Survival outcomes of esophageal cancer patients with recurrence after curative treatments

doi:10.21203/rs.3.rs-2983505/v1

Download PDF

Research Article

Survival outcomes of esophageal cancer patients with recurrence after curative treatments

https://doi.org/10.21203/rs.3.rs-2983505/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background:

Little is known about predictive factors for survival outcomes of esophageal carcinoma (EC) patients who developed recurrence after undergoing multimodal therapies. We aimed to investigate long-term outcomes and identify prognostic factors in patients with relapsed EC, focusing especially on those with oligometastasis (OM).

Methods:

EC patients who developed recurrence after curative treatments (radical esophagectomy or definitive chemoradiotherapy (dCRT)) between 2010 and 2017 were reviewed. Multivariate Cox hazards models were applied to determine independent predictors of poor post-recurrence survival (PRS).

Results:

In total, 178 patients were included. The median PRS was 12.9 months. Of the 178 patients, 98 had OM and 80 non-OM (NOM) disease. The survival outcomes of patients with OM were significantly better than those of patients with NOM (P < 0.01). Surgical treatments provided significantly better survival outcomes than CRT or chemo-/radiotherapy alone (3-year overall survival (OS); 78.1% vs. 42.5% vs. 28.9%, P < 0.01), mainly due to prolonging survival after the recurrence (3-year PRS 62.9% vs. 16.7% vs. 16.2%, P < 0.01). Multivariable analysis focusing on patients with OM revealed cStage III-IV disease (P < 0.01), high GPS at the time of recurrence (P = 0.02) and non-curative treatments (P < 0.01), to be independently associated with poor PRS. In contrast, in patients with NOM, no independent predictors for poor PRS were identified.

Conclusions:

The survival outcomes of patients with relapsed EC remain poor. Surgical treatments provided significantly better survival outcomes than other treatment modalities, especially in patients with OM, mainly due to prolonging survival after the recurrence.

esophageal carcinoma

GPS

oligo metastasis

post-recurrence survival

recurrence

Esophageal cancer (EC) remains one of the refractory gastrointestinal malignancies [1, 2]. Recurrent disease is frequently observed even when curative treatments have achieved their objective [3]. Due to limited treatment options for disease relapses, the prognosis of patients who develop recurrence remains extremely poor [4, 5]. As part of the strategy for improving the survival outcomes of patients with recurrent EC, investigators have suggested several factors, such as time to recurrence, recurrence pattern and administering curative treatment for the recurrences, which might be useful for predicting post-recurrence survival [5–9].

Notably, patients with oligo metastasis (OM), a disease concept defined as a limited number of systemic metastatic tumors, reportedly have better survival outcomes than those with non-OM (NOM) disease [7, 10, 11]. In particular, a curative resection can provide a survival benefit for patients with OM, facilitating the provision of aggressive treatments for appropriately selected patients with OM [10, 12, 13].

Predictive factors for post-recurrence survival have been studied mainly in patients who developed OM after esophagectomy [8, 14]. Only a few studies have investigated factors predicting post-recurrence survival in patients undergoing multimodal therapies [7], although multimodal treatments including surgery and definitive chemoradiotherapy (dCRT) are currently applied for EC patients at all stages [1, 2].

Herein, we studied survival outcomes of patients who developed recurrence after receiving various multimodal therapies including surgery and dCRT. Furthermore, we investigated long-term outcomes and identified prognostic factors in patients with OM in comparison to those of patients with NOM.

Patients

From January 2010 to December 2017, 711 consecutive patients in total with pathologically confirmed EC were treated at the Saitama Cancer Center. Initial treatment included upfront surgery (n = 173), neoadjuvant chemo(radio)therapy (n = 229) and dCRT (n = 309). Of these 711 patients, those who developed recurrence after curative (R0) esophagectomy or a clinical complete response to dCRT were included in the study. The clinical records of these patients were retrospectively reviewed from a prospectively maintained database. At the time of the final follow-up (January 2023), the median follow-up period was 61.6 months for the survivors. This retrospective study was approved by the local ethics committee of Saitama Cancer Center (ID: 1604).

Studied criteria

Demographic data were collected prior to all treatments. Clinical and histological tumor staging was based on the TNM classification (UICC, 8th edition) [15]. As a nutritional parameter, Onodera's prognostic nutritional index (PNI: 10 × albumin + 0.005 × total lymphocyte count) was calculated [16]. The Glasgow prognostic score (GPS) was determined and the neutrophil-to-lymphocyte ratio (NLR) was estimated as an inflammatory marker, as previously described [17, 18].

Treatment strategy

Prior to treatment, the clinical stage was determined by each Multidisciplinary Tumor Board in accordance with the findings of esophagogastroduodenoscopy, computed tomography, endoscopic ultrasonography, and/or positron emission tomography. Patients were treated according to the Japan Esophageal Society guideline [19]. For patients with T1N1-3 or T2-4a (any N) disease, neoadjuvant chemotherapy followed by surgery was generally performed. For preoperative treatment, cisplatin (CDDP) plus 5-fluorouracil (5-FU) (CF) was administered as the standard therapy [20] and a regimen consisting of three drugs (CDDP, 5-FU, and docetaxel; DCF therapy) was optional [21]. As chemoradiotherapy, the CF regimen was added to radiation. For patients clinically diagnosed with cT4b disease and/or unresectable lymph node metastasis, dCRT was indicated as an initial treatment. Definitive chemoradiotherapy was also applied for those who preferred nonsurgical treatment, regardless of the tumor stage. The patients who failed dCRT were candidates for salvage esophagectomy (SALV), if curative resection was deemed feasible.

Surgical treatment

Our standard procedures consisted of subtotal esophagectomy along with en bloc lymph node dissection using a cervico-thoraco-abdominal approach. The operative thoracic approach was by video-assisted thoracoscopic surgery (VATS) or thoracotomy. A gastric conduit was passed through the retrosternal or posterior mediastinal route, and esophagogastric anastomosis was usually performed at the neck. The transmediastinal esophagectomy (abdominal-cervical approach) was selected for high-risk patients.

Definitive chemoradiotherapy

Definitive chemoradiotherapy is generally comprised of chemotherapy combined with 50.4 Gy of radiation or more to the main tumor and any metastases as well as more than 40 Gy of prophylactic radiation to the regional lymph nodes. As the first choice for the dCRT regimen, the standard-dose CF protocol of JCOG0303 was selected [22]. Additional CF therapy was continued as necessary following dCRT.

Post-treatment follow-up evaluation

Postoperative surveillance was performed based on the Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus [19]. All patients were routinely followed up at 3-month intervals for the first 2 years, at 6-month intervals for the subsequent 3 years, and annually thereafter. Posttreatment surveillance for cancer recurrence included measuring blood tumor markers (SCC, CYFRA, P53 and CEA) and obtaining CT scans every 3–6 months after the patients had been discharged, and esophagogastroduodenoscopy was performed annually. Positron emission tomography scanning was added for patients in whom recurrence was indicated by other diagnostic modalities.

Definitions of recurrence and oligo metastasis

Disease recurrences were classified as solely locoregional, solely distant, or combined [3]. Locoregional recurrences (LRRs) were located at the site of the primary tumor or in the locoregional lymph nodes, while distant recurrences were systemic or in nonregional lymph nodes, and combined recurrences were defined as the coexistence of locoregional and distant recurrences, regardless of the order of occurrence. Patients with recurrence at an anastomosis site or a regional lymph node in a cervical (including supraclavicular), mediastinal, or abdominal area were allocated to the LRR group. Patients with recurrence at a distant organ, such as the lung, brain, or liver, were allocated to the distant recurrence group; patients with recurrence at a lymph node surrounding the paraaortic regions were also included in this group.

In this study, OM was defined as fewer than five recurrences in one region, as previously reported [7, 10, 11].

Treatment for the recurrence

In all of the recurrent cases, we decided on the management of therapy at a multidisciplinary conference. Treatment intents for disease recurrence were divided into surgery, chemo(radio)therapy, radiotherapy, or best supportive care (BSC). We tended to choose resection of metastases basically when R0 resection was deemed possible. CRT was mainly comprised of 5-FU and CDDP (CF) combined with a radiation dose of 50–60 Gy. For patients unable to undergo local treatment, such as surgery or CRT/RT, due to extensive recurrence sites, chemotherapy (CTx) comprised mainly of CF and/or taxanes was administered. For patients whose general conditions were poor, or who did not want to receive treatment for recurrences, BSC was selected.

Statistical Analysis

Categorical variables were expressed in numerical figures and percentages and compared using Fisher’s exact test or the χ2 test, as appropriate. Continuous variables were expressed as the median values (range) and compared using Wilcoxon’s rank-sum test (A Mann-Whitney U test). Overall survival (OS) was calculated from the start of the initial treatment. The disease-free interval (DFI) was defined as the interval between initial therapy for the primary lesion and the date of identification of recurrence. Post-recurrence survival (PRS) was calculated from the date of recurrence detection until death from any cause. Survival curves were constructed employing the Kaplan-Meier method, and the log-rank test was used to determine statistical significance, as appropriate. A multivariate Cox proportional-hazards analysis was performed to identify independent prognostic factors. Clinically meaningful factors with p < 0.05 in a Cox proportional hazard model with univariable analysis were regarded as potential risk factors and were further analyzed by applying a multivariable Cox model. Statistical analyses were carried out using JMP 16.0.0 (SAS Institute, Cary, NC).

Characteristics of patients with recurrence after curative treatment

Figure 1 presents the study cohort. Among 400 patients who underwent curative (R0) esophagectomy, 136 developed recurrent diseases postoperatively. Of these, 70 had OM disease and 66 NOM disease (Fig. 1a). In the dCRT group, CR was achieved in 132 patients and curative (R0) SALV was performed in 16 patients (Fig. 1b). Among the 148 patients, 42 developed recurrences (28 OM, and 14 NOM). Definitive chemoradiotherapy was generally selected for patients with upper thoracic EC and cStage III-IV disease (Supplementary Table 1). The incidence of LRR was significantly higher and surgery was more frequently performed in the dCRT group than in the surgery group (Supplementary Table 1).

Clinicopathological characteristics of 178 EC patients with recurrence are summarized in Table 1. The median DFI and PRS were 10.8 months (range; 1.2–113.8) and 12.9 months (range; 0.1–112.5), respectively. Clinical stage, initial treatments and DFI did not differ significantly between patients with OM and those with NOM. Patients with OM had higher levels of inflammatory markers than those with NOM. Surgery was more frequently performed for OM than for NOM diseases (28.6% vs. 5.0%, P < 0.01).

Table 1. Characteristics of 178 patients with recurrence according to metastatic pattern

Variables	All	Non-oligo metastasis	Oligo metastasis	P value
Variables	(n=178)	(n=80)	(n=98)	P value
Age, y Median (range) Sex, male/female Tissue Type, SCC Location Lt-Ae Mt Ut-Ce cStage I/II III/IV Initial treatment Primary surgery NAC(RT) dCRT DFI, months; Median (range) Recurrence pattern LRR Distant Combined Data at the time of recurrence GPS 1-2 PNI, Median (range)　 NLR, Median (range) Elevated tumor marker Treatment for the recurrence Surgery CRT CTx or RT BSC PRS, months Median (range)	69 (39-84) 154 (86.5)/ 24 (13.5) 145 (81.5) 77 (43.3) 67 (37.6) 34 (19.1) 19 (10.7)/ 39 (21.9) 112 (62.9)/ 8 (4.5) 53 (29.8) 78 (46.6) 42 (23.6) 10.8 (1.2-113.8) 75 (42.1) 75 (41.0) 28 (16.9) 40 (22.9) 45.6 (27.8-61) 2.6 (0.5-28.9) 111 (62.4) 32 (18.0) 25 (14.0) 94 (52.8) 27 (15.2) 12.9 (0.1-102.5)	69 (39-82) 68 (85.0)/ 12 (15.0) 63 (78.8) 37 (46.3) 28 (35.0) 15 (18.7) 5 (6.3)/ 19 (23.8)/ 52 (65.0)/ 4 (5.0) 26 (32.5) 40 (50.0) 14 (17.5) 8.9 (1.2-76) 27 (33.8) 25 (31.3) 28 (35.0) 24 (30.0) 45.1 (27.8-61) 2.7 (0.8-28.9) 53 (66.3) 4 (5.0) 15 (18.8) 45 (56.3) 16 (20.0) 9 (0.1-100.7)	70 (45-84) 86 (87.8)/ 12 (12.2) 82 (83.7) 40 (40.8) 39 (29.8) 19 (19.4) 14 (14.3)/ 20 (20.4) 60 (61.2)/ 4 (4.1) 27 (27.6) 43 (43.9) 28 (28.6) 11.9 (1.4-113.8) 48 (48.9) 50 (51.1) 0 (-) 16 (16.5) 46.4 (29.2-57.9) 2.5 (0.5-12.8) 58 (59.2) 28 (28.6) 10 (10.2) 49 (50.0) 11 (11.2) 16.2 (0.1-102.5)	0.18 0.59 0.41 0.75 0.36 0.22 0.11 <0.01 0.03 0.09 0.04 0.33 <0.01 <0.01
Abbreviations: SCC, squamous cell carcinoma; NAC, neoadjuvant chemotherapy; NACRT, neoadjuvant chemoradiotherapy; dCRT, definitive chemoradiotherapy; DFI, disease-free interval; LRR, locoregional recurrence; GPS, Glasgow prognostic score; PNI, prognostic nutritional index; NLR, neutrophil lymphocyte ratio; CTx, chemotherapy; BSC, best supportive care; PRS, post-recurrence survival

Survival outcomes

The 3- and 5-year OS of EC patients with recurrence were 39.5% and 26.5%, respectively (Fig. 2a). The 1- and 3-year PRS of EC patients with recurrence were 55.4% and 22.6%, respectively (Fig. 2b). The survival outcomes of patients with OM were significantly better than those of patients with NOM (3-year OS; 52.2% vs. 24.1%, 1-year PRS 43.5% vs. 65.4%, both P < 0.01, Fig. 2c, d).

Treatments for disease recurrence included surgery (n = 32), CRT (n = 25), CTx alone (n = 71), RT alone (n = 23) and BSC (n = 27). Surgical treatments provided significantly better survival outcomes than CRT or CTx/RT (3-year OS; 78.1% vs. 42.5% vs. 28.9%, P < 0.01, Fig. 3a), mainly due to prolonging survival after the recurrence (3-year PRS 62.9% vs. 16.7% vs. 16.2%, P < 0.01, Fig. 3b, Supplementary Fig. 1).

Overall, post-recurrence survival is the major determinant of the long-term outcomes of EC patients with recurrence.

Factors predicting poor post-recurrence survival

Next, we endeavored to identify clinical factors potentially useful for predicting post-recurrence survival. Univariable analysis and subsequent application of the multivariable Cox proportional hazards model revealed shorter DFI (< 1 year) (HR 1.57, 95%CI 1.07–2.31, P = 0.02), GPS 1 or 2 (HR 1.81, 95%CI 1.08–3.03, P = 0.02) and non-surgical treatments (P < 0.01), to be independently associated with poor PRS outcomes (Table 2). The combination of DFI and GPS at the time of recurrence significantly stratified the survival of EC patients with recurrence (P < 0.01, Supplementary Fig. 2).

Table 2. Cox hazards model for survival after recurrence (n=178)

Variables	Univariable analysis			Multivariable analysis
Variables	HR	95% CI	P value	HR	95% CI	P value
Age >65 Male Histology, SCC cStage III-IV (vs. I-II) dCRT DFI < 1 year Data at recurrence GPS 1,2 (vs. GPS 0) PNI <45 NLR high (vs. low) elevated TM Non-Oligo (vs. oligo) Treatment for the recurrence Surgery CRT/CTx/RT BSC	0.96 1.19 0.92 1.41 0.76 1.82 2.86 1.62 1.29 1.39 2.09 Ref 3.44 8.65	0.64-1.29 0.73-1.97 0.59-1.40 0.98-2.04 0.51-1.13 1.29-2.55 1.94-4.21 1.16-2.28 0.92-1.79 0.99-1.98 1.50-2.93 2.09-5.67 4.76-15.75	0.59 0.47 0.69 0.06 0.16 <0.01 <0.01 <0.01 0.14 0.06 <0.01 <0.01 <0.01	1.57 1.81 1.07 1.37 Ref 3.19 6.74	1.07-2.31 1.08-3.03 0.71-1.61 0.96-1.96 1.84-5.54 3.43-13.25	0.02 0.02 0.76 0.08 <0.01 <0.01
Abbreviations: SCC, squamous cell carcinoma; dCRT, definitive chemoradiotherapy; GPS, Glasgow prognostic score; PNI, prognostic nutritional index; NLR, neutrophil lymphocyte ratio; TM, tumor marker; CTx, chemotherapy; BSC, best supportive care

Treatment details and prognostic factors in patients with OM

Last, we investigated prognostic factors focusing on patients with OM. The details of recurrence site and treatment modalities in these patients are shown in Supplementary Table 2 and Fig. 4. The incidence of oligo LRR was significantly higher in the dCRT group than in the surgery group (75.0% vs. 38.6%, P < 0.01, Supplementary Table 2). Nearly half of the patients with oligo LRR received surgery in the dCRT group (11/21, 52.4%), while curative resection was feasible for only a quarter of the patients with oligo LRR in the surgery group (5/27, 18.5%) (Fig. 4). A quarter of patients (11/43) with distant OM after curative surgery were treated surgically, whereas curative resection was not achievable in most of the patients with distant OM after dCRT (Fig. 4).

Multivariable analysis revealed cStage III-IV disease (HR 2.23, 95%CI 1.26–3.96, P < 0.01), GPS 1 or 2 (HR 2.44, 95%CI 1.12–5.31, P = 0.02) and non-curative treatments (P < 0.01), to be independently associated with poor PRS outcomes in patients with OM (Table 3). In patients with NOM, only BSC was an independent predictive factor for poor PRS outcomes (Table 3).

Table 3. Differences in prognostic factors between patients with OM and NOM

Variables	Univariable analysis			Multivariable analysis
Variables	HR	95% CI	P value	HR	95% CI	P value
Patients with OM Age >65 Histology, SCC cStage III-IV (vs. I-II) dCRT GPS 1,2 (vs. GPS 0) PNI <45 DFI < 1 year Treatment for the recurrence Surgery CRT/CTx/RT BSC Patients with NOM Age >65 Histology, SCC cStage III-IV (vs. I-II) dCRT GPS 1,2 (vs. GPS 0) PNI <45 DFI < 1 year Treatment for the recurrence Surgery CRT/CTx/RT BSC	0.68 1.27 1.89 0.81 3.07 1.69 1.93 Ref 3.78 10.92 1.11 0.75 0.88 0.85 2.18 1.43 1.72 Ref 1.51 3.34	0.42-1.12 0.63-2.57 1.09-3.24 0.47-1.38 1.68-5.62 1.03-2.75 1.17-3.16 1.94-7.39 4.58-26.03 0.67-1.85 0.43-1.29 0.54-1.45 0.47-1.53 1.29-3.68 0.89-2.28 1.08-2.76 0.54-4.19 1.09-10.23	0.13 0.51 0.02 0.43 <0.01 0.04 <0.01 <0.01 <0.01 0.69 0.29 0.63 0.59 <0.01 0.13 0.03 0.43 0.03	2.23 2.44 1.11 1.32 4.62 11.29 1.74 1.38 1.71 3.23	1.26-3.96 1.12-5.31 0.59-2.04 0.77-2.26 2.32-9.19 4.57-27.94 0.94-3.21 0.79-2.41 0.62-4.76 1.04-9.97	<0.01 0.02 0.75 0.31 <0.01 <0.01 0.08 0.25 0.31 0.04
Abbreviations: SCC, squamous cell carcinoma; dCRT, definitive chemoradiotherapy; GPS, Glasgow prognostic score; PNI, prognostic nutritional index; NLR, neutrophil lymphocyte ratio; TM, tumor marker; CTx, chemotherapy; BSC, best supportive care

The present study demonstrates the aggressive nature of EC with high recurrence rates after curative treatments [3]. In our series, approximately 30% of patients developed recurrent disease after curative treatments, 80% of all recurrences were detected within 2 years, and median post-recurrence survival was 12.9 months, observations which are in line with previous studies [4, 5, 8]. We also revealed survival outcomes of EC patients with recurrence to be mainly dependent on the post-recurrence survival; therefore, optimizing the treatment strategy for recurrence is crucial for improving the survival outcomes of EC patients [7].

Recent studies have revealed isolated recurrence, i.e., OM, to be associated with favorable outcomes after recurrence in EC patients [7, 8, 10, 12, 14]. The favorable survival outcomes of patients with OM are mainly due to the high probability of achieving curative treatment for their disease relapses. In fact, our present study revealed surgical treatments to provide significantly better survival outcomes than CRT or CTx/RT, mainly due to prolonging survival after the recurrence.

In the present study, we investigated factors other than the presence of curative treatments which might be useful for predicting post-recurrence survival. Our results show short DFI (< 1 year) and high GPS at the time of recurrence, as well as non-surgical treatments, to be independently associated with poor post-recurrence survival. We thus suggest a survival prediction model based on DFI and GPS to be useful for stratifying the survival of EC patients with recurrence.

The survival impacts of short DFI [5, 8, 17], type of recurrence [5, 6, 9, 14, 17], the presence of curative treatments for the recurrence [5, 7] and NLR [17] have been proposed in patients undergoing surgery for EC. Our study suggested these factors to be useful for predicting post-recurrence survival not only in patients undergoing surgery but also in those receiving multimodal therapies including surgery and dCRT. Of note, OM was not independently associated with good survival outcomes in our series. The rate of surgical resection was significantly higher in the OM group than in the non-OM group, thereby possibly diminishing the independent survival impact of OM.

Inflammation-based prognostic scores are reportedly useful for predicting long-term outcomes for EC patients with various tumor stages [18, 23, 24] and with recurrence [17]. Prior studies revealed short DFI to be associated with poor survival outcomes in patients with recurrence after EC surgery [5, 8, 17]. These factors are easily estimated at the timing of recurrence, thereby making them useful for clinicians aiming to estimate the survival outcomes of their patients.

It is noteworthy that we first studied predictive factors for post-recurrence survival in patients with OM in comparison to those with NOM [7, 8, 14]. In patients with OM, several factors (cStage III-IV, high GPS and non-surgical treatments) were identified as independent predictors of poor PRS. In marked contrast, in patients with NOM, only BSC independently predicted poor PRS. Our findings highlight the difference in prognostic factors between patients with OM and those with NOM. The survival outcomes of those with NOM were quite poor regardless of patient status, original tumor background and treatments.

We identified several factors useful for predicting survival in patients with OM. The finding that cStage III-IV disease is independently associated with poor PRS is in line with a recent study [14], although the precise mechanism has yet to be clarified. Importantly, our observations, together with those from previous studies [7, 12, 13], suggest that aggressive surgical treatment should be considered when the recurrent lesion is solitary or localized. Of note, short DFI was not an independent predictor of poor PRS in patients with OM. This finding suggests that surgeons should not hesitate to resect oligometastases even when the disease develops relatively soon after the attempt to achieve curative treatment [7, 14].

Although early identification and aggressive treatment for oligometastatic recurrence might improve survival [7, 8, 10, 12], optimal treatment strategies for recurrent EC have yet to be determined. Importantly, the significance of resection reportedly differs among organs harboring recurrent disease. Pulmonary metastasectomy is reportedly efficacious for solitary pulmonary metastasis [25–27]. On the other hand, the benefit of resection for hepatic metastases remains controversial [26, 28]. Still, patients should be considered for resection on an individual basis with the input of a multidisciplinary team of specialists [28].

Limitations need to be considered when interpreting the results of this study. First, the treatment strategy for each patient was discussed in the multidisciplinary team meeting, but there was selection bias for surgical indications and treatment modalities due to the lack of randomization. Second, our cohort was comprised of patients receiving various treatment modalities. Recurrence patterns and timing differ according to the initial treatments [3, 4, 29], which might have affected the results. Third, it is not possible to discern whether the observed isolated solid organ disease represents true OM or the first clinically apparent presentation of widespread metastatic disease. Finally, this was a single-institution, retrospective study. We anticipate that a multi-institutional collaborative study with a large cohort would achieve a more convincing result.

In conclusion, the survival outcomes of patients with relapsed EC remain poor. Surgical treatments provided significantly better survival outcomes than other treatment modalities, especially in patients with OM, mainly due to prolonging survival after the recurrence.

EC, Esophageal carcinoma; OM, oligo metastasis; dCRT, definitive chemoradiotherapy; PNI, prognostic nutritional index; GPS, Glasgow prognostic score; NLR, neutrophil-to-lymphocyte ratio; SALV, salvage surgery; VATS, video-assisted transthoracic surgery; LRR, locoregional recurrence; CTx, chemotherapy; BSC, best supportive care; OS, overall survival; DFI, disease-free interval; PRS, post-recurrence survival; HR, hazard ratios; CI, confidence intervals

Disclosure: The authors have no conflicts of interest to declare.

Human rights statement

All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

Informed consent

Informed consent was obtained from all individual participants in the form of opt-out on the website. Those who rejected participation, were excluded.

Contributions

The contributions of the authors to this study are as follows: Kotaro Sugawara and Takashi Fukuda are the authors mainly responsible for the study’s conception and design, acquisition of data, and analysis and interpretation of data. Daiji Oka, Hiroki Hara, Takako Yoshii, Hiroki Ushijima and Shigehiro Kudo contributed mainly to the drafting of the article and to revising it critically for important intellectual content. All authors have no conflicts of interest or financial ties to disclose.

Kitagawa Y, Ishihara R, Ishikawa H et al (2023) Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 1. Esophagus. 10.1007/s10388-023-00993-2.1-30
Kitagawa Y, Ishihara R, Ishikawa H et al (2023) Esophageal cancer practice guidelines 2022 edited by the Japan Esophageal Society: part 2. Esophagus. 10.1007/s10388-023-00994-1
Kalff MC, Henckens SPG, Voeten DM et al (2022) Recurrent Disease After Esophageal Cancer Surgery: A Substudy of The Dutch Nationwide Ivory Study. Ann Surg 276:806–813
Lou F, Sima CS, Adusumilli PS et al (2013) Esophageal cancer recurrence patterns and implications for surveillance. J Thorac Oncol 8:1558–1562
Yamashita K, Watanabe M, Mine S et al (2017) Patterns and Outcomes of Recurrent Esophageal Cancer After Curative Esophagectomy. World J Surg 41:2337–2344
Parry K, Visser E, van Rossum PS et al (2015) Prognosis and Treatment After Diagnosis of Recurrent Esophageal Carcinoma Following Esophagectomy with Curative Intent. Ann Surg Oncol 22(Suppl 3):S1292–1300
Ohkura Y, Shindoh J, Ueno M et al (2020) Clinicopathologic Characteristics of Oligometastases from Esophageal Cancer and Long-Term Outcomes of Resection. Ann Surg Oncol 27:651–659
Ghaly G, Harrison S, Kamel MK et al (2018) Predictors of Survival After Treatment of Oligometastases After Esophagectomy. Ann Thorac Surg 105:357–362
Miyata H, Yamasaki M, Kurokawa Y et al (2011) Survival factors in patients with recurrence after curative resection of esophageal squamous cell carcinomas. Ann Surg Oncol 18:3353–3361
Nobel TB, Sihag S, Xing X et al (2021) Oligometastases After Curative Esophagectomy Are Not One Size Fits All. Ann Thorac Surg 112:1775–1781
Morinaga T, Iwatsuki M, Yamashita K et al (2021) Oligometastatic recurrence as a prognostic factor after curative resection of esophageal squamous cell carcinoma. Surg Today 51:798–806
Depypere L, Lerut T, Moons J et al (2017) Isolated local recurrence or solitary solid organ metastasis after esophagectomy for cancer is not the end of the road. Dis Esophagus 30:1–8
Hiyoshi Y, Morita M, Kawano H et al (2015) Clinical significance of surgical resection for the recurrence of esophageal cancer after radical esophagectomy. Ann Surg Oncol 22:240–246
Tsai PC, Chien HC, Hsu PK et al (2022) Post-recurrence survival analysis in patients with oligo-recurrence after curative esophagectomy. BMC Cancer 22:637
Brierley JGMKWC (2017) TNM classification of malignant tumours, 8th Edition
Sugawara K, Yagi K, Okumura Y et al (2022) Survival Prediction Capabilities of Preoperative Inflammatory and Nutritional Status in Esophageal Squamous Cell Carcinoma Patients. World J Surg 46:639–647
Hoshino S, Takeuchi M, Kawakubo H et al (2021) Usefulness of Neutrophil to Lymphocyte Ratio at Recurrence for Predicting Long-Term Outcomes in Patients with Recurrent Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 28:3001–3008
Sugawara K, Mori K, Yagi K et al (2019) Association of preoperative inflammation-based prognostic score with survival in patients undergoing salvage esophagectomy. Dis Esophagus 32
Kitagawa Y, Uno T, Oyama T et al (2019) Esophageal cancer practice guidelines 2017 edited by the Japan Esophageal Society: part 1. Esophagus 16:1–24
Ando N, Kato H, Igaki H et al (2012) A Randomized Trial Comparing Postoperative Adjuvant Chemotherapy with Cisplatin and 5-Fluorouracil Versus Preoperative Chemotherapy for Localized Advanced Squamous Cell Carcinoma of the Thoracic Esophagus (JCOG9907). Ann Surg Oncol 19:68–74
Hara H, Tahara M, Daiko H et al (2013) Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma. Cancer Sci 104:1455–1460
Shinoda M, Ando N, Kato K et al (2015) Randomized study of low-dose versus standard-dose chemoradiotherapy for unresectable esophageal squamous cell carcinoma (JCOG0303). Cancer Sci 106:407–412
Sugawara K, Yagi K, Okumura Y et al (2020) Long-term outcomes of multimodal therapy combining definitive chemoradiotherapy and salvage surgery for T4 esophageal squamous cell carcinoma. Int J Clin Oncol 25:552–560
Sugawara K, Fukuda T, Kishimoto Y et al (2022) Impacts of pretreatment esophageal stenosis on survival of esophageal cancer patients. Ann Surg Oncol In Press
Ichikawa H, Kosugi S, Nakagawa S et al (2011) Operative treatment for metachronous pulmonary metastasis from esophageal carcinoma. Surgery 149:164–170
Ichida H, Imamura H, Yoshimoto J et al (2013) Pattern of postoperative recurrence and hepatic and/or pulmonary resection for liver and/or lung metastases from esophageal carcinoma. World J Surg 37:398–407
Kobayashi N, Kohno T, Haruta S et al (2014) Pulmonary metastasectomy secondary to esophageal carcinoma: long-term survival and prognostic factors. Ann Surg Oncol 21(Suppl 3):S365–369
Liu J, Wei Z, Wang Y et al (2018) Hepatic resection for post-operative solitary liver metastasis from oesophageal squamous cell carcinoma. ANZ J Surg 88:E252–e256
Shapiro J, van Lanschot JJB, Hulshof M et al (2015) Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 16:1090–1098

SupplementaryFigure1.tiff
Supplementary Figure 1. DFI and PRS according to treatment modalities and recurrence patterns
SupplementaryFigure2.tiff
Supplementary Figure 2. Survival outcomes according to DFI and GPS The combination of DFI and GPS at the time of recurrence significantly stratified the survival of EC patients with recurrence (P < 0.01).
SupplementaryTables.docx
Supplementary Table 1. Patient characteristics according to the initial treatments Supplementary Table 2. Characteristics of 98 patients with oligo metastasis

Download PDF

Version 1

posted

You are reading this latest preprint version

Survival outcomes of esophageal cancer patients with recurrence after curative treatments

Status:

Version 1

Abstract

Figures

Introduction

Patients and Methods

Studied criteria

Surgical treatment

Definitive chemoradiotherapy

Post-treatment follow-up evaluation

Definitions of recurrence and oligo metastasis

Statistical Analysis

Results

Characteristics of patients with recurrence after curative treatment

Survival outcomes

Factors predicting poor post-recurrence survival

Treatment details and prognostic factors in patients with OM

Discussion

Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1