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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 41-48

Esophageal cancer: Treatment challenges and controversies


Radiation Oncology Department, Shri Ram Murti Institute of Medical Sciences, Bareilly, Uttar Pradesh, India

Date of Submission20-May-2021
Date of Acceptance16-Jun-2021
Date of Web Publication31-Jul-2021

Correspondence Address:
Dr. Piyush Kumar
Shri Ram Murti Institute of Medical Sciences, Bareilly, Uttar Pradesh.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_13_21

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  Abstract 

The poor outcomes of esophageal malignancies in terms of local control and survival rates have perplexed radiation oncologists since long time. Chemoradiation has been recognized as a key definitive treatment modality with outcomes comparable to that of surgery. It offers a potential radical treatment option to patients unfit for surgery with the advantage of organ preservation. However, a clear consensus in terms of indications, dose schedules, and techniques of radiation is lacking. In pre- and post-operative settings, lower dose schedules of radiation are recommended. Some evidences suggest that patients receiving radical dose of radiation may derive survival benefit from increased doses. Low-quality emerging evidence suggests promising outcomes with brachytherapy but it needs to be testified further. A detailed review of the existing literature might help to address the controversies in clinical practice.

Keywords: Esophageal cancer, radiotherapy dose escalation, treatment controversies


How to cite this article:
Kumar P, Mehta A. Esophageal cancer: Treatment challenges and controversies. J Curr Oncol 2021;4:41-8

How to cite this URL:
Kumar P, Mehta A. Esophageal cancer: Treatment challenges and controversies. J Curr Oncol [serial online] 2021 [cited 2021 Dec 3];4:41-8. Available from: https://www.journalofcurrentoncology.org/text.asp?2021/4/1/41/322889




  Background Top


Worldwide, esophageal cancer is the 10th most common malignancy accounting for 3.1% of total cancer incidence and 5.5% of total cancer deaths.[1] In India, it is relatively common, being the 5th most common malignancy both in incidence and in mortality.[2] Despite numerous efforts, the outcomes in terms of local control and overall survival remain dismal.[3] Multiple strategies have been attempted to improve the poor outcomes that include advancements in investigation modalities, combined treatment approaches, and using advanced radiotherapy techniques with different radiotherapy dose schedules. However, it still remains a controversial domain with wide variation in clinical practices. This article aims to review various existing evidences and controversies in treatment strategies of cancer esophagus.


  Decision-Making of Surgery Vs. Radiotherapy Top


A clear superiority of one modality over the other has not been established particularly in squamous cell carcinoma (SCC); hence, there is no standard treatment approach. A retrospective review of 1230 cancer esophagus patients diagnosed with SCC treated from 2007 to 2014 concluded that there was significantly longer survival with surgery over chemoradiation (CRT). In locally advanced patients, combined modality approach of neoadjuvant treatment followed by surgery showed significantly higher survival rate than either modality alone.[4] As several evidences suggest better outcomes by incorporation of surgery, it is still advocated by many authors as the mainstay of treatment with CRT reserved for inoperable cases or as part of trimodality approach.[5],[6] However, there is selection bias in retrospective series as patients selected for CRT are with lower performance status, comorbidities, or cervical esophageal tumors.

Recent evidence suggests comparable outcomes with CRT as definitive treatment and concerns have been raised regarding the additional role of surgery.[7],[8] An increasing trend of utilization of definitive CRT has been observed especially for elderly population, frail, or co-morbid patients who are poor surgical candidates.[9]

A meta-analysis by Ma et al.[10] comparing surgery and CRT showed no significant difference in 2-year (P = 0.177) and 5-year (P = 0.796) survival rates. In node-positive patients, survival rates favored definitive CRT(P = 0.076). In the subset analysis according to ethnicity, all Asians had SCC cancer esophagus that demonstrated comparable survival among both the modalities. Comparatively, in western studies, 56% of the patients had adenocarcinoma (AC), and survival was significantly inferior (P=0.033) with CRT.

CRT is particularly a modality of choice in cervical esophageal tumors or those infiltrating to unresectable structures (cT4b).[11] However, in AC, CRT alone is clearly inferior and is necessarily contemplated by surgery. Surgery alone has also inferior outcomes compared with combination with chemotherapy or CRT.[12]


  Primary Radiotherapy Vs. CRT Top


A randomized study by Slabber et al.[13] of 70 patients conducted in the end of last century suggested no significant benefit of addition of concurrent chemotherapy to radiation. However, later on, vast majority of literature has favored combined modality approach. The landmark RTOG 85-01 trial compared radiation dose of 50 Gy with concurrent chemotherapy vs. 64 Gy radiation alone and emphasized that a higher radiation dose could not make up for benefits of adding chemotherapy. The radiosensitizing action of chemotherapy was significantly more efficacious in improving local control than increased dose of radiation. Further, probably, the elimination of distant micrometastasis by chemotherapy also significantly improved the distant control.[14] The trial update showed 26% 5-year survival in the CRT arm, whereas none of the patients in the radiation alone arm survived after 3 years of follow-up. Also, the late toxicities were comparable among both the arms.[15] Another large-scale meta-analysis by Zhu et al.[16] have also shown significant benefit of CRT over radiation alone in terms of complete and partial response rates and survival rates with comparable late toxicities.

Combined modality treatment is preferred in esophageal malignancies as radiation alone has merely any survival advantage, whereas radiation alone is reserved for palliative settings. In concurrent settings, combination of 5-FU and cisplatin is widely used and has been accepted as standard in SCC and AC of the esophagus.[17]


  Adjuvant Treatment After Surgery: Radiotherapy or Chemotherapy or CRT Top


Adjuvant radiotherapy after surgery

Pre-operative CRT is preferred owing to higher efficacy of radiation in well-vascularized regions. Still, a certain proportion of patients may undergo upfront surgery because of patients, physicians’ preferences or clinical understaging for T3 and T4 status, nodal involvement.

The National Cancer Database (NCDB) analysis showed significant impact of post-operative radiotherapy (PORT) in patients with positive margins with overall survival (OS) benefit (P<0.001) by doubling median OS (P = 0.009) over surgery alone. Also, in the subset analysis of patients receiving adjuvant chemotherapy, the addition of adjuvant radiotherapy significantly improved the survival rates (P < 0.001).[18] Xiao et al.[19] comparing PORT over surgery alone proved significant survival benefit (P 0.0265) only in patients with three or more positive lymph nodes but not with negative or one or two positive lymph nodes. The Retrospective Surveillance Epidemiology and End Results analysis further attempted to clarify the role of PORT and showed significant improvement of 3-year OS in stages T3N1 and T4N0-1 from 18.2% to 28.9% (P < 0.001) but not in stages T1N1, T2N1, and T3N0.[20]

The controversial role of PORT for T3N0 patients was specifically addressed by Zhang et al., which showed significant improvement in 5-year OS (P = 0.004) and disease-free survival (DFS) (P = 0.036) with adjuvant CRT over surgery alone. However, because of utilization of combined modality, the proportional advantage attributable to radiation alone cannot be ascertained.[21]

There are no standard consensus guidelines for adjuvant radiation in carcinoma esophagus, since standard recommendation is for pre-operative CRT. The largest analysis published till date analyzed patients receiving adjuvant radiation from 1977 to 2018, including 14 original studies with a total of 2738 patients. This study showed that local sites (tumor beds and anastomoses) and regional lymph nodes had 1.88% and 22.16% recurrences, respectively, implying that adjuvant radiation should focus on regional nodes.[22] The recent literature recommends the inclusion of the nodal volumes and omission of tumor bed and anastomotic site in contrast to previous recommendations.[23],[24] But in practice, this remains an area of controversy as many experts are reluctant to omit primary site inclusion. Further, the majority of literatures are retrospective in nature and as adjuvant radiotherapy is not the standard of care, these studies might have variation in clinical target volumes.

Adjuvant chemotherapy after surgery

The NCDB analysis of post-operative patients with node-positive AC of middle or lower one-third esophagus who did not receive induction chemotherapy showed significant improvement in 5-year survival (P = 0.008) with adjuvant chemotherapy, compared with observation. But chemotherapy was utilized only in half of the node-positive patients. The addition of radiation to chemotherapy could not improve survival (P = 0.35).[25]

A meta-analysis by Zhang et al.[26] included randomized and non-randomized studies on adjuvant chemotherapy and showed significant 3-year OS benefits in stage III and IV disease (P = 0.00001), but not in stages I and II. The 5-year DFS benefitted in node-positive patients. Another meta-analysis in SCC patients by Zhao et al.[27] which included three randomized and six retrospective studies showed OS (P = 0.002) and DFS (P < 0.001) to be significantly improved with post-operative chemotherapy.

In terms of adjuvant treatment, a clear consensus is presently lacking attributable to preference for pre-operative CRT, retrospective data, less number of randomized trials, and heterogeneity in study population. This demands further research in well-designed randomized settings to clearly guide adjuvant treatment.

Adjuvant CRT after surgery

A recent retrospective propensity score-matched study by Wang et al.[28] of 859 patients showed post-operative CRT to be significantly better in terms of OS compared with chemotherapy alone (57.3% vs. 36.4%, P = 0.007) in node-positive patients. In stage-wise analysis, particularly pT3-4 status had significantly better 5-year OS (P0.043) but for pT1-2, N1, and pN2–3 status, the significance was lost.

Another retrospective review by Kim et al.[29] showed significant benefit either with adjuvant chemotherapy or with CRT in terms of OS and DFS when compared with observation. The indications for adjuvant chemotherapy were node-positive patients, and indications for adjuvant radiation included positive resection margin, T3-4 status, and multiple positive lymph nodes. The loco-regional recurrence rates were significantly lower in the adjuvant radiation and CRT groups.

In a prospective study comparing outcomes of surgery alone, or in combination with pre-operative and post-operative CRT, a significant advantage was observed in median progression-free survival (PFS) (P = 0.033) and median OS (P = 0.015), which was seen with the addition of CRT over surgery alone. There was no significant differences in OS, PFS, and toxicities between the pre-operative and post-operative groups (P>0.05).[30] Similarly, the NCDB also showed similar outcomes between pre-operative and post-operative CRT, with no significant difference in 1-year recurrence rates (P = 0.269), DFS (P = 0.521), and OS (P = 0.258).[31]

These evidences highlight that patients who have not received pre-operative CRT may derive equivalent survival benefit with post-operative treatment. But a clear consensus on indications has not been arrived as a vast majority of literatures is retrospective. Post-operative CRT is recommended for patients with positive and close margins, T3, node-positive disease, and other poor prognostic factors such as poorly differentiated tumors, lymphovascular invasion, and perineural invasion.[32]


  Pre-operative CRT Followed by Surgery: Evidence for Standard of Care Top


CRT and surgery have been investigated to decrease the high incidence of locoregional failures with acceptable toxicities. The landmark CROSS (Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer) trial established a new benchmark for pre-operative CRT even in operable patients (non-metastatic T1N1 or T2-3N0-1). CRT with a radiation dose of 41.4 Gy in 23 fractions followed by surgery led to a significant OS benefit (P = 0.003) with a striking improvement in median overall survival to 48.6 months when compared with 24.0 months with surgery alone with comparable morbidity and mortality.[33]

Meta-analysis has also proven the significant impact of neoadjuvant CRT over surgery alone on all-cause mortality [hazard ratio (HR): 0.78; P<0.0001] both for SCC (HR: 0. 80; P = 0.004) and for AC (HR: 0.75; P = 0.02). Neoadjuvant chemotherapy was also significantly beneficial for all-cause mortality over surgery alone (HR: 0.87; P = 0.005), but less beneficial for SCC (HR: 0.92; P = 0.18) compared with AC (HR: 0.83; P = 0.01). Although the benefit for neoadjuvant CRT was more than that of neoadjuvant CT, a significant advantage (P = 0·07) was not established in the analysis.[34]

Another meta-analysis analyzing the role of pre-operative radiation failed to elicit a significant survival advantage. The vast majority of literature supports the role of pre-operative CRT attributable to its survival advantage over pre-operative RT alone. But the advantage of neoadjuvant CRT over neoadjuvant CT is still questionable.[35]


  Complete Response After Neoadjuvant CRT: Can Surgery Be Omitted? Top


This trimodality approach has proved promising results but, in an attempt, to reduce surgical morbidity, many attempted to compare its efficacy to that of definitive CRT. A Cochrane meta-analysis evaluated the impact of addition of esophagectomy to CRT. Patients in the surgery arm received radiation doses of up to 46 Gy only, whereas patients receiving CRT were treated with radiation doses of more than 65 Gy. In this meta-analysis, high-quality evidence suggests that addition of surgery had no significant impact on overall survival over CRT alone, contrary to the moderate-quality evidence, in which the addition of esophagectomy probably had a significant impact on locoregional relapse rates. Additionally, low-quality evidence suggested that surgery may significantly add to a higher treatment-related mortality. However, it remains unclear if surgery may have conferred a survival advantage when compared with standard dose chemoradiotherapy alone. In patients undergoing chemoradiotherapy alone, a significant proportion required salvage procedures, either dilation or stent placement, for dysphagia.[36]

Contrarily, the analysis of NCDB showed that addition of surgery to CRT has been shown to offer better survival outcomes.[37] However, the Cochrane meta-analysis described earlier evidence which suggests that addition of surgery to definitive CRT particularly may not have a survival benefit rather may it worsen the toxicity profile.[36] Still, it remains an ongoing and long-standing controversial issue.

This approach of omission of surgery after complete response is also being tested in the ongoing randomized SANO trial. In this trial, patients showing CR to CROSS regimen are being compared with active surveillance to patients undergoing esophagectomy. CR would be defined by endoscopic bite-on-bite biopsies reaching deeper layers of the esophageal wall, EUS-FNAC of the suspected lymph nodes, and PET-CT, all depicting no residual disease or distant metastasis after 12 weeks of CRT.[38]


  Increased Dose of Radiotherapy to Avoid Surgery: Controversial Issue Top


Many guidelines have endorsed a radical dose of 50.4 Gy in esophageal cancer, but this has not been uniformly embraced attributable to the high locoregional failure rates. In the RTOG 94-05 trial, a higher radiation dose of 64.8 Gy failed to elicit benefit in locoregional control or survival over the standard 50.4 Gy. Rather, higher mortality of 10% was observed in the high dose arm when compared to 2% in the standard dose arm. This led to interim closure of the trial but majority of the deaths in the high-dose arm (7 of 11) were seen before receiving dose of 50.4 Gy or lesser. However, a separate analysis of patients receiving the assigned dose of radiation also failed to elicit survival advantage with high dose.[39] This landmark trial discouraged the advent of dose escalation, but this trial has been criticized because of the conventional technique that explains higher incidence of toxicities.

A later conducted small-scale randomized study by Nayan et al.[40] of 28 patients compared same dose schedules in both the arms, which is utilized in RTOG 94-05 trial but with conformal techniques. There was no significant advantage in terms of complete response rates and OS with a dose of 64.8 Gy over 50.4 Gy schedule. But there were similar toxicity and mortality rates. This trial emphasized the potential of conformal technique demonstrating acceptable toxicities in settings of dose escalation.

Gemici et al.[41] showed that pre-operative CRT followed by surgery and definitive CRT had comparable 5-year survival rates of 50% and 59%, respectively (P=0.72). The radiation used was 46 Gy in pre-operative settings, 50 Gy for middle and lower thoracic tumors and ranging between 50.1 and 60 Gy for upper thoracic and cervical esophageal tumors. The analysis of the definitive CRT group revealed dose escalation beyond 50 Gy, which led to a huge and significant improvement in 5-year survival to 91% when compared with 50% with standard dose (P = 0.013).

A large-scale NCDB analysis comparing various dose schedules (50–50.4, 51–54, 55–60, and >60 Gy) revealed no appreciable difference in OS among all groups. The subgroup analysis by histological subtype and even with contemporary intensity modulated radiotherapy technique (IMRT) also failed to demonstrate advantage of dose escalation.[42]

Contrarily, another meta-analysis comprising eight studies in which most of the patients were treated by 3D conformal radiotherapy or IMRT with total dose ranging from 45 to 75.6 Gy, a significant benefit in favor of radiotherapy dose ≥ 60 Gy, was observed in terms of local recurrence-free survival, progression-free survival, and overall survival (P<0.001).[43] A recent meta-analysis comprising 12 studies compared low dose (38–60 Gy) and high dose radiotherapy (50.4–72Gy) in the patients treated by advanced radiation techniques, excluding the patients treated by brachytherapy. This meta-analysis reproduced the findings of NCDB analysis with no significant OS benefit (P = 0.43) in subgroups comparing dose of ≤ 50.4 to >50.4 Gy. In the other subgroup analysis, dose of ≥ 60 Gy led to substantial survival benefits when compared with dose of< 60 Gy (P< 0.0001). However, no significant differences were observed in toxicities in terms of grade 3–5 radiation pneumonitis (P = 0.89), grade 3–5 radiation esophagitis (P = 0.11), treatment-related death (P = 0.27), or distant metastasis (P = 0.17).[44]

The results of these two meta-analyses came as a major breakthrough inflicting that benefit of dose escalation may be apparent at higher doses of 60 Gy and above, but further conformation in randomized trials is still warranted. However, the results of the ARTDECO trial were also recently published, which showed that dose escalation up to 61.6 Gy only to the primary tumor by concomitant boost did not improve local control over 50.4 Gy increased toxicities.[45] Another ongoing clinical trial examined the effect of dose escalation with adaptive radiotherapy to the most PET avid part of the tumor and lymph nodes (gross tumor volume) with standard dose to clinical target volume and planning target volume, compared with uniform dose in the standard arm.[46]

Another analysis of patients treated up to a dose of 60 Gy by 3D-CRT technique showed a 5-year cumulative cardiac events occurrence of 16.3%. The incidence of cardiac events increased significantly with the magnitude of exposure.[47] The results suggested that optimizing cardiac dosimetry would likely improve the clinical outcomes of CRT.

There has been a tendency toward higher doses of radiation up to 66–70 Gy, particularly in cervical esophageal malignancies similar to head and neck malignancies, but the current literature is inconclusive with regard to its benefit.[11] This is due to aggressive behavior, abundant lymphatic drainage, extension toward the hypopharynx portending a relatively poor prognosis.

The driving thought behind dose escalation lies in radiobiological principles, stating that dose of 50.4 Gy is only enough for microscopic control.[48] The studies showing lack of advantage with dose escalation have been criticized due to an increase in the cardiopulmonary complications neutralizing the impact of local control on overall survival. Numerous attempts have been made to combat the increased toxicity by exploiting more conformal techniques and treatment volume reductions. Various factors such as cranio-caudal extent of tumor, extent of nodal irradiation, and volume of the organs at risk being irradiated need to be considered while interpreting the literature addressing the role of dose escalation [Table 1].
Table 1: Results of studies analyzing the role of dose escalation in definitive CRT

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Boost by brachytherapy

The intraluminal brachytherapy (ILBT) offers unique merits such as high precision, minimal target motion impact, and avoidance of dose to adjacent critical structures, but accompanying demerits are increased risks of local complications such as stricture, stenosis, and fistula formation.

A multi-institutional prospective trial RTOG 9207 evaluated the role of boost with ILBT (HDR 15 Gy in three fractions or LDR 20 Gy) with concurrent chemotherapy after 2 weeks of completion of external beam radiation therapy (EBRT) with 50 Gy in 25 fractions. The estimated survival rate at 12 months was 49%, with a median survival of only 11 months but life-threatening toxicity was observed in 24%, treatment-related fistula in 12%, and even deaths in 10% cases. The results were disappointing as merely any survival advantage was observed, but treatment-related mortality was quite high. Therefore, the protocol was amended and dose of ILBT reduced to 10 Gy in five fractions. The fact needs to be acknowledged that no patient developed fistula with reduced ILBT dose. The authors urged particular caution in use of ILBT with concurrent chemotherapy.[49]

The practice of ILBT is feared given the toxicity concerns. Retrospective studies suggest good response rates with acceptable toxicities.[50],[51],[52] But its clinical adoption demands research in randomized settings. It may emerge as a potential tool to combat the high incidence of locoregional failures.

Some studies focussed on identifying the risk factors for stricture development after EBRT. A significant correlation was found with female sex, extent of circumference involved, proximal site of the disease, and severe esophagitis.[53] Another study in patients attaining CR after EBRT proved hypoalbuminemia (P 0.03) and inability of endoscope passage (P< 0.001) to be significant risk factors. The authors recommended that these high-risk patients may be considered for prophylactic dilatations.[54] The actual incidence of stricture attributable to ILBT alone is difficult to ascertain, and comparative studies are required to differentiate it from post-EBRT sequelae. Although less is known presently about the survival impact of ILBT, it should not be disregarded as potential option just for the sake of strictures.

Dose escalation can be planned by optimizing the use of EBRT and ILBT. A suggestion may be that the radiation oncologist may exploit newer technologies such as IMRT and image-guided radiation therapy to plan and deliver another 6–10 Gy (total EBRT dose to 56–60 Gy in 28–30 fractions), keeping the dose to heart and lungs within acceptable constraints, and further deliver ILBT of 6 Gy in single fraction. Abstract of almost similar protocol had been published in 2021 ASCO Annual meeting. In the retrospective analysis of 69 patients treated from 2008 to 2016 with EBRT to a total dose of 59.4 Gy in 33, patients who received additional ILBT of 6 Gy in single fraction had significantly higher complete response rates (84.61% vs. 57.49%, P = 0.07) and overall survival (45.3 vs. 19.2 months, P = 0.005) with comparable incidence and severity of strictures. Further, none of the patients receiving ILBT developed a fistula.[55]


  Conclusion Top


The recent literature suggests that in esophageal SCC, definitive CRT has comparable results to that of combined modality approaches utilizing surgery, but in AC the surgery cannot be avoided. The preferred approach to combined modality treatment is pre-operative CRT followed by surgery. Radical CRT avoiding surgery has shown promising results, but radiotherapy dose or its escalation is still debatable. The standard dose schedules of 50.4 Gy are being questioned by recent meta-analysis, suggesting survival advantage with dose schedules of >60 Gy. The use of dose escalation in EBRT and addition of ILBT using optimal planning may help to reduce locoregional recurrence rates, post-treatment cardiopulmonary complications, and ILBT-induced strictures and fistulas.

Authors contribution

Dr. Ankita Mehta—Literature search and analysis, intellectual content, manuscript preparation, manuscript editing.

Dr. Piyush Kumar—Conception of design, intellectual content, manuscript preparation, manuscript editing, manuscript review, guarantor.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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