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Clinical outcomes and prognostic factors of chemoradiotherapy for postoperative lymph node recurrence of esophageal cancer

Clinical outcomes and prognostic factors of chemoradiotherapy for postoperative lymph node... Abstract Background The therapeutic strategies and prognostic risk factors in patients with lymph node (LN) recurrence of esophageal cancer remain controversial. We assessed clinical outcomes and prognostic factors related to the use of chemoradiotherapy (CRT) for LN recurrence of esophageal squamous cell carcinoma (ESCC) after curative resection. Methods We retrospectively evaluated survival and prognostic factors in 57 patients with LN recurrence of ESCC after curative resection. Patients received CRT using 5-fluorouracil plus cisplatin (FP) or docetaxel. Radiotherapy was delivered at 2 Gy (total dose, 60–66 Gy; median, 60 Gy). Results The median follow-up duration was 24 (range, 3–116) months. The overall survival (OS) rates at 2, 3 and 5 years were 43.7%, 36.9% and 27.6%, respectively. In the univariate analysis of OS, treatment with FP, a single LN recurrence, and a single regional recurrence were associated with a significantly better prognosis (P = 0.04, P = 0.027 and P = 0.0001, respectively). In the multivariate analysis, the combination chemotherapy regimen [hazard ratio (HR), 2.50; 95% confidence interval (CI), 1.23–5.07] and the number of the regional LNs with recurrence (HR, 5.76; 95% CI, 1.22–27.12) were independent prognostic factors. Conclusion Approximately 28% of ESCC patients with LN recurrence after curative resection could achieve long-term survival with CRT. Treatment with FP or patients with a single regional recurrence might improve the treatment outcome. postoperative lymph node recurrence of esophageal cancer, chemoradiotherapy, prognostic factor Introduction Esophagectomy remains a standard treatment for resectable esophageal cancer; however, 27.1–52.6% of patients who undergo this procedure experience postoperative recurrence, and 47.3–78.0% of these recurrences are locoregional (1–8). Treatments for such recurrences include surgical resection, chemoradiotherapy (CRT), radiotherapy (RT) or chemotherapy. A Phase II trial of CRT demonstrated this modality to be a safe and effective salvage option for postoperative locoregional recurrences of esophageal cancer (9,10). Surgery to remove recurrent lesions is also considered a good salvage option after curative resection (11–13). Long-term survivors with postoperative locoregional recurrence have been reported, and studies have suggested that patients with LN recurrence have better survival than those with local (anastomotic) recurrence (14,15). Controversy remains regarding the most effective therapeutic strategies and most accurate prognostic risk factors for LN recurrence of esophageal cancer. In our hospital, we perform CRT for LN recurrence of esophageal squamous cell carcinoma (ESCC) after curative resection. The main aim of this retrospective study was to evaluate the clinical outcomes and prognostic factors related to the use of CRT for LN recurrence after the curative resection of ESCC. Materials and methods Study population We retrospectively reviewed the medical records, RT treatment plans, and diagnostic images of patients with ESCC who satisfied the following criteria: (i) pathologically proven ESCC, (ii) Eastern Cooperative Oncology Group performance status of 0–2, (iii) treatment with definitive concurrent CRT, (iv) no other active cancer and (v) regional LN recurrence after complete resection (radical esophagectomy with 2- or 3-field LN dissection). Patients with para-aortic LN recurrence at the upper abdominal level were included. We excluded patients with distant metastases or anastomotic recurrences in addition to LN recurrence. LN recurrence was diagnosed comprehensively with ultrasonography, computed tomography, positron emission tomography and physical findings. Between April 2006 and January 2015, 57 patients with LN recurrence of ESCC after curative resection were treated with definitive concurrent CRT at Komagome Hospital and satisfied the selection criteria. Treatment External radiation therapy was administered with the 6- or 10-MV X-ray of a linear accelerator. The daily fractional dose of RT was 2.0 Gy, administered 5 days per week, and the total dose was 60–66 Gy. Four patients underwent irradiation with 66 Gy in the supraclavicular region, and the remaining 53 patients underwent irradiation with 60 Gy. A T-shaped field including the bilateral supraclavicular and mediastinal regions was used for 15 patients, and a local field covering recurrent tumors with a margin of 2–3 cm was used for 42 patients. Two-dimensional conventional RT (2D-RT) was used for 17 patients, and three-dimensional conformal RT (3D-CRT) was used for 40 patients. We used 2–4 fields to avoid the spinal cord. In the patients who received 2-field irradiation, the beam direction was changed after irradiation with 40 Gy. Before the introduction of 3D-CRT in September 2008, patients were treated with 2D-RT, in which T-shaped field was frequently used. Chemotherapy was combined with RT in all patients. Twenty-four patients received a chemotherapy regimen consisting of either 5-fluorouracil (5-FU; 700 mg/m2 on Day 1–4 per 4 weeks) plus cisplatin (cddp; 70 mg/m2 on Day 1 per 4 weeks). The remaining 33 patients received a chemotherapy regimen consisting of docetaxel (DOC; 20 mg/m2 on Day 1 per 1 week). DOC regimen was frequently used till December 2013 in patients refractory to neoadjuvant chemotherapy with FP regimen. FP regimen was used in all patients since January 2014. After the completion of therapy, the patients were followed at 1- or 3-month intervals. Follow-up evaluations included a history and physical examination, endoscopy, ultrasonography, computed tomography and positron emission tomography. The Response Evaluation Criteria in Solid Tumors criteria were used to determine the tumor response (16), and we defined disease progression as treatment failure (relapse) according to those criteria. Statistical analyses Survival was calculated from the start of treatment. Progression-free survival and overall survival (OS) were estimated with the Kaplan–Meier method, and the differences in survival in the univariate analysis were assessed with the log-rank test. Following previous studies, we entered the following parameters into the log-rank test: age (≥65 years versus <65 years), initial pathological stage [I and II versus III (UICC 2010) (17)], performance status [0 and 1 versus 2 (Eastern Cooperative Oncology Group) (18)], interval between surgery and recurrence (≥8 months versus <8 months), long diameter of the metastatic LN (≥35 mm versus <35 mm), number of recurrent nodes (single versus multiple), region of recurrent nodes (single region versus multiple regions), radiation field (T-shaped versus local), radiation technique (two-dimensional conventional RT versus three-dimensional conformal RT), and combination chemotherapy regimen (FP versus DOC) (10,12,14,15,19–25). Baseline variables with P values of <0.05 in the univariate analysis were included in the multivariable models. Cox’s regression analysis was used in the multivariate analysis. All statistical analyses were performed with EZR version 1.32 (26), and P values of <0.05 (two-sided) were considered statistically significant. Toxicity was assessed and documented according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (27). Grade 3 or worse toxicities were recorded and were defined as acute or late if they occurred within 3 months or longer than 3 months after treatment, respectively. The retrospective study protocol was reviewed and approved by the Komagome Hospital review board. Results Patients and tumor characteristics Table 1 shows a summary of patient and tumor characteristics. The median follow-up time for the patients was 24 months (range, 3–116 months). All patients completed the RT treatment, and 83.3% (20/24) and 100% (33/33) of patients received the FP or DOC regimen, respectively. The remaining patients received 1 cycle of FP. Table 1. Patient and tumor characteristics Patient and tumor characteristics  No. (%)  Median age no. (range)  66 (47–82)  Sex no. (%)     Male  46 (81)   Female  11 (19)  ECOG PS no.(%)     0  8 (14)   1  42 (74)   2  7 (12)  Location of primary tumor no. (%)     Cervix  1 (2)   Upper thorax  10 (17)   Middle thorax  34 (60)   Lower thorax  12 (21)  UICC 2010 pStage no. (%)     I  8 (14)   II  12 (21)   III  37 (65)  Interval to recurrence month (range)  7 (3–98)  Lymph node recurrence site no. (%)     Supraclavicular region  8 (14)   Mediastinal  35 (61)   Abdominal  2 (4)   Multiple  12 (21)  Chemotherapy regimen     FP  24 (42)   DOC  33 (58)  Patient and tumor characteristics  No. (%)  Median age no. (range)  66 (47–82)  Sex no. (%)     Male  46 (81)   Female  11 (19)  ECOG PS no.(%)     0  8 (14)   1  42 (74)   2  7 (12)  Location of primary tumor no. (%)     Cervix  1 (2)   Upper thorax  10 (17)   Middle thorax  34 (60)   Lower thorax  12 (21)  UICC 2010 pStage no. (%)     I  8 (14)   II  12 (21)   III  37 (65)  Interval to recurrence month (range)  7 (3–98)  Lymph node recurrence site no. (%)     Supraclavicular region  8 (14)   Mediastinal  35 (61)   Abdominal  2 (4)   Multiple  12 (21)  Chemotherapy regimen     FP  24 (42)   DOC  33 (58)  DOC, docetaxel; ECOG, Eastern Cooperative Oncology Group; FP, 5-fluorouracil and cisplatin; PS, performance status. Treatment outcome The overall response rate, including complete responses in 25 patients and partial responses in 22 patients, was 82.5% (Table 2). The 2-, 3- and 5-year progression-free survival rates were 26.3% (95% confidence interval [CI], 15.7–38.1), 21.7% (95% CI, 11.8–33.5) and 19.0% (95% CI, 9.6–30.9), respectively. The 2-, 3- and 5-year OS rates were 43.7% (95% CI, 30.3–56.3), 36.9% (95% CI, 23.9–49.8) and 27.6% (95% CI, 15.3–41.4), respectively, with a median survival time (MST) of 22.0 months (Fig. 1). Table 2. Treatment response Treatment response  No. (%)  Complete response  25 (44)  Partial response  22 (38)  Stable disease  10 (18)  Progression of disease  0  Treatment response  No. (%)  Complete response  25 (44)  Partial response  22 (38)  Stable disease  10 (18)  Progression of disease  0  Figure 1. View largeDownload slide Kaplan–Meier estimates of progression-free survival and overall survival. Figure 1. View largeDownload slide Kaplan–Meier estimates of progression-free survival and overall survival. Toxicity Grade 3 esophagitis was observed in one patient (1.8%) using T-shaped field. Grade 3 leukocytopenia was observed in six patients (25.0%) in FP regimen. No Grade 3 or worse late toxicities were observed. No Grade 4 or 5 toxicities were observed in any patient. Analysis of survival In the univariate analysis of OS, treatment with FP regimen, a single LN recurrence, and a single regional recurrence were associated with a significantly better prognosis (P = 0.04, P = 0.027, P = 0.0001, respectively; Table 3). In the multivariate analysis, the combination chemotherapy regimen [hazard ratio (HR), 2.50; 95% CI, 1.23–5.07] and the number of regional LNs with recurrence (HR, 5.76; 95% CI, 1.22–27.12) were the independent prognostic factors (Table 4). Table 3. Univariate analysis. Factor  Group  No.  MST (months)  P value  Age  ≥60 years  32  8  0.08    <60 years  25  22    Initial pStage  I/II  20  18  0.66    III  37  22    PS  0/1  50  22  0.35    2  7  10    Interval between surgery and recurrence  ≥8 months  27  24  0.35    <8 months  30  13.5    Long diameter of the metastatic lymph node  ≥35 mm  6  23  0.84    <35 mm  51  21    Number of recurrent nodes  Single  41  24  0.027    Multiple  16  10    Region of recurrent nodes  Single  45  24  <0.001    Multiple  12  9    Radiation field  T-shaped  15  21  0.38    Local  42  22    Radiation technique  2D-RT  17  19  0.64    3D-CRT  40  22    Combined chemotherapy regimen  FP  24  25  0.04    DOC  33  14    Factor  Group  No.  MST (months)  P value  Age  ≥60 years  32  8  0.08    <60 years  25  22    Initial pStage  I/II  20  18  0.66    III  37  22    PS  0/1  50  22  0.35    2  7  10    Interval between surgery and recurrence  ≥8 months  27  24  0.35    <8 months  30  13.5    Long diameter of the metastatic lymph node  ≥35 mm  6  23  0.84    <35 mm  51  21    Number of recurrent nodes  Single  41  24  0.027    Multiple  16  10    Region of recurrent nodes  Single  45  24  <0.001    Multiple  12  9    Radiation field  T-shaped  15  21  0.38    Local  42  22    Radiation technique  2D-RT  17  19  0.64    3D-CRT  40  22    Combined chemotherapy regimen  FP  24  25  0.04    DOC  33  14    CI, confidence interval; 3D-CRT, three-dimensional conformal radiotherapy; DOC, docetaxel; 2D-RT, two-dimensional conventional radiotherapy; FP, 5-fluorouracil and cisplatin; HR, hazard ratio; MST, median survival time; PS performance status Table 4. Multivariate analysis Factor  HR  95% CI  P value  Combined chemotherapy regimen (DOC vs. FP)  2.5  1.23–5.07  0.011  Region of recurrent nodes (multiple vs. single)  5.76  1.22–27.12  0.027  Factor  HR  95% CI  P value  Combined chemotherapy regimen (DOC vs. FP)  2.5  1.23–5.07  0.011  Region of recurrent nodes (multiple vs. single)  5.76  1.22–27.12  0.027  CI, confidence interval; DOC, docetaxel; FP, 5-fluorouracil and cisplatin; HR, hazard ratio. Discussion We retrospectively evaluated treatment outcomes and prognostic factors in a group of patients treated with CRT for LN recurrence of ESCC after curative resection. Our results showed that ~28% of patients could achieve long-term survival with CRT. The results also suggested that treatment with FP regimen or patients with a single regional recurrence might improve the treatment outcome. Other studies have examined the efficacy of CRT for treating the locoregional recurrence of esophageal cancer after curative resection (Table 5) (9,10,21,24,25,28–30) and have reported generally high response rates of >70%. However, survival varied greatly, with the MST ranging from 13 to 43 months, the 2-year OS ranging from 31% to 57%, and the 3-year OS ranging from 10.5% to 51.8%. Several factors might account for this discrepancy. First, those studies were primarily retrospective studies with small sample sizes, and therefore, selection bias may exist. Second, some studies included patients with anastomotic recurrence. Third, even among patients receiving CRT, the chemotherapy regimens were diverse. Finally, the treatment target volume definition and irradiation dose also varied. These factors could have had a remarkable influence on the clinical outcomes. Our study also had this discrepancy. However, the clinical outcome in our study was generally favorable compared with the outcomes of these previous studies. Table 5. Content and results of previous studies of outcomes for chemoradiotherapy for the treatment of postoperative recurrent esophageal cancer First author  Year  No.  Chemotherapy regimen  Median prescribed dose (Gy)  Response rate (%)  2-/3-year OS rate (%)  MST (months)  Tsuchida  2005  14  FP  60  86  57/NA  27  Nakamura  2008  22  FP or NDP + 5FU  56  82  NA/26.6  20.3  Lu  2010  31  FP  60  97  NA/10.5  17  Maruyama  2010  23  FP  60  60  31/24  13  Jingu  2012  30  NDP + 5FU  60  72  NA/38.4  21  Zhang  2012  50  FP or PTX + CDDP  60  72  NA/14  13.3  Bao  2013  83  FP or DOC + CDDP  60  75.9  NA/51.8  43  Ma  2014  49  CDDP  NA (62–70)  91.8  NA/46.9  35  Kobayashi  2014  42  FP or NDP + S1  60  97.6  51.3/41.1  24.3  Present study  2017  57  FP or DOC  60  82.5  43.9/35.5  22  First author  Year  No.  Chemotherapy regimen  Median prescribed dose (Gy)  Response rate (%)  2-/3-year OS rate (%)  MST (months)  Tsuchida  2005  14  FP  60  86  57/NA  27  Nakamura  2008  22  FP or NDP + 5FU  56  82  NA/26.6  20.3  Lu  2010  31  FP  60  97  NA/10.5  17  Maruyama  2010  23  FP  60  60  31/24  13  Jingu  2012  30  NDP + 5FU  60  72  NA/38.4  21  Zhang  2012  50  FP or PTX + CDDP  60  72  NA/14  13.3  Bao  2013  83  FP or DOC + CDDP  60  75.9  NA/51.8  43  Ma  2014  49  CDDP  NA (62–70)  91.8  NA/46.9  35  Kobayashi  2014  42  FP or NDP + S1  60  97.6  51.3/41.1  24.3  Present study  2017  57  FP or DOC  60  82.5  43.9/35.5  22  CDDP, cisplatin; DOC, docetaxel; 5FU, 5-fluorouracil; FP, 5-fluorouracil plus cisplatin; MST, median survival time; NA, information not available; NDP, nedaplatin; OS, overall survival; PTX, paclitaxel. Several prognostic factors for ESCC have been suggested (Table 6). For example, high RT dose, single node recurrence, single regional recurrence and the use of a combination taxane-based plus CDDP regimen are reportedly associated with better outcomes (10,12,14,15,19–25). Among studies reporting prognostic factors, we focused on those of Bao et al. and Zhang et al. In the former, a total of 83 patients with postoperative locoregional recurrence of ESCC were treated with concurrent CRT. Patients treated with the DOC + CDDP regimen had a 3-year OS rate (59.2%) superior to that of patients receiving FP regimen (43.3%) (24). In the latter study, 50 patients with postoperative locoregional recurrence of ESCC were treated with concurrent CRT. Patients who received the paclitaxel + CDDP regimen had an MST (median, 16.3 months) superior to that of patients who received FP regimen (median, 9.8 months) (25). These previous studies reported excellent results for patients receiving RT combined with a taxane-based regimen in a comparison with a regimen of RT combined with FP (FP-RT). However, the outcomes of treatment with RT combined with DOC alone (DOC-RT; MST, 14 months; 3-year OS rate, 30.5%) were worse than those of treatment with FP-RT (MST, 25 months; 3-year OS rate, 43.9%) in our study. These results suggest that CDDP may be a key drug in the RT treatment of postoperative LN recurrence of ESCC. Table 6. Prognostic factors confirmed in previous studies First author  Factor  Good  Poor  Shioyama  Long diameter of the metastatic lymph node  <35 mm  ≥35 mm  Nakamura  Number of recurrent nodes  Single  Multiple  Kosuga, Jingu, Ma  Region of recurrent nodes  Single  Multiple  Nemoto  Interval between surgery and recurrence  ≥8 months  <8 months  Zhang  Dose  ≥60 Gy  <60 Gy  Fakhrian  RT technique  3D-CRT  2D-RT  Bao  Combined chemotherapy regimen  DOC + CDDP  FP  Zhang  PTX + CDDP  FP  Present study  Region of recurrent nodes  Single  Multiple  Combined chemotherapy regimen  FP  DOC  First author  Factor  Good  Poor  Shioyama  Long diameter of the metastatic lymph node  <35 mm  ≥35 mm  Nakamura  Number of recurrent nodes  Single  Multiple  Kosuga, Jingu, Ma  Region of recurrent nodes  Single  Multiple  Nemoto  Interval between surgery and recurrence  ≥8 months  <8 months  Zhang  Dose  ≥60 Gy  <60 Gy  Fakhrian  RT technique  3D-CRT  2D-RT  Bao  Combined chemotherapy regimen  DOC + CDDP  FP  Zhang  PTX + CDDP  FP  Present study  Region of recurrent nodes  Single  Multiple  Combined chemotherapy regimen  FP  DOC  CDDP, cisplatin; 3D-CRT, three-dimensional conformal; DOC, docetaxel; 2D-RT, two-dimensional conventional radiotherapy; FP, 5-fluorouracil plus cisplatin; PS, performance status; PTX, paclitaxel. No previous studies have examined the effectiveness of RT combined with DOC alone (DOC-RT) for the treatment of postoperative LN recurrences of ESCC. The results of a Phase I trial demonstrated promising efficacy and an acceptable toxicity profile for DOC-RT in patients with inoperable esophageal cancer (31). Hematological toxicity (<10% Grade 3/4 toxicities) with this treatment was lower than that with FP-RT (26% Grade 3/4 toxicities). However, the MST (6 months) and 1-year OS (35%) were lower than those with FP-RT (MST, 13.1 months; 1-year OS, 56%) (32). The results of our study demonstrated that DOC-RT is a safe treatment for postoperative LN recurrences of ESCC, and the MST and OS for patients with DOC-RT were also lower than for those with FP-RT. Previous studies have reported excellent results with CRT for esophageal cancer patients with recurrence in a single region or single node after curative resection (8,10,12,14,22). Outcomes in patients with recurrence in a single region or single node were also significantly better than those for patients with recurrence in multiple regions or multiple nodes in our univariate analysis. This result supports our hypothesis that the concept of oligo-recurrence might be applicable to postoperative esophageal cancer (33). With regard to RT field size, a previous study has reported the use of CRT for postoperative locoregional recurrence. Jingu et al. have reported that the overall survival and irradiated-field control rates are significantly better in patients treated with involved field irradiation than in those treated with elective nodal irradiation (34). However, our study showed that RT field size was not associated with prognosis. With regard to toxicities, we considered that T-shaped field including elective irradiation was not necessary. The present study has several limitations associated with its retrospective design. First, we could not demonstrate a survival benefit of treatment with CRT compared with chemotherapy alone. A previous study suggested that CRT (MST, 20.3 months) is superior to chemotherapy alone or palliative care (MST, <12 months) for LN recurrence after esophagectomy (12). In our study, the MST was 24 months for patients with recurrence in a single region or single node. Given this result, CRT may be a recommended minimum treatment for patients with oligo-recurrence in the LNs in esophageal cancer. Second, this study has selection biases. We enrolled patients with LN recurrence, and there was non-uniformity in the combined chemotherapy regimens and RT techniques. Therefore, a prospective study with a uniform strategy such as FP-RT for cervical LN recurrence is essential. In conclusion, we found that CRT was a safe and effective salvage treatment for LN recurrence after curative resection in ESCC. Approximately 28% of patients could achieve long-term survival with CRT. Our results also suggest that treatment with FP regimen or patients with a single regional recurrence may provide superior outcomes. Conflict of interest statement The authors declare that they have no competing interests. Authors' contributions T.K. prepared the manuscript and the literature search; T.K. reviewed and edited the manuscript; and T.K., K.N., K.S. and K.K. reviewed the manuscript. All authors read and approved the final manuscript. Ethical statement This study used no human or animal subjects. Abbreviations ESCC esophageal squamous cell carcinoma; RT radiotherapy CRT chemoradiotherapy LN lymph node 2D-RT two-dimensional conventional radiotherapy 3D-CRT three-dimensional conformal radiotherapy OS overall survival MST median survival time FP 5-fluorouracil and cisplatin DOC docetaxel References 1 Bhansali MS, Fujita H, Kakegawa T, et al.  . 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Oligometastases and oligo-recurrence: the new era of cancer therapy. Jpn J Clin Oncol  2010; 40: 107– 11. Google Scholar CrossRef Search ADS PubMed  34 Jingu K, Umezawa R, Yamamoto T, et al.  . Elective nodal irradiation is not necessary in chemoradiotherapy for postoperative loco-regional recurrent esophageal cancer. Jpn J Clin Oncol  2017; 47: 200– 5. Google Scholar PubMed  © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Clinical outcomes and prognostic factors of chemoradiotherapy for postoperative lymph node recurrence of esophageal cancer

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Oxford University Press
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10.1093/jjco/hyx171
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29190352
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Abstract

Abstract Background The therapeutic strategies and prognostic risk factors in patients with lymph node (LN) recurrence of esophageal cancer remain controversial. We assessed clinical outcomes and prognostic factors related to the use of chemoradiotherapy (CRT) for LN recurrence of esophageal squamous cell carcinoma (ESCC) after curative resection. Methods We retrospectively evaluated survival and prognostic factors in 57 patients with LN recurrence of ESCC after curative resection. Patients received CRT using 5-fluorouracil plus cisplatin (FP) or docetaxel. Radiotherapy was delivered at 2 Gy (total dose, 60–66 Gy; median, 60 Gy). Results The median follow-up duration was 24 (range, 3–116) months. The overall survival (OS) rates at 2, 3 and 5 years were 43.7%, 36.9% and 27.6%, respectively. In the univariate analysis of OS, treatment with FP, a single LN recurrence, and a single regional recurrence were associated with a significantly better prognosis (P = 0.04, P = 0.027 and P = 0.0001, respectively). In the multivariate analysis, the combination chemotherapy regimen [hazard ratio (HR), 2.50; 95% confidence interval (CI), 1.23–5.07] and the number of the regional LNs with recurrence (HR, 5.76; 95% CI, 1.22–27.12) were independent prognostic factors. Conclusion Approximately 28% of ESCC patients with LN recurrence after curative resection could achieve long-term survival with CRT. Treatment with FP or patients with a single regional recurrence might improve the treatment outcome. postoperative lymph node recurrence of esophageal cancer, chemoradiotherapy, prognostic factor Introduction Esophagectomy remains a standard treatment for resectable esophageal cancer; however, 27.1–52.6% of patients who undergo this procedure experience postoperative recurrence, and 47.3–78.0% of these recurrences are locoregional (1–8). Treatments for such recurrences include surgical resection, chemoradiotherapy (CRT), radiotherapy (RT) or chemotherapy. A Phase II trial of CRT demonstrated this modality to be a safe and effective salvage option for postoperative locoregional recurrences of esophageal cancer (9,10). Surgery to remove recurrent lesions is also considered a good salvage option after curative resection (11–13). Long-term survivors with postoperative locoregional recurrence have been reported, and studies have suggested that patients with LN recurrence have better survival than those with local (anastomotic) recurrence (14,15). Controversy remains regarding the most effective therapeutic strategies and most accurate prognostic risk factors for LN recurrence of esophageal cancer. In our hospital, we perform CRT for LN recurrence of esophageal squamous cell carcinoma (ESCC) after curative resection. The main aim of this retrospective study was to evaluate the clinical outcomes and prognostic factors related to the use of CRT for LN recurrence after the curative resection of ESCC. Materials and methods Study population We retrospectively reviewed the medical records, RT treatment plans, and diagnostic images of patients with ESCC who satisfied the following criteria: (i) pathologically proven ESCC, (ii) Eastern Cooperative Oncology Group performance status of 0–2, (iii) treatment with definitive concurrent CRT, (iv) no other active cancer and (v) regional LN recurrence after complete resection (radical esophagectomy with 2- or 3-field LN dissection). Patients with para-aortic LN recurrence at the upper abdominal level were included. We excluded patients with distant metastases or anastomotic recurrences in addition to LN recurrence. LN recurrence was diagnosed comprehensively with ultrasonography, computed tomography, positron emission tomography and physical findings. Between April 2006 and January 2015, 57 patients with LN recurrence of ESCC after curative resection were treated with definitive concurrent CRT at Komagome Hospital and satisfied the selection criteria. Treatment External radiation therapy was administered with the 6- or 10-MV X-ray of a linear accelerator. The daily fractional dose of RT was 2.0 Gy, administered 5 days per week, and the total dose was 60–66 Gy. Four patients underwent irradiation with 66 Gy in the supraclavicular region, and the remaining 53 patients underwent irradiation with 60 Gy. A T-shaped field including the bilateral supraclavicular and mediastinal regions was used for 15 patients, and a local field covering recurrent tumors with a margin of 2–3 cm was used for 42 patients. Two-dimensional conventional RT (2D-RT) was used for 17 patients, and three-dimensional conformal RT (3D-CRT) was used for 40 patients. We used 2–4 fields to avoid the spinal cord. In the patients who received 2-field irradiation, the beam direction was changed after irradiation with 40 Gy. Before the introduction of 3D-CRT in September 2008, patients were treated with 2D-RT, in which T-shaped field was frequently used. Chemotherapy was combined with RT in all patients. Twenty-four patients received a chemotherapy regimen consisting of either 5-fluorouracil (5-FU; 700 mg/m2 on Day 1–4 per 4 weeks) plus cisplatin (cddp; 70 mg/m2 on Day 1 per 4 weeks). The remaining 33 patients received a chemotherapy regimen consisting of docetaxel (DOC; 20 mg/m2 on Day 1 per 1 week). DOC regimen was frequently used till December 2013 in patients refractory to neoadjuvant chemotherapy with FP regimen. FP regimen was used in all patients since January 2014. After the completion of therapy, the patients were followed at 1- or 3-month intervals. Follow-up evaluations included a history and physical examination, endoscopy, ultrasonography, computed tomography and positron emission tomography. The Response Evaluation Criteria in Solid Tumors criteria were used to determine the tumor response (16), and we defined disease progression as treatment failure (relapse) according to those criteria. Statistical analyses Survival was calculated from the start of treatment. Progression-free survival and overall survival (OS) were estimated with the Kaplan–Meier method, and the differences in survival in the univariate analysis were assessed with the log-rank test. Following previous studies, we entered the following parameters into the log-rank test: age (≥65 years versus <65 years), initial pathological stage [I and II versus III (UICC 2010) (17)], performance status [0 and 1 versus 2 (Eastern Cooperative Oncology Group) (18)], interval between surgery and recurrence (≥8 months versus <8 months), long diameter of the metastatic LN (≥35 mm versus <35 mm), number of recurrent nodes (single versus multiple), region of recurrent nodes (single region versus multiple regions), radiation field (T-shaped versus local), radiation technique (two-dimensional conventional RT versus three-dimensional conformal RT), and combination chemotherapy regimen (FP versus DOC) (10,12,14,15,19–25). Baseline variables with P values of <0.05 in the univariate analysis were included in the multivariable models. Cox’s regression analysis was used in the multivariate analysis. All statistical analyses were performed with EZR version 1.32 (26), and P values of <0.05 (two-sided) were considered statistically significant. Toxicity was assessed and documented according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (27). Grade 3 or worse toxicities were recorded and were defined as acute or late if they occurred within 3 months or longer than 3 months after treatment, respectively. The retrospective study protocol was reviewed and approved by the Komagome Hospital review board. Results Patients and tumor characteristics Table 1 shows a summary of patient and tumor characteristics. The median follow-up time for the patients was 24 months (range, 3–116 months). All patients completed the RT treatment, and 83.3% (20/24) and 100% (33/33) of patients received the FP or DOC regimen, respectively. The remaining patients received 1 cycle of FP. Table 1. Patient and tumor characteristics Patient and tumor characteristics  No. (%)  Median age no. (range)  66 (47–82)  Sex no. (%)     Male  46 (81)   Female  11 (19)  ECOG PS no.(%)     0  8 (14)   1  42 (74)   2  7 (12)  Location of primary tumor no. (%)     Cervix  1 (2)   Upper thorax  10 (17)   Middle thorax  34 (60)   Lower thorax  12 (21)  UICC 2010 pStage no. (%)     I  8 (14)   II  12 (21)   III  37 (65)  Interval to recurrence month (range)  7 (3–98)  Lymph node recurrence site no. (%)     Supraclavicular region  8 (14)   Mediastinal  35 (61)   Abdominal  2 (4)   Multiple  12 (21)  Chemotherapy regimen     FP  24 (42)   DOC  33 (58)  Patient and tumor characteristics  No. (%)  Median age no. (range)  66 (47–82)  Sex no. (%)     Male  46 (81)   Female  11 (19)  ECOG PS no.(%)     0  8 (14)   1  42 (74)   2  7 (12)  Location of primary tumor no. (%)     Cervix  1 (2)   Upper thorax  10 (17)   Middle thorax  34 (60)   Lower thorax  12 (21)  UICC 2010 pStage no. (%)     I  8 (14)   II  12 (21)   III  37 (65)  Interval to recurrence month (range)  7 (3–98)  Lymph node recurrence site no. (%)     Supraclavicular region  8 (14)   Mediastinal  35 (61)   Abdominal  2 (4)   Multiple  12 (21)  Chemotherapy regimen     FP  24 (42)   DOC  33 (58)  DOC, docetaxel; ECOG, Eastern Cooperative Oncology Group; FP, 5-fluorouracil and cisplatin; PS, performance status. Treatment outcome The overall response rate, including complete responses in 25 patients and partial responses in 22 patients, was 82.5% (Table 2). The 2-, 3- and 5-year progression-free survival rates were 26.3% (95% confidence interval [CI], 15.7–38.1), 21.7% (95% CI, 11.8–33.5) and 19.0% (95% CI, 9.6–30.9), respectively. The 2-, 3- and 5-year OS rates were 43.7% (95% CI, 30.3–56.3), 36.9% (95% CI, 23.9–49.8) and 27.6% (95% CI, 15.3–41.4), respectively, with a median survival time (MST) of 22.0 months (Fig. 1). Table 2. Treatment response Treatment response  No. (%)  Complete response  25 (44)  Partial response  22 (38)  Stable disease  10 (18)  Progression of disease  0  Treatment response  No. (%)  Complete response  25 (44)  Partial response  22 (38)  Stable disease  10 (18)  Progression of disease  0  Figure 1. View largeDownload slide Kaplan–Meier estimates of progression-free survival and overall survival. Figure 1. View largeDownload slide Kaplan–Meier estimates of progression-free survival and overall survival. Toxicity Grade 3 esophagitis was observed in one patient (1.8%) using T-shaped field. Grade 3 leukocytopenia was observed in six patients (25.0%) in FP regimen. No Grade 3 or worse late toxicities were observed. No Grade 4 or 5 toxicities were observed in any patient. Analysis of survival In the univariate analysis of OS, treatment with FP regimen, a single LN recurrence, and a single regional recurrence were associated with a significantly better prognosis (P = 0.04, P = 0.027, P = 0.0001, respectively; Table 3). In the multivariate analysis, the combination chemotherapy regimen [hazard ratio (HR), 2.50; 95% CI, 1.23–5.07] and the number of regional LNs with recurrence (HR, 5.76; 95% CI, 1.22–27.12) were the independent prognostic factors (Table 4). Table 3. Univariate analysis. Factor  Group  No.  MST (months)  P value  Age  ≥60 years  32  8  0.08    <60 years  25  22    Initial pStage  I/II  20  18  0.66    III  37  22    PS  0/1  50  22  0.35    2  7  10    Interval between surgery and recurrence  ≥8 months  27  24  0.35    <8 months  30  13.5    Long diameter of the metastatic lymph node  ≥35 mm  6  23  0.84    <35 mm  51  21    Number of recurrent nodes  Single  41  24  0.027    Multiple  16  10    Region of recurrent nodes  Single  45  24  <0.001    Multiple  12  9    Radiation field  T-shaped  15  21  0.38    Local  42  22    Radiation technique  2D-RT  17  19  0.64    3D-CRT  40  22    Combined chemotherapy regimen  FP  24  25  0.04    DOC  33  14    Factor  Group  No.  MST (months)  P value  Age  ≥60 years  32  8  0.08    <60 years  25  22    Initial pStage  I/II  20  18  0.66    III  37  22    PS  0/1  50  22  0.35    2  7  10    Interval between surgery and recurrence  ≥8 months  27  24  0.35    <8 months  30  13.5    Long diameter of the metastatic lymph node  ≥35 mm  6  23  0.84    <35 mm  51  21    Number of recurrent nodes  Single  41  24  0.027    Multiple  16  10    Region of recurrent nodes  Single  45  24  <0.001    Multiple  12  9    Radiation field  T-shaped  15  21  0.38    Local  42  22    Radiation technique  2D-RT  17  19  0.64    3D-CRT  40  22    Combined chemotherapy regimen  FP  24  25  0.04    DOC  33  14    CI, confidence interval; 3D-CRT, three-dimensional conformal radiotherapy; DOC, docetaxel; 2D-RT, two-dimensional conventional radiotherapy; FP, 5-fluorouracil and cisplatin; HR, hazard ratio; MST, median survival time; PS performance status Table 4. Multivariate analysis Factor  HR  95% CI  P value  Combined chemotherapy regimen (DOC vs. FP)  2.5  1.23–5.07  0.011  Region of recurrent nodes (multiple vs. single)  5.76  1.22–27.12  0.027  Factor  HR  95% CI  P value  Combined chemotherapy regimen (DOC vs. FP)  2.5  1.23–5.07  0.011  Region of recurrent nodes (multiple vs. single)  5.76  1.22–27.12  0.027  CI, confidence interval; DOC, docetaxel; FP, 5-fluorouracil and cisplatin; HR, hazard ratio. Discussion We retrospectively evaluated treatment outcomes and prognostic factors in a group of patients treated with CRT for LN recurrence of ESCC after curative resection. Our results showed that ~28% of patients could achieve long-term survival with CRT. The results also suggested that treatment with FP regimen or patients with a single regional recurrence might improve the treatment outcome. Other studies have examined the efficacy of CRT for treating the locoregional recurrence of esophageal cancer after curative resection (Table 5) (9,10,21,24,25,28–30) and have reported generally high response rates of >70%. However, survival varied greatly, with the MST ranging from 13 to 43 months, the 2-year OS ranging from 31% to 57%, and the 3-year OS ranging from 10.5% to 51.8%. Several factors might account for this discrepancy. First, those studies were primarily retrospective studies with small sample sizes, and therefore, selection bias may exist. Second, some studies included patients with anastomotic recurrence. Third, even among patients receiving CRT, the chemotherapy regimens were diverse. Finally, the treatment target volume definition and irradiation dose also varied. These factors could have had a remarkable influence on the clinical outcomes. Our study also had this discrepancy. However, the clinical outcome in our study was generally favorable compared with the outcomes of these previous studies. Table 5. Content and results of previous studies of outcomes for chemoradiotherapy for the treatment of postoperative recurrent esophageal cancer First author  Year  No.  Chemotherapy regimen  Median prescribed dose (Gy)  Response rate (%)  2-/3-year OS rate (%)  MST (months)  Tsuchida  2005  14  FP  60  86  57/NA  27  Nakamura  2008  22  FP or NDP + 5FU  56  82  NA/26.6  20.3  Lu  2010  31  FP  60  97  NA/10.5  17  Maruyama  2010  23  FP  60  60  31/24  13  Jingu  2012  30  NDP + 5FU  60  72  NA/38.4  21  Zhang  2012  50  FP or PTX + CDDP  60  72  NA/14  13.3  Bao  2013  83  FP or DOC + CDDP  60  75.9  NA/51.8  43  Ma  2014  49  CDDP  NA (62–70)  91.8  NA/46.9  35  Kobayashi  2014  42  FP or NDP + S1  60  97.6  51.3/41.1  24.3  Present study  2017  57  FP or DOC  60  82.5  43.9/35.5  22  First author  Year  No.  Chemotherapy regimen  Median prescribed dose (Gy)  Response rate (%)  2-/3-year OS rate (%)  MST (months)  Tsuchida  2005  14  FP  60  86  57/NA  27  Nakamura  2008  22  FP or NDP + 5FU  56  82  NA/26.6  20.3  Lu  2010  31  FP  60  97  NA/10.5  17  Maruyama  2010  23  FP  60  60  31/24  13  Jingu  2012  30  NDP + 5FU  60  72  NA/38.4  21  Zhang  2012  50  FP or PTX + CDDP  60  72  NA/14  13.3  Bao  2013  83  FP or DOC + CDDP  60  75.9  NA/51.8  43  Ma  2014  49  CDDP  NA (62–70)  91.8  NA/46.9  35  Kobayashi  2014  42  FP or NDP + S1  60  97.6  51.3/41.1  24.3  Present study  2017  57  FP or DOC  60  82.5  43.9/35.5  22  CDDP, cisplatin; DOC, docetaxel; 5FU, 5-fluorouracil; FP, 5-fluorouracil plus cisplatin; MST, median survival time; NA, information not available; NDP, nedaplatin; OS, overall survival; PTX, paclitaxel. Several prognostic factors for ESCC have been suggested (Table 6). For example, high RT dose, single node recurrence, single regional recurrence and the use of a combination taxane-based plus CDDP regimen are reportedly associated with better outcomes (10,12,14,15,19–25). Among studies reporting prognostic factors, we focused on those of Bao et al. and Zhang et al. In the former, a total of 83 patients with postoperative locoregional recurrence of ESCC were treated with concurrent CRT. Patients treated with the DOC + CDDP regimen had a 3-year OS rate (59.2%) superior to that of patients receiving FP regimen (43.3%) (24). In the latter study, 50 patients with postoperative locoregional recurrence of ESCC were treated with concurrent CRT. Patients who received the paclitaxel + CDDP regimen had an MST (median, 16.3 months) superior to that of patients who received FP regimen (median, 9.8 months) (25). These previous studies reported excellent results for patients receiving RT combined with a taxane-based regimen in a comparison with a regimen of RT combined with FP (FP-RT). However, the outcomes of treatment with RT combined with DOC alone (DOC-RT; MST, 14 months; 3-year OS rate, 30.5%) were worse than those of treatment with FP-RT (MST, 25 months; 3-year OS rate, 43.9%) in our study. These results suggest that CDDP may be a key drug in the RT treatment of postoperative LN recurrence of ESCC. Table 6. Prognostic factors confirmed in previous studies First author  Factor  Good  Poor  Shioyama  Long diameter of the metastatic lymph node  <35 mm  ≥35 mm  Nakamura  Number of recurrent nodes  Single  Multiple  Kosuga, Jingu, Ma  Region of recurrent nodes  Single  Multiple  Nemoto  Interval between surgery and recurrence  ≥8 months  <8 months  Zhang  Dose  ≥60 Gy  <60 Gy  Fakhrian  RT technique  3D-CRT  2D-RT  Bao  Combined chemotherapy regimen  DOC + CDDP  FP  Zhang  PTX + CDDP  FP  Present study  Region of recurrent nodes  Single  Multiple  Combined chemotherapy regimen  FP  DOC  First author  Factor  Good  Poor  Shioyama  Long diameter of the metastatic lymph node  <35 mm  ≥35 mm  Nakamura  Number of recurrent nodes  Single  Multiple  Kosuga, Jingu, Ma  Region of recurrent nodes  Single  Multiple  Nemoto  Interval between surgery and recurrence  ≥8 months  <8 months  Zhang  Dose  ≥60 Gy  <60 Gy  Fakhrian  RT technique  3D-CRT  2D-RT  Bao  Combined chemotherapy regimen  DOC + CDDP  FP  Zhang  PTX + CDDP  FP  Present study  Region of recurrent nodes  Single  Multiple  Combined chemotherapy regimen  FP  DOC  CDDP, cisplatin; 3D-CRT, three-dimensional conformal; DOC, docetaxel; 2D-RT, two-dimensional conventional radiotherapy; FP, 5-fluorouracil plus cisplatin; PS, performance status; PTX, paclitaxel. No previous studies have examined the effectiveness of RT combined with DOC alone (DOC-RT) for the treatment of postoperative LN recurrences of ESCC. The results of a Phase I trial demonstrated promising efficacy and an acceptable toxicity profile for DOC-RT in patients with inoperable esophageal cancer (31). Hematological toxicity (<10% Grade 3/4 toxicities) with this treatment was lower than that with FP-RT (26% Grade 3/4 toxicities). However, the MST (6 months) and 1-year OS (35%) were lower than those with FP-RT (MST, 13.1 months; 1-year OS, 56%) (32). The results of our study demonstrated that DOC-RT is a safe treatment for postoperative LN recurrences of ESCC, and the MST and OS for patients with DOC-RT were also lower than for those with FP-RT. Previous studies have reported excellent results with CRT for esophageal cancer patients with recurrence in a single region or single node after curative resection (8,10,12,14,22). Outcomes in patients with recurrence in a single region or single node were also significantly better than those for patients with recurrence in multiple regions or multiple nodes in our univariate analysis. This result supports our hypothesis that the concept of oligo-recurrence might be applicable to postoperative esophageal cancer (33). With regard to RT field size, a previous study has reported the use of CRT for postoperative locoregional recurrence. Jingu et al. have reported that the overall survival and irradiated-field control rates are significantly better in patients treated with involved field irradiation than in those treated with elective nodal irradiation (34). However, our study showed that RT field size was not associated with prognosis. With regard to toxicities, we considered that T-shaped field including elective irradiation was not necessary. The present study has several limitations associated with its retrospective design. First, we could not demonstrate a survival benefit of treatment with CRT compared with chemotherapy alone. A previous study suggested that CRT (MST, 20.3 months) is superior to chemotherapy alone or palliative care (MST, <12 months) for LN recurrence after esophagectomy (12). In our study, the MST was 24 months for patients with recurrence in a single region or single node. Given this result, CRT may be a recommended minimum treatment for patients with oligo-recurrence in the LNs in esophageal cancer. Second, this study has selection biases. We enrolled patients with LN recurrence, and there was non-uniformity in the combined chemotherapy regimens and RT techniques. Therefore, a prospective study with a uniform strategy such as FP-RT for cervical LN recurrence is essential. In conclusion, we found that CRT was a safe and effective salvage treatment for LN recurrence after curative resection in ESCC. Approximately 28% of patients could achieve long-term survival with CRT. 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Journal

Japanese Journal of Clinical Oncology – Oxford University Press

Published: Mar 1, 2018

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