemoradiotherapy results in a high percentage of false positive findings as a result of inflammatory reactions after radiotherapy. Therefore, restaging should currently use invasive techniques, although FDG-PET may help to guide these procedures. Although the optimal restaging strategy is yet unknown, it should at least take place as soon as possible after the completion of the induction treatment to avoid long interruptions in the scheduled radiotherapy if no downstaging has been achieved.

Despite initial expression of interest in EORTC study 08981 by 10 large European cancer institutes, the Medical Ethical Boards of five institutes considered the tri-modality approach too controversial for this particular group of patients and did not gave their approval. On the other hand, in the centers that received Medical Ethical Boards permission, competing studies targeting the same patient group appeared to be ongoing afterwards. The prevailing view of many Medical Ethical Boards that a tri-modality approach for stage III NSCLC is inappropriate, is very debatable, given the fact that, for example in superior sulcus tumors, a tri-modality approach is the standard of care [39], [40], [41].

The recent results of the EORTC 08941 and the Intergroup study 0139 have shown however, that the extent of surgery determines the postoperative mortality and that in a subgroup in which the resection was confined to a lobectomy there was a survival benefit. Although these two studies have not been designed to explore the effect of the extent of the resection, this subgroup analyses suggest that especially right-sided pneumonectomies should be avoided [5], [12].

Although the number of participants in this trial is low and no final conclusion can be drawn, the results of the five included patients are disappointing with a high rate of pneumonectomies, major complications after a right-sided pneumonectomy and poor overall survival.

In conclusion, although this study illustrates that the conduct of a tri-modality study across Europe appeared to be difficult in the 1990s, the number of centers with highly qualified and experienced specialists involved in this kind of multi-modality approaches has rapidly increased since then. Future initiatives should, therefore, certainly be encouraged. Therefore it is very important to ensure full commitment of all investigators involved in tri-modality treatment. Minimally invasive procedures such as EUS and EBUS should preferably be used for up-front mediastinal staging, mediastinoscopy with or without EUS should preferably be reserved for restaging, and especially right-sided pneumonectomies should be avoided. Though evident, the feasibility to complete the study within a reasonable time period is still a condition sine qua non.

Conflict of interest statement 

None declared.