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Pathologic Complete Response to Preoperative Chemotherapy Predicts Cure in Early-Stage Non–Small-Cell Lung Cancer: Combined Analysis of Two IFCT Randomized Trials
Original Article
Pathologic Complete Response to Preoperative Chemotherapy Predicts Cure in Early-Stage Non–Small-Cell Lung Cancer Combined Analysis of Two IFCT Randomized Trials Guillaume Mouillet, Msc,* Elisabeth Monnet, MD,† Bernard Milleron, MD,‡ Marc Puyraveau, MSc,§ Elisabeth Quoix, MD, Philippe David, MD,¶ Alain Ducoloné, MD, Olivier Molinier, MD,# Gérard Zalcman, MD, PhD,** Alain Depierre, MD* and Virginie Westeel, MD, PhD*†† on behalf of the Intergroupe Francophone de Cancérologie Thoracique (IFCT) Introduction: Our study aimed to evaluate whether pathologic complete response (pCR) in early-stage non–small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy resulted in improved outcome, and to determine predictive factors for pCR. Methods: Eligible patients with stage-IB or -II NSCLC were included in two consecutive Intergroupe Francophone de Cancérologie Thoracique phase-III trials evaluating platinum-based neoadjuvant chemotherapy, with pCR defined by the absence of viable cancer cells in the resected surgical specimen. Results: Among the 492 patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year overall survival was 80.0% compared with 55.8% in the non-pCR group (p = 0.0007). In multivariate analyses, pCR was a favorable prognostic factor of overall survival (relative risk = 0.34; 95% confidence interval = 0.18–0.64) in addition to squamous-cell carcinoma, weight loss less than or equal to 5%, and stage-IB disease. Five-year disease-free survival was 80.1% in the pCR group compared to 44.8% in the non-pCR group (p < 0.0001). Two patients (4.9%) in the pCR group experienced disease recurrence compared to 193 patients (42.8%) in the non-pCR group. SCC subtype was the only independent predictor of pCR (odds ratio [OR] = 4.30; 95% confidence interval = 1.90–9.72). *Chest Disease Department, Jean Minjoz University Hospital, Besancon, France; †EA 4266, “Pathogenic Agents and Inflammation,” University of Franche-Comté, Besancon, France; ‡Chest Disease Department, Tenon University Hospital, Paris, France; §Clinical Methodology Center, University Hospital, Besancon, France; Chest Disease Department, Nouvel Hôpital Civil, Strasbourg, France; ¶Chest Disease Department, General Hospital, Elbeuf, France; #Chest Disease Department, General Hospital, Le Mans, France; **Chest Disease Department, University Hospital, Caen, France; ††EA3181, University of Franche-Comté, Besançon, France. Disclosure: Drs. Milleron and Westeel have received honorarium for speaking and serve on the advisory board for Lilly. Dr. Quoix was paid honorarium for serving on advisory board for Lilly and Bristol Myers Squib. Dr. Zalcman has received honorarium for speaking and serving on the advisory boards for Lilly and Bristol Myers Squib. Address for correspondence: Virginie Westeel, MD, PhD, Service de Pneumologie, CHU Jean Minjoz, Boulevard Fleming, 25030 Besançon Cedex, France. E-mail: [email protected]. Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/841-849
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Conclusion: Our results showed that pCR after preoperative chemotherapy was a favorable prognostic factor in stage-IB–II NSCLC. Our study is the largest published series evaluating pCRs after preoperative chemotherapy. The only factor predictive of pCR was squamous-cell carcinoma. Identifying molecular predictive markers for pCR may help in distinguishing patients likely to benefit from neoadjuvant chemotherapy and in choosing the most adequate preoperative chemotherapy regimen. Key Words: Pathologic complete response, Preoperative chemotherapy, Neoadjuvant chemotherapy, Early-stage, Non–small-cell lung cancer. (J Thorac Oncol. 2012;7: 841–849)
T
reatment strategies combining chemotherapy and surgery have been developed to improve the survival of patients with early-stage non–small-cell lung cancer (NSCLC). Metaanalyses of phase-III trials, particularly a recent one based on individual patient data, revealed a significant 5-year overall survival (OS) benefit of 5% when using preoperative chemotherapy in operable NSCLC.1–4 Similar to adjuvant chemotherapy, neoadjuvant chemotherapy aims to eradicate systemic micrometastases and reduce the risk of recurrence especially in the case of distant metastases. One advantage of neoadjuvant chemotherapy over adjuvant chemotherapy is that it allows for assessing tumor response and therefore tumor chemosensitivity. Previous studies on breast and rectal cancers have demonstrated that pathologic complete responses (pCR) after preoperative therapy were associated with improved OS and disease-free survival (DFS). Furthermore, pCR was considered to be a surrogate endpoint for long-term DFS.5–7 In NSCLC, responses and particularly mediastinal downstaging after preoperative chemotherapy or chemoradiation were shown to be associated with improved survival.8–12 However, there is little data on the prognostic value of pCR after preoperative chemotherapy.11,13–16 As pCR was shown not to exceed 17% after neoadjuvant chemotherapy, published reports on pCRs included only small series of patients.9,17–20 In these studies, mainly involving stage-IIIA N2 NSCLC
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patients, pCR after preoperative chemotherapy or chemoradiotherapy was shown to be a favorable prognostic factor. However, in these series, too few pCRs were observed to permit a thorough analysis. Our study was based on the datasets from two consecutive French multicenter randomized phase-III trials from the Intergroupe Francophone de Cancérologie Thoracique (IFCT)9,21 on neoadjuvant chemotherapy, involving large series of patients with long-term follow-up. Because of the sufficiently high number of pCR observed in these two trials, we were able to analyze the prognostic value of pCR, and determine positive predictors for pCR after neoadjuvant chemotherapy.
PATIENTS AND METHODS Data Sources The current analysis was performed using databases from two phase-III randomized trials evaluating neoadjuvant chemotherapy: Depierre9 trial (trial I) and IFCT0002 trial (trial II)21. In trial I undertaken between 1991 and 1997, patients were randomized to either undergo immediate thoracic surgery or receive two cycles of chemotherapy before surgery plus two further postsurgery cycles in responders, with chemotherapy consisting of mitomycin, ifosfamide, and cisplatin (MIC) combination (Fig. 1). In trial II undertaken between 2001 and 2006, two different chemotherapy strategies were compared: (1) two cycles before surgery plus two further presurgery cycles in responders (preoperative chemotherapy arms) and (2) two cycles before surgery plus two further postsurgery cycles in responders (perioperative chemotherapy arms). Chemotherapy comprised carboplatin-paclitaxel (CP) or gemcitabine-cisplatin (Fig. 2). Additional details regarding the different treatment modalities were provided in previous publications.9,21 In both trials, eligible patients were aged between 18 and 75 years, with a World Health Organization performance status (PS) less than or equal to 2, and histologically proven stage-IB, -IIA, or -IIB NSCLC. In addition, stage IIIA was included in trial I and stage IA in trial II. In both studies, initial staging investigations involved chest radiograph, thoracic and abdominal computed-tomography (CT), fiberoptic bronchoscopy, and brain CT-scan or magnetic resonance imaging. In trial II, a mediastinoscopy was required before the randomization of patients with mediastinal lymph nodes more than 1 cm in their smallest diameter on CT-scan. Patients should undergo the same surgery they would have needed before neoadjuvant therapy, regardless of response. The follow-up procedures in the two trials included a physical examination and chest radiograph every 3 months, and a fiberoptic bronchoscopy and chest CT-scan every 6 months for the first 2 years. In trial I, from the third to the seventh year, follow-up consisted of a chest radiograph every 6 months, and fiberoptic bronchoscopy and chest CT-scan every year. After 8 years, the investigators were invited to set up an annual clinic visit. In trial II, an annual followup was scheduled to occur from the third to the fifth year
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FIGURE 1. Trial I design.
involving a fiberoptic bronchoscopy and chest CT-scan, and thereafter a chest radiograph. Both trials were approved by the Human Investigations Committee of Franche-Comté, France. In total, 883 patients were included in the two randomized trials, with median follow-up being 13.8 years (range: 10.4–16.6) in trial I and 5 years (range, 3.0–7.6) in trial II.
Study Population In our analysis, only patients treated with preoperative chemotherapy followed by surgery were included. As stage IA patients were ineligible for trial I and stage IIIA patients for trial II, these patients were excluded from our analysis. Thus, only stage-IB and -II NSCLC patients were considered for our analysis (Fig. 3). All stages were redefined using the sixth tumor, node, metastasis, classification, which was used during trial II.22
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 5, May 2012 Pathologic Complete Response after Neoadjuvant Chemotherapy
FIGURE 3. Flow chart. FIGURE 2. Trial II design.
Assessment of Response Clinical response was assessed according to World Health Organization criteria23 by means of chest CT-scan and fiberoptic bronchoscopy undertaken before surgery. Clinical complete response (cCR) was defined as the complete disappearance of all target lesions without any residual lesions. The absence of cancer cells in bronchial biopsy specimens was a requisite for cCR. Clinical partial response (cPR) was defined as more than 50% decrease in tumor mass, without progression of target lesions or appearance of new lesions. Stable disease was considered as less than 50% decrease or less than 25% increase in tumor mass without appearance of new lesions. Clinical progressive disease was defined as more than 25% increase in tumor mass or the appearance of new lesions. Last, pCR was defined as the absence of viable tumor detected in the resected surgical specimen on pathologic examination.
Statistical Methods Differences in baseline patient characteristics according to pathologic responses were assessed using chi-squared or Fisher’s exact tests. The primary objective was to compare postoperative OS according to pathologic responses. OS was defined as the time from surgery to any-cause death, date of last news, or date of trial endpoint. DFS was defined as the time from surgery to date of recurrence or date of death for patients who died without recurrence. In patients alive without recurrence, DFS was determined from the date of surgery to the date of last news or trial endpoint. The distinction between the recurrence of the original lung cancer and onset of a second primary lung cancer was based on the definition of Martini and Melamed.24 At the endpoint date (December, 31 2007 in trial I and December, 31 2008 in trial II), the physicians in charge were invited to contact patients to determine their vital status. OS and DFS rates along with SDs were estimated using the Kaplan–Meier method. Differences
Copyright © 2012 by the International Association for the Study of Lung Cancer
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in OS and DFS according to pathologic responses were tested for significance using the log-rank test. Unadjusted risk ratios along with their 95% confidence intervals (CI) were estimated by means of univariate Cox models, and used to describe the relationship between pCR and the main prognostic factors with OS and DFS. Multivariate analyses using Cox models stratified by randomization arm were performed for OS and DFS to test the prognostic value of pCR after adjusting for other prognostic factors. All variables relating to OS and DFS with a p value less than or equal to 0.20 in Cox univariate analysis were included in the multivariate analyses. Proportional hazard assumptions were examined for each Cox model variable using graphical methods or testing an interaction term with time for significance. Finally, predictive factors of pCR were identified using multivariable logistic regression, with pCR status as
a dependant variable and baseline patient characteristics as independent variables. p values were two-sided, with values < 0.05 considered statistically significant. All analysis were performed using SAS 9.3 (SAS Institute, Cary, NC)
RESULTS Patient Characteristics In total, 492 patients were eligible for inclusion in the current analysis, comprising 91 trial-I patients (18.5%) and 401 trial-II patients (81.5%) (Fig. 3). Pretreatment patient and tumor characteristics are summarized in Table 1. Median age at randomization was 61 years (range, 34–75 years). The majority of patients were men (83.9%), former or current smokers (94.3%) having a PS of 0 (77.0%) and stage-IB disease (60.0%). Overall, there were 51.0% of squamous-cell–carcinoma
TABLE 1. Patient Characteristics by Pathologic Response Pathologic Response Total Characteristics
No.
Total Age, years ≤70 >70 Sex Male Female Smoking status Non-smoker Current Smoker Former smoker Histology Non-squamous Squamous WHO PS 0 1 2 Weight loss ≤5% >5% cT 1 2 3 cN 0 1 Clinical stage IB IIA IIB
492
(%) (100)
Incomplete
Complete
No.
(%)
No.
(%)
451
(91.7)
41
(8.3)
P
445 47
(90.5) (9.5)
406 45
(90.0) (10.0)
39 2
(95.1) (4.9)
0.409a
413 79
(83.9) (16.1)
378 73
(83.8) (16.2)
35 6
(85.4) (14.6)
0.795b
28 330 134
(5.7) (67.1) (27.2)
28 303 120
(6.2) (67.2) (26.6)
0 27 14
(0.0) (65.8) (34.2)
0.188b
241 251
(49.0) (51.0)
233 218
(51.7) (48.3)
8 33
(19.5) (80.5)
<0.0001b
379 110 3
(77.0) (22.4) (0.6)
349 99 3
(77.4) (21.9) (0.7)
30 11 0
(73.2) (26.8) (0.0)
0.659a
450 42
(91.5) (8.5)
414 37
(91.8) (8.2)
36 5
(87.8) (12.2)
0.378a
18 428 46
(3.7) (87.0) (9.3)
16 390 45
(3.5) (86.5) (10.0)
2 38 1
(4.9) (92.7) (2.4)
0.193a
0.055b 341 151
(69.3) (30.7)
318 133
(70.5) (29.5)
23 18
(56.1) (43.9)
295 18 179
(60.0) (3.6) (36.4)
273 16 162
(60.5) (3.6) (35.9)
22 2 17
(53.6) (4.9) (41.5)
0.972b
-squared test. Fisher’s exact test. WHO, World Health Organization; PS, performance status. Bold indicates significance. a b
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(SCC) patients but the proportion of SCC was higher in trial-I patients (73.6% versus. 45.9% in trial II). Overall, 41 patients (8.3%) achieved pCR. The proportion of SCC was significantly higher among pCR patients (80.5% versus 48.3% in non-pCR patients). Administered treatments according to pCR status are presented in Table 2. Between the pCR and non-pCR groups there were no statistically significant differences regarding trials, chemotherapy regimens, and therapeutic strategies (preoperative or perioperative chemotherapy). All patients with pCR were considered to be clinically responders, with five (12.2%) patients achieving cCR and 36 (87.82%) cPR. In the non-pCR group, six (2.2%) patients were considered to have cCR. In the pCR group 87.8% of patients underwent lobectomy or bilobectomy versus 68.7% in the non-pCR group (p = 0.011).
Postoperative OS and Disease Free Survival Vital status was available for 98% of patients at the trial closing date, with 10 patients lost to follow-up including one pCR group patient after a delay of 5.5 years. Median follow-up was 5.6 years (range, 3.0–16.6 years). Comparison of Kaplan–Meier survival curves according to pathologic responses revealed significantly improved OS in pCR patients (Fig. 4). During follow-up, 10 (24.4%) patients died in the pCR group versus 217 (48.1%) in the non-pCR group, with 5-year OS rates being 80.0% (±7.0) and 55.8% (±2.5), respectively (log rank test, p = 0.0007). Median OS was not reached in the pCR group, whereas it was 69.6 months (95% CI = 59.21–95.34) in the non-pCR group. In the pCR group, two patients died from the evolution of their primary tumor, one from intercurrent disease, two from treatment-related death, one from ear, nose, and throat cancer, and four from unknown
reason. Treatment-related deaths included: one death from a pulmonary infection 7 days after bilobectomy and one death from a stroke 4 days after surgery. The intercurrent disease consisted of a stroke 12 years after surgery. Table 3 shows unadjusted risk ratios for OS and DFS estimated using univariate analysis Cox models. Univariate analysis revealed pCR to reduce the risk of death by 65% (relative risk [RR] = 0.35; 95% CI = 0.18–0.66). In univariate analysis, other significant factors were histological type (RR = 0.65; 95% CI = 0.50–0.84 for SCC compared to non-SCC) and weight loss more than 5% (RR = 1.59; 95% CI = 1.06–2.37). Multivariate Cox regression models showed that pCR significantly reduced the risk of death (RR = 0.34; 95% CI = 0.18–0.64) as did squamous-cell histological type (RR = 0.66; 95% CI = 0.50–0.87) (Table 4). In contrast, weight loss more than 5% (RR = 1.64; 95% CI = 1.09–2.47) and stage-IIB disease (RR = 1.40; 95% CI = 1.06–1.84) were significantly related to a higher risk of death. Furthermore, 5-year DFS was significantly improved in patients with pCR compared with non-pCR patients (80.1% ± 7.1% versus 44.8% ± 2.5%, respectively; log-rank test, p < 0.0001). The only other variable significantly associated with improved DFS in univariate analysis was SCC (RR = 0.55; 95% CI = 0.43–0.71 for SCC compared to non-SCC) (Table 3). Multivariate analysis using Cox regression models showed a favorable effect of pCR (RR = 0.29; 95% CI = 0.16–0.56), SCC (RR = 0.56; 95% CI = 0.44–0.73) on DFS, whereas stage-IIB disease compared to stage-IB disease (RR = 1.41; 95% CI = 1.09–1.81) was significantly related to poorer DFS (Table 4).
TABLE 2. Patient Treatments by Pathologic Response Pathologic response Incomplete
Total Characteristics
No.
Total Trial Trial I Trial II Randomization arm MIC PERI GP PRE GP PERI CT PRE CT PERI Chemotherapy strategy PRE PERI Type of surgery Lobectomy/Bilobectomy Pneumonectomy
492
(%) (100)
Complete
No.
(%)
No.
(%)
451
(91.7)
41
(8.3)
pa
91 401
(18.5) (81.5)
80 371
(17.7) (82.3)
11 30
(26.8) (73.2)
0.151
91 106 97 101 97
(18.5) (21.6) (19.7) (20.5) (19.7)
80 100 89 89 93
(17.8) (22.2) (19.7) (19.7) (20.6)
11 6 8 12 4
(26.8) (14.6) (19.5) (29.3) (9.8)
0.159
207 285
(42.1) (57.9)
189 262
(41.9) (58.1)
18 23
(43.9) (56.1)
0.804
346 146
(70.3) (29.7)
310 141
(68.7) (31.3)
36 5
(87.8) (12.2)
0.011
a -squared test MIC, mitomycin–ifosfamide–cisplatin; perioperative; PRE, preoperative.
GP,
gemcitabine–cisplatin;
Copyright © 2012 by the International Association for the Study of Lung Cancer
CT,
carboplatin–placitaxel;
PERI,
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TABLE 3. Unadjusted Risk Ratios (univariate Cox model) for Postoperative Overall and Disease-Free Survival by Patient Characteristics at Baseline Overall survival Characteristics No.
FIGURE 4. Kaplan–Meier survival plots according to pathologic response: (A) Overall survival (B) Disease-free survival. *Log-rank test.
Recurrences and Second Primary Cancers Among the 492 patients, 195 (39.6%) experienced disease recurrence. However, recurrence occurred in only two pCR patients (4.9%) compared with 193 non-pCR patients (42.8%). In the non-pCR group, 131 recurrences (67.9%) were considered distant. The most common sites of recurrence were the brain (24.1%), lung (17.4%), and mediastinum (15.4%). Regarding the two cases of disease recurrence in the pCR group, one involved a trial-I patient who was male, former smoker, aged 69 years, with PS 0, and weight loss less than 5%. The patient was diagnosed with cT2N0M0 SCC, achieved cPR after two cycles of MIC regimen, and underwent surgical lobectomy. The histologically proven recurrence occurred in the trachea, carina, and left main bronchus 17 months after surgery. The other pCR patient experiencing a recurrence was treated for a cT2N0M0 large-cell carcinoma in trial II, having undergone four cycles of CP before lobectomy. This patient was a 47-year-old female, with PS 0 and weight loss less than 5%. She achieved cPR after preoperative chemotherapy, with multiple lung metastases occurring 27 months after surgery.
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Age, yr ≤70 >70 Sex Male Female Smoking status Never smoker Smoker Histology Non-squamous Squamous WHO PS 0 ≥1 Weight loss ≤5% >5% cT 1 2 3 cN 0 1 Clinical Stage IB IIA IIB Trial Trial I Trial II Randomization arm MIC PERI GP PRE GP PERI CT PRE CT PERI Chemotherapy strategy PRE PERI pCR No Yes
RR
95% CI
pa
Disease-free survival RR
95% CI
0.480 445 47
1 0.84 0.51–1.73
413 79
1 0.98 0.68–1.43
28 464
1 1.06 0.58–1.94
241 251
1 0.65 0.50–0.84
379 113
1 1.02 0.75–1.38
450 42
1 1.59 1.06–2.37
18 428 46
1 0.99 0.47–2.12 1.76 0.78–4.01
341 151
1 0.95 0.71–1.27
295 18 179
1 1.02 0.48–2.18 1.22 0.93–1.60
91 401
1 0.96 0.69–1.33
0.351 1 0.81 0.52–1.26
0.933
0.946 1 1.01 0.72–1.42
0.855
0.802 1 0.94 0.56–1.58
0.001
<0.0001 1 0.55 0.43–0.71
0.913
0.595 1 0.93 0.69–1.23
0.023
0.100 1 1.39 0.94–2.05
0.011
0.073 1 1.12 0.55–2.26 1.70 0.78–3.69
0.736
0.865 1 1.02 0.79–1.33
0.338
0.257 1 0.93 0.45–1.89 1.22 0.95–1.57
0.785
0.721 1 1.09 0.80–1.48
0.587 91 106 97 101
1 0.86 0.56–1.32 0.97 0.64–1.48 1.15 0.77–1.72
97
0.83 0.53–1.30
0.946 1 1.08 0.73–1.59 1.05 0.71–1.57 1.17 0.80–1.73 1.03 0.69–1.55
0.645 207 285
1 0.94 0.71–0.12
451 41
1 0.35 0.18–0.66
pa
0.497 1 0.92 0.71–1.18
0.0007
<0.0001 1 0.28 0.15–0.53
Score test. Bold indicates significance. RR, relative risk; pCR, pathologic complete response; MIC, mitomycin–ifosfamide– cisplatin; GP, gemcitabine–cisplatin; CT, carboplatin–placitaxel; PERI, perioperative; PRE, preoperative; CI, confidence interval. a
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TABLE 4. Adjusted Risk Ratios (Multivariate Cox Analysis)a for Postoperative Overall and Disease-Free Survival Overall Survival Characteristics pCR No Yes Histology Non-squamous Squamous Weight Loss ≤5% >5% Clinical Stage IB IIA IIB
RR
95% CI
Disease-free survival pb
RR
95% CI
pb
1 0.34
0.18–0.64
0.0009
1 0.29
0.16–0.56
0.0002
1 0.66
0.50–0.87
0.003
1 0.56
0.44–0.73
<0.0001
1 1.64
1.09–2.47
0.017
1 1.47
0.99–2.19
0.057
1 1.19 1.40
0.55–2.60 1.06–1.84
0.654 0.019
1 1.00 1.41
0.49–2.06 1.09–1.81
0.999 0.009
Stratified by randomization arm. Wald Test. RR, relative risk; CI, confidence interval; pCR, pathologic complete response.
a b
She continued to smoke throughout the disease. Both patients died from NSCLC. During follow-up, six pCR patients (14.6%) experienced a second primary cancer (two NSCLC, three ENT cancers, and one prostate cancer) versus 47 patients (10.4%) in the non-pCR group (16 NSCLC, 11 colorectal cancers, seven prostate cancers, and 19 other-site cancers).
Predictive Factors of pCR In univariate analysis, only the histological type was significantly related to pCR, with a significantly higher proportion of pCR among SCC patients (Table 1). The histological type was the only independent predictive factor of pCR in multivariate analyses, with SCC patients being more likely to achieve pCR (OR = 4.30; 95% CI = 1.90–9.72; p < 0.0005). Whereas randomization arm and stage were not correlated with the occurrence of pCR.
DISCUSSION Our study revealed 5-year postoperative OS and DFS rates of 80.0% in pCR patients versus 55.8% and 44.8%, respectively in non-pCR patients, demonstrating that pCR after neoadjuvant chemotherapy was a strong, favorable prognostic factor of OS (RR = 0.34; 95% CI = 0.18–0.64) and DFS (RR = 0.29; 95% CI = 0.16–0.56). To our knowledge, our study included the largest series of pCR after preoperative chemotherapy for NSCLC patients (n = 41), published to date. The 73 stage-IIIA patients of trial I and the 89 stage-IA patients of trial II were not included in the present analysis, with the aim of a homogeneous population. In the other phase-III trials evaluating neoadjuvant chemotherapy, the rate of pCR ranged from 3.7% (one patient)17 to 10.5% (19 patients)18. Given the small pCR patient samples, few conclusions may be drawn from these studies with respect to patient outcome. Nonetheless, the phase-III study by Felip et al.18 evaluated 5-year DFS rates in pCR patients treated with
preoperative CP for stage-IA (tumor size > 2 cm), -IB, -II, or -T3N1 NSCLC. In this report, DFS was estimated at 59% in the 19 pCR patients compared to 38.3% in the entire preoperative chemotherapy group. Pisters et al.13 reported the outcome of a hospital series of 21 pCR patients following preoperative chemotherapy with mitomycin, vinca alkaloid, and cisplatin for stage-IIIA NSCLC between 1983 and 1992. The 5-year survival rate of 54% was significantly higher than that of a series of 35 non-pCR patients undergoing complete resection for stage-IIIA N2 NSCLC after preoperative chemotherapy (5-year survival = 15%) in the same institution. In a phase-II study involving 34 patients, Elias et al.15 reported a recurrence in two out of six pCR patients compared to four out of six non-pCR patients with mediastinal nodal clearance following cisplatin, 5-fluorouracil, and leucovorin chemotherapy for stage-IIIA N2 NSCLC. In a phase-II trial investigating the efficacy of neoadjuvant docetaxel-cisplatin in stage-IIIA N2 NSCLC patients, the Swiss Group for Clinical Cancer Research reported a total of 13 pCR among 75 patients undergoing tumor resection after three cycles of chemotherapy.11 However, contrary to the trials cited above and our own study, pCR was defined as necrosis more than or equal to 95% and fibrosis at pathologic examination. Consequently, patients with a small number of persistent viable tumor cells were considered pCR patients. In univariate analysis, pCR was found to be predictive of improved OS and event-free survival, decreased risk of local relapse, and distant metastases. Although our study findings confirm this improved outcome in cases of pCR after preoperative chemotherapy, it must be stressed that our analysis was based on a larger and homogeneous sample of 41 early-stage NSCLC patients, who were prospectively assessed in two multicenter randomized phase-III trials, with pCR strictly defined as the absence of cancer cells in the surgically resected specimens. Among our 41 pCR patients, only two experienced disease recurrence, with loco-regional metastases observed in
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one patient and multiple lung metastases in the other. Pisters et al.13 reported eight patients experiencing disease recurrence, mainly brain metastases (n = 5), from a series of 21 pCR following neoadjuvant chemotherapy for stage-III NSCLC. In a retrospective analysis reported by Chen et al.25 211 patients were treated with neoadjuvant chemotherapy or chemoradiotherapy for stage-IIIA or -IIIB NSCLC, with 51 pCRs being observed, 29 after chemotherapy and 22 after chemoradiation. Disease recurrence occurred in 31 patients with the first site of recurrence being the brain in 22 patients. In these published series, the more advanced disease was likely to account for the higher risk of recurrence despite pCR, and for the high rate of brain metastases. In the study of Chen et al.25 the combination of chemotherapy and radiotherapy may have contributed in reducing the loco-regional risk of recurrence. Given the small number of recurrences observed in our study, we are not able to determine whether there is a preferential site of relapse for stage-IB and -II NSCLC in pCR patients following neoadjuvant chemotherapy. Previous results strongly suggested that neoadjuvant chemotherapy decreases the risk of metastases.9 In case of pCR after neoadjuvant chemotherapy for early-stage NSCLC, the risk of recurrence is very low, with most patients achieving disease cure. As pCR seems to be a predictor of cure, the selection of patients who may achieve a complete response is of clinical interest. Several models were tested in our study, including randomization arm or trial, as well as cT and cN status or clinical stage. The results based on these models were similar, revealing that SCC was the only and strongly independent prognostic factor of pCR (OR = 4.30; 95% CI = 1.90–9.72). Among the 492 patients, 251 patients (51%) were diagnosed with SCC. Tripletcombination chemotherapy was shown to increase response rates in advanced disease.26 The proportion of SCC was higher in trial I (73.6% versus 45.9% in trial II), which used a triplet regimen. However, no interaction between histological type and trial was shown in multivariate analyses. Therefore, the use of a three-drug combination is unlikely to account for the higher proportion of complete responders among SCC patients. Another explanation may be the use of the cisplatin-gemcitabine combination, because gemcitabine was reported to be associated with improved survival as compared to pemetrexed in SCC patients with advanced NSCLC.27,28 However, in trial II, 14 patients experienced pCR after cisplatin–gemcitabine compared to 16 patients after paclitaxel–carboplatin. In advanced NSCLC, SCC was rarely reported to be more sensitive to chemotherapy than the other histological types.29,30 Indeed, adenocarcinoma was shown to be more frequently associated with increased response rates.31 Nevertheless, extrapolating findings observed in cases of advanced NSCLC may not be the best approach to explain results achieved in patients with more limited disease.32,33 Studies using molecular predictive markers of response would probably be more valuable. Among the 11 clinical complete responders, six experienced pCR. All patients with pCR were clinically considered to be responders, either complete (n = 5) or partial responders (n = 36). Our results confirm the previously reported findings, which were based solely on trial I data, showing that cCR was predictive of pCR, and that CT assessments likely underestimated pCR rates.34
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To conclude, our results revealed that pCR after preoperative chemotherapy was a robust favorable prognostic factor in clinical stage-IB and -II NSCLC. Our study involved the largest series of pCRs after preoperative chemotherapy, published to date. The only predictive factor of pCR was SCC. In operable NSCLC, as in more advanced diseases, treatment personalization may lead to improved results. Identifying molecular predictive markers for pCR may help in distinguishing patients who may benefit from neoadjuvant chemotherapy, and in choosing the most adequate preoperative chemotherapy regimen.
Acknowledgment
Dr. Gabrielle Cremer helped to edit the English text. REFERENCES 1. Berghmans T, Paesmans M, Meert AP, et al. Survival improvement in resectable non-small cell lung cancer with (neo)adjuvant chemotherapy: results of a meta-analysis of the literature. Lung Cancer 2005;49:13–23. 2. Burdett S, Stewart LA, Rydzewska L. A systematic review and metaanalysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol 2006;1:611–621. 3. Song WA, Zhou NK, Wang W, et al. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol 2010;5:510–516. 4. Burdett S, Rydzewska L, Tierney JF, et al. Pre-operative chemotherapy improves survival and reduces recurrence in operable non-small cell lung cancer: preliminary results of a systematic review and meta-analysis of individual patient data from 13 randomised trials. J Thorac Oncol 2011;6:S374–S375. 5. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:2672–2685. 6. Kuerer HM, Sahin AA, Hunt KK, et al. Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 1999;230:72–78. 7. de Campos-Lobato LF, Stocchi L, da Luz Moreira A, et al. Pathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence. Ann Surg Oncol 2011;18:1590–1598. 8. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880–1892. 9. Depierre A, Milleron B, Moro-Sibilot D, et al.; French Thoracic Cooperative Group. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 2002;20:247–253. 10. Betticher DC, Hsu Schmitz SF, Tötsch M, et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 nonsmall-cell lung cancer: a multicenter phase II trial. J Clin Oncol 2003;21:1752–1759. 11. Betticher DC, Hsu Schmitz SF, Tötsch M, et al.; Swiss Group for Clinical Cancer Research (SAKK). Prognostic factors affecting longterm outcomes in patients with resected stage IIIA pN2 non-smallcell lung cancer: 5-year follow-up of a phase II study. Br J Cancer 2006;94:1099–1106. 12. van Meerbeeck JP, Kramer GW, Van Schil PE, et al.; European Organisation for Research and Treatment of Cancer-Lung Cancer Group. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442–450. 13. Pisters KM, Kris MG, Gralla RJ, Zaman MB, Heelan RT, Martini N. Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: implications for the design of
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future non-small-cell lung cancer combined modality trials. J Clin Oncol 1993;11:1757–1762. 14. Recine D, Rowland K, Reddy S, et al. Combined modality therapy for locally advanced non-small cell lung carcinoma. Cancer 1990;66:2270–2278. 15. Elias AD, Skarin AT, Leong T, et al. Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC). Lung Cancer 1997;17:147–161. 16. Li J, Dai CH, Shi SB, Bao QL, Yu LC, Wu JR. Induction concurrent chemoradiotherapy compared with induction radiotherapy for superior sulcus non-small cell lung cancer: a retrospective study. Asia Pac J Clin Oncol 2010;6:57–65. 17. Rosell R, Gómez-Codina J, Camps C, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer 1999;26:7–14. 18. Felip E, Rosell R, Maestre JA, et al.; Spanish Lung Cancer Group. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010;28:3138–3145. 19. Gilligan D, Nicolson M, Smith I, et al. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 2007;369:1929–1937. 20. Ahmed S, Birnbaum AE, Safran HP, et al. Pathologic response after neoadjuvant carboplatin and weekly paclitaxel for early-stage lung cancer: a Brown University oncology group phase II study. J Thorac Oncol 2011;6:1432–1434. 21. Quoix E, Lavole A, Westeel V, et al. Phase III study comparing preoperative and perioperative chemotherapy (CT) with two different regimens in resectable non-small cell lung cancer (NSCLC): the results of the IFCT0002 study. J Thorac Oncol 2009;4:S887–S888. 22. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–1717. 23. WHO Handbook for Reporting Results of Cancer Treatment. Geneva Switzerland: World Health Organization Offset Publication N.48, 1979. 24. Martini N Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70:606–612. 25. Chen AM, Jahan TM, Jablons DM, Garcia J, Larson DA. Risk of cerebral metastases and neurological death after pathological complete response
to neoadjuvant therapy for locally advanced nonsmall-cell lung cancer: clinical implications for the subsequent management of the brain. Cancer 2007;109:1668–1675. 26. Azim HA Jr, Elattar I, Loberiza FR Jr, Azim H, Mok T, Ganti AK. Third generation triplet cytotoxic chemotherapy in advanced non-small cell lung cancer: a systematic overview. Lung Cancer 2009;64:194–198. 27. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543–3551. 28. Scagliotti G, Brodowicz T, Shepherd FA, et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011;6:64–70. 29. Fukuoka M, Masuda N, Furuse K, et al. A randomized trial in inoperable non-small-cell lung cancer: vindesine and cisplatin versus mitomycin, vindesine, and cisplatin versus etoposide and cisplatin alternating with vindesine and mitomycin. J Clin Oncol 1991;9:606–613. 30. Shinkai T, Eguchi K, Sasaki Y, et al. A prognostic-factor risk index in advanced non-small-cell lung cancer treated with cisplatin-containing combination chemotherapy. Cancer Chemother Pharmacol 1992;30:1–6. 31. Hirsch FR, Spreafico A, Novello S, Wood MD, Simms L, Papotti M. The prognostic and predictive role of histology in advanced non-small cell lung cancer: a literature review. J Thorac Oncol 2008;3:1468–1481. 32. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26:2450–2456. 33. Goss GD, Lorimer I, Tsao MS, et al. A phase III randomized, doubleblind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinb in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19. ASCO Meeting Abstracts 2010;28:LBA7005. 34. Milleron B, Westeel V, Quoix E, et al.; French Thoracic Cooperative Group. Complete response following preoperative chemotherapy for resectable non-small cell lung cancer: accuracy of clinical assessment using the French trial database. Chest 2005;128:1442–1447.
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Pathologic Complete Response to Preoperative Chemotherapy Predicts Cure in Early-Stage Non–Small-Cell Lung Cancer Combined Analysis of Two IFCT Randomized Trials Guillaume Mouillet, Msc,* Elisabeth Monnet, MD,† Bernard Milleron, MD,‡ Marc Puyraveau, MSc,§ Elisabeth Quoix, MD, Philippe David, MD,¶ Alain Ducoloné, MD, Olivier Molinier, MD,# Gérard Zalcman, MD, PhD,** Alain Depierre, MD* and Virginie Westeel, MD, PhD*†† on behalf of the Intergroupe Francophone de Cancérologie Thoracique (IFCT) Introduction: Our study aimed to evaluate whether pathologic complete response (pCR) in early-stage non–small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy resulted in improved outcome, and to determine predictive factors for pCR. Methods: Eligible patients with stage-IB or -II NSCLC were included in two consecutive Intergroupe Francophone de Cancérologie Thoracique phase-III trials evaluating platinum-based neoadjuvant chemotherapy, with pCR defined by the absence of viable cancer cells in the resected surgical specimen. Results: Among the 492 patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year overall survival was 80.0% compared with 55.8% in the non-pCR group (p = 0.0007). In multivariate analyses, pCR was a favorable prognostic factor of overall survival (relative risk = 0.34; 95% confidence interval = 0.18–0.64) in addition to squamous-cell carcinoma, weight loss less than or equal to 5%, and stage-IB disease. Five-year disease-free survival was 80.1% in the pCR group compared to 44.8% in the non-pCR group (p < 0.0001). Two patients (4.9%) in the pCR group experienced disease recurrence compared to 193 patients (42.8%) in the non-pCR group. SCC subtype was the only independent predictor of pCR (odds ratio [OR] = 4.30; 95% confidence interval = 1.90–9.72). *Chest Disease Department, Jean Minjoz University Hospital, Besancon, France; †EA 4266, “Pathogenic Agents and Inflammation,” University of Franche-Comté, Besancon, France; ‡Chest Disease Department, Tenon University Hospital, Paris, France; §Clinical Methodology Center, University Hospital, Besancon, France; Chest Disease Department, Nouvel Hôpital Civil, Strasbourg, France; ¶Chest Disease Department, General Hospital, Elbeuf, France; #Chest Disease Department, General Hospital, Le Mans, France; **Chest Disease Department, University Hospital, Caen, France; ††EA3181, University of Franche-Comté, Besançon, France. Disclosure: Drs. Milleron and Westeel have received honorarium for speaking and serve on the advisory board for Lilly. Dr. Quoix was paid honorarium for serving on advisory board for Lilly and Bristol Myers Squib. Dr. Zalcman has received honorarium for speaking and serving on the advisory boards for Lilly and Bristol Myers Squib. Address for correspondence: Virginie Westeel, MD, PhD, Service de Pneumologie, CHU Jean Minjoz, Boulevard Fleming, 25030 Besançon Cedex, France. E-mail: [email protected]. Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/841-849
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Conclusion: Our results showed that pCR after preoperative chemotherapy was a favorable prognostic factor in stage-IB–II NSCLC. Our study is the largest published series evaluating pCRs after preoperative chemotherapy. The only factor predictive of pCR was squamous-cell carcinoma. Identifying molecular predictive markers for pCR may help in distinguishing patients likely to benefit from neoadjuvant chemotherapy and in choosing the most adequate preoperative chemotherapy regimen. Key Words: Pathologic complete response, Preoperative chemotherapy, Neoadjuvant chemotherapy, Early-stage, Non–small-cell lung cancer. (J Thorac Oncol. 2012;7: 841–849)
T
reatment strategies combining chemotherapy and surgery have been developed to improve the survival of patients with early-stage non–small-cell lung cancer (NSCLC). Metaanalyses of phase-III trials, particularly a recent one based on individual patient data, revealed a significant 5-year overall survival (OS) benefit of 5% when using preoperative chemotherapy in operable NSCLC.1–4 Similar to adjuvant chemotherapy, neoadjuvant chemotherapy aims to eradicate systemic micrometastases and reduce the risk of recurrence especially in the case of distant metastases. One advantage of neoadjuvant chemotherapy over adjuvant chemotherapy is that it allows for assessing tumor response and therefore tumor chemosensitivity. Previous studies on breast and rectal cancers have demonstrated that pathologic complete responses (pCR) after preoperative therapy were associated with improved OS and disease-free survival (DFS). Furthermore, pCR was considered to be a surrogate endpoint for long-term DFS.5–7 In NSCLC, responses and particularly mediastinal downstaging after preoperative chemotherapy or chemoradiation were shown to be associated with improved survival.8–12 However, there is little data on the prognostic value of pCR after preoperative chemotherapy.11,13–16 As pCR was shown not to exceed 17% after neoadjuvant chemotherapy, published reports on pCRs included only small series of patients.9,17–20 In these studies, mainly involving stage-IIIA N2 NSCLC
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patients, pCR after preoperative chemotherapy or chemoradiotherapy was shown to be a favorable prognostic factor. However, in these series, too few pCRs were observed to permit a thorough analysis. Our study was based on the datasets from two consecutive French multicenter randomized phase-III trials from the Intergroupe Francophone de Cancérologie Thoracique (IFCT)9,21 on neoadjuvant chemotherapy, involving large series of patients with long-term follow-up. Because of the sufficiently high number of pCR observed in these two trials, we were able to analyze the prognostic value of pCR, and determine positive predictors for pCR after neoadjuvant chemotherapy.
PATIENTS AND METHODS Data Sources The current analysis was performed using databases from two phase-III randomized trials evaluating neoadjuvant chemotherapy: Depierre9 trial (trial I) and IFCT0002 trial (trial II)21. In trial I undertaken between 1991 and 1997, patients were randomized to either undergo immediate thoracic surgery or receive two cycles of chemotherapy before surgery plus two further postsurgery cycles in responders, with chemotherapy consisting of mitomycin, ifosfamide, and cisplatin (MIC) combination (Fig. 1). In trial II undertaken between 2001 and 2006, two different chemotherapy strategies were compared: (1) two cycles before surgery plus two further presurgery cycles in responders (preoperative chemotherapy arms) and (2) two cycles before surgery plus two further postsurgery cycles in responders (perioperative chemotherapy arms). Chemotherapy comprised carboplatin-paclitaxel (CP) or gemcitabine-cisplatin (Fig. 2). Additional details regarding the different treatment modalities were provided in previous publications.9,21 In both trials, eligible patients were aged between 18 and 75 years, with a World Health Organization performance status (PS) less than or equal to 2, and histologically proven stage-IB, -IIA, or -IIB NSCLC. In addition, stage IIIA was included in trial I and stage IA in trial II. In both studies, initial staging investigations involved chest radiograph, thoracic and abdominal computed-tomography (CT), fiberoptic bronchoscopy, and brain CT-scan or magnetic resonance imaging. In trial II, a mediastinoscopy was required before the randomization of patients with mediastinal lymph nodes more than 1 cm in their smallest diameter on CT-scan. Patients should undergo the same surgery they would have needed before neoadjuvant therapy, regardless of response. The follow-up procedures in the two trials included a physical examination and chest radiograph every 3 months, and a fiberoptic bronchoscopy and chest CT-scan every 6 months for the first 2 years. In trial I, from the third to the seventh year, follow-up consisted of a chest radiograph every 6 months, and fiberoptic bronchoscopy and chest CT-scan every year. After 8 years, the investigators were invited to set up an annual clinic visit. In trial II, an annual followup was scheduled to occur from the third to the fifth year
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FIGURE 1. Trial I design.
involving a fiberoptic bronchoscopy and chest CT-scan, and thereafter a chest radiograph. Both trials were approved by the Human Investigations Committee of Franche-Comté, France. In total, 883 patients were included in the two randomized trials, with median follow-up being 13.8 years (range: 10.4–16.6) in trial I and 5 years (range, 3.0–7.6) in trial II.
Study Population In our analysis, only patients treated with preoperative chemotherapy followed by surgery were included. As stage IA patients were ineligible for trial I and stage IIIA patients for trial II, these patients were excluded from our analysis. Thus, only stage-IB and -II NSCLC patients were considered for our analysis (Fig. 3). All stages were redefined using the sixth tumor, node, metastasis, classification, which was used during trial II.22
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 5, May 2012 Pathologic Complete Response after Neoadjuvant Chemotherapy
FIGURE 3. Flow chart. FIGURE 2. Trial II design.
Assessment of Response Clinical response was assessed according to World Health Organization criteria23 by means of chest CT-scan and fiberoptic bronchoscopy undertaken before surgery. Clinical complete response (cCR) was defined as the complete disappearance of all target lesions without any residual lesions. The absence of cancer cells in bronchial biopsy specimens was a requisite for cCR. Clinical partial response (cPR) was defined as more than 50% decrease in tumor mass, without progression of target lesions or appearance of new lesions. Stable disease was considered as less than 50% decrease or less than 25% increase in tumor mass without appearance of new lesions. Clinical progressive disease was defined as more than 25% increase in tumor mass or the appearance of new lesions. Last, pCR was defined as the absence of viable tumor detected in the resected surgical specimen on pathologic examination.
Statistical Methods Differences in baseline patient characteristics according to pathologic responses were assessed using chi-squared or Fisher’s exact tests. The primary objective was to compare postoperative OS according to pathologic responses. OS was defined as the time from surgery to any-cause death, date of last news, or date of trial endpoint. DFS was defined as the time from surgery to date of recurrence or date of death for patients who died without recurrence. In patients alive without recurrence, DFS was determined from the date of surgery to the date of last news or trial endpoint. The distinction between the recurrence of the original lung cancer and onset of a second primary lung cancer was based on the definition of Martini and Melamed.24 At the endpoint date (December, 31 2007 in trial I and December, 31 2008 in trial II), the physicians in charge were invited to contact patients to determine their vital status. OS and DFS rates along with SDs were estimated using the Kaplan–Meier method. Differences
Copyright © 2012 by the International Association for the Study of Lung Cancer
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in OS and DFS according to pathologic responses were tested for significance using the log-rank test. Unadjusted risk ratios along with their 95% confidence intervals (CI) were estimated by means of univariate Cox models, and used to describe the relationship between pCR and the main prognostic factors with OS and DFS. Multivariate analyses using Cox models stratified by randomization arm were performed for OS and DFS to test the prognostic value of pCR after adjusting for other prognostic factors. All variables relating to OS and DFS with a p value less than or equal to 0.20 in Cox univariate analysis were included in the multivariate analyses. Proportional hazard assumptions were examined for each Cox model variable using graphical methods or testing an interaction term with time for significance. Finally, predictive factors of pCR were identified using multivariable logistic regression, with pCR status as
a dependant variable and baseline patient characteristics as independent variables. p values were two-sided, with values < 0.05 considered statistically significant. All analysis were performed using SAS 9.3 (SAS Institute, Cary, NC)
RESULTS Patient Characteristics In total, 492 patients were eligible for inclusion in the current analysis, comprising 91 trial-I patients (18.5%) and 401 trial-II patients (81.5%) (Fig. 3). Pretreatment patient and tumor characteristics are summarized in Table 1. Median age at randomization was 61 years (range, 34–75 years). The majority of patients were men (83.9%), former or current smokers (94.3%) having a PS of 0 (77.0%) and stage-IB disease (60.0%). Overall, there were 51.0% of squamous-cell–carcinoma
TABLE 1. Patient Characteristics by Pathologic Response Pathologic Response Total Characteristics
No.
Total Age, years ≤70 >70 Sex Male Female Smoking status Non-smoker Current Smoker Former smoker Histology Non-squamous Squamous WHO PS 0 1 2 Weight loss ≤5% >5% cT 1 2 3 cN 0 1 Clinical stage IB IIA IIB
492
(%) (100)
Incomplete
Complete
No.
(%)
No.
(%)
451
(91.7)
41
(8.3)
P
445 47
(90.5) (9.5)
406 45
(90.0) (10.0)
39 2
(95.1) (4.9)
0.409a
413 79
(83.9) (16.1)
378 73
(83.8) (16.2)
35 6
(85.4) (14.6)
0.795b
28 330 134
(5.7) (67.1) (27.2)
28 303 120
(6.2) (67.2) (26.6)
0 27 14
(0.0) (65.8) (34.2)
0.188b
241 251
(49.0) (51.0)
233 218
(51.7) (48.3)
8 33
(19.5) (80.5)
<0.0001b
379 110 3
(77.0) (22.4) (0.6)
349 99 3
(77.4) (21.9) (0.7)
30 11 0
(73.2) (26.8) (0.0)
0.659a
450 42
(91.5) (8.5)
414 37
(91.8) (8.2)
36 5
(87.8) (12.2)
0.378a
18 428 46
(3.7) (87.0) (9.3)
16 390 45
(3.5) (86.5) (10.0)
2 38 1
(4.9) (92.7) (2.4)
0.193a
0.055b 341 151
(69.3) (30.7)
318 133
(70.5) (29.5)
23 18
(56.1) (43.9)
295 18 179
(60.0) (3.6) (36.4)
273 16 162
(60.5) (3.6) (35.9)
22 2 17
(53.6) (4.9) (41.5)
0.972b
-squared test. Fisher’s exact test. WHO, World Health Organization; PS, performance status. Bold indicates significance. a b
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Journal of Thoracic Oncology • Volume 7, Number 5, May 2012 Pathologic Complete Response after Neoadjuvant Chemotherapy
(SCC) patients but the proportion of SCC was higher in trial-I patients (73.6% versus. 45.9% in trial II). Overall, 41 patients (8.3%) achieved pCR. The proportion of SCC was significantly higher among pCR patients (80.5% versus 48.3% in non-pCR patients). Administered treatments according to pCR status are presented in Table 2. Between the pCR and non-pCR groups there were no statistically significant differences regarding trials, chemotherapy regimens, and therapeutic strategies (preoperative or perioperative chemotherapy). All patients with pCR were considered to be clinically responders, with five (12.2%) patients achieving cCR and 36 (87.82%) cPR. In the non-pCR group, six (2.2%) patients were considered to have cCR. In the pCR group 87.8% of patients underwent lobectomy or bilobectomy versus 68.7% in the non-pCR group (p = 0.011).
Postoperative OS and Disease Free Survival Vital status was available for 98% of patients at the trial closing date, with 10 patients lost to follow-up including one pCR group patient after a delay of 5.5 years. Median follow-up was 5.6 years (range, 3.0–16.6 years). Comparison of Kaplan–Meier survival curves according to pathologic responses revealed significantly improved OS in pCR patients (Fig. 4). During follow-up, 10 (24.4%) patients died in the pCR group versus 217 (48.1%) in the non-pCR group, with 5-year OS rates being 80.0% (±7.0) and 55.8% (±2.5), respectively (log rank test, p = 0.0007). Median OS was not reached in the pCR group, whereas it was 69.6 months (95% CI = 59.21–95.34) in the non-pCR group. In the pCR group, two patients died from the evolution of their primary tumor, one from intercurrent disease, two from treatment-related death, one from ear, nose, and throat cancer, and four from unknown
reason. Treatment-related deaths included: one death from a pulmonary infection 7 days after bilobectomy and one death from a stroke 4 days after surgery. The intercurrent disease consisted of a stroke 12 years after surgery. Table 3 shows unadjusted risk ratios for OS and DFS estimated using univariate analysis Cox models. Univariate analysis revealed pCR to reduce the risk of death by 65% (relative risk [RR] = 0.35; 95% CI = 0.18–0.66). In univariate analysis, other significant factors were histological type (RR = 0.65; 95% CI = 0.50–0.84 for SCC compared to non-SCC) and weight loss more than 5% (RR = 1.59; 95% CI = 1.06–2.37). Multivariate Cox regression models showed that pCR significantly reduced the risk of death (RR = 0.34; 95% CI = 0.18–0.64) as did squamous-cell histological type (RR = 0.66; 95% CI = 0.50–0.87) (Table 4). In contrast, weight loss more than 5% (RR = 1.64; 95% CI = 1.09–2.47) and stage-IIB disease (RR = 1.40; 95% CI = 1.06–1.84) were significantly related to a higher risk of death. Furthermore, 5-year DFS was significantly improved in patients with pCR compared with non-pCR patients (80.1% ± 7.1% versus 44.8% ± 2.5%, respectively; log-rank test, p < 0.0001). The only other variable significantly associated with improved DFS in univariate analysis was SCC (RR = 0.55; 95% CI = 0.43–0.71 for SCC compared to non-SCC) (Table 3). Multivariate analysis using Cox regression models showed a favorable effect of pCR (RR = 0.29; 95% CI = 0.16–0.56), SCC (RR = 0.56; 95% CI = 0.44–0.73) on DFS, whereas stage-IIB disease compared to stage-IB disease (RR = 1.41; 95% CI = 1.09–1.81) was significantly related to poorer DFS (Table 4).
TABLE 2. Patient Treatments by Pathologic Response Pathologic response Incomplete
Total Characteristics
No.
Total Trial Trial I Trial II Randomization arm MIC PERI GP PRE GP PERI CT PRE CT PERI Chemotherapy strategy PRE PERI Type of surgery Lobectomy/Bilobectomy Pneumonectomy
492
(%) (100)
Complete
No.
(%)
No.
(%)
451
(91.7)
41
(8.3)
pa
91 401
(18.5) (81.5)
80 371
(17.7) (82.3)
11 30
(26.8) (73.2)
0.151
91 106 97 101 97
(18.5) (21.6) (19.7) (20.5) (19.7)
80 100 89 89 93
(17.8) (22.2) (19.7) (19.7) (20.6)
11 6 8 12 4
(26.8) (14.6) (19.5) (29.3) (9.8)
0.159
207 285
(42.1) (57.9)
189 262
(41.9) (58.1)
18 23
(43.9) (56.1)
0.804
346 146
(70.3) (29.7)
310 141
(68.7) (31.3)
36 5
(87.8) (12.2)
0.011
a -squared test MIC, mitomycin–ifosfamide–cisplatin; perioperative; PRE, preoperative.
GP,
gemcitabine–cisplatin;
Copyright © 2012 by the International Association for the Study of Lung Cancer
CT,
carboplatin–placitaxel;
PERI,
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TABLE 3. Unadjusted Risk Ratios (univariate Cox model) for Postoperative Overall and Disease-Free Survival by Patient Characteristics at Baseline Overall survival Characteristics No.
FIGURE 4. Kaplan–Meier survival plots according to pathologic response: (A) Overall survival (B) Disease-free survival. *Log-rank test.
Recurrences and Second Primary Cancers Among the 492 patients, 195 (39.6%) experienced disease recurrence. However, recurrence occurred in only two pCR patients (4.9%) compared with 193 non-pCR patients (42.8%). In the non-pCR group, 131 recurrences (67.9%) were considered distant. The most common sites of recurrence were the brain (24.1%), lung (17.4%), and mediastinum (15.4%). Regarding the two cases of disease recurrence in the pCR group, one involved a trial-I patient who was male, former smoker, aged 69 years, with PS 0, and weight loss less than 5%. The patient was diagnosed with cT2N0M0 SCC, achieved cPR after two cycles of MIC regimen, and underwent surgical lobectomy. The histologically proven recurrence occurred in the trachea, carina, and left main bronchus 17 months after surgery. The other pCR patient experiencing a recurrence was treated for a cT2N0M0 large-cell carcinoma in trial II, having undergone four cycles of CP before lobectomy. This patient was a 47-year-old female, with PS 0 and weight loss less than 5%. She achieved cPR after preoperative chemotherapy, with multiple lung metastases occurring 27 months after surgery.
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Age, yr ≤70 >70 Sex Male Female Smoking status Never smoker Smoker Histology Non-squamous Squamous WHO PS 0 ≥1 Weight loss ≤5% >5% cT 1 2 3 cN 0 1 Clinical Stage IB IIA IIB Trial Trial I Trial II Randomization arm MIC PERI GP PRE GP PERI CT PRE CT PERI Chemotherapy strategy PRE PERI pCR No Yes
RR
95% CI
pa
Disease-free survival RR
95% CI
0.480 445 47
1 0.84 0.51–1.73
413 79
1 0.98 0.68–1.43
28 464
1 1.06 0.58–1.94
241 251
1 0.65 0.50–0.84
379 113
1 1.02 0.75–1.38
450 42
1 1.59 1.06–2.37
18 428 46
1 0.99 0.47–2.12 1.76 0.78–4.01
341 151
1 0.95 0.71–1.27
295 18 179
1 1.02 0.48–2.18 1.22 0.93–1.60
91 401
1 0.96 0.69–1.33
0.351 1 0.81 0.52–1.26
0.933
0.946 1 1.01 0.72–1.42
0.855
0.802 1 0.94 0.56–1.58
0.001
<0.0001 1 0.55 0.43–0.71
0.913
0.595 1 0.93 0.69–1.23
0.023
0.100 1 1.39 0.94–2.05
0.011
0.073 1 1.12 0.55–2.26 1.70 0.78–3.69
0.736
0.865 1 1.02 0.79–1.33
0.338
0.257 1 0.93 0.45–1.89 1.22 0.95–1.57
0.785
0.721 1 1.09 0.80–1.48
0.587 91 106 97 101
1 0.86 0.56–1.32 0.97 0.64–1.48 1.15 0.77–1.72
97
0.83 0.53–1.30
0.946 1 1.08 0.73–1.59 1.05 0.71–1.57 1.17 0.80–1.73 1.03 0.69–1.55
0.645 207 285
1 0.94 0.71–0.12
451 41
1 0.35 0.18–0.66
pa
0.497 1 0.92 0.71–1.18
0.0007
<0.0001 1 0.28 0.15–0.53
Score test. Bold indicates significance. RR, relative risk; pCR, pathologic complete response; MIC, mitomycin–ifosfamide– cisplatin; GP, gemcitabine–cisplatin; CT, carboplatin–placitaxel; PERI, perioperative; PRE, preoperative; CI, confidence interval. a
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 5, May 2012 Pathologic Complete Response after Neoadjuvant Chemotherapy
TABLE 4. Adjusted Risk Ratios (Multivariate Cox Analysis)a for Postoperative Overall and Disease-Free Survival Overall Survival Characteristics pCR No Yes Histology Non-squamous Squamous Weight Loss ≤5% >5% Clinical Stage IB IIA IIB
RR
95% CI
Disease-free survival pb
RR
95% CI
pb
1 0.34
0.18–0.64
0.0009
1 0.29
0.16–0.56
0.0002
1 0.66
0.50–0.87
0.003
1 0.56
0.44–0.73
<0.0001
1 1.64
1.09–2.47
0.017
1 1.47
0.99–2.19
0.057
1 1.19 1.40
0.55–2.60 1.06–1.84
0.654 0.019
1 1.00 1.41
0.49–2.06 1.09–1.81
0.999 0.009
Stratified by randomization arm. Wald Test. RR, relative risk; CI, confidence interval; pCR, pathologic complete response.
a b
She continued to smoke throughout the disease. Both patients died from NSCLC. During follow-up, six pCR patients (14.6%) experienced a second primary cancer (two NSCLC, three ENT cancers, and one prostate cancer) versus 47 patients (10.4%) in the non-pCR group (16 NSCLC, 11 colorectal cancers, seven prostate cancers, and 19 other-site cancers).
Predictive Factors of pCR In univariate analysis, only the histological type was significantly related to pCR, with a significantly higher proportion of pCR among SCC patients (Table 1). The histological type was the only independent predictive factor of pCR in multivariate analyses, with SCC patients being more likely to achieve pCR (OR = 4.30; 95% CI = 1.90–9.72; p < 0.0005). Whereas randomization arm and stage were not correlated with the occurrence of pCR.
DISCUSSION Our study revealed 5-year postoperative OS and DFS rates of 80.0% in pCR patients versus 55.8% and 44.8%, respectively in non-pCR patients, demonstrating that pCR after neoadjuvant chemotherapy was a strong, favorable prognostic factor of OS (RR = 0.34; 95% CI = 0.18–0.64) and DFS (RR = 0.29; 95% CI = 0.16–0.56). To our knowledge, our study included the largest series of pCR after preoperative chemotherapy for NSCLC patients (n = 41), published to date. The 73 stage-IIIA patients of trial I and the 89 stage-IA patients of trial II were not included in the present analysis, with the aim of a homogeneous population. In the other phase-III trials evaluating neoadjuvant chemotherapy, the rate of pCR ranged from 3.7% (one patient)17 to 10.5% (19 patients)18. Given the small pCR patient samples, few conclusions may be drawn from these studies with respect to patient outcome. Nonetheless, the phase-III study by Felip et al.18 evaluated 5-year DFS rates in pCR patients treated with
preoperative CP for stage-IA (tumor size > 2 cm), -IB, -II, or -T3N1 NSCLC. In this report, DFS was estimated at 59% in the 19 pCR patients compared to 38.3% in the entire preoperative chemotherapy group. Pisters et al.13 reported the outcome of a hospital series of 21 pCR patients following preoperative chemotherapy with mitomycin, vinca alkaloid, and cisplatin for stage-IIIA NSCLC between 1983 and 1992. The 5-year survival rate of 54% was significantly higher than that of a series of 35 non-pCR patients undergoing complete resection for stage-IIIA N2 NSCLC after preoperative chemotherapy (5-year survival = 15%) in the same institution. In a phase-II study involving 34 patients, Elias et al.15 reported a recurrence in two out of six pCR patients compared to four out of six non-pCR patients with mediastinal nodal clearance following cisplatin, 5-fluorouracil, and leucovorin chemotherapy for stage-IIIA N2 NSCLC. In a phase-II trial investigating the efficacy of neoadjuvant docetaxel-cisplatin in stage-IIIA N2 NSCLC patients, the Swiss Group for Clinical Cancer Research reported a total of 13 pCR among 75 patients undergoing tumor resection after three cycles of chemotherapy.11 However, contrary to the trials cited above and our own study, pCR was defined as necrosis more than or equal to 95% and fibrosis at pathologic examination. Consequently, patients with a small number of persistent viable tumor cells were considered pCR patients. In univariate analysis, pCR was found to be predictive of improved OS and event-free survival, decreased risk of local relapse, and distant metastases. Although our study findings confirm this improved outcome in cases of pCR after preoperative chemotherapy, it must be stressed that our analysis was based on a larger and homogeneous sample of 41 early-stage NSCLC patients, who were prospectively assessed in two multicenter randomized phase-III trials, with pCR strictly defined as the absence of cancer cells in the surgically resected specimens. Among our 41 pCR patients, only two experienced disease recurrence, with loco-regional metastases observed in
Copyright © 2012 by the International Association for the Study of Lung Cancer
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one patient and multiple lung metastases in the other. Pisters et al.13 reported eight patients experiencing disease recurrence, mainly brain metastases (n = 5), from a series of 21 pCR following neoadjuvant chemotherapy for stage-III NSCLC. In a retrospective analysis reported by Chen et al.25 211 patients were treated with neoadjuvant chemotherapy or chemoradiotherapy for stage-IIIA or -IIIB NSCLC, with 51 pCRs being observed, 29 after chemotherapy and 22 after chemoradiation. Disease recurrence occurred in 31 patients with the first site of recurrence being the brain in 22 patients. In these published series, the more advanced disease was likely to account for the higher risk of recurrence despite pCR, and for the high rate of brain metastases. In the study of Chen et al.25 the combination of chemotherapy and radiotherapy may have contributed in reducing the loco-regional risk of recurrence. Given the small number of recurrences observed in our study, we are not able to determine whether there is a preferential site of relapse for stage-IB and -II NSCLC in pCR patients following neoadjuvant chemotherapy. Previous results strongly suggested that neoadjuvant chemotherapy decreases the risk of metastases.9 In case of pCR after neoadjuvant chemotherapy for early-stage NSCLC, the risk of recurrence is very low, with most patients achieving disease cure. As pCR seems to be a predictor of cure, the selection of patients who may achieve a complete response is of clinical interest. Several models were tested in our study, including randomization arm or trial, as well as cT and cN status or clinical stage. The results based on these models were similar, revealing that SCC was the only and strongly independent prognostic factor of pCR (OR = 4.30; 95% CI = 1.90–9.72). Among the 492 patients, 251 patients (51%) were diagnosed with SCC. Tripletcombination chemotherapy was shown to increase response rates in advanced disease.26 The proportion of SCC was higher in trial I (73.6% versus 45.9% in trial II), which used a triplet regimen. However, no interaction between histological type and trial was shown in multivariate analyses. Therefore, the use of a three-drug combination is unlikely to account for the higher proportion of complete responders among SCC patients. Another explanation may be the use of the cisplatin-gemcitabine combination, because gemcitabine was reported to be associated with improved survival as compared to pemetrexed in SCC patients with advanced NSCLC.27,28 However, in trial II, 14 patients experienced pCR after cisplatin–gemcitabine compared to 16 patients after paclitaxel–carboplatin. In advanced NSCLC, SCC was rarely reported to be more sensitive to chemotherapy than the other histological types.29,30 Indeed, adenocarcinoma was shown to be more frequently associated with increased response rates.31 Nevertheless, extrapolating findings observed in cases of advanced NSCLC may not be the best approach to explain results achieved in patients with more limited disease.32,33 Studies using molecular predictive markers of response would probably be more valuable. Among the 11 clinical complete responders, six experienced pCR. All patients with pCR were clinically considered to be responders, either complete (n = 5) or partial responders (n = 36). Our results confirm the previously reported findings, which were based solely on trial I data, showing that cCR was predictive of pCR, and that CT assessments likely underestimated pCR rates.34
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To conclude, our results revealed that pCR after preoperative chemotherapy was a robust favorable prognostic factor in clinical stage-IB and -II NSCLC. Our study involved the largest series of pCRs after preoperative chemotherapy, published to date. The only predictive factor of pCR was SCC. In operable NSCLC, as in more advanced diseases, treatment personalization may lead to improved results. Identifying molecular predictive markers for pCR may help in distinguishing patients who may benefit from neoadjuvant chemotherapy, and in choosing the most adequate preoperative chemotherapy regimen.
Acknowledgment
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