University of Groningen
Modern view on multimodality treatment of esophageal cancer
Faiz, Zohra
DOI:
10.33612/diss.98628913
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Publication date: 2019
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Faiz, Z. (2019). Modern view on multimodality treatment of esophageal cancer: thoughts on Patient Selection and Outcome. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.98628913
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Site of residual locoregional
esophageal cancer after
neo-adjuvant chemoradiotherapy
regarding anatomical layers and
radiation target fields:
a histopathologic evaluation
Z. Faiz, G. Kats-Ugurlu, V. Mul, A. Karrenbeld, J.G.M. Burgerhof, J.T.M. Plukker and C. T. Muijs.
Background
Neoadjuvant chemoradiotherapy (nCRT) leads to a considerable rate of pathologic complete response (pCR) in curatively resec- table esophageal cancer (EC). Though clinical complete responders are potential candidates, a watchful waiting strategy remains question-able.
Methods
Between 2009 and 2018, we included resec-tion specimens from 151 consecutive EC patients (85% adenocarcinoma) with marked radiation target fields after treatment with car-boplatin/paclitaxel and 41.4Gy radiotherapy (CROSS regimen).
Results
In radically resected (R0) specimens, 19.8% (27/136) had a pCR and 14% (19/136) nearly no response (TRG 4-5). Residual tumor was limited to the esophagus (ypT+N0) in 57.8% and commonly in the adventitia (43.1%), while 7.3% was in the mucosa (ypT1a), 16.5% in the submucosa (ypT1b) and 6.4% only in lymph nodes (ypT0N+). In TRG 2-5 R0 specimens, macroscopic residue was in- and outside the gross tumor volume (GTV) in 33.3% and 8.9%, while microscopic residue in- and outside the clinical target volume (CTV) margin only in 58.9% and 1.1%, respectively. Residual nodal disease was ob-served proximally and distally to the CTV in two and 5 patients, respectively. Disease Free Survival (DFS) decreased if macroscopic tumor was outside the GTV (9 vs. 27 months; p=0.009) and in ypT2-4aN+ (p=0.002).
Conclusion
After nCRT, 19.8 % of the R0 resected spec-imens showed a pCR and 7.3% a ypT1aN0. In patients with ypT0, about 6.4% had nodal disease at the cranial or caudal end of the CTV. The DFS decreased significantly if macroscopic tumor was detected outside the GTV and in partial responders with nodal residual disease.
Introduction
Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the treatment of choice in patients with potentially curable locally ad-vanced esophageal cancer (EC). The assumed benefit of nCRT is to downsize or sterilize the primary tumor and tumor positive nodes and anticipated hematogenous micrometastases. This will increase the radical resectability (R0) rate and reduce locoregional recurrences subsequently improving survival outcomes [1, 2]. Several studies have shown a signifi-cant higher survival in pathologic complete responders (pCR) after nCRT plus surgery compared with those harboring residual dis-ease in the resected specimens [3-5]. In the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS), nearly 50% of the patients with esophageal squamous cell carcinomas (ESCC) and 23% with adenocarcinomas (EAC) had a pCR after treatment [1, 3]. As these patients have a significant better long-term outcome, sur-gery might be less beneficial pertaining the associated high risk mortality and morbidity [6-8]. However, for good decision-making accurate selection in identifying “real com-plete responders” on restaging is essential [9, 10]. Currently the accuracy of restaging in the post-CRT setting by endoscopic ultrasonog-raphy (EUS) and positron emission tomog-raphy with computed tomogtomog-raphy (PET/ CT) remains deprived, whereas additional improvement of magnetic resonance imaging (MRI) on response prediction is still under investigation [10-13]. Pathologic examina-tion of the resected specimen is still the gold standard to assess complete response after nCRT, but optimal definition and inter-ob-server consistency remains difficult. In our previously described institutional method, which allows adequate evaluation of resid-ual EC to the radiotherapy treatment target fields, microscopic residue was found outside the radiation target volumes in 14% of the patients [14].
The aim of this study was to evaluate the anatomical site of residual cancer after nCRT in the esophageal wall layers in relation with tumor target volumes at pathologic examina-tion according to the described instituexamina-tional method [14] and to get more insight in the clinical impact of the site of residue on pa-tients’ outcome.
Methods and materials
Patients and treatment
For this retrospective study, we included 151 of 386 patients in a prospectively maintained database with potentially resectable locally advanced EC. The patients were treated with curative intent at the University Medical Center Groningen (UMCG) between Octo-ber 2009 and March 2018. The study was approved by the Ethical Institutional Board. In all included resection specimens, the radia-tion target volumes were marked according to the previously described institutional method. This procedure is based on preoperative EUS information and intraoperative demarcation using anatomical reference points to pro-vide more accurate information regarding tumor location at pathologic evaluation [14]. Patients were staged according to the seventh TNM classification system, based on CT and/ or PET-CT and EUS with eventually fine needle aspiration biopsy (FNA) [15].
Patients were treated according to the CROSS regimen with 5 weekly cycles of paclitaxel (50 mg/m2) and carboplatin (AUC Z 2), combined with 41.4 Gy radiotherapy in daily fractions of 1.8 Gy, 5 times per week. A transthoracic open or minimally invasive esophagectomy with 2- field lymphadenecto-my was performed 6 to 10 weeks after com-pletion of nCRT. Patients were restaged with CT or PET/CT before the planned surgical resection and those with distance metastasis were excluded. Gross tumor volume (GTV) containing the primary tumor and clinical pathologic lymph nodes (LN), was delineated by experienced radiation oncologists on a planning CT scan, using all available diag-nostic information (EUS/PET/CT) [16]. Since 2011 an internal target volume (ITV) was generated encompassing the target volume in all breathing phases, to account for breath-ing movements. The clinical target volume (CTV) was obtained by adding 1 cm margin in the transversal plane and 3.5 cm margin in the cranio-caudal directions
(2.5 cm margin if the tumor expanded into the stomach until 2014; afterwards 3.5 cm) to the primary tumor, adjusted to anatomi-cal structures, with a minimal margin of 5 mm. For pathologic LNs, a 1 cm margin was used. The planning target volume (PTV) was generated by expanding the CTV with 5 mm margin to account for setup uncertainties. If the information was available, the radiothe- rapy treatment field borders (GTV and CTV) were demarcated, during surgery on the in-vi-vo esophageal specimen defined just before definitive dissection related to the described intra-operative reference measure points [14].
Histopathologic examination and follow up
After careful fixation and inking of the re-sected specimen, which was directly pinned ex-vivo to a foam board to minimalize shrinkage, the specimen was sliced and the tissue sections were evaluated with hema-toxylin and eosin stain. Presence of macro-scopic tumor outside the GTV was confirmed microscopically. If microscopic tumor was within 1 mm of the surgical margins, the re-section was considered as R1 according to the Royal College of Pathologists (RCP) [17, 18]. Tumor response to nCRT was evaluated using the Mandard tumor regression grade (TRG) system [19]. Pathologic evaluations were per-formed by two experienced gastrointestinal pathologists. Pathologic complete response (pCR i.e ypT0N0) was defined as absence of tumor cells in the resected specimen. Data was extracted from revised pathology reports including presence of positive resection mar-gins, macroscopic and microscopic residual tumor outside the GTV and CTV related to target volumes, nodal involvement and tumor invasion in surrounding tissue, including lymph-angio invasion.
Follow-up after surgery was performed every 3 months in the first year, every 4 months in the second year and yearly thereafter. If there was any suspicion of recurrence, it was com-monly confirmed by CT or PET-CT.
Statistics
Survival curves were estimated using the Kaplan–Meier curves. The log-rank test was used for comparing disease free survival (DFS), defined as the time from the start of nCRT till the date of recurrence or death. Patients were censored at the last point of known contact during follow-up without acquiring the outcomes of interest. In addi-tion, patients who died within 90 days after surgery were excluded from the survival analysis. Statistical analysis was performed using SPSS 23.0 software
Patients and histopathological characteristics
The median age of the 151 patients was 66 (range 44-86) years and 78.8% were male patients (Table 1). Around 85% (n=128) had an adenocarcinoma (AC), commonly located in distal esophagus. Most resection speci-mens revealed tumor extension beyond the muscularis propria into surrounding adven-titia (37.7%). Microscopic radical resection (R0) was achieved in 136 of the 151 patients (90%) after nCRT. Approximately 19.8% (27/136) of the R0 resected group had a pCR (ypT0N0) i.e. TRG1 according to the Mandard grading system (Table 1), whereas 14% (n=19) had nearly no response (pNR; TRG 4-5). In the remaining 109 R0 resection specimens with residual tumor, the residue was macroscopic in 41 specimens (37.6%), while 61 specimens (55.9%) had microscopic tumor within different esophageal wall layers. Of the 15 patients with a R1 resection, 9 had a partial response (pPR) and the other 6 no response at all (pNR).
Anatomical site of residual cancer
In patients with R0 resection with persistent tumor, 90/109 (82.5%) had a partial response (Mandard TRG score 2-3). Residual tumor was only observed in the esophageal wall (ypT+N0) in 58.9% (n=53). In 7.8% (n=7) it was only in lymph nodes (ypT0N+), whereas 33.3% (n=30) had tumor in both the esopha-geal layers and lymph nodes (ypT+N+). Table 2 illustrates the distribution of the residues in the esophageal wall. In 24 specimens the residual tumor was limited to the superficial layers; in 7 specimens (7.8%) in the mus-cularis mucosae (ypT1a) and in 17 (18.9%; ypT1b) in the submucosa. In 18 specimens (20%) it was in muscularis propria (ypT2), while 41 specimens still had tumor in the adventitia (ypT3:45.5%). In 83 specimens with tumor localized to the esophageal wall, residual cancer was observed in in 6 (6.7%) beyond the esophageal wall. In 14 specimens with R1 resection, residual cancer was found in or outside of the adventitia, while in 1 it was localized in muscularis propria. In 7
specimens (46.7%) the residue was only in the esophageal wall (ypT+N0) and in the other 8 specimens the lymph nodes were also involved (ypT+N+) (data not shown). Of the 119 specimens with a clinical T3/T4a tumor (R0 + R1), 35 (29.4%) achieved a substantial reduction to ypT1/T2 (supplementary table1).
Site of residual cancer with regard to the radiation fields
Among the 109 R0 resection specimens with histopathologically confirmed residual tumor, macroscopic residue was found inside the gross tumor volume (GTV) in 38 (34.9%) and outside the GTV in 13 (11.9%). Microscopic residual cells were seen inside the clinical target volume (CTV) in 70 (64.2%) and also outside the CTV margins in 18 (16.5 %), while it was only observed outside the CTV margins in 1 specimen (0.9%) (Table 2-3). In the TRG 2-3 group, macroscopic residual tumor was within and outside the GTV in 30 (33.3%) and 8 specimens (8.9%) respec-tively, while microscopic residue was within and outside the CTV in 53 (58.9%) and 15 (16.7%), respectively. Among the non-re-sponding (TRG 4-5) (n=19) group the rates of residual disease were high with macro-scopic tumor within the GTV in 8 (42.1%) and microscopic tumor within the CTV in 17 patients (89.5%), while the residue was mi-croscopic outside CTV in 3 (15.8%) patients (Table 3). The most common anatomical site of residual cancer in R0 resection specimens was the adventitia (Table 3 A and B). Residual tumor in lymph nodes (ypT0N+/ ypT+N+) was observed in 46 (42.2%) spec-imens. These were located outside the CTV in 7 (6.4%). With regard to the ypN stage in 90 TRG 2-3 resection specimens, the nodal residue was found in 37 cases (41.1%), but was unknown regarding the exact location of nodal residue in 13 (14.4%). The distribution of the nodal residue in respect to the different parts of the target volumes and yN-stages are shown in Table 4A. In 2 (2.2%) of the spec-imens with TRG 2-3 the residue was present at the cranial and in 5 (5.5%) at the caudal
end of the CTV margin. One of these patients had ypT0N+ residual nodal disease outside the CTV. Residual nodal tumor was in 27 of the 37 specimens in ypN1 stages (72.9%) and in the CTV region (64.8%), however about 24.3% (n=9) had even more than two positive nodes. In the 15 TRG 4-5 specimens the residual lymph node metastases were more or less equally distributed between the CTV and GTV (Table 4B). Among the 15 R1 resection specimens, macroscopic residual tumor was found outside the GTV in 3 patients (20.0%), whereas in 9 of these patients microscopic residual tumor cells were also seen outside the CTV (60.0%) (data not shown).
Outcome
The median disease free survival (DFS) of the whole group of patients with R0 plus R1 resections, who were alive > 90 days after surgery was 33(20-45) months. Patients with superficial residual disease (ypT0-1N+ (44 months) or ypT1-4aN0 (33 months)) had a better median DFS than patients with deeper located residue (ypT2-4aN+ (18 months)) (p=0.002) (Figure 1). DFS seemed also to be related with residue in the anatomical layer in TRG 1-5 (n=143) specimens, including muscularis mucosae, submucosa, muscularis propria, and adventitia (median DFS: 16-29 months; p=0.028). Among the TRG 2-3 group (n=118), the median DFS was 26 (19-32) months. Patients with macroscopic residual tumor had a significantly worse DFS com-pared to patient with only microscopic tumor (16 vs. 33 months; p=0.022) (Figure 2). There was no significant difference in the DFS in patients with ypT1, ypT2 and > ypT2-4a (me-dian DFS: 22 to 33 months; p=0.4). However, patients with macroscopic residual tumor in the adventitia with radical resection had a significant worse DFS compared to patients with only microscopic residue in the adventi-tia (mean DFS: 14 vs. 51 months; p=0.039). Patients with TRG 2-5 (n=118) with histo-pathologically confirmed macroscopic tumor outside the GTV(n=15) had a lower DFS (9 vs. 27 months; p=0.009).
Discussion
In this retrospective study of locally advanced EC (cT1N+/ T2-4aN0-3/M0) patients treated with neoadjuvant chemoradiotherapy plus surgery according to the CROSS regimen, we have analyzed the site of residual tumor regarding anatomical wall layers and radia-tion target fields. We have shown that among patients with microscopic radical resection (R0) after nCRT, 19.8% had a pCR (ypT0/ N0), 7.3% a ypT1aN0 and 16.5% a ypT1bN0. About 7.8% of the non-complete responders with ypT0 had residual tumor in regional lymph nodes (LNs) and even residual tumor outside the CTV. Residual tumor was located in about 93.6% of the R0 resected specimens within the esophageal wall, most commonly in the adventitia. These results are important because a substantial proportion (20-35%) of the R0 resections has a pCR after nCRT [3-5]. Based on these findings, an organ preserv-ing “watch-and-wait” approach is currently considered and evaluated by some investiga-tors in absence of residual tumor at restaging imaging after nCRT [20]. EC patients with a pCR seem to have better long-term outcomes with lower rates of local recurrences than those with residual tumor [21]. However, it remains difficult to reliably identify clini-cal complete response (cCR) with current staging methods as a surrogate for pCR to avoid esophageal resection safely [21-23]. Moreover, our results show in 8-18% of the resected specimens superficially located residual primary tumor with a ypN0. In these patients the question arises whether organ preservation using an endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) could be an effective organ sparing approach. Though this approach was found to be feasible in a recent meta-analysis, diagnostic accuracy remains mandatory to perform these individualized treatment proce-dures safely [24]. Today the commonly used imaging techniques EUS-FNA and CT or PET-CT are not sufficient enough for a proper selection in the restaged EC patients after
nCRT [13]. The proposed bite to bite biop-sies at EUS before surgery may contribute to improved results, but its value is controver-sial with a sensitivity of less than 35% [25, 26]. These disappointing results seem to be in concordance with our findings that residual tumor is more frequently beyond the muscu-lar layer, and this is probably also related to the histological tumor type. In concordance with our results another study has also report-ed a preference of residual tumor beyond the muscular layer and adventitia in adenocarci-noma in contrast to the superficial layers in squamous cell carcinoma (ESCC) [21]. In our combined group microscopic residual tumor was present in 7.8% in the mucosa and in 12.2% in the submucosa of the TRG 2-3 re-sected specimens. Moreover, in ESCC, Chao et al. still found in patients with ypT0 in 14% positive LNs after nCRT [21, 27]. Shapiro et al. found these isolated residual LNs only in 3% of the EC patients after CROSS and more limited to a single lymph node [28]. In the present study we also observed a high rate of residual ypT0N+ (4.6%) and even with > 2 positive LNs (10%) which significantly decreased the DFS. In addition, Schurink et al. have shown positive LNs within the radi-ation target fields in the majority of ypT0N+ patients and in one-third outside the radiation field [29]. In our study we have identified five patients with positive lymph nodes within the CTV, while it was in LNs cranially of the CTV in one (14.3%) patient and unknown in another. In 3 of these 7 patients there was a discrepancy between the pathological N stage and clinical N stage, with progression in one patient (supplementary table 3). In addition, we have shown that in 14 of 15 patients with R1resection, residual tumor was found in or beyond the adventitia. In 8 of these patients (53.3%) the lymph nodes were also involved (ypT+N+). The poor response in the R1 group can be seen as an indication of aggres-sive biological behavior. In the group of R0 resection specimens, only 11.9% had
macroscopic tumor outside the GTV and in 16.5% microscopic tumor was found outside the CTV. Even after caudal expansion of the target area by 1 cm since 2014, there was no significant decrease in the incidence of mi-croscopic residue outside the target volumes, suggesting the presence of treatment resis-tance due to poor tumor biology. This was also shown in the significant worse DFS in patients with macroscopic residual tumor in the adventitia compared to patients with only microscopic residue in the adventitia. In con-cordance to other studies we likewise found a worse prognosis in ypT0N+ compared with ypT0N0 patients (Fig.2), indicating the need for improved treatment options, better inter-pretation regarding the histological types and a more appropriate selection using potential useful biomarkers [30-32]. Promising is the image quantification with radiomics as a future tool in predicting nCRT response after EC treatment [33]. Moreover, magnetic reso-nance imaging (MRI) is becoming increasing-ly used due to technical improvements with diffusion-weighted imaging (DWI) and its specificity for T stage with equal sensitivity as EUS for lymph node. Future efforts to im-prove the outcome is the delivery of RT more accurately, reducing high rates of in-field and distant relapses or better systemic treatment regimens [34, 35]. Better imaging methods are therefore needed not only in optimization of staging, but also for more accurate de- lineation of target volumes reducing the chance of residual disease. Proton radiothera-py could allow for dose escalation, aiming at less residual tumor and infield relapses.
Conclusion
After nCRT, 19.8 % of the R0 resected spec-imens showed a pCR and 7.3% a ypT1aN0. In patients with ypT0, about 6.4% had nodal disease at the cranial or caudal end of the CTV. The DFS was significantly lower if histopathologically confirmed macroscopic tumor was detected outside the GTV and in partial responders with nodal residual disease.
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