Cancer Letters 357 (2015) 69–74

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Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

Involved field irradiation for the treatment of esophageal cancer: Is it better than elective nodal irradiation? Liyang Jiang a,1, Xin Zhao b,1, Xue Meng a, Jinming Yu a,* a b

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China Department of Cardiothoracic Surgery, Qilu Hospital, Shandong University, Jinan, China

A R T I C L E

I N F O

Article history: Received 9 October 2014 Received in revised form 19 November 2014 Accepted 19 November 2014 Keywords: Esophageal cancer Involved field irradiation Elective nodal irradiation

A B S T R A C T

Esophageal cancer (EC) is an extremely aggressive and lethal malignancy with an increasing incidence worldwide. Currently, the combination of radiotherapy and concurrent chemotherapy is performed for nonsurgical EC. However, there is no clear consensus on the accurate definition of the clinical target volume. Still, elective nodal irradiation (ENI) is the conventional remedy adopted for EC patients, while severe radiotherapy-related toxicities would occur in at least half of patients. Involved field irradiation (IFI) is a selective way to decrease the irradiation volume and thereby to decline toxicities. This review centers on the modality of IFI and compares the treatment efficacy between IFI and ENI. © 2014 Elsevier Ireland Ltd. All rights reserved.

Introduction Esophageal cancer (EC) is the sixth leading cause of cancerrelated mortality worldwide, and an estimated 18,170 new cases were diagnosed in the United States, with 15,450 deaths, in 2014 [1,2]. The standard treatment for patients with localized EC who choose nonsurgical management involves combined-modality treatment with radiotherapy plus concurrent chemotherapy, as established by the results of Radiation Therapy Oncology Group (RTOG) trials [3,4]. However, there is no international consensus regarding the accurate definition of the clinical target volume (CTV), because EC is greatly capable of metastasising with an extensive and not clearly defined range of invasion [5]. Taking into consideration microscopic spread, the radiation fields of many trials involve larger ranges and have included elective nodal irradiation (ENI), i.e., nodal target volume that covers both metastatic lymph nodes and

Abbreviations: EC, esophageal cancer; ENI, elective nodal irradiation; IFI, involved field irradiation; RTOG, Radiation Therapy Oncology Group; CTV, clinical target volume; MHCI, major histocompatibility complex class I; CTL, cytotoxic lymphocyte; GTV, gross target volume; CT, computed tomography; PET, positron emission tomography; GTVt, gross target volume of visible primary tumor; GTVn, gross target volume of metastatic lymph nodes; CTVt, clinical target volume of visible primary tumor; CTVn, clinical target volume of metastatic lymph nodes; LRC, locoregional control; PFS, progression-free survival; DFS, disease-free survival; CFRT, conventional fractionated radiation; LCAHRT, late-course accelerated hyperfractionated radiotherapy; HFR, hypofractionated radiation; OS, overall survival; CR, complete response; NEIL1, nei endonuclease VIII-like 1; EAC, esophageal adenocarcinoma. * Correspondence author. Tel.: +86 531 87984729; fax: +86 531 87984079. E-mail address: [email protected] (J. Yu). 1 Equal contributors (co-first author). http://dx.doi.org/10.1016/j.canlet.2014.11.045 0304-3835/© 2014 Elsevier Ireland Ltd. All rights reserved.

regional nodes. Although the choice of ENI may seem logical when considering the benefit from three-field lymphadenectomy of EC [6] and it theoretically provides a better local tumor control, radiotherapy-related toxicities cannot be ignored, and severe toxicities would appear in at least 50% of patients if ENI were adopted [3,4,7,8]. Theoretically, treatment-related toxicities would decline if the irradiation volume was diminished. Involved field irradiation (IFI, i.e., nodal target volume that includes only the metastatic nodes) is a selective way of decreasing the irradiation volume. Moreover, there have been studies of a series of cases treated with IFI, and these studies have shown that administration of IFI is feasible [9–17]. In light of the ongoing controversy over the scope of the CTV, in this review we summarize the available data on the modality of IFI compared with ENI and the following questions are discussed: What is the theoretical foundation of IFI? How should IFI be implemented? Which is superior, IFI or ENI? What is the suitable patient population for adopting IFI?

The theoretical foundation of IFI As is well known, EC is associated with multicentric disease or submucosal “skip” invasion due to the extensive and longitudinal interconnecting system of lymphatics. However, many studies have reported a low incidence of isolated out-field nodal failure, which is discrepant with the above notion. The reason for the inconsistency might be that many patients have died before the regional disease becomes clinically apparent or that micro-metastases are adequately controlled by the immune system or incidental nodal irradiation.

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Radiotherapy to enhance body immunity The tumor microenvironment is a sophisticated collection of cells that includes a number of leukocytes. The overall effect of the microenvironment is to support tumor growth and restrain immune responses. Radiation treatment can modify the tumor microenvironment. The modifications result in induction of the expression of inflammatory cytokines and the upregulation of death receptors, such as Fas, which can boost the availability and presentation of antigen, normalize vessels, increase the expression of major histocompatibility molecules, increase localization of T cell and induce danger signals [18]. Radiation can also upregulate other immunologically important molecules such as major histocompatibility complex class I (MHCI). Moreover, radiation works in conjunction with adoptive transfer of tumor-specific cytotoxic lymphocyte (CTL) to improve the antitumor effect of transferred cells [19,20]. Additionally, novel proteins that are brought forth by the tumor can be presented on the MHCI molecules and recognized by the CTL. With radiation treatment, well-established tumors that are expressing low levels of antigen will produce transient upregulation of major histocompatibility complexes on stromal cells and the appearance of tumor antigen. Therefore, it is the combination of tumor antigen and the adoptive transfer of pre-activated CTL that causes tumor regression. Thus, it might be possible that the radiation treatment changes the tumor microenvironment, and then, the enhanced body immune system destroys the established tumors and the pre-clinical niduses. Therefore, by the mechanisms described above, it might be possible for IFI to restrain the development of micro-metastases. The effect of incidental nodal irradiation Among the possible reasons why micro-metastases can be controlled, incidental nodal irradiation cannot be omitted. Ji et al. [10] quantified the incidental irradiation doses to esophageal lymph node stations when treating T1-4N0M0 EC patients using IFI and provided a convincing evidence of micro-metastatic control from incidental nodal irradiation. In that study, the mean equivalent uniform dose was greater than 40 Gy in most high-risk nodal regions under a prescribed 60 Gy dose, but all these regions likely do not acquire high enough incidental irradiation doses in all patients studied. It has been reported that worthwhile treatment benefits can be achieved by lower doses and that a radiation dose as low as 24 Gy could reduce metastases by 30–50% [21–23], so the low out-field failure might be attributed to the incidental irradiation of elective nodal regions. Additionally, with patients who had positive lymph node metastases, the incidental irradiation dose to high-risk regions would be much higher. To conclude, incidental irradiation may also play a role in the control of micro-metastases. The current implementation pattern of IFI Determining the adequate radiotherapy target volume in radiotherapy planning When patients are treated with radiotherapy, it is crucial for the delineation of the target volume to be accurate because inaccurate or inappropriate delivery could potentially cause locoregional recurrence attributed to missed nodes within a CTV or excess toxicity attributed to unnecessarily large treatment volumes. With the development of examination techniques, the gross target volume (GTV) has been localized using techniques that range from computed tomography (CT) and esophagogastroduodenoscopy to endoscopic ultrasonography and positron emission tomography (PET)/CT, which can more accurately identify the submucosal

extension and lymphadenopathy and exclude metastatic disease [24,25]. In regard to the delineation of IFI, the GTV is any visible primary tumor (GTVt) and includes metastatic lymph nodes (GTVn). The metastatic node criteria were as follows: Nodes greater than 1.0 cm in the shortest axis in the intrathoracic and intra-abdominal region [9,13,15] and greater than 0.5 cm beside the recurrent nerve [9,13] on CT scans or with a high standardized uptake value-max of 18F-deoxyglucose avid on PET/CT images [15]. The CTV encompasses an adequate margin around the GTV. As for the definition of adequate margins, there is still no globally concordant opinion or high-quality evidence-based medical definition for this. To date, most trials define the CTVt as 3 cm superoinferior margins and a 0.5–1.0 cm lateral margin from the GTVt, and the CTVn is defined as the GTVn plus a 0.5–1.0 cm radial margin. Moreover, prophylactic nodal irradiation should not be included. The dose of the radiation regimen Although RTOG 94-05 demonstrated that patients did not benefit from 64.8 Gy compared with 50.4 Gy, this trial did not give a clear reason for this finding. Moreover, the majority of patients were of non-Asian race; only one Asian person participated in this trial. Since then, some East Asian researchers have determined that highdose radiotherapy (≥60 Gy) was associated with improved locoregional control (LRC), progression-free survival (PFS) and/or disease-free survival (DFS) without a remarkable increase in treatment-related mortalities or toxicities [26,27]. Accordingly, the radiation dose of the East Asian patients was higher than that of the Western patients because of the non-conformity of tumor radiosensitivity and histological types between East Asian and Western populations, regardless of whether they were prescribed ENI or IFI. Thus, in trials using IFI, a dose of 60 Gy in 30 fractions was given for the majority of Chinese and Japanese patients [10,12,13,15,17], while Button et al. from the United Kingdom [11] treated patients with a dose of 50 Gy in 25 fractions. In our opinion, to receive a better therapeutic effect, prescribing a higher dose might be more reasonable because of the shrunken radiation field and decreased treatment-related toxicities which are described below. Radiotherapy with different types of fractionation For the treatment of EC, many trials have adopted conventional fractionated radiation (CFRT), that is, 2.0 Gy per day, 5 fractions weekly, for a total dose of 50–60 Gy. However, other types of fractionation have come into existence through demonstrations of some researches. Improved local control and relatively long-term survival have been reported in patients receiving late-course accelerated hyperfractionated radiotherapy (LCAHRT) compared with CFRT [28]. Some papers have attributed one of the major reasons for the treatment failure of EC to rapid proliferation of surviving tumor clonogen during CFRT [29,30]. Moreover, three independent meta-analyses from China have illustrated that LCAHRT was favorable in EC and had benefits compared with CFRT for EC [31–33]. Of the available studies on IFI, Zhao et al. [9] achieved a satisfactory result by applying LCAHRT, which consisted of receiving CFRT at 1.8 Gy per day for the first two-thirds of treatment for a dose of 41.4 Gy in 23 fractions, followed by LCAHRT using reduced fields, at 1.5 Gy per fraction twice daily, with an interval of ≥6 hours between fractions, for a dose of approximately 27 Gy. The total dose was 68.4 Gy in 41 fractions. Some studies have reported that radiation enhanced the expression of cancer stem cell markers of radiation resistance [34,35], which could result in local failure. In addition, CFRT has been shown to have reduced radiobiologically tumoricidal effects in radioresistant EC [36]. Thus, increasing the fraction dose (i.e., hypofractionated radiation [HFR]) might be theoretically possible. At present several papers suggested that HFR for locally advanced

L. Jiang et al./Cancer Letters 357 (2015) 69–74

non-small cell lung cancer was feasible and tolerable [37,38], but there are insufficient results concerning HFR for esophageal cancer. Ma et al. [14] conducted a trial to assess the efficacy and safety of HFR in patients with EC by applying IFI and indicated that moderate HFR, such as a dose of 54–60 Gy with a fraction of 3 Gy, had significantly better 3- and 5-year local control rates than CFRT (81.4% and 50.0% versus 71.8% and 44.1%, respectively, P = 0.02), but the 3and 5-year overall survival (OS) rates (43.2% and 38.8% versus 38.2% and 28.0%, respectively, P = 0.268) were not different between the two arms. Comparison of efficacy between IFI and ENI Response, survival and LRC In RTOG 85–01, the boundary of the CTV extended from the supraclavicular region to the gastroesophageal junction [3]. Subsequently, despite the fact that the RTOG 94–05 study shrank the CTV to 5 cm longitudinal margins and a 2 cm lateral margin beyond the borders of the primary tumor [4], the median survival times and the 2-year OS rates of the RTOG 94-05 trial were frustratingly comparable to those of the RTOG 85-01 trial (18.1 months and 40% versus 14.1 months and 36%, respectively). Similarly, the LRC rate remained unsatisfactory, with 2-year locoregional persistence or relapse rates of 47% in the RTOG 85-01 trial. In addition, RTOG 94-05 failed to show an improvement in the LRC rate, with a rate of 52–56%. Both trials adopted ENI. Data similar of that of ENI are found in the following studies that used IFI as the conventional treatment. Ma et al. [16] conducted a prospectively randomized trial to compare ENI with IFI in patients with cervical and upper-thoracic EC and found a median survival time of 33.7 months for the IFI group versus 32.7 months for the ENI group. However, no significant difference was found in the 3-year OS and LRC rates between the IFI and ENI groups (32.0%, 80.1%, versus 41.3%, 85.7%, respectively). Zhao et al. [9] found that the median survival and PFS intervals were 30 months and 17 months, respectively, with 1-, 3-, and 5-year OS and PFS rates of 77%, 56%, 41%, and 77%, 55%, 36%, respectively, with encouraging datum of a 3-year LRC rate of 62% by altering the fractionation schedule. A report by Button et al. [11] showed that the median survival and DFS intervals were 15 months and 10 months, respectively, with a 2-year OS rate of 37%, which was due to the fact that three-quarters of the patients had stage III–IVA disease. Likewise, a retrospectively study of locally advanced stage EC performed by Zhang et al. [15] observed a median survival and PFS intervals of 14.4 months and 11.3 months, respectively, with 1-, 2-, and 3-year OS and PFS rates of 86.3%, 30%, 18.8%, and 41.3%, 18.9%, 11.3%, respectively, and a complete response (CR) in 23.75% of patients. Kawaguchi et al. [13] treated stage I thoracic EC using IFI and found that the 3-year OS and DFS rates were 76% and 66%, respectively. For patients aged 75 and older, Uno et al. [17] demonstrated that older patients could also benefit from aggressive treatment, and obtained a CR in 6 of 22 patients (27.3%) with a median survival time of 9 months and a 1-year OS rate of 39%. In summary, omitting ENI did not sacrifice OS, which therefore suggested that IFI was feasible for EC. However, both types of radiotherapy had bad CR of 20–40% [15,17,39] because most patients were resistant to chemoradiotherapy. Furthermore, some studies proved that survival benefits can only be acquired by patients with a histological CR [40,41]. Hence, it would be helpful to predict which tumors have a higher likelihood of responding to treatment. In addition, achieving LRC is important in reducing disease burden and dissemination and thereby increasing survival, but it did not reach a significant difference between IFI and ENI, perhaps for the following reasons: First, the prophylactic lymphatic regions could still receive 60–70% of the prescribed dose due to the adoption of 2 anterior oblique fields even though IFI was used for patients.

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Second, the accuracy of pre-therapeutic staging with respect to lymph node metastasis needs to be improved in the future. Therefore, by varying the radiotherapy volumes, it becomes feasible to obtain levels of LRC rate of around 55%–65% [42]. Patterns of treatment failure The esophageal wall has a rich network of lymphatic drainage, and EC, especially esophageal squamous cell carcinoma, has a higher potential for lymphatic metastases along the esophageal axis to multiple level nodes or to the nodes distant from the primary lesion. In the research by Onozawa et al. [39], the first failure of local, distant, and elective nodal failures (i.e., the recurrence of initially uninvolved lymph nodes within the ENI field) were 16%, 15%, and 1.7% of the 60 patients who achieved a CR, respectively, which suggested that ENI may prevent elective nodal failure. Similarly, in the study of Kato et al. [43], 27% of the locoregional residual and recurrent disease experienced no distant metastases, whereas 16% of 51 patients had distant metastases. In addition, the rate of elective nodal failure was only 7% in the RTOG 94-05 trial [4]. Given that failure often occurs in multiple lymph node regions, each with low numbers, it is unlikely that targeting additional regional lymph node drainage with radiotherapy would significantly improve clinical outcomes. Similarly, Kawaguchi et al. [13] found that IFI did not result in a significant increased incidence (8.9%) of regional lymph node involvement for patients with stage I EC patients. Zhao et al. [9] reported that the rate of in-field recurrence (i.e., recurrent esophageal lesion and regional nodes that occurred inside the planning tumor volume) was 44%, yet only 8% of patients had isolated outof-field nodal recurrence (i.e., recurrence that occurred outside the planning tumor volume). Uno et al. [17] found no isolated regional lymph node recurrence for EC patients aged 75 and older. Ma et al. [16] determined that cumulative regional lymph node failure only occurred in 9.8% and 7.8% of patients in the IFI and ENI groups, respectively, whereas local esophageal failure occurred in 11.7% and 9.8%, respectively, with only a 2% out-field nodal failure rate in the IFI group. Meanwhile, Zhang et al. [15] investigated patterns of first site failure using IFI for locally advanced EC and found no significant difference in the median survival with or without an outfield regional lymph node failure pattern (14.5% versus 14.5%, respectively, P = 0.665). All the above research concluded that regional lymph node failure was not the main pattern of recurrence in patients with EC, regardless of whether the radiotherapy was IFI or ENI. Moreover, many patients tended to die long before their regional nodal failure became clinically apparent or a threat to life because of the high incidences of local failure and distant metastases. Hence, the relatively high regional control acquired with ENI might not be transformed into the benefit of OS. Furthermore, for patients who had the solitary regional failure, salvage therapy such as chemotherapy, palliative radiotherapy and surgery might have a survival benefit [15,43,44]. Treatment-related toxicities As the standard treatment for EC has evolved from single modality to multimodality, outcome has been prolonged but with considerably more severe toxicity, such as esophagitis, hemorrhage, dysphagia, stricture, pneumonitis, and other toxicities. In RTOG trials [3,4,45], 25%–60% and 23%–29% of patients experienced grade 3 or greater acute and late toxicities, respectively. Wang et al. [46] reported that with LCAHRT and a dose of 59.6 Gy in 34 fractions, grade 3 or greater acute esophagitis and leucopenia occurred in 26.4% and 32.4% of patients, respectively. Kato et al. [44] reported that with a dose of 60 Gy in 30 fractions, the rates of grade 3 or greater acute esophagitis, nausea, infection and hyponatremia were 17%, 17%, 12%, and 16%, respectively, whereas grade 3 or greater late toxicities included pericardial (16%) and pleural (9%)

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Table 1 Studies of radiotherapy using IFI and/or ENI in esophageal cancer. Radiation modality

Authors

IFI IFI IFI IFI IFI IFI IFI ENI ENI ENI ENI ENI ENI

Zhao et al. [9] Button et al. [11] Kawaguchi et al. [13] Uno et al. [17] Zhang et al. [15] Ma et al. [14] Ma et al. [16] Cooper et al. [3] Minsky et al. [4] Onozawa et al. [39] Kato et al. [44] Wang et al. [46]

N

53 145 68 22 80 76 51 51 61 109 102 76 68

Stage

I–III I–IVA I I–IVB I–III II–III I–III I–III I–III I–III I–IVB II–III II–IV

OS(%)

41 (3-yr) 37 (2-yr) 76 (3-yr) 39 (1-yr) 18.8 (3-yr) 28.0 (5-yr) 32.0 (3-yr) 41.3 (3-yr) 26 (5-yr) 31 (2-yr) 43 (3-yr) 44.7 (3-yr) 46.5 (3-yr)

Grade ≥ 3 toxicities (%)

LRC(%)

P = 0.583

62 (3-yr) NR 85 (3-yr) NR NR 44.1 (5-yr) 80.1 (3-yr) 85.7 (3-yr) 47 (2-yr) 56 (2-yr) NR NR NR

P = 0.366

Acute

Late

9 NR NR 9 NR 50.0 5.9a 19.6a NR 76 NR 12a 32.4a

6 NR 3 NR NR 22.4 2.0b 5.9b 29 46 NR 16c 4.4d

P = 0.008

P > 0.05

Abbreviations: IFI, involved field irradiation; ENI, elective nodal irradiation; N, numbers of patients; OS, overall survival; LRC, locoregional control; NR, not reported. a Hematologic toxicity including infection. b Skin-related cosmetic effects. c Pericardial effusion. d Gastrointestinal hemorrhage.

effusions, and pneumonitis (4%), which caused 4 deaths. Disappointingly, even worse data were shown by using 50.4 Gy in 25 fractions, which was also published by Kato et al. [43], and all the aforementioned papers were based on a regimen of ENI. In other words, severe toxicities reduced the tolerance of patients to the effective treatment, thereby diminishing the benefits of the chemoradiotherapy. In comparison, when using IFI, Zhao et al. [9], who also used LCAHRT, reported that the rates of grade 3 acute and late toxicities were 9% and 6%, respectively, and no patients had acute or late grade 4 or 5 toxicity. Ma et al. [16] showed a significant difference between the IFI and ENI groups in hematologic toxicity, including infection (27.4% versus 64.7%, p = 0.008) and vomiting (25.4% versus 54.9%, p = 0.028). There are few data on radiation-related toxicity in elderly (age 75 and older) patients, but one Japanese research did address this issue. Uno et al. [17] evaluated the efficacy and toxicity of chemoradiotherapy in elderly patients with EC; and found that although 19 out of 22 patients completed the planned remedy, only 2 patients experienced grade 3 acute toxicities, both of which were leukopenia. Moreover, grade 2 or greater hematologic toxicities occurred less frequently in patients who received IFI compared to those who received ENI (30% versus 92%, p = 0.006). In summary, substantial acute and late toxicities may mitigate the survival benefits, but when patients with EC adopt IFI, the rate and severity of radiation-related toxicities are markedly reduced or alleviated compared with ENI, and this finding is similar to the results of IFI versus ENI in lung cancer [47]. The concept of “a lot (of dose) to a little (of volume)’’ therefore seems to be better tolerated than ‘‘a little to a lot’’ [48]. Involved studies about IFI and ENI are summarized in Table 1.

In addition, the use of PET/CT could also predict response or outcome [53]. Some researchers have observed that the nei endonuclease VIIIlike 1 (NEIL1) glycosylase may increase tissue radiosensitivity and cause more serious radiation toxicity [54,55]. Chen et al. [56] observed that one single nucleotide polymorphism near the 3′ region of the NEIL1 gene (rs4462560; C → G) may serve as a predictor of acute radiation-related esophageal toxicity and radiation pneumonitis risk but not of OS, that is, patients who had the NEIL1 rs4462560 GC/CC genotype had a significantly lower risk of both grade 2 or greater acute radiation-related toxicity and radiation pneumonitis than patients who had the GG genotype. In addition, using IFI means a lower incidence of treatment-related toxicities, so IFI would be more recommended for patients of older ages. In Western countries, esophageal adenocarcinoma (EAC) predominantly occurred in the lower, gastric and distal esophagi [57,58]. Therefore, when considering EAC patients, celiac nodal failure should be given particular attention compared with other areas of regional lymph node failure. The celiac axis acts like a gateway to the abdomen, suggesting that those with celiac nodal failure might have a higher risk of metastasis and a poorer OS. As a result, it seems reasonable that celiac lymph nodes should be irradiated during treatment for EC, especially for distal EC. However, a trial by Amini et al. found no differences in survival between the IFI and ENI groups [59]. Therefore, irradiating the celiac nodes is prudent regardless of the use of IFI or ENI. In addition, we also suggest that IFI should be performed based on clinical and pathological factors, such as small, shallowly invasive tumors and well-differentiated EC.

What is the suitable patient population for adopting IFI?

Chemoradiotherapy has become the primary treatment modality for EC, and IFI is a selective way of decreasing the irradiation volume for this treatment. Compared with ENI, IFI does not sacrifice OS or LRC, the regional lymph node failure has little effect on OS, and the solitary regional failure with salvage therapy has a survival benefit. Furthermore, the treatment-related toxicity of IFI is much lower than that of ENI, so patients who are suffering from EC, especially elderly patients, tend to tolerate IFI better than ENI. In summary, IFI is feasible for patients with EC, notably for elderly patients. Molecular markers may help to select treatment in the future. Just as Rackley et al. [60] described the treatment of EC as

At present, there is still no unanimous opinion on whether IFI can replace ENI for the treatment of EC, despite the fact that some researchers have indeed concluded that IFI was superior to ENI. Patients who have a greater possibility of responding to treatment may be more suitable for IFI because survival benefits can only be acquired by patients with histological CR. Moreover, some studies have documented that some markers have been correlated with response and/or outcome such as p53, Ki-67, epidermal growth factor receptor, vascular endothelial growth factor and sirtuin-3 [49–52].

Conclusion

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