Departments of 1 Radiation Oncology, 2 Thoracic Surgery, 3 Respiratory Physiology and 4 Radiology, Università Cattolica del S. Cuore; 5 Department of Medical Oncology, Libera Università Campus Bio-Medico, Rome, Italy
Received 24 March 2003; revised 1 August 2003; accepted 17 December 2003
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ABSTRACT |
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To report the efficacy of induction treatment (IT) protocol with concurrent radiochemotherapy in locally advanced non-small-cell lung cancer (NSCLC), and to analyze downstaging as a surrogate end point.
Patients and methods:
Patients with histo- or cytologically confirmed stage IIIA or IIIB NSCLC were treated according to an IT protocol followed by surgery. Downstaging was assessed for all resected patients.
Results:
In the period between February 1992 and July 2000, 92 patients were enrolled in the study (57 IIIA, 35 IIIB). Response was observed in 63 patients; 56 patients underwent radical resection. Patients downstaged to stage 0I (DS 0I) showed a statistically significant improved disease-free survival (26.2 months pStage 0I versus 11.2 months pStage IIIII; P = 0.0116) and overall survival (median 32.5 months pStage 0I versus 18.3 months pStage IIIII; P = 0.025). Patients with DS 0I had a significantly lower probability (P = 0.0353) of developing distant metastases estimated in 0.2963 odds ratio.
Conclusion:
Neoadjuvant radiochemotherapy is feasible with good pathological DS results. Pathological downstaging was confirmed to have high predictive value. Its use is suggested in the short-term evaluation of induction protocols efficacy in locally advanced NSCLC.
Key words: concurrent radiochemotherapy, downstaging, integrated therapies, neoadjuvant radiotherapy, non-small cell lung cancer, stage IIIA-IIIB
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Introduction |
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Today there are variations in standard of care for patients with locally advanced disease: surgery may remain the main option for selected N2 patients, while an induction treatment protocol may be applied for marginally resectable disease [1]. Chemoradiation is offered for patients ineligible for surgery who can tolerate it [2]. Recent data show that survival in locally advanced NSCLC is improved by the addition of chemotherapy to radiotherapy and/or surgery [36].
Several studies have explored the use of induction therapy (IT) followed by surgical resection [611]. These studies have shown good results in terms of survival provided that radical surgical resection could be feasible, morbidity rate being in the range 3038.5% [6, 1214] and mortality 2.58% [6, 10, 15]. Initially criticized because of the presumed higher incidence of postoperative morbidity and mortality, IT protocols based on the concurrent administration of chemoradiation are now applied.
There are no well-established criteria to assess the value of an IT protocol (overall efficacy), because overall 5-year survival has proved to be an impractical end point. This is due the high mortality rate in the first 3 years. For these reasons some authors have used surrogate end points such as shorter-term overall survival (3 years) [16] for the evaluation of an IT protocol efficacy. Several studies have explored some surrogate end points such as tumor regression [1719] or nodal clearance [20] as short-term predictors of long-term survival.
We report herein our experience with concurrent radiochemotherapy in locally advanced clinical stage IIIA and IIIB NSCLC. Downstaging was assessed per se in order to analyze it as a surrogate end point in the evaluation of efficacy of an IT protocol and its possible predictive value in terms of overall long-term survival. Furthermore we here explored the impact of this parameter in order to evaluate the effect of local control on survival.
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Patients and methods |
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Generic eligibility criteria for oncologic treatment, including adequate blood chemistry, hepatic and renal function, no pulmonary or cardiovascular contraindications and life expectancy longer than 6 months were applied. Informed consent was obtained from all patients prior to the start of induction protocol.
Assessment procedure
Pre-treatment evaluation included patient history, physical examination, performance status, standard chest X-ray, complete blood chemistry, tumor markers, CT of the chest, brain and upper abdomen, whole-body radionuclide scan, fiberoptic bronchoscopy. Standard X-ray and CT were performed to rule out suspicion of bone metastasis. Upon suspect CT, mediastinal involvement has always been confirmed cyto- or histologically, by mediastinoscopy. In addition to the staging procedure, cardiopulmonary and lung function tests, electrocardiogram and echocardiogram were performed to assess the general status of each patient.
CEA, TPA, NSE, CYFRA 21.1 and LDH have been investigated at diagnosis and during follow-up (except CYFRA which was routinely introduced in our center in 1999), but data are incomplete and no analysis has been performed. During treatment, complete blood count and clinical examination were carried out every week; furthermore, blood chemistry was repeated before every chemotherapeutic cycle; a control chest X-ray was performed when the dose of 2025 Gy had been reached. A complete clinical and radiological re-evaluation was performed 4 weeks after the end of treatment.
Before treatment and after restaging procedures, all patients were carefully evaluated by an interdisciplinary team composed of a pneumologist, a thoracic surgeon, a medical and radiation oncologist and a radiologist. The clinical response to IT was assessed according to the World Health Organization (WHO) criteria. The sum of the complete response rate plus the partial response rate was defined as major clinical response.
Treatment design
The treatment plan is illustrated in Figure 1. Radiotherapy was administered with an angled field technique to include in the isodose 100% (± 5%) area all the target volume, with a maximum dose to the spinal cord of 36 Gy. The median International Commission on Radiation Units and Measurements (ICRU) total referred dose was 50.4 Gy with classical (1.8 Gy/day) or hyper (1.2 Gy/b.i.d.) fractionation. The planned target volume (PTV) consisted of primary tumor, nodal metastasis and first uninvolved nodal chain with 1.5 cm margin. Elective nodal irradiation was not administered. The treatment was CT planned with lung parenchyma correctional factors, and a linear photon accelerator (nominal energy 610 MV) was used in all cases. Advanced 2D technique was used for treatment planning. All patients were immobilized by customized devices.
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From 1992 to 2000 we have observed an improvement in delivering radiotherapy due to a better definition of target volume and the development of conformal therapy. Pneumonectomy rate decreased, testifying a valid organ sparing effect. The switch in chemotherapy regimen was based on the good tolerability of the original scheme (CBCDA) and the better enhancement ratio with CDDP5-FU with a likely better systemic control (spatial co-operation).
If necessary, antiemetics, antibiotics, sedatives, steroids, hematopoietic growth factors and gastric protectors were administered. When grade 23 esophageal, pulmonary and cardiac toxicity or grade 34 hematological and skin toxicity (RTOG scale [21]) appeared, treatment was temporarily interrupted, pending resolution. No change in the total dose of chemoradiation was adopted for grade 2 non-hematological toxicity or grade 3 hematological toxicity. A 25% dose reduction in chemotherapy was applied in case of grade 3 non-hematological toxicity or grade 4 hematological toxicity. Radiotherapy was discontinued in case of grade 4 non-hematological toxicity or persistent side effects (>14 days). Systemic chemotherapy was planned for all patients 1 month after surgical resection and for those judged inoperable. In every case three cycles of a two-drug chemotherapy with cisplatin was planned (with etoposide or vinorelbine); the exclusion criteria were a post-operative ECOG performance status 2 or patients refusal.
Statistical analysis
The disease-free survival (DFS; time to local plus distant event) time to event curve has been calculated with the KaplanMeier method [22] and statistical significance of the difference has been assessed with the log-rank test [23, 24]. A similar procedure was carried out to compare the time to event survival curves. Hazard ratio with 95% confidence interval was calculated as well for DFS and overall survival (OS). Differences between groups were compared adopting the Fisher exact test [25]; the relative risk (RR) with 95% confidence interval (CI) has been calculated with the Woolf approximation.
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Results |
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Clinical staging of the 19 pneumonectomized patients was as follows: 10 IIIBT4, nine IIIAN2 (including four T3 patients). Three patients with clinical N3 disease (confirmed at mediastinoscopy) did not show any residual disease at CT re-evaluation. Redo mediastinoscopy was carried out and biopsies were taken in the same area of the first procedure. Upon frozen section confirmation of tumor absence, the operation proceeded with thoracotomy.
Mortality
The perioperative mortality rate (within 30 days) was 11.4% (seven of 61). Five of seven patients were treated with pneumonectomy, one with bilobectomy and one with lobectomy. Causes of death were a cardiovascular disease in four patients, massive post-operative bleeding in one, respiratory failure in one and pleural empyema and septicemia in one due to persistent broncho-pleural fistula; six of seven patients were in the CBCDART group (six of 43; 13.9%), one in the FUPLART group (one of 18; 5.5%).
Morbidity
The major morbidity rate was 14.7% (nine of 61 patients); it included one pulmonary abscess, one acute hemorrhage (re-thoracotomy), one pleural empyema, one bronchopleural fistula, two myocardial infarctions, two pulmonary failures and one pulmonary embolism plus pneumonia. Three of these patients received pneumonectomy and three bilobectomy; in the remaining three patients lobectomy, lobectomy plus wall resection and thoracotomy were performed. Of these nine patients, nine of 43 (16.2%) were treated with CBCDART, two of 18 (11.1%) with FUPLART.
Definitive histological assessment and pathological downstaging
The overall downstaging rate was 75% (Table 4). Sixteen of 56 (28.6%) patients were downstaged to stage 0, 10 of 56 to stage I (17.8%), 16 of 56 (28.6%) to stage II. Stage III persisted in 14 of 56 (25%) patients. In Tables 5 and 6 clinical T and N are compared with pathological stages.
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Seven of 56 (12.5%) patients had brain metastasis as first and single site of recurrence: three were classified at pathological restaging as stage IIIII, and four as stage 0I; five patients had adenocarcinoma and two squamous cell carcinoma: five were classified at diagnosis as IIIA, two as IIIB (one T4N2 and one T2N3).
Adjuvant chemotherapy
Among the 56 patients who underwent radical resection, in 36 patients adjuvant chemotherapy was started; 28 received three to six cycles. In eight patients treatment was stopped early due to hematological toxicity in four patients, one for deep venous thrombosis, one for early brain recurrence (3 months after re-evaluation), one for decline in performance status and one due to a delayed bronchial fistula (80 days after surgery).
The causes of the 20 withdrawals from adjuvant treatment were seven post-operative deaths, four because of patients refusal, three for PS >2, one for pulmonary insufficiency after surgery, one for onset of new cancer (colon), one for patients oncologist refusal, and one patient was lost after surgery.
Survival
Overall survival (OS) for all study patients was 19% at 3 years and 15% at 5 years (Table 8 and Figure 2). Significant differences were found when the so-called responders, who underwent radical resection, were compared with patients who did not undergo surgery (median survival was 25.4 months in the operated versus 10.2 months in the not operated patients; P <0.0001; Figure 3). Five patients who underwent surgery, but without radical interventions, had a median survival of 14.2 months.
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Discussion |
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When surgery is not reasonably feasible, any therapy that by downstaging the tumor makes the patient re-enter resectability criteria has a direct impact on the local control rate and thus on the general outcome. To date, discussion is focused on two major problems: which is the best multi-modality approach, and is there an end point different from overall long-term survival for the evaluation of the effectiveness of an induction protocol? Regarding the first question, the most popular scheme is to perform chemo or radiochemo induction protocol as neoadjuvant to surgery.
The studies so far have addressed and explored the feasibility and efficacy of multi-modality neoadjuvant treatments and yet an extreme lack of homogeneity is present regarding the kind of chemotherapeutic agent or agents used, concomitant or sequential radiotherapy and its characteristics (energy source, technique, fractionation, total dose, irradiated volume). For these reasons definitive conclusions cannot be drawn to assess which is to date the best induction treatment.
In our opinion a general beneficial effect in terms of efficacy may be identified when a multimodality approach is used combining neoadjuvant irradiation and chemotherapy, which we here demonstrated to be feasible [29] with limited volume and low total dose. Table 10 shows the published trial where trimodality treatment was explored.
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In the ESSEN trial [8] patients were treated with a mixed approach, which includes three cycles of induction chemotherapy with CDDP 60 mg/m2 on days 1 and 7 (or 8) and VP-16 150 mg/m2 on days 3, 4 and 5 repeated every 22 days, and one cycle concurrent with radiotherapy of CDDP 50 mg/m2 on days 1 and 7 (or 8) and VP-16 100 mg/m2 on days 3, 4 and 5. Hyperfractionated radiotherapy was adopted with 1.5 Gy b.i.d. for a total dose of 45 Gy. Seventy-five of 94 enrolled patients (79.7%) were considered eligible for surgery after IT protocol; 60 of 75 (80%) underwent radical surgery. The mortality rate was 5.3% (four of 75) with a 40% (24 of 60) pathological complete response.
In our study, 61 of 91 evaluable patients (67%) were eligible for surgery, and 56 of 61 (91.8%) underwent radical resection. In this series we observed a better survival for patients downstaged to pathological stage 0I, with a median survival of 32.5 months and a 3-year survival of 49%. The results of DFS are interesting with a median value of 26.2 months and of 37% at 3 years. These results are similar to those reported by the SWOG and ESSEN trials, where radically resected patients with N0 disease had a 3-year survival of 44% and 38%, respectively.
We report a mortality rate of 11.4% (seven of 61), similar to that of the SWOG trial. An important factor to be underlined is that five of seven patients received pneumonectomy: we share Martin et al.s hypothesis [14] that pneumonectomy is the major risk factor of mortality ratter than the type of induction therapy protocol adopted. As for the morbidity rate, Faber et al. [30] and Weiden and Piantadosi [31] reported a major morbidity rate of 22.5% (14 of 62 patients who underwent surgery) and 25.9% (14 of 54), respectively, while we reported a rate of 14.7% (nine of 61).
From the beginning of this trial we have adopted a radiotherapy approach with a low total dose and limited irradiated volume (only primary tumor with macroscopically involved lymph nodes) without elective nodal irradiation (ENI), because our goal was the re-enter resectability. This approch explains the low acute and late non-hematological toxicity as well as the morbidity rate. We believe that these two issues with conformal 3D radiotherapy technique could modify the morbidity rate after neoadjuvant concurrent chemoradiation.
The role of surgery was recently evidenced by the early results of the Intergroup Trial 0139 [32], where definitive chemoradiation was compared to a neoadjuvant chemoradiation in IIIAN2 (at proven mediastinoscopy) stage. In the ongoing analysis of the trial a significantly longer progression-free survival has been observed in patients who received surgery after neoadjuvant concurrent chemoradiation (14 versus 11.7 months; P = 0.002). A better overall 3-year survival (38% versus 33%) was also observed, but these data are not yet mature enough to determine a statistically significant difference.
The Paris trial [33] explored the trimodality treatment approach in IIIB patients. Eligibility criteria included a potentially resectable disease, defined as T4 disease with the involvement of the intrapericardial pulmonary artery, trachea, carina, left atrium or superior vena cava, and N3 patients. Induction treatment included a three-drug chemotherapy with 5-FU 1 g/m2 from days 1 to 3 and days 3133, CDDP 100 mg/m2 on days 1 and 31 and vinblastine 4 mg/m2 on days 1 and 31. Concurrent radiotherapy was applied with a split course of 21 Gy delivered as 1.5 Gy per fraction b.i.d. from days 1 to 9; a rest of 1015 days and other 21 Gy with the same fractionation beginning on day 21. If resectable and medically operable, surgery was performed with a midline sterno-laparotomy, radical resection of tumor mass, extensive mediastinal lymph node dissection (bilateral for N3 disease) and preventive bronchial omentoplasty. Forty patients were enrolled (21 with T4 disease, 19 with N3); 29 underwent thoracotomy and 24 were radical resected; 18 pneumonectomies were performed. In spite of aggressive surgery the mortality rate was 7% with 24% morbidity rate. Survival was strictly associated with post induction nodal status (N01) and radical resection.
In our series, 35 patients with stage IIIB were enrolled: 30 patients with the same type of T4 disease and only five carefully selected N3 patients who underwent lateral thoracotomy only with negative redone mediastinoscopy. We believe that for these patients, especially for those with T4 disease, a multimodality approach including surgery could be applied.
We have explored the opportunity to analyze downstaging per se as a surrogate end point for the evaluation of the efficacy of a neoadjuvant approach. There is some evidence of the impact of tumor downstaging on other types of neoplasm such as rectal [17, 18] or esophageal tumors [19], while in lung cancer lymph-node clearance [20] has already been documented. We have shown that downstaging to pStage 0I was significantly correlated with better long-term survival if compared to pStage IIIII. These results substantially confirmed the reports by Choi et al. [34] and Martin et al. [16]. As compared to Martins experience, we explored the value of downstaging in a more homogeneous group of patients. In fact, we have evaluated patients with clinical stages IIIA and IIIB only.
In this trial we have investigated the correlation between pathological downstaging and survival and distant recurrence rate. We have found that downstaging is directly and significantly correlated with disease-free survival and distant recurrence rate. This underlines the impact of local control on metastasis and survival. The disease-free interval seems to be a more reliable parameter, when the efficacy of an IT protocol is explored. Moreover the DFS has presumably a significant impact on the quality of life of patients (no cancer, no treatment; no treatment, no side-effects). To our best knowledge, this kind of correlation has never been explored.
Downstaging based on only radiotherapy is poor [35], while neoadjuvant chemotherapy shows a pathological complete response that ranges from 0% reported by Roth et al. [11] and Sugarbaker et al. [9] to 16.7% in Martini et al. [10]. Also in these cases the pCR has been translated with best overall survival. The role of adjuvant chemotherapy is still controversial: in our experience, 28 of 56 radically resected patients completed planned chemotherapy, but no significant influence on systemic spread was recorded. This small evidence is similar to the ALPI [36] and ECOG trials [37], which showed no benefit from adjuvant chemotherapy, while recent results of the IALT trial [38] re-considered the role of adjuvant chemotherapy with a small benefit of 4% at 5 years.
In the series of Robnett et al. [39], crude and 2-year actuarial rates of brain metastases of 19 and 30% respectively were recorded. On multivariate analysis independent prognostic factors were stage (IIIB versus IIIA) and timing of chemoradiation (sequential versus concurrent). In our analysis, seven patients had a brain metastasis as first site of recurrence and this small number did not provide any information about the impact of histology, staging at diagnosis or downstaging on the potential impact of prophylactic cranial irradiation for such patients.
Finally, pathological downstaging rate could be a reasonable surrogate end point to compare different IT protocols. In our series we observed a better rate of downstaging in those patients who received hyperfractionated radiotherapy and CDDP + 5-FU chemotherapy, but no data are available in the literature concerning an improvement in pathological response using different radiotherapy fractionations. A possible explanation could be that chemotherapy, as radiosensitizer, might have a better enhancement ratio with twice daily radiotherapy. In order to improve the pathological downstage rate, we have already explored in a phase I trial the maximum tolerated dose of weekly gemcitabine and concurrent radiotherapy [40]. The feasibility and pathological response of this combination treatment [41] is under investigation in a phase II trial.
On the basis of the reported experiences we can conclude that: treatment of locally advanced NSCLC remains challenging and there is still room for investigation; concurrent neoadjuvant radiochemotherapy is feasible with limited volume and low total dose; downstaging to early stages (0I) represents a direct indication of the effectiveness of any multimodality approach and is significantly correlated with disease-free interval and distant recurrence rate; the rate of downstaging seems better in neoadjuvant combined chemoradiation than chemotherapy and radiotherapy as only treatment; in this setting the main advantage of long-term outcome in planning an induction protocol in locally advanced NSCLC is the opportunity to obtain a significant pathological downstage rate.
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FOOTNOTES |
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