Is there still a place for radiotherapy in gastric cancer?

Gastric cancer represents the second most common cause of cancer death worldwide [1]. Most patients relapse after curative resection and approximately 50% of patients present with advanced disease at the time of diagnosis. It is a highly heterogeneous disease from an intra- and inter-tumoral perspective [2, 3, 4]. Likely molecular differences in tumours arising in patients from Eastern countries compared with those from Western Countries also need to be considered [1,5]. The tumour diversity seen within these cancers drives the tempo of disease and results in a wide variation in treatment responses that makes the definition of ‘standard’ treatment extremely challenging [2,3,6, 7, 8, 9, 10].

The main focus of this review is to discuss whether there is a place for radiotherapy (RT) in the management of gastric cancer. Genetic alterations in the DNA damage response pathway, which may confer sensitivity to RT, are found in approximately a quarter of advanced gastric adenocarcinomas [11,12]. Furthermore, impressive advances in radiation technology, treatment platforms and algorithms have enabled the safe and tolerable delivery of RT to the stomach, with the ability to limit radiation dose received to surrounding organs at risk [13,14]. Clearly, the potential benefit of RT for patients with gastric cancer is entirely context dependent; In the non-metastatic setting, several important trials evaluating the role of chemoradiotherapy (CRT), scheduled either before or after surgery, with the aim of improving rates of cure, have been recently reported or are currently ongoing. Given that gastric cancer patients often present with symptoms including gastrointestinal bleeding as well as pain due to distant metastases, RT remains a useful tool in symptom control for patients with this disease [15,16]. In addition, Stereotactic Body Radiotherapy (SBRT) has the potential to provide durable responses in patients with oligometastatic liver disease.

More than 90% of early gastric cancer (T1N0M0) is curative with surgical resection alone. For patients with locally advanced gastric cancer (T2-4aN0-3M0) which represents the majority of patients with localised disease, gastrectomy with dissection of D2 lymph nodes is recommended to achieve the best chance of cure [17,18]. Despite this more extensive lymphadenectomy, mortality in patients with localised disease at initial diagnosis remains high.

The potential benefit of CRT in the postoperative setting has been considered in several randomised trials. First, the US Intergroup-0116 (INT-0116) trial, reported over 20 years ago, investigated the effect of surgery plus adjuvant CRT on the survival of patients with resectable adenocarcinoma of the stomach or gastro-oesophageal junction. A total of 556 patients were randomly assigned to surgery plus adjuvant CRT or surgery alone. In the experimental arm, 45Gy in 25 daily fractions over 5 weeks was delivered with concurrent fluorouracil plus leucovorin. One month after the completion of CRT, two 5-day cycles of fluorouracil plus leucovorin were given one month apart. The investigators observed a significant improvement in survival with adjuvant CRT compared with surgery alone (median survival 36 months versus 27 months and 40% versus 28% at 5 years, respectively). However, the main criticism of this study is that the improvement in survival could be related to less extensive lymphadenectomy resulting in a compensatory effect of CRT for inadequate surgery. Furthermore, convincing randomised data observed in the UK MRC MAGIC study [19] and, more recently, the German FLOT4 trial [20] has led to the international adoption of perioperative chemotherapy (CT) for patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma. In Asian countries, D2 gastrectomy followed by S1 monotherapy for 1 year or capecitabine plus oxaliplatin for 6 months has been the standard of care [21,22]. In the Korean ARTIST1 trial, the investigators tested whether the addition of radiotherapy to adjuvant CT following D2 gastrectomy improved disease-free survival (DFS) [23,24]. Although the primary endpoint was not met, a longer DFS was observed in the CRT arm for gastric cancer patients with positive lymph nodes, higher lymph node ratios or in the intestinal type subtype by Lauren classification [25].

Two recently published randomised controlled trials, one from the West and one from the East, investigated the benefit of adding RT to perioperative CT in patients undergoing D2 gastrectomy, allowing a comprehensive deep dive into this previously controversial subject (Table 1). The Dutch Gastric Cancer Study Group undertook the CRITICS study [26] in which 788 patients with stage Ib-IVa resectable gastric or gastro-oesophageal adenocarcinoma were included. Patients received pre-operative platinum-based CT followed by post-operative CT or CRT. CT consisted of three pre-operative 21-day cycles and three post-operative cycles of intravenous epirubicin, cisplatin or oxaliplatin, and capecitabine (ECX or EOX). CRT consisted of 45Gy in 25 daily fractions delivered in 1.8Gy per fraction over 5 weeks. The intent-to-treat analysis of the CRITICS trial did not show a survival benefit for patients in the CRT versus CT arm. However, in the post protocol analysis (only 478 out of 788 patients started post-operative treatment according to protocol; 233 (59%) patients in the CT arm and 245 (62%) patients in the CRT group) with a median follow up of 6.7 years since the start of post-operative treatment, the 5-year overall survival (OS) was 57.9% in the CT group compared with 45.5% in the CRT group, confirming that the CT group had a significantly better 5-year OS compared with the CRT group. An important analysis of the patterns of recurrence within this study revealed that peritoneal metastases were seen less frequently in the CT group compared with the CRT group (2-year cumulative incidences, 4% versus 11%, P = 0.005).

In contrast, the Korean Adjuvant chemoRadioTherapy In Stomach Tumours (ARTIST) 2 trial [27] multicentre randomised trial recruited a total of 546 patients and compared two adjuvant CT regimens (single agent S1 and S1 with oxaliplatin (SOX)) and CRT (SOXRT) in patients with D2-resected stage II or III node positive gastric cancer. Despite the differences in CT regimens compared with the CRITICS study, the aim of ARTIST2 was also to define the optimal adjuvant treatment regimen in gastric cancer. Compliance with study treatment was high in all treatment arms (71%, 85% and 83% for S-1, SOX and SOXRT, respectively) and the most common reason for premature discontinuation was consent withdrawal mostly owing to frequent outpatient visits compared with off-study CT. In the SOXRT arm, patients received 45Gy in 25 fractions, 1.8Gy per fraction daily, 5 days a week, over 5 weeks. No cross over of treatment regimens was allowed in this study. The investigators observed that the addition of RT to CT did not significantly reduce the rate of recurrence after D2 gastrectomy. Given that gastric cancer is a heterogeneous disease, the investigators also considered molecular subtypes and clinical features as potential factors in influencing treatment outcome. However, they found that DFS rates between patients treated with adjuvant CT and CRT were similar across all subgroups.

Taken together, these trials confirm that adjuvant CRT is not the standard of care for patients with locally advanced gastric cancer who have undergone complete surgical resection with D2 gastrectomy [28]. The earliest data showing some survival benefit of adjuvant CRT was likely as a result of the compensatory effect of CRT in treating microscopic nodal disease in cases of inadequate lymphadenectomy. Peri-operative CT may be advantageous in decreasing rates of peritoneal metastases. However, a significant proportion of patients find it difficult to complete post-operative CT, particularly in the Western trials. In cases of incomplete (R1) resections, CRT following surgery is still considered a reasonable choice with the aim of reducing local recurrence [29].

In the quest for improving complete response rates and locoregional control in patients with locally advanced gastric cancer, an international collaboration led by the Australian Gastro-Intestinal Trials Group (AGITG) and the NCIC Clinical Trials Group undertook the TOPGEAR trial, a randomised phase III trial that investigates whether the addition of CRT to CT is superior to CT alone in the neoadjuvant setting by improving pathological complete response (pCR) rates and OS in patients undergoing D2 gastrectomy for resectable gastric cancer. [30]. A planned interim analysis of the first 120 patients has been reported; Overall, 92% of patients allocated to preoperative CRT received this treatment which is a vast improvement in compliance compared with the adjuvant CRT studies already discussed in this review [31]. In addition, the proportion of patients proceeding to surgery was high at 85%. There appeared to be no differences in surgical complications or toxicity between the two arms, indicating that neo-adjuvant CRT plus peri-operative CT is as well tolerated as the CT arm of the trial. This trial is currently in follow-up and the mature outcome data from this trial is eagerly awaited. An important piece of work assessing radiation therapy quality assurance (RTQA) within the context of this trial revealed that the initial RTQA pass rate was 72% and there was no significant difference in the initial pass rate between the high and low volume centres [32].

An important advantage for neoadjuvant CRT is that it can be well tolerated scheduled before surgery and easier to deliver compared to the same regimen delivered in the post-operative period. From a technical perspective, volume delineation is more precise when macroscopic disease is visible on imaging rather than estimating the tumour bed. In addition, treatment verification is likely to be more accurate when there is visible disease. The Dutch CRITICS-II trial is a three-armed, multicentre randomised phase II trial that is currently recruiting in several centres in The Netherlands (NCT02661971) [33]. This clinical study has considered the low rates of patient compliance in the post operative phase of treatment. Therefore, the investigators set out to optimise preoperative treatment by comparing three neoadjuvant treatment modalities; (1) CT, (2) CT plus CRT, and (3) CRT. The primary objective is to compare 1 year event-free survival between the groups, defined as the interval between randomisation and recurrence, progression or death from any cause. Secondary endpoints are toxicity, R0 rates, pathological tumour response, disease recurrence, OS and health related quality of life. Interestingly, exploratory endpoints include translational endpoints such as the identification of new predictive and prognostic biomarkers as well as genomic changes in circulating tumour DNA.

Radiotherapy is commonly used to palliate symptoms for patients with metastatic gastric cancer and can be effective especially for the management of bony pain and the treatment of bleeding from the primary tumour. As yet, there are no reported randomised controlled trials in patients with oligometastatic gastric cancer. Oligometastatic cancer is described as a clinical state between locally confined and systemic metastasised disease with distinct tumour biology in which local treatment (such as surgery, ablation or stereotactic body RT (SBRT)) could provide long-term disease control or even be curative in a proportion of patients [34, 35, 36∗]. According to multidisciplinary tumour boards in Europe, it is reasonable for gastric cancer to be considered as oligometastatic if confined to one organ with 3–5 or fewer metastases or one extra-regional lymph node station [37], although no consensus has yet been reached [36]. A systemic review of the literature and meta-analysis revealed that the liver is the most common metastatic site and that local treatment for oligometastatic gastric cancer was associated with improved OS compared with systemic therapy alone [38,39] although OS remains poor [40]. Liver SBRT can result in high rates of local control [41] (Figure 1) and recent advances in image guided, adaptive radiation therapy [42] as well as the use of heavy particles [43] represent potentially advantageous technical advances in the management of this disease.

留言 (0)

沒有登入
gif