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Phase II study of metabolic response to one-cycle chemotherapy in patients with locally advanced esophageal squamous cell carcinoma
Journal of the Formosan Medical Association (2019) 118, 1024e1030
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Original Article
Phase II study of metabolic response to one-cycle chemotherapy in patients with locally advanced esophageal squamous cell carcinoma Ta-Chen Huang a,e, Chia-Chi Lin a,e, Yun-Chun Wu f, Jason Chia-Hsien Cheng a,e, Jang-Ming Lee b, Hsiu-Po Wang c, Pei-Ming Huang b, Feng-Ming Hsu a,e, Kun-Huei Yeh a,e,g,h, Ann-Lii Cheng a,e, Kai-Yuan Tzen d, Chih-Hung Hsu a,e,h,i,* a
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan c Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan d Department of Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan e Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan f Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan g Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan h National Taiwan University Cancer Center, Taipei, Taiwan i Graduate Institute of Oncology, National Taiwan University College of Medicine, No 1, Jen Ai Road Section 1, Taipei, 10051, Taiwan b
Received 24 June 2018; received in revised form 5 September 2018; accepted 9 November 2018
KEYWORDS Esophageal squamous cell carcinoma; Neoadjuvant chemoradiotherapy; Metabolic response; Positron emission tomography; Pathological complete response
Background: In the treatment of esophageal squamous cell carcinoma (ESCC), the optimal use of 18 fluorodeoxyglucose positron emission tomography (PET) in measuring metabolic tumor response is undetermined. We launched a phase II trial to evaluate early metabolic response to one-cycle induction chemotherapy in patients with locally advanced ESCC. Methods: ESCC patients in stage classification T3N0, N1M0, or M1a (American Joint Committee on Cancer, 6th edition) received one-cycle chemotherapy comprising paclitaxel, cisplatin, and 24-h infusional 5-fluorouracil and leucovorin on days 1 and 8, followed by neoadjuvant chemoradiotherapy, 40 Gy, with paclitaxel/cisplatin and then esophagectomy. PET was performed at baseline and day 14 of chemotherapy. The primary endpoint was pathologic complete response
* Corresponding author. Department of Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Road, Taipei, 10002, Taiwan. Fax: þ886 2 23711174. E-mail address: [email protected] (C.-H. Hsu). https://doi.org/10.1016/j.jfma.2018.11.003 0929-6646/Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Early PET response in neo-CRT in ESCC
1025
(pCR). We hypothesized early metabolic responders with >35% reduction in maximum standardized uptake value (SUVmax), would have better pCR Results. Results: Sixty-six patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 16 months (95% confidence interval [CI], 9e27) and 22 months (16e40), respectively. The early metabolic response rate was 55%; and the pCR rate was 34% in the esophagectomy population. The early metabolic response was not associated with pCR or survival. In an exploratory analysis, the postchemotherapy SUVmax was an independent prognostic factor for pCR, PFS, and OS. Conclusion: Our study failed to validate the predefined early metabolic response for pCR to neoadjuvant chemoradiotherapy in locally advanced ESCC patients. However, postchemotherapy SUVmax may be prognostic and predictive, and warrants further study. Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction Esophageal cancer is the sixth leading cause of cancer death worldwide.1 The endemic areas for esophageal squamous cell carcinoma (ESCC) include east and central Asia, eastern and southern Africa, and some parts of South America. At diagnosis, most esophageal cancer patients present with locally advanced disease, which is generally treated with multimodal therapies with curative intent. However, a considerable proportion of these patients experience tumor recurrence or an impaired quality of life resulting from aggressive treatment. One of the commonly used multimodal therapies for locoregional esophageal cancer is neoadjuvant chemoradiotherapy (CRT), followed by radical surgery. The CROSS trial, a randomized phase III trial, demonstrated an unequivocal survival benefit for neoadjuvant CRT with weekly paclitaxel/carboplatin plus radiation (41.8 Gy) compared with surgery alone.2 Cumulative data have demonstrated that patients whose surgical specimens have pathologic complete response [pCR] to neoadjuvant CRT have better outcomes than do those without pCR.3,4 However, the efficient surrogates, which can be measured and applied before esophagectomy, for pCR in ESCC are currently unknown. 18 Fluorodeoxyglucose (FDG) positron emission tomography (PET) measures in vivo glucose metabolism and can be used to evaluate the tumor response to therapeutics as a complement to conventional imaging modalities based on tumor size changes. PET has been evaluated as a prognostic and predictive assay tool for many types of cancers, including esophageal cancer. A meta-analysis of 7 studies on the prognostic value of the baseline standard uptake value (SUV) measured by PET revealed that a higher SUV was significantly correlated with poorer survival in patients with esophageal cancer (hazards ratio, 1.86, 95% confidence interval [CI], 1.53e2.27).5 Several studies have investigated the PET evaluation after neoadjuvant CRT, and correlated it with the pCR and survivals of patients with ESCC.6e8 However, these studies failed to unequivocally confirm the correlation between post-CRT PET and either pCR or patient survivals. Other studies have advocated the use of clinical response, including the metabolic response, at earlier time
points in the management of patients with locoregional upper aerodigestive tract cancers. A study of advanced laryngeal cancer demonstrated the feasibility of a treatment algorithm guided by the early clinical response (evaluated through laryngoscopy) to one-cycle induction chemotherapy.9 In esophageal adenocarcinoma, an early metabolic response, defined as a 35% reduction of SUV at day 14 of the 3-month neoadjuvant chemotherapy, predicted improved surgical outcomes and patient survival.10,11 In the MUNICON I and II trials, the early metabolic response evaluated after a 2-week cycle of induction chemotherapy was used to stratify responders and nonresponders to different treatments.12,13 We hypothesized that the early metabolic response to one-cycle induction chemotherapy, which is a surrogate for in vivo chemoresponsiveness, may predict the treatment outcomes in locally advanced ESCC patients receiving neoadjuvant CRT, followed by surgery. We thus designed this phase II clinical trial by including a 21-dayecycle induction chemotherapy treatment before the standard neoadjuvant CRT plus esophagectomy for locally advanced ESCC. This study planned to verify the hypothesis that the early metabolic response, predefined as a >35% reduction of maximum SUV (SUVmax) on day 14 of the one-cycle induction chemotherapy, could predict the patient survival and pCR to neoadjuvant CRT.
Patients and methods Study design This was a single-arm, nonrandomized phase II study conducted at a single referral medical center in Taiwan.
Patient population The target population was locally advanced ESCC, defined as pathologically proven squamous cell carcinoma of esophagus, with clinical stages of TNM classification: T3N0M0, T1e3N1M0, or T1e3N0e1M1a, according to the American Joint Committee on Cancer Staging System (6th edition). Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status 2,
1026 age 18 years, and adequate medical and laboratory status for undergoing chemotherapy. Patients with synchronous squamous cell carcinoma of the aerodigestive tract (other than the esophagus) and those who refused surgery were excluded. The staging procedures included endoscopy, endoscopic ultrasound, computed tomography (CT) scan of the chest and abdomen, and PET scan. The study was approved by the Institutional Review Board of National Taiwan University Hospital and was registered at www. ClinicalTrial.gov (NCT01034332).
Protocol treatment Patients received protocol-defined therapy in 3 stages: onecycle induction chemotherapy, neoadjuvant CRT, and radical surgery. The one-cycle induction chemotherapy was a 21-day TP-HDFL regimen (1-h intravenous infusion [IVF] of paclitaxel [70 mg/m2] on days 1 and 8, 2-h IVF of cisplatin [30 mg/m2] on days 2 and 9, and 24-h IVF of fluorouracil [2000 mg/m2] and leucovorin [300 mg/m2] on days 2 and 9). Neoadjuvant CRT involving a twice-weekly TP regimen (TPCRT) was commenced on day 22 of the one-cycle induction TP-HDFL. TP-CRT comprised 1-h IVF of paclitaxel (35 mg/ m2) on Monday and Thursday, 2-h IVF of cisplatin (15 mg/ m2) on Tuesday and Friday, and radiotherapy (2 Gy/fraction/day) from Monday to Friday for a total of 20 fractions. Radical surgery involving right thoracic approach esophagectomy with 2-field lymph node dissection and gastric tube reconstruction was scheduled at 4e6 weeks after the completion of neoadjuvant TP-CRT.4 If patients did not receive surgery after the post-CRT evaluation, TP-CRT was readministered with a cumulative radiation dose of 60e66 Gy.
Imaging studies Baseline PET was performed during initial staging before the initiation of the protocol treatment. PET was repeated on day 14 of the one-cycle induction TP-HDFL. Patients fasted for at least 6 h before PET imaging to ensure standardized glucose metabolism. Blood glucose levels were measured before each PET study. Patients with a blood glucose level greater than 150 mg/dL were excluded. Imaging data were normalized for the injected dose of FDG and patients’ body weight, with measurement of SUVmax at the regions with abnormal tumor uptake. The SUVmax of the primary esophageal tumor was recorded through baseline and repeat PET scans. Patients with an SUVmax reduction of more than 35% were defined as metabolic responders.
Response evaluation and patient follow-up In addition to PET, endoscopic ultrasound and CT scans of the chest and abdomen were performed at 4 weeks after the completion of neoadjuvant CRT for post-CRT clinical response evaluation. For patients receiving esophagectomy, all the resected samples, including those of the esophagus and regional lymph nodes, were subject to routine pathological examination. After esophagectomy, the clinical follow-up involved a clinical evaluation, an
T.-C. Huang et al. endoscopy, and CT scans of the chest and abdomen every 3 months for the first year and every 4 months for the second year, followed by the same evaluations every 6 months for another 3 years. Progression-free survival (PFS) is the time from enrollment to the first evidence of progression, recurrence of the cancer, or death. Overall survival (OS) is the time from enrollment to death.
Statistical consideration and analysis The primary endpoint of this study was pCR. The secondary endpoints were PFS and OS. For the primary endpoint, analyses of the esophagectomy population were performed. The association between early metabolic response and pCR was tested through logistic regression. For the secondary endpoints, analyses were performed in the entire enrolled population. The association between early metabolic response and PFS or OS was tested using Cox regression models. All quantitative data are expressed as mean standard deviation. The impacts of the baseline characteristics and parameters of PET scans on pCR were determined through univariate and multivariate analyses using logistic regression models. The impacts of the baseline characteristics and parameters of PET scans on PFS and OS were determined through univariate and multivariate analyses using Cox regression models. The prediction models were established using factors selected from the analyses. The statistical analysis was processed using R2.11.1 (www.r-project.org).
Results Study population Between February 2008 and March 2012, 66 enrolled patients underwent baseline PET scans. Five patients withdrew from the study, and another 8 patients were not evaluable because the FDG uptake of their tumors was too low for quantitative analysis. Hence, only 53 patients underwent the second PET scan (assessable patients). Fortyseven patients received surgery. Three patients showed disease progression after neoadjuvant CRT and did not receive surgery. Eleven patients refused surgery and received additional CRT. Forty-two of the patients who received surgery were assessable through both PET scans (Fig. 1). The patient characteristics are summarized in Table 1.
Treatment response and survival Baseline SUVmax in the assessable patients was 17 7. The SUVmax significantly decreased to 10 5 in the second PET scan that was evaluated on day 14 of induction chemotherapy (P < .001; Table 2). Among the 42 assessable patients who received surgery, R0 resection was achieved in 41 patients; only one patient had microscopic residual tumor at the section margin (ie, R1 resection) and received adjuvant postoperative CRT. Among 47 patients receiving esophagectomy, 16 exhibited pCR. The pCR rate was 34%. At a median follow-up
Early PET response in neo-CRT in ESCC
1027 the early metabolic response to one-cycle chemotherapy and the pCR to neoadjuvant CRT.
Factors associated with pCR, PFS, and OS
Figure 1 Number of enrolled patients, assessable patients, and assessable patients with surgery.
period of 61 months (range, 50e93 months), 20 patients remained alive. The median OS Results were 22 months (95% CI, 16e40 months), 25 months (95% CI, 18e80 months), and 26 months (95% CI, 18e71 months) in all patients, assessable patients, and assessable patients with surgery, respectively (Fig. 2). The median PFS results were 16 months (95% CI, 9e27 months), 20 months (95% CI, 11e53 months), and 20 months (95% CI, 12e34 months) in all patients, assessable patients, and assessable patients with surgery, respectively (Appendix Figure A1).
Early metabolic response and pCR Early metabolic response, defined as 35% SUVmax reduction from the baseline, was achieved in 50% of the assessable patients with surgery (21 patients); among them, 8 achieved pCR. However, even among the 21 patients who did not exhibit an early metabolic response, 8 achieved pCR. Therefore, no correlation was established between
Figure 2
Factors included in the univariate analysis were basic characteristics (age, sex, and ECOG performance status), cancer status (stage and location), nutrition status (weight loss and serum albumin levels), and PET parameters (baseline SUVmax, postinduction chemotherapy SUVmax, and SUVmax reduction rate). Univariate analysis for pCR revealed that postinduction chemotherapy SUVmax was a significant factor for pCR and that serum albumin levels, weight loss, baseline SUVmax trended to associate with pCR (Table 3). Multivariate analysis indicated that weight loss and postinduction chemotherapy SUVmax were significant factors. Univariate analysis for PFS and OS revealed that early metabolic response did not meet the secondary endpoints, with hazard ratios of 0.79 (P Z .49) and 0.75 (P Z .42) for PFS and OS, respectively. However, age and postinduction chemotherapy SUVmax were significant factors for OS and PFS and remained significant in the multivariate analysis (Appendix Table A1). In an exploratory analysis, we established a prediction model for pCR by combining postinduction chemotherapy SUVmax and weight loss, through logistic regression (Fig. 3). The area under the curve (AUC) of the prediction model was 0.84. The prediction models based on SUVmax reduction rate and weight loss was relatively less efficient, with AUCs of 0.75 (Appendix Figure A2).
Discussion This prospective study failed to validate the predefined cut-off value of the early metabolic response to one-cycle induction chemotherapy for predicting pCR after neoadjuvant CRT in locally advanced ESCC. A retrospective analysis suggested that the SUVmax of the postinduction chemotherapy PET scans in combination with weight loss might be an efficient model for predicting pCR. The definition of early metabolic response (ie, an SUVmax reduction of more than 35%) adopted in our study was based
Overall survival curves for all enrolled patients, assessable patients, and assessable patients with surgery.
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T.-C. Huang et al. Table 2 Metabolic chemotherapy. SUVmax
Baseline Mean SD Post-chemotherapy Mean SD Reduction (%) Mean SD
response
after
one-cycle
Assessable patients (N Z 53)
Assessable patients with surgery (N Z 42)
17 7
16 7
10 5
10 5
38 28
36 27
baseline SUV post chemotherapy SUV SUVmax reduction (%) Z baseline SUV
Figure 3 Prediction model for pathologic complete response. The model comprises two parameters: postinduction SUVmax and weight loss, which are both significant factors in multivariate analysis.
on the findings of 2 published studies enrolling patients with adenocarcinoma of the esophagogastric junction exclusively: the first prospective study discovered the optimal cut-off value,10 which was then validated by the second prospective study.11 In these two published studies, patients received neoadjuvant chemotherapy, followed by surgery at 3e4 weeks after completing chemotherapy. The chemotherapy regimen was cisplatin plus infusional 5fluorouracil (PF regimen) and additional paclitaxel only
Table 1
Clinical characteristics.
Parameters
All patients Assessable (N Z 66) patients (N Z 53)
Age (years) Mean SD 55 8 53 7 Gender Male 61 (92%) 49 (92%) Female 5 (8%) 4 (8%) ECOG performance status 0 36 (59%) 34 (65%) 1 25 (41%) 18 (35%) Stage II or III 56 (85%) 46 (87%) IV 10 (15%) 7 (13%) Tumor site Upper 18 (27%) 16 (30%) Middle 32 (49%) 26 (49%) Lower 16 (24%) 11 (21%) Albumin (g/dl) Mean SD 4.5 0.3 4.5 0.3 Weight loss (%) Mean SD 6 6 66
Assessable patients with surgery (N Z 42) 52 7 39 (93%) 3 (7%) 29 (71%) 12 (29%) 36 (86%) 6 (14%) 14 (33%) 22 (53%) 6 (14%) 4.6 0.3 57
for Siwert type 1 adenocarcinoma of the esophagogastric junction. The different histologic types and different treatment protocols may underlie the failure of this predefined early metabolic response in the current study, which exclusively enrolled patients with squamous cell carcinoma. To date, 2 studies have evaluated the role of the early metabolic tumor response in patients with ESCC. In one study, 38 ESCC patients received 5-fluorouracilebased neoadjuvant CRT, followed by surgery.7 Patients received PET evaluation before therapy, at 2 weeks after the initiation of neoadjuvant CRT, and preoperatively. The study reported that the changes in tumor metabolic activity after 14 days of neoadjuvant CRT were significantly correlated with the pathologic response and patient survival. The optimal cut-off value for the early metabolic response was 30%. In another study, 16 ESCC patients received a course of induction chemotherapy (PF regimen), followed by definitive PF-CRT.14 The early metabolic response was assessed from 12 to 24 days after initiating induction chemotherapy. The optimal cut-off value (55%) was associated with the clinical complete response and 1-year OS. None of these cut-off values for ESCC have been validated. In the current study, when we tried the above-mentioned two cut-off values of early PET response, we could not find their association with pCR or patients’ survivals (data not shown). Our study retrospectively demonstrated that the SUVmax of the postinduction chemotherapy PET scan was an independent factor for pCR and survival. The potential explanation of this finding is that the postinduction chemotherapy PET scan is a composite measurement of both the baseline value and tumor response to one cycle of chemotherapy. A low baseline SUV and a large reduction in SUV by the treatment, both of which contribute to low postinduction chemotherapy SUVs, are indicative of a good prognosis. By contrast, a predefined SUV reduction rate does not consider the impact of the baseline SUV and may not be adequately sensitive to those with low baseline SUVs. The ultimate goal of the clinical application of early metabolic response is to help personalize treatment strategies. Patients who have a good response to CRT and favorable prognosis may avoid unnecessary therapies such as esophagectomy15,16; by contrast, those who have a poor response to current CRT regimens may warrant other aggressive regimens or experimental approaches. CALGB
Early PET response in neo-CRT in ESCC Table 3
1029
Univariate and multivariate analysis for pathologic complete response.
Parameters
Pathologic complete response Multivariate analysis (N Z 42)
Univariate analysis
Age Gender Male (ref) Female ECOG performance status 0 (ref) 1 Stage II/III IV (ref) Tumor site Upper Middle Lower (ref) Albumin (g/dl) Weight loss (%) Baseline SUVmax Post-chemotherapy SUVmax SUVmax reduction (%) metabolic response
OR (95% C.I.)
p
1 (0.9e1.1)
0.46
1 4 (0.4e51)
0.25
1 0.4 (0.08e1.5)
0.15
4 (0.4e33) 1
0.26
4 (0.4e41) 5 (0.5e44) 1 8 (0.9e75) 0.9 (0.7e1) 0.9 (0.8e1) 0.8 (0.7e1) 1. (1e1) 1 (0.3e3)
0.46 0.24
80803 is a prospective randomized phase II study evaluating the metabolic response to induction chemotherapy for directing the selection of chemotherapy regimens (FOLFOX6 or paclitaxel plus carboplatin) for neoadjuvant CRT in patients with locoregional esophageal and gastroesophageal junction adenocarcinoma.17 Patients randomized to one regimen for induction chemotherapy would receive the other regimen for neoadjuvant CRT if no metabolic response to the induction chemotherapy was observed. The study revealed that altering the chemotherapy regimen in metabolic nonresponders led to a pCR rate of 15.6% compared with a historical control of 5%.17 In conclusion, the present study failed to validate the cut-off value of an early metabolic response in neoadjuvant TP-CRT for locally advanced ESCC patients. The SUVmax after one-cycle chemotherapy may have prognostic and predictive significance and warrants further study.
Conflicts of interest The authors have no conflicts of interest relevant to this article.
Acknowledgement We thank the Sinphar Pharmaceutical Corporation (Yilan, Taiwan) for providing paclitaxel for this study. This work is supported by a grant for investigator initiated trials (NCTRC200909), from National Clinical Trial and Research Center of National Taiwan University Hospital, Taiwan, and a grant (MOST 105-2314-B-002-186-MY3) from the Ministry of Science and Technology of the Executive
0.064 0.052 0.070 0.031 0.32 1
OR (95% C.I.)
p
0.8 (0.7e0.9)
0.018
0.8 (0.6e0.9)
0.010
Yuan, Taiwan. The role of the funding sources is to support scientific research in Taiwan.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2018.11.003.
References 1. Globocan. http://gco.iarc.fr. 2. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366(22):2074e84. 3. Guo JC, Huang TC, Lin CC, Hsieh MS, Chang CH, Huang PM, et al. Postchemoradiotherapy pathologic stage classified by the American Joint committee on the cancer staging System predicts prognosis of patients with locally advanced esophageal squamous cell carcinoma. J Thorac Oncol 2015;10(10):1481e9. 4. Lin CC, Hsu CH, Cheng JC, Wang HP, Lee JM, Yeh KH, et al. Concurrent chemoradiotherapy with twice weekly paclitaxel and cisplatin followed by esophagectomy for locally advanced esophageal cancer. Ann Oncol 2007;18(1):93e8. 5. Pan L, Gu P, Huang G, Xue H, Wu S. Prognostic significance of SUV on PET/CT in patients with esophageal cancer: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2009;21(9):1008e15. 6. Jayachandran P, Pai RK, Quon A, Graves E, Krakow TE, La T, et al. Postchemoradiotherapy positron emission tomography predicts pathologic response and survival in patients with esophageal cancer. Int J Radiat Oncol Biol Phys 2012;84(2):471e7. 7. Wieder HA, Brucher BL, Zimmermann F, Becker K, Lordick F, Beer A, et al. Time course of tumor metabolic activity during
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chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 2004;22(5):900e8. Monjazeb AM, Riedlinger G, Aklilu M, Geisinger KR, Mishra G, Isom S, et al. Outcomes of patients with esophageal cancer staged with [(1)(8)F]fluorodeoxyglucose positron emission tomography (FDG-PET): can postchemoradiotherapy FDG-PET predict the utility of resection? J Clin Oncol 2010;28(31): 4714e21. Urba S, Wolf G, Eisbruch A, Worden F, Lee J, Bradford C, et al. Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: a new treatment paradigm. J Clin Oncol 2006;24(4):593e8. Weber WA, Ott K, Becker K, Dittler HJ, Helmberger H, Avril NE, et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 2001;19(12):3058e65. Ott K, Weber WA, Lordick F, Becker K, Busch R, Herrmann K, et al. Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction. J Clin Oncol 2006;24(29):4692e8. Lordick F, Ott K, Krause BJ, Weber WA, Becker K, Stein HJ, et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 2007;8(9): 797e805.
T.-C. Huang et al. 13. zum Buschenfelde CM, Herrmann K, Schuster T, Geinitz H, Langer R, Becker K, et al. 18)F-FDG PET-guided salvage neoadjuvant radiochemotherapy of adenocarcinoma of the esophagogastric junction: the MUNICON II trial. J Nucl Med 2011;52(8):1189e96. 14. Ishihara R, Yamamoto S, Iishi H, Nagai K, Matui F, Kawada N, et al. Predicting the effects of chemoradiotherapy for squamous cell carcinoma of the esophagus by induction chemotherapy response assessed by positron emission tomography: toward PET-response-guided selection of chemoradiotherapy or esophagectomy. Int J Clin Oncol 2012;17(3):225e32. 15. Bedenne L, Michel P, Bouche O, Milan C, Mariette C, Conroy T, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 2007;25(10):1160e8. 16. Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 2005;23(10):2310e7. 17. Goodman KA, Niedzwiecki D, Hall N, Bekaii-Saab TS, Ye X, Meyers MO. Initial results of CALGB 80803 (Alliance): a randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer. J Clin Oncol 2017;35(Suppl. 4S). abstract 1.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Original Article
Phase II study of metabolic response to one-cycle chemotherapy in patients with locally advanced esophageal squamous cell carcinoma Ta-Chen Huang a,e, Chia-Chi Lin a,e, Yun-Chun Wu f, Jason Chia-Hsien Cheng a,e, Jang-Ming Lee b, Hsiu-Po Wang c, Pei-Ming Huang b, Feng-Ming Hsu a,e, Kun-Huei Yeh a,e,g,h, Ann-Lii Cheng a,e, Kai-Yuan Tzen d, Chih-Hung Hsu a,e,h,i,* a
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan c Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan d Department of Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan e Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan f Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan g Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan h National Taiwan University Cancer Center, Taipei, Taiwan i Graduate Institute of Oncology, National Taiwan University College of Medicine, No 1, Jen Ai Road Section 1, Taipei, 10051, Taiwan b
Received 24 June 2018; received in revised form 5 September 2018; accepted 9 November 2018
KEYWORDS Esophageal squamous cell carcinoma; Neoadjuvant chemoradiotherapy; Metabolic response; Positron emission tomography; Pathological complete response
Background: In the treatment of esophageal squamous cell carcinoma (ESCC), the optimal use of 18 fluorodeoxyglucose positron emission tomography (PET) in measuring metabolic tumor response is undetermined. We launched a phase II trial to evaluate early metabolic response to one-cycle induction chemotherapy in patients with locally advanced ESCC. Methods: ESCC patients in stage classification T3N0, N1M0, or M1a (American Joint Committee on Cancer, 6th edition) received one-cycle chemotherapy comprising paclitaxel, cisplatin, and 24-h infusional 5-fluorouracil and leucovorin on days 1 and 8, followed by neoadjuvant chemoradiotherapy, 40 Gy, with paclitaxel/cisplatin and then esophagectomy. PET was performed at baseline and day 14 of chemotherapy. The primary endpoint was pathologic complete response
* Corresponding author. Department of Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Road, Taipei, 10002, Taiwan. Fax: þ886 2 23711174. E-mail address: [email protected] (C.-H. Hsu). https://doi.org/10.1016/j.jfma.2018.11.003 0929-6646/Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Early PET response in neo-CRT in ESCC
1025
(pCR). We hypothesized early metabolic responders with >35% reduction in maximum standardized uptake value (SUVmax), would have better pCR Results. Results: Sixty-six patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 16 months (95% confidence interval [CI], 9e27) and 22 months (16e40), respectively. The early metabolic response rate was 55%; and the pCR rate was 34% in the esophagectomy population. The early metabolic response was not associated with pCR or survival. In an exploratory analysis, the postchemotherapy SUVmax was an independent prognostic factor for pCR, PFS, and OS. Conclusion: Our study failed to validate the predefined early metabolic response for pCR to neoadjuvant chemoradiotherapy in locally advanced ESCC patients. However, postchemotherapy SUVmax may be prognostic and predictive, and warrants further study. Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction Esophageal cancer is the sixth leading cause of cancer death worldwide.1 The endemic areas for esophageal squamous cell carcinoma (ESCC) include east and central Asia, eastern and southern Africa, and some parts of South America. At diagnosis, most esophageal cancer patients present with locally advanced disease, which is generally treated with multimodal therapies with curative intent. However, a considerable proportion of these patients experience tumor recurrence or an impaired quality of life resulting from aggressive treatment. One of the commonly used multimodal therapies for locoregional esophageal cancer is neoadjuvant chemoradiotherapy (CRT), followed by radical surgery. The CROSS trial, a randomized phase III trial, demonstrated an unequivocal survival benefit for neoadjuvant CRT with weekly paclitaxel/carboplatin plus radiation (41.8 Gy) compared with surgery alone.2 Cumulative data have demonstrated that patients whose surgical specimens have pathologic complete response [pCR] to neoadjuvant CRT have better outcomes than do those without pCR.3,4 However, the efficient surrogates, which can be measured and applied before esophagectomy, for pCR in ESCC are currently unknown. 18 Fluorodeoxyglucose (FDG) positron emission tomography (PET) measures in vivo glucose metabolism and can be used to evaluate the tumor response to therapeutics as a complement to conventional imaging modalities based on tumor size changes. PET has been evaluated as a prognostic and predictive assay tool for many types of cancers, including esophageal cancer. A meta-analysis of 7 studies on the prognostic value of the baseline standard uptake value (SUV) measured by PET revealed that a higher SUV was significantly correlated with poorer survival in patients with esophageal cancer (hazards ratio, 1.86, 95% confidence interval [CI], 1.53e2.27).5 Several studies have investigated the PET evaluation after neoadjuvant CRT, and correlated it with the pCR and survivals of patients with ESCC.6e8 However, these studies failed to unequivocally confirm the correlation between post-CRT PET and either pCR or patient survivals. Other studies have advocated the use of clinical response, including the metabolic response, at earlier time
points in the management of patients with locoregional upper aerodigestive tract cancers. A study of advanced laryngeal cancer demonstrated the feasibility of a treatment algorithm guided by the early clinical response (evaluated through laryngoscopy) to one-cycle induction chemotherapy.9 In esophageal adenocarcinoma, an early metabolic response, defined as a 35% reduction of SUV at day 14 of the 3-month neoadjuvant chemotherapy, predicted improved surgical outcomes and patient survival.10,11 In the MUNICON I and II trials, the early metabolic response evaluated after a 2-week cycle of induction chemotherapy was used to stratify responders and nonresponders to different treatments.12,13 We hypothesized that the early metabolic response to one-cycle induction chemotherapy, which is a surrogate for in vivo chemoresponsiveness, may predict the treatment outcomes in locally advanced ESCC patients receiving neoadjuvant CRT, followed by surgery. We thus designed this phase II clinical trial by including a 21-dayecycle induction chemotherapy treatment before the standard neoadjuvant CRT plus esophagectomy for locally advanced ESCC. This study planned to verify the hypothesis that the early metabolic response, predefined as a >35% reduction of maximum SUV (SUVmax) on day 14 of the one-cycle induction chemotherapy, could predict the patient survival and pCR to neoadjuvant CRT.
Patients and methods Study design This was a single-arm, nonrandomized phase II study conducted at a single referral medical center in Taiwan.
Patient population The target population was locally advanced ESCC, defined as pathologically proven squamous cell carcinoma of esophagus, with clinical stages of TNM classification: T3N0M0, T1e3N1M0, or T1e3N0e1M1a, according to the American Joint Committee on Cancer Staging System (6th edition). Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status 2,
1026 age 18 years, and adequate medical and laboratory status for undergoing chemotherapy. Patients with synchronous squamous cell carcinoma of the aerodigestive tract (other than the esophagus) and those who refused surgery were excluded. The staging procedures included endoscopy, endoscopic ultrasound, computed tomography (CT) scan of the chest and abdomen, and PET scan. The study was approved by the Institutional Review Board of National Taiwan University Hospital and was registered at www. ClinicalTrial.gov (NCT01034332).
Protocol treatment Patients received protocol-defined therapy in 3 stages: onecycle induction chemotherapy, neoadjuvant CRT, and radical surgery. The one-cycle induction chemotherapy was a 21-day TP-HDFL regimen (1-h intravenous infusion [IVF] of paclitaxel [70 mg/m2] on days 1 and 8, 2-h IVF of cisplatin [30 mg/m2] on days 2 and 9, and 24-h IVF of fluorouracil [2000 mg/m2] and leucovorin [300 mg/m2] on days 2 and 9). Neoadjuvant CRT involving a twice-weekly TP regimen (TPCRT) was commenced on day 22 of the one-cycle induction TP-HDFL. TP-CRT comprised 1-h IVF of paclitaxel (35 mg/ m2) on Monday and Thursday, 2-h IVF of cisplatin (15 mg/ m2) on Tuesday and Friday, and radiotherapy (2 Gy/fraction/day) from Monday to Friday for a total of 20 fractions. Radical surgery involving right thoracic approach esophagectomy with 2-field lymph node dissection and gastric tube reconstruction was scheduled at 4e6 weeks after the completion of neoadjuvant TP-CRT.4 If patients did not receive surgery after the post-CRT evaluation, TP-CRT was readministered with a cumulative radiation dose of 60e66 Gy.
Imaging studies Baseline PET was performed during initial staging before the initiation of the protocol treatment. PET was repeated on day 14 of the one-cycle induction TP-HDFL. Patients fasted for at least 6 h before PET imaging to ensure standardized glucose metabolism. Blood glucose levels were measured before each PET study. Patients with a blood glucose level greater than 150 mg/dL were excluded. Imaging data were normalized for the injected dose of FDG and patients’ body weight, with measurement of SUVmax at the regions with abnormal tumor uptake. The SUVmax of the primary esophageal tumor was recorded through baseline and repeat PET scans. Patients with an SUVmax reduction of more than 35% were defined as metabolic responders.
Response evaluation and patient follow-up In addition to PET, endoscopic ultrasound and CT scans of the chest and abdomen were performed at 4 weeks after the completion of neoadjuvant CRT for post-CRT clinical response evaluation. For patients receiving esophagectomy, all the resected samples, including those of the esophagus and regional lymph nodes, were subject to routine pathological examination. After esophagectomy, the clinical follow-up involved a clinical evaluation, an
T.-C. Huang et al. endoscopy, and CT scans of the chest and abdomen every 3 months for the first year and every 4 months for the second year, followed by the same evaluations every 6 months for another 3 years. Progression-free survival (PFS) is the time from enrollment to the first evidence of progression, recurrence of the cancer, or death. Overall survival (OS) is the time from enrollment to death.
Statistical consideration and analysis The primary endpoint of this study was pCR. The secondary endpoints were PFS and OS. For the primary endpoint, analyses of the esophagectomy population were performed. The association between early metabolic response and pCR was tested through logistic regression. For the secondary endpoints, analyses were performed in the entire enrolled population. The association between early metabolic response and PFS or OS was tested using Cox regression models. All quantitative data are expressed as mean standard deviation. The impacts of the baseline characteristics and parameters of PET scans on pCR were determined through univariate and multivariate analyses using logistic regression models. The impacts of the baseline characteristics and parameters of PET scans on PFS and OS were determined through univariate and multivariate analyses using Cox regression models. The prediction models were established using factors selected from the analyses. The statistical analysis was processed using R2.11.1 (www.r-project.org).
Results Study population Between February 2008 and March 2012, 66 enrolled patients underwent baseline PET scans. Five patients withdrew from the study, and another 8 patients were not evaluable because the FDG uptake of their tumors was too low for quantitative analysis. Hence, only 53 patients underwent the second PET scan (assessable patients). Fortyseven patients received surgery. Three patients showed disease progression after neoadjuvant CRT and did not receive surgery. Eleven patients refused surgery and received additional CRT. Forty-two of the patients who received surgery were assessable through both PET scans (Fig. 1). The patient characteristics are summarized in Table 1.
Treatment response and survival Baseline SUVmax in the assessable patients was 17 7. The SUVmax significantly decreased to 10 5 in the second PET scan that was evaluated on day 14 of induction chemotherapy (P < .001; Table 2). Among the 42 assessable patients who received surgery, R0 resection was achieved in 41 patients; only one patient had microscopic residual tumor at the section margin (ie, R1 resection) and received adjuvant postoperative CRT. Among 47 patients receiving esophagectomy, 16 exhibited pCR. The pCR rate was 34%. At a median follow-up
Early PET response in neo-CRT in ESCC
1027 the early metabolic response to one-cycle chemotherapy and the pCR to neoadjuvant CRT.
Factors associated with pCR, PFS, and OS
Figure 1 Number of enrolled patients, assessable patients, and assessable patients with surgery.
period of 61 months (range, 50e93 months), 20 patients remained alive. The median OS Results were 22 months (95% CI, 16e40 months), 25 months (95% CI, 18e80 months), and 26 months (95% CI, 18e71 months) in all patients, assessable patients, and assessable patients with surgery, respectively (Fig. 2). The median PFS results were 16 months (95% CI, 9e27 months), 20 months (95% CI, 11e53 months), and 20 months (95% CI, 12e34 months) in all patients, assessable patients, and assessable patients with surgery, respectively (Appendix Figure A1).
Early metabolic response and pCR Early metabolic response, defined as 35% SUVmax reduction from the baseline, was achieved in 50% of the assessable patients with surgery (21 patients); among them, 8 achieved pCR. However, even among the 21 patients who did not exhibit an early metabolic response, 8 achieved pCR. Therefore, no correlation was established between
Figure 2
Factors included in the univariate analysis were basic characteristics (age, sex, and ECOG performance status), cancer status (stage and location), nutrition status (weight loss and serum albumin levels), and PET parameters (baseline SUVmax, postinduction chemotherapy SUVmax, and SUVmax reduction rate). Univariate analysis for pCR revealed that postinduction chemotherapy SUVmax was a significant factor for pCR and that serum albumin levels, weight loss, baseline SUVmax trended to associate with pCR (Table 3). Multivariate analysis indicated that weight loss and postinduction chemotherapy SUVmax were significant factors. Univariate analysis for PFS and OS revealed that early metabolic response did not meet the secondary endpoints, with hazard ratios of 0.79 (P Z .49) and 0.75 (P Z .42) for PFS and OS, respectively. However, age and postinduction chemotherapy SUVmax were significant factors for OS and PFS and remained significant in the multivariate analysis (Appendix Table A1). In an exploratory analysis, we established a prediction model for pCR by combining postinduction chemotherapy SUVmax and weight loss, through logistic regression (Fig. 3). The area under the curve (AUC) of the prediction model was 0.84. The prediction models based on SUVmax reduction rate and weight loss was relatively less efficient, with AUCs of 0.75 (Appendix Figure A2).
Discussion This prospective study failed to validate the predefined cut-off value of the early metabolic response to one-cycle induction chemotherapy for predicting pCR after neoadjuvant CRT in locally advanced ESCC. A retrospective analysis suggested that the SUVmax of the postinduction chemotherapy PET scans in combination with weight loss might be an efficient model for predicting pCR. The definition of early metabolic response (ie, an SUVmax reduction of more than 35%) adopted in our study was based
Overall survival curves for all enrolled patients, assessable patients, and assessable patients with surgery.
1028
T.-C. Huang et al. Table 2 Metabolic chemotherapy. SUVmax
Baseline Mean SD Post-chemotherapy Mean SD Reduction (%) Mean SD
response
after
one-cycle
Assessable patients (N Z 53)
Assessable patients with surgery (N Z 42)
17 7
16 7
10 5
10 5
38 28
36 27
baseline SUV post chemotherapy SUV SUVmax reduction (%) Z baseline SUV
Figure 3 Prediction model for pathologic complete response. The model comprises two parameters: postinduction SUVmax and weight loss, which are both significant factors in multivariate analysis.
on the findings of 2 published studies enrolling patients with adenocarcinoma of the esophagogastric junction exclusively: the first prospective study discovered the optimal cut-off value,10 which was then validated by the second prospective study.11 In these two published studies, patients received neoadjuvant chemotherapy, followed by surgery at 3e4 weeks after completing chemotherapy. The chemotherapy regimen was cisplatin plus infusional 5fluorouracil (PF regimen) and additional paclitaxel only
Table 1
Clinical characteristics.
Parameters
All patients Assessable (N Z 66) patients (N Z 53)
Age (years) Mean SD 55 8 53 7 Gender Male 61 (92%) 49 (92%) Female 5 (8%) 4 (8%) ECOG performance status 0 36 (59%) 34 (65%) 1 25 (41%) 18 (35%) Stage II or III 56 (85%) 46 (87%) IV 10 (15%) 7 (13%) Tumor site Upper 18 (27%) 16 (30%) Middle 32 (49%) 26 (49%) Lower 16 (24%) 11 (21%) Albumin (g/dl) Mean SD 4.5 0.3 4.5 0.3 Weight loss (%) Mean SD 6 6 66
Assessable patients with surgery (N Z 42) 52 7 39 (93%) 3 (7%) 29 (71%) 12 (29%) 36 (86%) 6 (14%) 14 (33%) 22 (53%) 6 (14%) 4.6 0.3 57
for Siwert type 1 adenocarcinoma of the esophagogastric junction. The different histologic types and different treatment protocols may underlie the failure of this predefined early metabolic response in the current study, which exclusively enrolled patients with squamous cell carcinoma. To date, 2 studies have evaluated the role of the early metabolic tumor response in patients with ESCC. In one study, 38 ESCC patients received 5-fluorouracilebased neoadjuvant CRT, followed by surgery.7 Patients received PET evaluation before therapy, at 2 weeks after the initiation of neoadjuvant CRT, and preoperatively. The study reported that the changes in tumor metabolic activity after 14 days of neoadjuvant CRT were significantly correlated with the pathologic response and patient survival. The optimal cut-off value for the early metabolic response was 30%. In another study, 16 ESCC patients received a course of induction chemotherapy (PF regimen), followed by definitive PF-CRT.14 The early metabolic response was assessed from 12 to 24 days after initiating induction chemotherapy. The optimal cut-off value (55%) was associated with the clinical complete response and 1-year OS. None of these cut-off values for ESCC have been validated. In the current study, when we tried the above-mentioned two cut-off values of early PET response, we could not find their association with pCR or patients’ survivals (data not shown). Our study retrospectively demonstrated that the SUVmax of the postinduction chemotherapy PET scan was an independent factor for pCR and survival. The potential explanation of this finding is that the postinduction chemotherapy PET scan is a composite measurement of both the baseline value and tumor response to one cycle of chemotherapy. A low baseline SUV and a large reduction in SUV by the treatment, both of which contribute to low postinduction chemotherapy SUVs, are indicative of a good prognosis. By contrast, a predefined SUV reduction rate does not consider the impact of the baseline SUV and may not be adequately sensitive to those with low baseline SUVs. The ultimate goal of the clinical application of early metabolic response is to help personalize treatment strategies. Patients who have a good response to CRT and favorable prognosis may avoid unnecessary therapies such as esophagectomy15,16; by contrast, those who have a poor response to current CRT regimens may warrant other aggressive regimens or experimental approaches. CALGB
Early PET response in neo-CRT in ESCC Table 3
1029
Univariate and multivariate analysis for pathologic complete response.
Parameters
Pathologic complete response Multivariate analysis (N Z 42)
Univariate analysis
Age Gender Male (ref) Female ECOG performance status 0 (ref) 1 Stage II/III IV (ref) Tumor site Upper Middle Lower (ref) Albumin (g/dl) Weight loss (%) Baseline SUVmax Post-chemotherapy SUVmax SUVmax reduction (%) metabolic response
OR (95% C.I.)
p
1 (0.9e1.1)
0.46
1 4 (0.4e51)
0.25
1 0.4 (0.08e1.5)
0.15
4 (0.4e33) 1
0.26
4 (0.4e41) 5 (0.5e44) 1 8 (0.9e75) 0.9 (0.7e1) 0.9 (0.8e1) 0.8 (0.7e1) 1. (1e1) 1 (0.3e3)
0.46 0.24
80803 is a prospective randomized phase II study evaluating the metabolic response to induction chemotherapy for directing the selection of chemotherapy regimens (FOLFOX6 or paclitaxel plus carboplatin) for neoadjuvant CRT in patients with locoregional esophageal and gastroesophageal junction adenocarcinoma.17 Patients randomized to one regimen for induction chemotherapy would receive the other regimen for neoadjuvant CRT if no metabolic response to the induction chemotherapy was observed. The study revealed that altering the chemotherapy regimen in metabolic nonresponders led to a pCR rate of 15.6% compared with a historical control of 5%.17 In conclusion, the present study failed to validate the cut-off value of an early metabolic response in neoadjuvant TP-CRT for locally advanced ESCC patients. The SUVmax after one-cycle chemotherapy may have prognostic and predictive significance and warrants further study.
Conflicts of interest The authors have no conflicts of interest relevant to this article.
Acknowledgement We thank the Sinphar Pharmaceutical Corporation (Yilan, Taiwan) for providing paclitaxel for this study. This work is supported by a grant for investigator initiated trials (NCTRC200909), from National Clinical Trial and Research Center of National Taiwan University Hospital, Taiwan, and a grant (MOST 105-2314-B-002-186-MY3) from the Ministry of Science and Technology of the Executive
0.064 0.052 0.070 0.031 0.32 1
OR (95% C.I.)
p
0.8 (0.7e0.9)
0.018
0.8 (0.6e0.9)
0.010
Yuan, Taiwan. The role of the funding sources is to support scientific research in Taiwan.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2018.11.003.
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