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Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer?
Lung Cancer (2006) 53, 323—330
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/lungcan
Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer? Byeong-Bae Park a, Joon Oh Park a, Hojoong Kim b, Yong Chan Ahn c, Yong Soo Choi d, Kwhanmien Kim d, Jhingook Kim d, Young Mog Shim d, Jin Seok Ahn a, Keunchil Park a,∗ a
Divisions of Hematology—Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, Republic of Korea b Division of Pulmonology and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea c Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea d Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Received 18 February 2006; received in revised form 21 May 2006; accepted 24 May 2006
KEYWORDS Neoadjuvant; Concurrent; Chemoradiotherapy; Stage IIIA; Non-small cell lung cancer
∗
Summary Background: Neoadjuvant treatment followed by surgery is currently being investigated for locally advanced non-small cell lung cancer (NSCLC). This study reports efficacy, toxicity and feasibility of neoadjuvant chemotherapy with concurrent radiotherapy (CCRT) in stage IIIA, N2 positive NSCLC. Methods: From March 2001 to February 2004, 52 patients with histologically confirmed stage IIIA, N2 positive NSCLC were registered. Patients received preoperative CCRT that consisted of weekly paclitaxel plus platinum chemotherapy and concurrent radiotherapy followed by surgery. Results: Overall response rate was 76.9% (95% CI, 64—88%). The major grade 3—4 toxicities were radiation esophagitis (15.4%) and neutropenia (11.5%), and treatment-related mortality rate was 1.9%. Forty-two of 52 patients (80.8%) subsequently underwent surgical resection and 35 of 52 patients (67.3%) underwent complete resection. Among them, pathological complete response was obtained in 4.8%. Pathological downstaging rate to N0—1 and stage 0—II at surgery were 69.0% and 66.7%, respectively. The perioperative major morbidity rate was 23.8% and perioperative mortality was 2.4%. At a median follow-up of 33.9 months (range: 16.4—49.9), the median progression-free survival and overall survival were 16.5 months (95% CI, 6.2—26.8) and 25.6 months (95% CI, 14.6—36.6), respectively. Multivariate analyses identified that patients
Corresponding author. Tel. +82 2 3410 3459; fax: +82 2 3410 0041. E-mail address: [email protected] (K. Park).
0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2006.05.024
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B.-B. Park et al. achieved mediastinal nodal clearance (downstage to pathological N0 or N1) after CCRT (p = 0.02) and age at diagnosis < 60 years (p = 0.01) showed significantly improved survival. Conclusion: Neoadjuvant CCRT showed a high overall response rate with tolerable toxicity profile. Downstaging after CCRT may increase the rate of complete tumor resection and result in survival benefit in stage IIIA, N2 positive NSCLC patients. © 2006 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2.2. Assessments
Locally advanced NSCLC still represents a therapeutic challenge. The long-term survival of these patients treated with single therapeutic option (chemotherapy, radiotherapy, or surgery) is extremely poor. This has been the rationale for many multidisciplinary attempts at therapeutic improvement in the recent years. Currently, there are variations in the standard of care for patients with locally advanced disease. While surgery remains the main option for selected N2 positive patients, a neoadjuvant treatment protocol may be applied for marginally resectable disease, and chemoradiation may be offered to patients ineligible for surgery who can tolerate it [1]. Recent data show that survival in locally advanced NSCLC is improved by the addition of chemotherapy to radiotherapy and/or surgery [2—4]. Radiotherapy in combination with chemotherapy plays a leading role in the treatment of locally advanced unresectable NSCLC, although its role in the management of resectable N2 disease is still controversial. Several studies have evaluated neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgical resection in locally advanced NSCLC [4—12]. These studies have shown good results in terms of survival benefit provided radical surgical resection is feasible, without increasing morbidity and mortality rate [13]. This present study reports efficacy, toxicity and feasibility of neoadjuvant CCRT with newer drugs (paclitaxel and platinum) in N2 positive stage IIIA NSCLC. Downstaging after CCRT was also assessed in order to analyze it as an end point in the evaluation of efficacy of a neoadjuvant therapy and its possible predictive value for overall long-term survival.
Pretreatment evaluation included patient’s history, physical examination, performance status, standard chest X-ray, complete blood count, blood chemistry, CT scan of the chest including upper abdomen, whole-body bone scan, fiberoptic bronchoscopy. Brain MRI had been performed for patients with histology of adenocarcinoma. All patients were histologically confirmed N2 by mediastinoscopic biopsy that was included as a part of clinical staging. In addition to the staging procedure, pulmonary function tests, electrocardiogram and echocardiogram were performed to assess the general status and eligibility of each patient for surgery. During treatment, complete blood counts, blood chemistry, and clinical examination including chest X-rays were repeated prior to each chemotherapeutic cycle. Restaging procedures with complete clinical and radiological evaluation were performed within 3 weeks following the completion of CCRT treatment. Clinical response to CCRT was assessed according to the response evaluation criteria in solid tumors and complete resection was defined as removal of all known disease neither with microscopic involvement of the margins of resection, nor of the upper mediastinal lymph nodes sampled at thoracotomy (ATS station 2). Patients undergoing surgery were evaluated by chest CT scan every 3 months for 2 years following surgery, and then every 6 months thereafter.
2. Patients and methods 2.1. Patients’ selection Fifty-two patients were enrolled between March 2001 and February 2004. All of them had histologically or cytologically confirmed NSCLC and mediastinoscopic biopsy-proven stage IIIA, N2 disease. T3N1 disease was excluded. Performance status was ECOG 0—1. None of them had either undergone any previous oncologic treatment or had any concurrent medical illnesses that would contraindicate surgery. The bone marrow, liver, and renal function had to be within predefined limits (absolute neutrophil count ≥1.5 × 109 /l; platelet count ≥100 × 109 /l; total bilirubin ≤2.0 mg/dl; AST and ALT ≤2 × the upper normal limit; serum creatinine ≤1.4 mg/dl and creatinine clearance ≥60 ml/min. Written informed consent was required from all patients before the start of treatment.
2.3. Treatments Neoadjuvant CCRT included chemotherapy and concurrent thoracic radiotherapy (TRT). The chemotherapy regimens consisted of weekly paclitaxel (50 mg/m2 /week IV) plus cisplatin (25 mg/m2 /week IV) or weekly paclitaxel (50 mg/m2 /week IV) plus carboplatin (AUC 1.5/week IV) for 5 weeks. Concurrent TRT dose was 45 Gy over 5 weeks (1.8 Gy/fraction/day, 5 fractions/week) using 10 MV X-rays. The TRT target volume included the primary tumor plus the ipsilateral hilar and mediastinal lymphatics with 1.5—2 cm peripheral margins. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, Version 2.0. Weekly treatment was deferred in cases with grade 4 hematological toxicity or grades 3—4 non-hematological toxicity. Chemotherapy was discontinued if these toxicities persisted for two consecutive weeks. However, if the patient recovered from these adverse effects after interruption of treatment for a week, chemotherapy was resumed in accordance with the pre-scheduled doses and schedule. The planned dose of paclitaxel was reduced by 25% in cases with grades 2—3 hematological toxicity during the week following the interruption of chemotherapy. Surgical resection
Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer? was planned at around 4 weeks following the completion of neoadjuvant CCRT. Postoperative radiation therapy (18 Gy in 10 fractions) was administered in the event of persistent histologically positive N2 lymph node, positive multi-N1 lymph nodes, or positive resection margin at the time of surgery.
2.4. Statistical analysis The overall survival (OS) duration was calculated from the first day of the neoadjuvant CCRT until the date of death or the latest documented follow-up. Progression-free survival (PFS) duration was calculated until the date of the first documented progression or the latest follow-up. Kaplan—Meier survival curves were generated, and the statistical significance of the difference was assessed using log-rank test. Differences between groups were compared using Pearson 2 -test. Multivariate analyses of the independent prognostic factors for survival were performed using the Cox proportional hazards regression model with 95% confidence interval. Simon’s two-stage minimax design was used to determine the sample size and decision criteria for this phase II study. With the target downstage rate of 60% and the lowest downstage rate of interest set at 40%, we needed 46 evaluable patients with an 80% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Allowing for a 10% loss to follow-up rate, a total of 51 patients were needed.
3. Results 3.1. Patients’ characteristics Clinical characteristics of the 52 enrollees are depicted in Table 1. Median age was 58 years (range: 23—72) and all patients had a good performance status of ECOG 0—1. Histologic types consisted of adenocarcinoma (26; 50.0%), squamous cell carcinoma (22; 42.3%), large cell carcinoma (2; 3.8%), and non-small cell carcinoma (2; 3.8%). Nine of 52 patients (17.3%) had a bulky-N2 disease (node size >2 cm) in CT scan before start of therapy. Numbers of patients treated with paclitaxel plus cisplatin (TP) and paclitaxel plus carboplatin (TC) were 41 (78.8%) and 11 (21.2%), respectively.
3.2. Neoadjuvant CCRT The given dose densities of chemotherapy in CCRT were 49.0 mg/m2 /week of paclitaxel, 24.5 mg/m2 /week of cisplatin, and AUC 1.47/week of carboplatin. Five of 52 patients (9.6%) had experienced interruption of CCRT for a week due to toxicities, but the planned doses of chemotherapy and radiotherapy were successfully administered to these five patients. Incomplete planned doses of chemotherapy were delivered in seven patients (13.5%). Of these, five patients were given insufficient number of chemotherapy cycles, and two patients were treated with 25% reduced dosage of paclitaxel for two cycles of chemotherapy due to hematological toxicity. TRT was administered as planned
Table 1
325
Patients characteristics
No. of patients
52
Age Median Range
58 years 23—72
Sex Male Female
43 (82.7%) 9 (17.3%)
ECOG performance status 0 1
8 (15.4%) 44 (84.6%)
Histologic type Adenocarcinoma Squamous cell Large cell Others
26 (50.0%) 22 (42.3%) 2 (3.8%) 2 (3.8%)
Stage (IIIa) T1N2 T2N2 T3N2
12 (23.1%) 34 (65.4%) 6 (11.5%)
Bulky-N2 disease by CT scan Yes No
9 (17.3%) 43 (82.7%)
in 50 patients (96.2%). Grade 3—4 toxicities of CCRT are shown in Table 2. Unfortunately, one patient succumbed to treatment-related death during CCRT due to neutropenic sepsis. Clinical response to CCRT at restaging was observed in 40 of 52 patients (76.9%; 95% CI, 64—88%) including five radiologically complete responses (CRs; 9.6%). Five of 52 patients (9.6%) showed stable disease (SD) and 7 of 52 patients (13.5%) developed progressive disease (PD). Five of seven patients had distant disease progression while two had loco-regional PD. In univariate subgroup analysis of the clinical response rates, the histological type of squamous cell had better response to CCRT than the non-squamous cell type (p = 0.04).
Table 2
Grade 3—4 toxicities of CCRT (N = 52, %)
Hematological Neutropenia Thrombocytopenia Neutropenic infection*
6 (11.5) 2 (3.8) 1 (1.9)
Non-hematological Radiation esophagitis Nausea/vomiting Radiation pneumonitis Myalgia Hepatotoxicity Hemoptysis Edema Pneumonia
8 (15.4) 4 (7.7) 3 (5.8) 2 (3.8) 2 (3.8) 1 (1.9) 1 (1.9) 1 (1.9)
*
TRM: treatment-related mortality.
326 Table 3
B.-B. Park et al. Results of surgery (N = 42, %)
Types of surgery Lobectomy Pneumonectomy Bilobectomy
33 (78.6) 6 (14.3) 3 (7.1)
Resection margin Positive Negative
5 (11.9) 37 (88.1)
Pathological response CR PR SD PD
2 (4.8) 33 (78.6) 4 (9.5) 3 (7.1)
Postoperative radiotherapy Yes No
20 (47.6) 22 (52.4)
3.3. Surgery After restaging work-up, 42 of 52 patients (80.8%) underwent radical resection, including complete mediastinal lymph node dissection. Ten patients who were withdrawn from surgery included seven patients with PD, and three patients who refused surgery. Surgical procedures included 33 lobectomies, 3 bilobectomies and 6 pneumonectomies. After surgery, upper mediastinal lymph nodes involvements were found in two patients and another five patients were positive resection margin. Therefore, 35 patients (67.3%) achieved complete resection. Postoperative adjuvant radiotherapy was administered to 20 patients (47.6%). Postoperative pathological response rate to CCRT was 83.3% in 42 resected patients including two (4.8%) pathological complete responses (pCR) (Table 3). Postoperative mortality occurred in one patient (2.4%) who died from acute respiratory distress syndrome (ARDS). Ten of 42 resected patients (23.8%) had postoperative morbidities. These included four bronchopleural fistulas, three pneumonias, two empyemas, and one ARDS.
3.4. Survival and downstaging At the time of this analysis, median follow-up period was 33.9 months (range 16.4—49.9 months). Nineteen patients
Fig. 1
Table 4
Postoperative pathological downstaging
IIIA (N = 42, %)
N2 (N = 42, %)
T1 (N = 11, %) T2 (N = 28, %) T3 (N = 3, %)
pStage 0—I
pStage II
pStage IIIA
16 (38.1)
12 (28.6)
14 (33.3)
pN0
pN1
pN2
16 (38.1)
13 (30.9)
13 (30.9)
pT0
pT1
pT2
pT3
— 5 (17.9) —
9 (81.8) 14 (50.0) —
2 (18.2) 7 (25.0) 2 (66.7)
— 2 (7.1) 1 (33.3)
pStage: postoperative pathological stage.
(36.5%) are still disease-free, seven patients (13.5%) have had disease progression, and 26 patients (50.0%) have died. All of the 10 unresected patients (100.0%) and 17 of the 42 resected patients (40.5%) had disease progression. The median PFS after CCRT treatment was 16.5 months (95% CI, 6.2—26.8; Fig. 1). In the 17 patients with disease progression after surgery (including eight patients with loco-regional recurrence, eight patients with distant recurrence, and one patient with both), nine patients were administered palliative chemotherapy while the others received supportive treatment or local radiotherapy. There were distant progressions in nine patients after surgery. It was consisted of two brain, two liver, two lung-to-lung, two cervical LNs, and one adrenal gland metastasis, which were first detected site. Only one of two patients with brain disease was adenocarcinoma. The median duration of overall survival was 25.6 months (95% CI, 14.6—36.6; Fig. 1). Overall survival rates of all patients at 1, 2 and 3 years were 64.8%, 50.1% and 44.9%, respectively. Patients who underwent surgery had statistical significant improvement in OS and PFS compared to unresected patients (p < 0.001). Two patients who achieved pCR are still alive and disease-free for 46.3 months and 44.4 months, respectively. Overall, 66.7% of the resected patients were downstaged. Sixteen of 42 patients (38.1%) were downstaged to pathological stage (pStage) 0—I and 12 (28.6%) to pStage II. pStage IIIA persisted in 14 of 42 patients (33.3%). Overall T and N downstaging was achieved in 21 of 42 patients (50.0%) and 29 of 42 patients (69.0%), respectively. Table 4 compares clinical T and N stages with pStages.
Overall survival (OS) and progression-free survival (PFS) of the all patients.
Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer?
Fig. 2
Table 5
327
OS and PFS according to downstaging to pN0—N1.
Multivariate analysis of prognostic factors for overall survival P-value
Age ≥60 Male sex ECOG PS 0 LDH > upper normal limit Histology of squamous cell carcinoma Tumor stage 3 Bulky-N2 stage Multi-N2 stage Negative resection margin Mediastinal nodal clearance (pN0—1)
0.01 0.66 0.57 0.37 0.91 0.75 0.28 0.83 0.44 0.02
Better OS and PFS were achieved in patients who were downstaged to pN0 or pN1 than those who with pN2 (p = 0.02, 0.04; Fig. 2). In multivariate analysis of prognostic factors for overall survival in resected patients, mediastinal nodal clearance (downstaging to pN0—1; p = 0.02) and age under 60 years (p = 0.01) at diagnosis were statistically significant good prognostic factors (Table 5).
4. Discussion Many previous studies on neoadjuvant chemoradiotherapy followed by surgery for stage IIIA NSCLC have demonstrated that a complete pathological response can be achieved with combination chemotherapy in addition to a relatively low dose of radiation, and that downstaging was a major determinant for improved long-term survival. More recently, phase III trials conducted by West Japan Lung Cancer Group suggest a benefit of concurrent chemoradiation versus the sequential approach [14]. Neoadjuvant CCRT, therefore, has become a preferred treatment modality for stage IIIA NSCLC. We have previously reported preliminary results of neoadjuvant CCRT with etoposide and cisplatin followed by surgery in patients of stage IIIA NSCLC [15] and recently updated the outcomes [16]. This study showed 71.7% of resection rate, 50.0% of downstaging rate, 27 months of median OS, and 44.3% of 3-year survival, which outcomes are comparable to those of other previous studies. In present study, paclitaxel and platinum were used in neoadjuvant
Relative risk
8.53 1.58 1.95 2.86 0.91 1.54 2.51 1.19 0.46 0.17
95% CI Lower
Upper
2.12 0.20 0.19 0.28 0.19 0.11 0.47 0.23 0.06 0.04
34.34 12.08 19.97 29.12 4.29 21.58 13.29 5.99 3.21 0.73
CCRT. Since both paclitaxel and platinum is newer drugs and have radiosensitizing effects [17,18], it seems logical to use them concurrently with radiation in locally advanced disease. Moreover, previous studies have demonstrated the efficacy of paclitaxel and platinum in neoadjuvant CCRT for locally advanced NSCLC [19,20]. Although many other studies have included stage IIIB, the outcomes of present study after CCRT (clinical response rate in 76.9% and complete resection rate in 67.3%) are comparable to that of previous studies with other chemotherapeutic regimens [4—12]. Toxicity of weekly paclitaxel and platinum in CCRT has been reported to be acceptable, and has compared favorably with other regimens [21]. Toxicity profiles of the present study were similar to other reports. The major nonhematological side effect, grade 3—4 esophagitis, occurred in 15.4% of patients, but abated shortly after therapy was completed. Complete intended dosages of chemotherapy, including cases of delayed chemotherapy schedule due to hematological toxicities, was administered to 86.5% of all patients. TRT was administered as planned in 96.2% of all patients. SWOG trial was the largest phase II trial that explored neoadjuvant CCRT [4]. In this trial, 126 patients were enrolled and treated with two cycles of cisplatin plus etoposide every 3 weeks and radiotherapy of 45 Gy. After concurrent chemoradiotherapy, 101 of 126 patients (80.1%) underwent surgery. Of these, 89 patients (70.6%) had a complete resection, with treatment-related mortality (TRM)
328 rate of 12.8% (13 of 101). In 19 out of 89 patients (21.3%), no tumor was found in the pathological specimens. In stage IIIA, N2 positive patients, median survival was 13 months (2year survival rates, 37%; 3-year survival rates, 27%). In the present study, 42 of 52 patients (80.8%) underwent surgery, and 37 of 52 (71.2%) had complete resection. The TRM rate was 3.8% (2 of 52) and pCR rate was 4.8% (2 of 42). We observed a median overall survival of 25.6 months, 2-year survival of 50.1% and 3-year survival of 44.9%, all of which favorably compare with the SWOG trial. In another prospective study of neoadjuvant CCRT for locally advanced NSCLC by Choi et al. [11], consisting of only N2 positive stage IIIA patients, 42 patients were enrolled and treated with two preoperative courses of cisplatin, vinblastine, fluorouracil (5-FU), and 42 Gy concurrent radiation in two fractions per day. TRM and pCR rates were noted to be 7.1% and 9.5%, respectively. The median overall survival rate was 25 months and overall survival rates were 66% and 37% at 2 and 3 years, respectively. These outcomes are quite similar to the present study. It has been well established that tumor downstaging and mediastinal nodal clearance after neoadjuvant treatments are highly predictive of long-term survival [6,10,11,22]. In the present study, we have investigated the correlation between pathological downstaging and survival. We observed mediastinal nodal clearance (downstaging to pN0—1) was correlated with statistically significant improvement in OS and PFS (p = 0.02, p = 0.04), compared to pN2. Multivariate analysis demonstrated downstaging to pN0—1 (p = 0.02) and age <60 years at diagnosis (p = 0.01) to be independent prognostic factors for OS. Pathological downstaging is a direct indicator of the effectiveness of the neoadjuvant protocols and is significantly correlated with OS, particularly in younger patients. As for the perioperative morbidity rate, Weiden and Piantadosi [7] and Faber et al. [8] reported morbidity rates of 22.5% (14 of 62 patients who underwent surgery) and 25.9% (14 of 54), respectively. Our experience was quite similar, with a morbidity rate of 21.4% (9 of 42). Neoadjuvant CCRT in the present study did not increase the perioperative morbidity and mortality, but a relatively low pCR rate was obtained compared to other neoadjuvant CCRT trials. However, it is comparable to that observed in previous neoadjuvant chemotherapy trials [22—25]. Although we investigated neoadjuvant CCRT, these results are quite similar to those of neoadjuvant chemotherapy alone. It appears that the planned dose intensity of chemotherapy or radiotherapy in CCRT was suboptimal for disease control. The best regimen and optimal dosages of CCRT in neoadjuvant protocols have not been established, especially with the newer chemotherapeutic agents. In a phase I study of paclitaxel and concurrent radiation in the treatment of stage IIIA/B NSCLC, maximum tolerated dose of paclitaxel was determined to be 86 mg/m2 weekly [26]. In another similar phase I study, although the paclitaxel dosage was increased to 55 mg/m2 on days 1, 8, 15, 22, 29, 36, and 43, the maximum tolerated dose was not attained [27]. We used paclitaxel 50 mg/m2 /week for 5 weeks in CCRT, which may have been insufficient for disease eradication. In contrast, in previous studies of neoadjuvant chemotherapy with paclitaxel containing combination chemotherapy for stage IIIA NSCLC, paclitaxel 175 or 200 mg/m2 was given every 3 weeks for two
B.-B. Park et al. to three times, and the achieved pCR rates varied from 17% to 21% [28—31]. Kuten et al. studied neoadjuvant CCRT with weekly paclitaxel and carboplatin, followed by surgery in locally advanced NSCLC [12]. With their regimen of weekly paclitaxel 45 mg/m2 and carboplatin 100 mg/m2 for 5 weeks and concurrent radiotherapy with 50.4 Gy, the pCR rate was 11%, which is relatively low. The dose intensities of cisplatin and carboplatin in the present study were also relatively low when compared to the previous studies. Therefore, the composition of the present chemotherapy regimen in CCRT may well be one of the possible causes of the observed low pCR rate. Radiation dose and schedule should also be considered when evaluating outcomes such as pCR and local disease control. Loco-regional treatment failures were observed in approximately one half of patients after the present CCRT followed by surgery. It seems that a total dose of 45 Gy with classical fractionated radiotherapy is suboptimal in achieving local control. Alternative radiation strategies, such as radiation dose escalation, altered fractionation schedules, and application of modern radiotherapy techniques in CCRT may help achieve a better local control. In general, pCR rates reported in neoadjuvant chemotherapy trials have been lower than those in neoadjuvant CCRT trials, but the long-term survival rates have been similar in both treatment groups [32]. A definitive correlation between pCR and long-term survival in the neoadjuvant setting may argue for the usefulness of additional preoperative radiotherapy. However, a thorough literature search did not reveal any reported randomized trials of neoadjuvant CCRT versus induction chemotherapy in stage IIIA NSCLC. Therefore, randomized phase III trials are required to define the exact role of radiotherapy as a component of neoadjuvant setting. Radiotherapy continues to play an important role of treatment of locally advanced NSCLC, but its optimal timing with respect to surgery has not been defined yet. A randomized phase III trial of the German Lung Cancer Cooperative Group, which compared the addition of CCRT to neoadjuvant chemotherapy, followed by surgery with chemotherapy alone before surgery and postoperative radiotherapy (PORT) in stage III NSCLC, concluded that additional preoperative CCRT had no impact on survival but contributed to significantly higher rates of grade 3/4 esophagitis versus PORT arm [33]. Although survival outcomes according to radiation timing will be revealed in further investigations, the advantage of preoperative radiotherapy seems to be suspected in recent trials. Another current issue in treatment of locally advanced NSCLC is the role of surgery after CCRT. Initial results from the recent intergroup trial 0139 (RTOG9309), comparing CCRT followed by surgery with definitive CCRT for N2 positive NSCLC [34], showed superior PFS in the surgical arm, although the OS was not statistically different between the two arms. In another trial of EORTC 08941 study, which compared radical surgery with TRT in patients with stage IIIA, N2 positive NSCLC after response to induction chemotherapy [35], surgery improved neither OS nor PFS when compared to TRT. Although long-term follow-up results of these trials are needed to determine if surgery significantly prolongs OS, it might provide an avenue to avoid the risk of perioperative morbidities and mortalities.
Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer? In summary, neoadjuvant CCRT for N2 positive NSCLC patients demonstrated a high overall response rate with acceptable toxicity profile and an improvement in the frequency of complete tumor resection. Improved survival benefit may be expected in the younger population and in patients with mediastinal nodal clearance following neoadjuvant CCRT. Randomized controlled trials of neoadjuvant CCRT versus neoadjuvant chemotherapy alone in stage IIIA NSCLC are eagerly awaited to address the important issue of whether the addition of radiotherapy to chemotherapy in neoadjuvant setting improves the therapeutic outcomes. There remains a need to develop optimal sequencing of combined modality treatments using newer drugs and radiotherapy techniques.
Conflict of interest All authors disclose any financial or personal relationship with other people or organizations that could inappropriately influence their work.
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Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer? Byeong-Bae Park a, Joon Oh Park a, Hojoong Kim b, Yong Chan Ahn c, Yong Soo Choi d, Kwhanmien Kim d, Jhingook Kim d, Young Mog Shim d, Jin Seok Ahn a, Keunchil Park a,∗ a
Divisions of Hematology—Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, Republic of Korea b Division of Pulmonology and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea c Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea d Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Received 18 February 2006; received in revised form 21 May 2006; accepted 24 May 2006
KEYWORDS Neoadjuvant; Concurrent; Chemoradiotherapy; Stage IIIA; Non-small cell lung cancer
∗
Summary Background: Neoadjuvant treatment followed by surgery is currently being investigated for locally advanced non-small cell lung cancer (NSCLC). This study reports efficacy, toxicity and feasibility of neoadjuvant chemotherapy with concurrent radiotherapy (CCRT) in stage IIIA, N2 positive NSCLC. Methods: From March 2001 to February 2004, 52 patients with histologically confirmed stage IIIA, N2 positive NSCLC were registered. Patients received preoperative CCRT that consisted of weekly paclitaxel plus platinum chemotherapy and concurrent radiotherapy followed by surgery. Results: Overall response rate was 76.9% (95% CI, 64—88%). The major grade 3—4 toxicities were radiation esophagitis (15.4%) and neutropenia (11.5%), and treatment-related mortality rate was 1.9%. Forty-two of 52 patients (80.8%) subsequently underwent surgical resection and 35 of 52 patients (67.3%) underwent complete resection. Among them, pathological complete response was obtained in 4.8%. Pathological downstaging rate to N0—1 and stage 0—II at surgery were 69.0% and 66.7%, respectively. The perioperative major morbidity rate was 23.8% and perioperative mortality was 2.4%. At a median follow-up of 33.9 months (range: 16.4—49.9), the median progression-free survival and overall survival were 16.5 months (95% CI, 6.2—26.8) and 25.6 months (95% CI, 14.6—36.6), respectively. Multivariate analyses identified that patients
Corresponding author. Tel. +82 2 3410 3459; fax: +82 2 3410 0041. E-mail address: [email protected] (K. Park).
0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2006.05.024
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B.-B. Park et al. achieved mediastinal nodal clearance (downstage to pathological N0 or N1) after CCRT (p = 0.02) and age at diagnosis < 60 years (p = 0.01) showed significantly improved survival. Conclusion: Neoadjuvant CCRT showed a high overall response rate with tolerable toxicity profile. Downstaging after CCRT may increase the rate of complete tumor resection and result in survival benefit in stage IIIA, N2 positive NSCLC patients. © 2006 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2.2. Assessments
Locally advanced NSCLC still represents a therapeutic challenge. The long-term survival of these patients treated with single therapeutic option (chemotherapy, radiotherapy, or surgery) is extremely poor. This has been the rationale for many multidisciplinary attempts at therapeutic improvement in the recent years. Currently, there are variations in the standard of care for patients with locally advanced disease. While surgery remains the main option for selected N2 positive patients, a neoadjuvant treatment protocol may be applied for marginally resectable disease, and chemoradiation may be offered to patients ineligible for surgery who can tolerate it [1]. Recent data show that survival in locally advanced NSCLC is improved by the addition of chemotherapy to radiotherapy and/or surgery [2—4]. Radiotherapy in combination with chemotherapy plays a leading role in the treatment of locally advanced unresectable NSCLC, although its role in the management of resectable N2 disease is still controversial. Several studies have evaluated neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgical resection in locally advanced NSCLC [4—12]. These studies have shown good results in terms of survival benefit provided radical surgical resection is feasible, without increasing morbidity and mortality rate [13]. This present study reports efficacy, toxicity and feasibility of neoadjuvant CCRT with newer drugs (paclitaxel and platinum) in N2 positive stage IIIA NSCLC. Downstaging after CCRT was also assessed in order to analyze it as an end point in the evaluation of efficacy of a neoadjuvant therapy and its possible predictive value for overall long-term survival.
Pretreatment evaluation included patient’s history, physical examination, performance status, standard chest X-ray, complete blood count, blood chemistry, CT scan of the chest including upper abdomen, whole-body bone scan, fiberoptic bronchoscopy. Brain MRI had been performed for patients with histology of adenocarcinoma. All patients were histologically confirmed N2 by mediastinoscopic biopsy that was included as a part of clinical staging. In addition to the staging procedure, pulmonary function tests, electrocardiogram and echocardiogram were performed to assess the general status and eligibility of each patient for surgery. During treatment, complete blood counts, blood chemistry, and clinical examination including chest X-rays were repeated prior to each chemotherapeutic cycle. Restaging procedures with complete clinical and radiological evaluation were performed within 3 weeks following the completion of CCRT treatment. Clinical response to CCRT was assessed according to the response evaluation criteria in solid tumors and complete resection was defined as removal of all known disease neither with microscopic involvement of the margins of resection, nor of the upper mediastinal lymph nodes sampled at thoracotomy (ATS station 2). Patients undergoing surgery were evaluated by chest CT scan every 3 months for 2 years following surgery, and then every 6 months thereafter.
2. Patients and methods 2.1. Patients’ selection Fifty-two patients were enrolled between March 2001 and February 2004. All of them had histologically or cytologically confirmed NSCLC and mediastinoscopic biopsy-proven stage IIIA, N2 disease. T3N1 disease was excluded. Performance status was ECOG 0—1. None of them had either undergone any previous oncologic treatment or had any concurrent medical illnesses that would contraindicate surgery. The bone marrow, liver, and renal function had to be within predefined limits (absolute neutrophil count ≥1.5 × 109 /l; platelet count ≥100 × 109 /l; total bilirubin ≤2.0 mg/dl; AST and ALT ≤2 × the upper normal limit; serum creatinine ≤1.4 mg/dl and creatinine clearance ≥60 ml/min. Written informed consent was required from all patients before the start of treatment.
2.3. Treatments Neoadjuvant CCRT included chemotherapy and concurrent thoracic radiotherapy (TRT). The chemotherapy regimens consisted of weekly paclitaxel (50 mg/m2 /week IV) plus cisplatin (25 mg/m2 /week IV) or weekly paclitaxel (50 mg/m2 /week IV) plus carboplatin (AUC 1.5/week IV) for 5 weeks. Concurrent TRT dose was 45 Gy over 5 weeks (1.8 Gy/fraction/day, 5 fractions/week) using 10 MV X-rays. The TRT target volume included the primary tumor plus the ipsilateral hilar and mediastinal lymphatics with 1.5—2 cm peripheral margins. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, Version 2.0. Weekly treatment was deferred in cases with grade 4 hematological toxicity or grades 3—4 non-hematological toxicity. Chemotherapy was discontinued if these toxicities persisted for two consecutive weeks. However, if the patient recovered from these adverse effects after interruption of treatment for a week, chemotherapy was resumed in accordance with the pre-scheduled doses and schedule. The planned dose of paclitaxel was reduced by 25% in cases with grades 2—3 hematological toxicity during the week following the interruption of chemotherapy. Surgical resection
Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer? was planned at around 4 weeks following the completion of neoadjuvant CCRT. Postoperative radiation therapy (18 Gy in 10 fractions) was administered in the event of persistent histologically positive N2 lymph node, positive multi-N1 lymph nodes, or positive resection margin at the time of surgery.
2.4. Statistical analysis The overall survival (OS) duration was calculated from the first day of the neoadjuvant CCRT until the date of death or the latest documented follow-up. Progression-free survival (PFS) duration was calculated until the date of the first documented progression or the latest follow-up. Kaplan—Meier survival curves were generated, and the statistical significance of the difference was assessed using log-rank test. Differences between groups were compared using Pearson 2 -test. Multivariate analyses of the independent prognostic factors for survival were performed using the Cox proportional hazards regression model with 95% confidence interval. Simon’s two-stage minimax design was used to determine the sample size and decision criteria for this phase II study. With the target downstage rate of 60% and the lowest downstage rate of interest set at 40%, we needed 46 evaluable patients with an 80% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Allowing for a 10% loss to follow-up rate, a total of 51 patients were needed.
3. Results 3.1. Patients’ characteristics Clinical characteristics of the 52 enrollees are depicted in Table 1. Median age was 58 years (range: 23—72) and all patients had a good performance status of ECOG 0—1. Histologic types consisted of adenocarcinoma (26; 50.0%), squamous cell carcinoma (22; 42.3%), large cell carcinoma (2; 3.8%), and non-small cell carcinoma (2; 3.8%). Nine of 52 patients (17.3%) had a bulky-N2 disease (node size >2 cm) in CT scan before start of therapy. Numbers of patients treated with paclitaxel plus cisplatin (TP) and paclitaxel plus carboplatin (TC) were 41 (78.8%) and 11 (21.2%), respectively.
3.2. Neoadjuvant CCRT The given dose densities of chemotherapy in CCRT were 49.0 mg/m2 /week of paclitaxel, 24.5 mg/m2 /week of cisplatin, and AUC 1.47/week of carboplatin. Five of 52 patients (9.6%) had experienced interruption of CCRT for a week due to toxicities, but the planned doses of chemotherapy and radiotherapy were successfully administered to these five patients. Incomplete planned doses of chemotherapy were delivered in seven patients (13.5%). Of these, five patients were given insufficient number of chemotherapy cycles, and two patients were treated with 25% reduced dosage of paclitaxel for two cycles of chemotherapy due to hematological toxicity. TRT was administered as planned
Table 1
325
Patients characteristics
No. of patients
52
Age Median Range
58 years 23—72
Sex Male Female
43 (82.7%) 9 (17.3%)
ECOG performance status 0 1
8 (15.4%) 44 (84.6%)
Histologic type Adenocarcinoma Squamous cell Large cell Others
26 (50.0%) 22 (42.3%) 2 (3.8%) 2 (3.8%)
Stage (IIIa) T1N2 T2N2 T3N2
12 (23.1%) 34 (65.4%) 6 (11.5%)
Bulky-N2 disease by CT scan Yes No
9 (17.3%) 43 (82.7%)
in 50 patients (96.2%). Grade 3—4 toxicities of CCRT are shown in Table 2. Unfortunately, one patient succumbed to treatment-related death during CCRT due to neutropenic sepsis. Clinical response to CCRT at restaging was observed in 40 of 52 patients (76.9%; 95% CI, 64—88%) including five radiologically complete responses (CRs; 9.6%). Five of 52 patients (9.6%) showed stable disease (SD) and 7 of 52 patients (13.5%) developed progressive disease (PD). Five of seven patients had distant disease progression while two had loco-regional PD. In univariate subgroup analysis of the clinical response rates, the histological type of squamous cell had better response to CCRT than the non-squamous cell type (p = 0.04).
Table 2
Grade 3—4 toxicities of CCRT (N = 52, %)
Hematological Neutropenia Thrombocytopenia Neutropenic infection*
6 (11.5) 2 (3.8) 1 (1.9)
Non-hematological Radiation esophagitis Nausea/vomiting Radiation pneumonitis Myalgia Hepatotoxicity Hemoptysis Edema Pneumonia
8 (15.4) 4 (7.7) 3 (5.8) 2 (3.8) 2 (3.8) 1 (1.9) 1 (1.9) 1 (1.9)
*
TRM: treatment-related mortality.
326 Table 3
B.-B. Park et al. Results of surgery (N = 42, %)
Types of surgery Lobectomy Pneumonectomy Bilobectomy
33 (78.6) 6 (14.3) 3 (7.1)
Resection margin Positive Negative
5 (11.9) 37 (88.1)
Pathological response CR PR SD PD
2 (4.8) 33 (78.6) 4 (9.5) 3 (7.1)
Postoperative radiotherapy Yes No
20 (47.6) 22 (52.4)
3.3. Surgery After restaging work-up, 42 of 52 patients (80.8%) underwent radical resection, including complete mediastinal lymph node dissection. Ten patients who were withdrawn from surgery included seven patients with PD, and three patients who refused surgery. Surgical procedures included 33 lobectomies, 3 bilobectomies and 6 pneumonectomies. After surgery, upper mediastinal lymph nodes involvements were found in two patients and another five patients were positive resection margin. Therefore, 35 patients (67.3%) achieved complete resection. Postoperative adjuvant radiotherapy was administered to 20 patients (47.6%). Postoperative pathological response rate to CCRT was 83.3% in 42 resected patients including two (4.8%) pathological complete responses (pCR) (Table 3). Postoperative mortality occurred in one patient (2.4%) who died from acute respiratory distress syndrome (ARDS). Ten of 42 resected patients (23.8%) had postoperative morbidities. These included four bronchopleural fistulas, three pneumonias, two empyemas, and one ARDS.
3.4. Survival and downstaging At the time of this analysis, median follow-up period was 33.9 months (range 16.4—49.9 months). Nineteen patients
Fig. 1
Table 4
Postoperative pathological downstaging
IIIA (N = 42, %)
N2 (N = 42, %)
T1 (N = 11, %) T2 (N = 28, %) T3 (N = 3, %)
pStage 0—I
pStage II
pStage IIIA
16 (38.1)
12 (28.6)
14 (33.3)
pN0
pN1
pN2
16 (38.1)
13 (30.9)
13 (30.9)
pT0
pT1
pT2
pT3
— 5 (17.9) —
9 (81.8) 14 (50.0) —
2 (18.2) 7 (25.0) 2 (66.7)
— 2 (7.1) 1 (33.3)
pStage: postoperative pathological stage.
(36.5%) are still disease-free, seven patients (13.5%) have had disease progression, and 26 patients (50.0%) have died. All of the 10 unresected patients (100.0%) and 17 of the 42 resected patients (40.5%) had disease progression. The median PFS after CCRT treatment was 16.5 months (95% CI, 6.2—26.8; Fig. 1). In the 17 patients with disease progression after surgery (including eight patients with loco-regional recurrence, eight patients with distant recurrence, and one patient with both), nine patients were administered palliative chemotherapy while the others received supportive treatment or local radiotherapy. There were distant progressions in nine patients after surgery. It was consisted of two brain, two liver, two lung-to-lung, two cervical LNs, and one adrenal gland metastasis, which were first detected site. Only one of two patients with brain disease was adenocarcinoma. The median duration of overall survival was 25.6 months (95% CI, 14.6—36.6; Fig. 1). Overall survival rates of all patients at 1, 2 and 3 years were 64.8%, 50.1% and 44.9%, respectively. Patients who underwent surgery had statistical significant improvement in OS and PFS compared to unresected patients (p < 0.001). Two patients who achieved pCR are still alive and disease-free for 46.3 months and 44.4 months, respectively. Overall, 66.7% of the resected patients were downstaged. Sixteen of 42 patients (38.1%) were downstaged to pathological stage (pStage) 0—I and 12 (28.6%) to pStage II. pStage IIIA persisted in 14 of 42 patients (33.3%). Overall T and N downstaging was achieved in 21 of 42 patients (50.0%) and 29 of 42 patients (69.0%), respectively. Table 4 compares clinical T and N stages with pStages.
Overall survival (OS) and progression-free survival (PFS) of the all patients.
Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer?
Fig. 2
Table 5
327
OS and PFS according to downstaging to pN0—N1.
Multivariate analysis of prognostic factors for overall survival P-value
Age ≥60 Male sex ECOG PS 0 LDH > upper normal limit Histology of squamous cell carcinoma Tumor stage 3 Bulky-N2 stage Multi-N2 stage Negative resection margin Mediastinal nodal clearance (pN0—1)
0.01 0.66 0.57 0.37 0.91 0.75 0.28 0.83 0.44 0.02
Better OS and PFS were achieved in patients who were downstaged to pN0 or pN1 than those who with pN2 (p = 0.02, 0.04; Fig. 2). In multivariate analysis of prognostic factors for overall survival in resected patients, mediastinal nodal clearance (downstaging to pN0—1; p = 0.02) and age under 60 years (p = 0.01) at diagnosis were statistically significant good prognostic factors (Table 5).
4. Discussion Many previous studies on neoadjuvant chemoradiotherapy followed by surgery for stage IIIA NSCLC have demonstrated that a complete pathological response can be achieved with combination chemotherapy in addition to a relatively low dose of radiation, and that downstaging was a major determinant for improved long-term survival. More recently, phase III trials conducted by West Japan Lung Cancer Group suggest a benefit of concurrent chemoradiation versus the sequential approach [14]. Neoadjuvant CCRT, therefore, has become a preferred treatment modality for stage IIIA NSCLC. We have previously reported preliminary results of neoadjuvant CCRT with etoposide and cisplatin followed by surgery in patients of stage IIIA NSCLC [15] and recently updated the outcomes [16]. This study showed 71.7% of resection rate, 50.0% of downstaging rate, 27 months of median OS, and 44.3% of 3-year survival, which outcomes are comparable to those of other previous studies. In present study, paclitaxel and platinum were used in neoadjuvant
Relative risk
8.53 1.58 1.95 2.86 0.91 1.54 2.51 1.19 0.46 0.17
95% CI Lower
Upper
2.12 0.20 0.19 0.28 0.19 0.11 0.47 0.23 0.06 0.04
34.34 12.08 19.97 29.12 4.29 21.58 13.29 5.99 3.21 0.73
CCRT. Since both paclitaxel and platinum is newer drugs and have radiosensitizing effects [17,18], it seems logical to use them concurrently with radiation in locally advanced disease. Moreover, previous studies have demonstrated the efficacy of paclitaxel and platinum in neoadjuvant CCRT for locally advanced NSCLC [19,20]. Although many other studies have included stage IIIB, the outcomes of present study after CCRT (clinical response rate in 76.9% and complete resection rate in 67.3%) are comparable to that of previous studies with other chemotherapeutic regimens [4—12]. Toxicity of weekly paclitaxel and platinum in CCRT has been reported to be acceptable, and has compared favorably with other regimens [21]. Toxicity profiles of the present study were similar to other reports. The major nonhematological side effect, grade 3—4 esophagitis, occurred in 15.4% of patients, but abated shortly after therapy was completed. Complete intended dosages of chemotherapy, including cases of delayed chemotherapy schedule due to hematological toxicities, was administered to 86.5% of all patients. TRT was administered as planned in 96.2% of all patients. SWOG trial was the largest phase II trial that explored neoadjuvant CCRT [4]. In this trial, 126 patients were enrolled and treated with two cycles of cisplatin plus etoposide every 3 weeks and radiotherapy of 45 Gy. After concurrent chemoradiotherapy, 101 of 126 patients (80.1%) underwent surgery. Of these, 89 patients (70.6%) had a complete resection, with treatment-related mortality (TRM)
328 rate of 12.8% (13 of 101). In 19 out of 89 patients (21.3%), no tumor was found in the pathological specimens. In stage IIIA, N2 positive patients, median survival was 13 months (2year survival rates, 37%; 3-year survival rates, 27%). In the present study, 42 of 52 patients (80.8%) underwent surgery, and 37 of 52 (71.2%) had complete resection. The TRM rate was 3.8% (2 of 52) and pCR rate was 4.8% (2 of 42). We observed a median overall survival of 25.6 months, 2-year survival of 50.1% and 3-year survival of 44.9%, all of which favorably compare with the SWOG trial. In another prospective study of neoadjuvant CCRT for locally advanced NSCLC by Choi et al. [11], consisting of only N2 positive stage IIIA patients, 42 patients were enrolled and treated with two preoperative courses of cisplatin, vinblastine, fluorouracil (5-FU), and 42 Gy concurrent radiation in two fractions per day. TRM and pCR rates were noted to be 7.1% and 9.5%, respectively. The median overall survival rate was 25 months and overall survival rates were 66% and 37% at 2 and 3 years, respectively. These outcomes are quite similar to the present study. It has been well established that tumor downstaging and mediastinal nodal clearance after neoadjuvant treatments are highly predictive of long-term survival [6,10,11,22]. In the present study, we have investigated the correlation between pathological downstaging and survival. We observed mediastinal nodal clearance (downstaging to pN0—1) was correlated with statistically significant improvement in OS and PFS (p = 0.02, p = 0.04), compared to pN2. Multivariate analysis demonstrated downstaging to pN0—1 (p = 0.02) and age <60 years at diagnosis (p = 0.01) to be independent prognostic factors for OS. Pathological downstaging is a direct indicator of the effectiveness of the neoadjuvant protocols and is significantly correlated with OS, particularly in younger patients. As for the perioperative morbidity rate, Weiden and Piantadosi [7] and Faber et al. [8] reported morbidity rates of 22.5% (14 of 62 patients who underwent surgery) and 25.9% (14 of 54), respectively. Our experience was quite similar, with a morbidity rate of 21.4% (9 of 42). Neoadjuvant CCRT in the present study did not increase the perioperative morbidity and mortality, but a relatively low pCR rate was obtained compared to other neoadjuvant CCRT trials. However, it is comparable to that observed in previous neoadjuvant chemotherapy trials [22—25]. Although we investigated neoadjuvant CCRT, these results are quite similar to those of neoadjuvant chemotherapy alone. It appears that the planned dose intensity of chemotherapy or radiotherapy in CCRT was suboptimal for disease control. The best regimen and optimal dosages of CCRT in neoadjuvant protocols have not been established, especially with the newer chemotherapeutic agents. In a phase I study of paclitaxel and concurrent radiation in the treatment of stage IIIA/B NSCLC, maximum tolerated dose of paclitaxel was determined to be 86 mg/m2 weekly [26]. In another similar phase I study, although the paclitaxel dosage was increased to 55 mg/m2 on days 1, 8, 15, 22, 29, 36, and 43, the maximum tolerated dose was not attained [27]. We used paclitaxel 50 mg/m2 /week for 5 weeks in CCRT, which may have been insufficient for disease eradication. In contrast, in previous studies of neoadjuvant chemotherapy with paclitaxel containing combination chemotherapy for stage IIIA NSCLC, paclitaxel 175 or 200 mg/m2 was given every 3 weeks for two
B.-B. Park et al. to three times, and the achieved pCR rates varied from 17% to 21% [28—31]. Kuten et al. studied neoadjuvant CCRT with weekly paclitaxel and carboplatin, followed by surgery in locally advanced NSCLC [12]. With their regimen of weekly paclitaxel 45 mg/m2 and carboplatin 100 mg/m2 for 5 weeks and concurrent radiotherapy with 50.4 Gy, the pCR rate was 11%, which is relatively low. The dose intensities of cisplatin and carboplatin in the present study were also relatively low when compared to the previous studies. Therefore, the composition of the present chemotherapy regimen in CCRT may well be one of the possible causes of the observed low pCR rate. Radiation dose and schedule should also be considered when evaluating outcomes such as pCR and local disease control. Loco-regional treatment failures were observed in approximately one half of patients after the present CCRT followed by surgery. It seems that a total dose of 45 Gy with classical fractionated radiotherapy is suboptimal in achieving local control. Alternative radiation strategies, such as radiation dose escalation, altered fractionation schedules, and application of modern radiotherapy techniques in CCRT may help achieve a better local control. In general, pCR rates reported in neoadjuvant chemotherapy trials have been lower than those in neoadjuvant CCRT trials, but the long-term survival rates have been similar in both treatment groups [32]. A definitive correlation between pCR and long-term survival in the neoadjuvant setting may argue for the usefulness of additional preoperative radiotherapy. However, a thorough literature search did not reveal any reported randomized trials of neoadjuvant CCRT versus induction chemotherapy in stage IIIA NSCLC. Therefore, randomized phase III trials are required to define the exact role of radiotherapy as a component of neoadjuvant setting. Radiotherapy continues to play an important role of treatment of locally advanced NSCLC, but its optimal timing with respect to surgery has not been defined yet. A randomized phase III trial of the German Lung Cancer Cooperative Group, which compared the addition of CCRT to neoadjuvant chemotherapy, followed by surgery with chemotherapy alone before surgery and postoperative radiotherapy (PORT) in stage III NSCLC, concluded that additional preoperative CCRT had no impact on survival but contributed to significantly higher rates of grade 3/4 esophagitis versus PORT arm [33]. Although survival outcomes according to radiation timing will be revealed in further investigations, the advantage of preoperative radiotherapy seems to be suspected in recent trials. Another current issue in treatment of locally advanced NSCLC is the role of surgery after CCRT. Initial results from the recent intergroup trial 0139 (RTOG9309), comparing CCRT followed by surgery with definitive CCRT for N2 positive NSCLC [34], showed superior PFS in the surgical arm, although the OS was not statistically different between the two arms. In another trial of EORTC 08941 study, which compared radical surgery with TRT in patients with stage IIIA, N2 positive NSCLC after response to induction chemotherapy [35], surgery improved neither OS nor PFS when compared to TRT. Although long-term follow-up results of these trials are needed to determine if surgery significantly prolongs OS, it might provide an avenue to avoid the risk of perioperative morbidities and mortalities.
Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer? In summary, neoadjuvant CCRT for N2 positive NSCLC patients demonstrated a high overall response rate with acceptable toxicity profile and an improvement in the frequency of complete tumor resection. Improved survival benefit may be expected in the younger population and in patients with mediastinal nodal clearance following neoadjuvant CCRT. Randomized controlled trials of neoadjuvant CCRT versus neoadjuvant chemotherapy alone in stage IIIA NSCLC are eagerly awaited to address the important issue of whether the addition of radiotherapy to chemotherapy in neoadjuvant setting improves the therapeutic outcomes. There remains a need to develop optimal sequencing of combined modality treatments using newer drugs and radiotherapy techniques.
Conflict of interest All authors disclose any financial or personal relationship with other people or organizations that could inappropriately influence their work.
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