Multimodality management has become a core treatment principle for locally advanced esophageal, gastroesophageal junction (GEJ), and gastric cancer. Radiotherapy serves an important role for optimizing patient outcomes. This article reviews the evolving role of radiotherapy in the multidisciplinary management of esophageal, GEJ, and gastric cancer, summarizing the results of recent clinical trials leading to contemporary accepted treatment approaches. A major theme is the evidence supporting the role of radiotherapy in combined modality management, particularly the trend toward its delivery in the neoadjuvant setting. Also reviewed are novel radiotherapy paradigms and newer radiation technologies such as image-guided radiotherapy and MRI-guided radiotherapy.
Key points
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This article reviews the evolving role of radiotherapy in the multidisciplinary management of esophageal, gastroesophageal junction (GEJ), and gastric cancer, summarizing the results of recent clinical trials leading to contemporary accepted treatment approaches.
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A major theme is the evidence supporting the role of radiotherapy in combined modality management, particularly the trend toward its delivery in the neoadjuvant setting.
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The article also reviews novel radiotherapy paradigms and newer radiation technologies such as image-guided radiotherapy and MRI-guided radiotherapy.
Introduction
Esophageal and gastric cancers remain a major national and global health problem. In the United States, it was estimated that there would be 26,000 new diagnosed gastric cancer cases and 17,000 new cases of esophageal cancers in 2016. For the United States in 2016, gastric cancers were estimated to lead to 10,000 deaths and esophageal cancers to over 15,000 deaths. In China in 2015, the incidence of esophageal and gastric cancers was approximately 478,000 and 679,000 cases, respectively, and the mortality was estimated at 375,000 and 498,000 deaths, respectively. Of particular concern is that in recent decades, the incidence of gastroesophageal junction (GEJ) adenocarcinomas has been increasing. To improve cure rates for these patients with poor prognosis, combining chemotherapy, radiotherapy, and surgery in treatment has become a core strategy.
Many strategies of incorporating chemotherapy, radiotherapy, and surgery have been tried over the decades. Using radiation therapy as a way of shrinking tumors or to treat regional disease in esophageal and gastric cancers has an extensive history. In the modern era, radiotherapy has become more refined both in its indications and in its delivery. For example, improved accuracy of delivery has allowed radiation oncologists to treat the gross tumor with smaller margins, sparing normal tissue toxicities along the way. The range of therapeutic radiation dosages, radiation fields, and incorporation with systemic therapy are now better understood. With that refinement, there is now considerable evidence supporting radiation’s role in multiple settings for treatments of both esophageal and gastric cancer. As radiotherapy techniques become more precise and radiation toxicities lower, the wider therapeutic window in an anatomically sensitive region will hopefully translate to better clinical outcomes.
This article breaks down radiotherapy’s roles in several common clinical settings in the management of localized esophageal and gastric cancers. Radiotherapy has moved earlier in the multimodality management sequence of a patient’s treatment, and greater emphasis is placed on using technologies to minimize serious adverse effects. This article emphasizes the increasingly important roles of radiotherapy in the neoadjuvant chemoradiation setting before surgery or in the definitive chemoradiation setting with nonsurgical management. Incremental improvements in the various modalities involved in the care of these patients have led to improved survival of patients with localized esophageal and gastric cancer. There remain many opportunities for the radiation oncology community to further improve outcomes in these diseases, which remain high in incidence and mortality.
Introduction
Esophageal and gastric cancers remain a major national and global health problem. In the United States, it was estimated that there would be 26,000 new diagnosed gastric cancer cases and 17,000 new cases of esophageal cancers in 2016. For the United States in 2016, gastric cancers were estimated to lead to 10,000 deaths and esophageal cancers to over 15,000 deaths. In China in 2015, the incidence of esophageal and gastric cancers was approximately 478,000 and 679,000 cases, respectively, and the mortality was estimated at 375,000 and 498,000 deaths, respectively. Of particular concern is that in recent decades, the incidence of gastroesophageal junction (GEJ) adenocarcinomas has been increasing. To improve cure rates for these patients with poor prognosis, combining chemotherapy, radiotherapy, and surgery in treatment has become a core strategy.
Many strategies of incorporating chemotherapy, radiotherapy, and surgery have been tried over the decades. Using radiation therapy as a way of shrinking tumors or to treat regional disease in esophageal and gastric cancers has an extensive history. In the modern era, radiotherapy has become more refined both in its indications and in its delivery. For example, improved accuracy of delivery has allowed radiation oncologists to treat the gross tumor with smaller margins, sparing normal tissue toxicities along the way. The range of therapeutic radiation dosages, radiation fields, and incorporation with systemic therapy are now better understood. With that refinement, there is now considerable evidence supporting radiation’s role in multiple settings for treatments of both esophageal and gastric cancer. As radiotherapy techniques become more precise and radiation toxicities lower, the wider therapeutic window in an anatomically sensitive region will hopefully translate to better clinical outcomes.
This article breaks down radiotherapy’s roles in several common clinical settings in the management of localized esophageal and gastric cancers. Radiotherapy has moved earlier in the multimodality management sequence of a patient’s treatment, and greater emphasis is placed on using technologies to minimize serious adverse effects. This article emphasizes the increasingly important roles of radiotherapy in the neoadjuvant chemoradiation setting before surgery or in the definitive chemoradiation setting with nonsurgical management. Incremental improvements in the various modalities involved in the care of these patients have led to improved survival of patients with localized esophageal and gastric cancer. There remain many opportunities for the radiation oncology community to further improve outcomes in these diseases, which remain high in incidence and mortality.
Radiotherapy in esophageal cancer
Neoadjuvant Chemoradiation in Esophageal Cancer
Chemoradiotherapy before surgical resection (eg, neoadjuvant chemoradiation) in locally advanced esophageal cancer, while sound in principle, only recently has gained broad acceptance as a preferred standard of care treatment option. Critiques and limitations of earlier trials limited the acceptance of the neoadjuvant chemoradiation approach, including issues related to sample size, trial design, and antiquated radiation techniques and doses.
In this context, the CROSS study (chemo radiotherapy for oesophageal cancer followed by surgery study) has become the most influential study in the management of locally advanced esophageal cancer in the past decade, due to the unprecedented survival outcome with acceptable toxicity for patients enrolled in the multimodality management arm of the trial. The CROSS study was a large phase III trial of 366 patients that compared neoadjuvant chemoradiation (41.4 Gy concurrent with weekly carboplatin/paclitaxel) followed by surgery versus surgical resection alone. The results of the CROSS study showed a remarkable median overall survival (OS) of 49.4 months for patients who received neoadjuvant chemoradiation followed by surgical resection versus 24.0 months for those patients who received surgery alone. Toxicities were also reasonable, with less than 20% grade 3 or worse toxicity in the combined modality arm. The results of the neoadjuvant chemoradiation arm in the CROSS study were impressive, not only in demonstrating a marked improvement in local control of the disease, but a significant improvement in negative margin resection rates (92% vs 67%, P <.001) and all patterns of recurrence. Local regional control, distant metastatic control, and overall survival outcomes were all on a scale that has now changed standard practice globally. Notably, the pathologic complete response rate in the trimodality arm was 29%. However, in patients with squamous cell histology, the pathologic complete response rate was 49% (18 of 37 patients) compared with 23% (28 of 121 patients) in patients with adenocarcinoma histology. In each arm, 23% of the patients had squamous cell histology. These results suggest that, with the right imaging or blood biomarkers for selecting a favorable response, perhaps half of the patient population with esophageal cancer with squamous cell histology would not require surgery after chemoradiotherapy. Such an approach would further limit the overall treatment morbidity in this subset of the patient population.
Neoadjuvant chemoradiotherapy preceding surgery to improve outcomes was not a newly proposed concept before the CROSS study. Two decades ago, the Dublin Trial had explored the role of neoadjuvant chemoradiation in a prospective, randomized trial randomizing 118 patients with combined chemoradiotherapy (CRT) and surgery compared with surgery alone. The patients on the chemoradiation arm received cisplatin/5-fluorouracil (5-FU) concurrently with esophageal radiotherapy to 40 Gy. The results showed a survival benefit from combined modality arm with a median survival of 16 months, but the poor outcomes of the surgical control group (median OS of 11 months) were raised as a critique of this study. This provocative ground-breaking trial hinted that neoadjuvant chemoradiation may be a superior approach, but it was not convincing enough to those who still favored a surgical approach alone.
Given the results of the Dublin study, the Cancer and Leukemia Group B (CALGB) launched the CALGB 9781 trial. CALGB 9781 differed from the Dublin study in that this phase III study utilized a higher dose of radiation (50.4 Gy with cisplatin and 5-FU), and it had planned to randomize a larger population of patients to receive chemoradiation followed by surgery versus surgery alone. Like the Dublin study, CALGB 9781 also showed a survival benefit with the combined modality approach. After a median patient follow-up of 6 years, overall survival was significantly better in the preoperative chemoradiotherapy cohort over the surgery-alone cohort (5 year OS of 39% vs 16%, P <.008). Furthermore, the rate of complete pathologic response was an unprecedented 40%. Yet skeptics noted that the trial did not accrue many patients—56 patients of a planned 500 patient target accrual—and the conclusions were challenged because of the trial’s small patient sample size. It is important to note that a statistically significant improvement in survival was found despite CALGB 9781 being an underpowered study.
Given the limitations and critiques of the Dublin study and the CALGB 9781 study, neoadjuvant treatment remained a contested concept. A meta-analysis comparing neoadjuvant chemoradiation with surgery alone in esophageal cancer also affirmed superiority of the combined modality approach. This meta-analysis reviewed 12 trials and over 1800 patients and favored neoadjuvant chemoradiotherapy with a hazard ratio (HR) of 0.78 (95% confidence interval (CI), 0.70–0.88 l, P = .001). Combined with the later impressive results of the CROSS trial, many of the critiques of the earlier trials may have been addressed, and the recent clinical studies support neoadjuvant chemoradiation as an optimal treatment strategy in this disease.
There were several notable findings from CROSS that will influence radiation oncology management and serve as important benchmarks. The radiation dose delivered, 41.4 Gy in 23 fractions, is lower than traditional doses of 45 to 50 Gy or higher. In the setting of concurrent carboplatin/taxol chemotherapy, it has been suggested that radiation doses necessary to sterilize microscopic disease in the primary site may be lower than previous assumptions. This reduced dose may potentially reduce the risk associated with subsequent surgical resection (a similar 4% in-hospital mortality rate for both arms), a widely cited concern with neoadjuvant chemoradiation. There are institutional divides with regards to the radiation dose currently utilized for neoadjuvant chemoradiation in esophageal cancer, and doses ranging from 41.4 Gy to 45 Gy to 50 Gy are currently accepted.
One commonly raised issue is that while the CROSS study establishes neoadjuvant chemoradiation as a standard treatment approach, it has not been established whether chemoradiation is superior to chemotherapy alone as the neoadjuvant approach. The German preoperative chemotherapy or radiochemotherapy in esophago-gastric adenocarcinoma trial (POET) provides some insight into these comparative approaches. Like CALGB 9781, the trial did not meet its accrual target, accruing only 119 patients of a target accrual of 354 patients. Yet this underpowered study did note a trend toward improved 3-year survival for the neoadjuvant chemoradiation arm, with a 3-year OS rate of 47.4% versus 27.7% ( P = .07) and improved median overall survival (33.1 months vs 21.1 months) over neoadjuvant chemotherapy followed by resection. Furthermore, the pathologic complete response rate was higher with neoadjuvant chemoradiation over neoadjuvant chemotherapy (16% vs 2%). The results of these key trials are summarized in Table 1 . While the POET trial was underpowered, the difference in clinical outcomes would suggest that neoadjuvant chemoradiation should remain the favored strategy moving forward.
| Trial | Reference | Comparative Arms | Number of Patients | pCR Rates | Outcome |
|---|---|---|---|---|---|
| The CROSS study | van Hagen et al, 2012; Shapiro et al, 2015 | Neoadjuvant CRT + surgery vs surgery alone | 366 | 29% (neoadjuvant CRT) | Median OS: 49.4 mo (neoadjuvant CRT) vs 24 mo (surgery) |
| The Dublin study | Walsh et al, 1996 | Neoadjuvant CRT + surgery vs surgery alone | 103 | 25% (neoadjuvant CRT) | Median OS: 16 mo (neoadjuvant CRT) vs 11 mo (surgery) |
| CALGB 9781 | Tepper et al, 2008 | Neoadjuvant CRT + surgery vs surgery alone | 56 | 40% (neoadjuvant CRT) | Median OS: 54 mo (neoadjuvant CRT) vs 21.6 mo (surgery) |
| The POET study | Stahl et al, 2009 | Neoadjuvant CRT + surgery vs neoadjuvant chemotherapy + surgery | 119 | 16% (neoadjuvant CRT) vs 2% (neoadjuvant chemotherapy) | Median OS: 33.1 mo (neoadjuvant CRT) vs 21.1 mo (neoadjuvant chemotherapy) |
Definitive chemoradiation in esophageal cancer
Surgical resection remains a central treatment modality for patients with localized esophageal cancer and provides potentially curative treatment. However, there is now significant clinical evidence that definitive chemoradiation is quite effective in esophageal cancer. The landmark RTOG (radiation therapy oncology group) 0851 trial compared dose-escalated radiation versus chemoradiation, with the latter arm showing a superior 5 year OS rate of 26% versus 0%. Most importantly, long-term survivors were noted with localized esophageal cancer patients in RTOG 0851, showing that chemoradiation potentially could be a curative option.
After RTOG 8501 established chemoradiation as a definitive treatment option, the Intergroup 0123 trial examined whether radiation dose escalation could improve outcomes in localized esophageal patients. The 2 arms of the study tested 50.4 Gy versus 64.8 Gy given concurrently with cisplatin/5-FU. The results of this trial were somewhat unexpected as there were a high number of early deaths in the higher dose arm. It is important to note that in intergroup- 0123, many of the deaths in the high-dose arm occurred prior to the lower dose of 50.4 Gy. Retrospective review of this trial has raised the issue of uneven distribution of patients with significant comorbidities, as these patients did not die of esophageal cancer but of cardiac and pulmonary disease. Regardless of interpretation, the dose-escalated arm in this trial did worse (median OS of 18 months vs 13 months).
Several clinical trials have tried to compare definitive chemoradiation versus chemoradiation followed by surgical resection, particularly in the squamous cell carcinoma population, without clear answers. The results of the German Esophageal Cancer Study Group, the GOCSG trial of 172 patients, showed no significant difference in median overall survival in chemoradiation versus chemoradiation with surgery (median OS of 14.9 months vs 16.4 months respectively, nonsignificant P value [NS]). The results of the French FFCD 9102 study of 444 patients also showed similar survival (median OS of 19.3 months for chemoradiation vs 17.7 months for chemoradiation and surgery, P = NS). Along with the results of the CROSS study, the results from the GOCSG trial and the FFCD 9102 study would suggest that definitive chemoradiation may be a reasonable standard treatment option for localized esophageal cancer with squamous cell histology.
To further test the definitive chemoradiation strategy, a recent phase II study, RTOG 0246, tested a selective surgical salvage resection strategy after a definitive chemoradiotherapy approach. The study showed that selective salvage surgery was feasible with 23 of the 43 patients able to receive chemoradiation without salvage surgery and a 1-year-overall survival of 71%. A large retrospective multicenter study of 848 patients comparing planned esophagectomy versus salvage esophagectomy following chemoradiotherapy found no significant difference in survival or in-hospital mortality. Selective surgery after definitive chemoradiation remains an area of active investigation.
Similar to the uncertainty regarding dose in the neoadjuvant chemoradiotherapy setting, it currently is unclear what radiation dose is needed in the definitive management of localized esophageal cancer. Would dose escalated chemoradiation lead to excessive toxicities as suggested by intergroup-0123, or was that a misleading outlier result of that arm? Doses ranging from 50.4 Gy to 60 Gy for definitive chemoradiotherapy are often utilized in practice. Would modern radiotherapy technologies, such as intensity-modulated radiation therapy (IMRT), enable dose escalation where it would have been excessively toxic with older technologies? Potential of widening the therapeutic window with newer radiotherapy technologies, including IMRT, image-guided radiotherapy (IGRT), particle therapy, and MRI guided therapy will be addressed later in this article.
In conclusion, in the era of improved radiotherapy technologies, definitive chemoradiation may be a reasonable standard treatment option for locally advanced esophageal cancer patients, particularly for those with squamous cell carcinoma. Selective surgery after definitive chemoradiation may be a feasible alternative treatment option for situations where it may be preferable to reserve surgery as an elective option. Finally, definitive chemoradiation without surgery may serve as a potential curative option for inoperable patients.
Radiotherapy in gastric cancer
Adjuvant Chemoradiation in Gastric Cancer
Surgical resection is the cornerstone of treatment for gastric cancer treatment. Over recent decades with successive clinical trials, the value of multimodality management for improved outcomes in locally advanced disease has become firmly established. The basis behind its rationale is the high rate of nodal metastases and subsequent locoregional relapse with surgical resection alone.
In a seminal work on second-look surgeries after initial curative surgeries, local recurrences or regional lymph node metastases were found in 88% of 107 examined patients. The most common sites of local relapse are in the gastric bed, the gastric remnant, and regional lymph nodes. These findings provided early evidence that surgery alone is inadequate treatment for patients with locally advanced gastric cancer.
Given the known high rate of local failures, clinical investigators asked whether adjuvant therapy after surgery could improve survival. Intergroup 0116 was a landmark phase III trial that randomized patients between surgery alone versus surgery with adjuvant chemoradiation. The trial randomized 556 patients to either observation or chemoradiotherapy after surgical resection, and the chemoradiation arm was 4 months of 5-FU/leucovorin with 45 Gy of radiotherapy. The results of that seminal study changed practice, as the adjuvant chemoradiation arm showed a superior median overall survival of 36 months versus 27 months for surgery alone. Following its publication, surgical resection followed by chemoradiation became a standard of care treatment option widely utilized for treating patients with locally advanced stage gastric cancer.
This survival difference from Intergroup-0116 has remained significant over long-term follow-up. Long-term analysis with greater than 10 year median follow-up results from Intergroup 0116 still show a substantial overall survival advantage to adjuvant chemoradiation. These results showing an overall survival benefit in stage II-IV non-metastatic gastric adenocarcinoma patients when adjuvant chemoradiotherapy was given after surgery have been validated in multiple large analyses using the Surveillance, Epidemiology, and End Results (SEER) database and large literature-based meta-analyses.
The other landmark trial that has influenced management of locally advanced gastric cancer patients is the UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. In the MAGIC trial, 503 patients were randomized to either surgery alone versus surgery with perioperative chemotherapy. The chemotherapy used was 3 cycles of epirubicin, cisplatin, and 5-FU (ECF) before surgery, followed by 3 cycles of ECF after surgery. This study also showed superior outcomes to a combined treatment approach, favoring the perioperative chemotherapy arm with a 36% 5-year survival rate versus 23% 5 year survival rate for surgery alone. With the results of the MAGIC trial, perioperative chemotherapy also became a widely utilized treatment strategy.
Given the long-term results of the Intergroup 0116 trial and the results of the MAGIC trial, the adjuvant chemoradiation approach and the perioperative approach have become the 2 most common approaches taken toward localized gastric cancer. To date, it is not apparent whether adjuvant chemoradiotherapy with the Intergroup 0116 trial or perioperative chemotherapy through the MAGIC trial should be the preferred strategy in the management of locally advanced gastric cancer patients. What is evident is that some form of combined-modality treatment rather than surgical resection alone is best for this high-risk population.
The optimal adjuvant strategy after surgical resection has also become blurred with more recent studies. The Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial randomized 458 patients to either adjuvant chemotherapy (capecitabine/cisplatin) versus adjuvant chemotherapy followed by adjuvant capecitabine-based chemoradiation. From that trial, the addition of adjuvant chemoradiation to adjuvant capecitabine/cisplatin chemotherapy did not statistically significantly improve survival. However, the node-positive subgroup did appear to gain a disease-free survival advantage ( P <.05), leading to the currently accruing ARTIST-II trial, which will test the same strategies in node-positive gastric cancer populations.
Within the past year, investigators from another important phase III study, the Chemoradiotherapy After Induction Chemotherapy of Cancer in the Stomach (CRITICS) trial, have reported their unpublished results. The CRITICS study randomized 788 patients to either perioperative chemotherapy (epirubicin, cisplatin, and capecitabine) versus preoperative chemotherapy followed by adjuvant cisplatin/capecitabine-based chemoradiation. With 4.2 years of median follow-up, there was no statistical difference in overall survival between the 2 arms, 3.5 years (perioperative chemo) versus 3.3 years (pre-operative chemo with adjuvant chemoradiation). Of note, only 47% and 52% of patients were able to complete the perioperative chemotherapy and chemoradiotherapy arms, respectively, putting the spotlight again on the importance of improving the tolerability of the multimodality strategy.
The limited percentage of enrolled patients who were able to complete the intended treatment strategies in CRITICS could potentially affect the interpretation of this unpublished study. Nonetheless, the early reported results suggest that postoperative chemoradiation following preoperative chemotherapy and surgery would require better patient selection to demonstrate potential benefit. The population in whom this aggressive approach may be warranted would be those patients who can tolerate more aggressive therapy and those patients who can be predicted to have a greater likelihood of responding to adjuvant chemoradiation. It has been shown in several phase II trials that response to neoadjuvant chemotherapy predicts for survival. The tailoring of response to treatment strategy is the key concept being tested in a currently accruing national clinical trial, Alliance A021302. The Alliance trial will use early fluorodeoxyglucose positron emission tomography (FDG- PET) treatment response to preoperative chemotherapy to direct further treatment, including potentially resection and adjuvant chemoradiotherapy for nonresponders. The results of this important trial may lead toward a more tailored approach to multimodality gastric cancer management.
Related posts:
The Management of Esophagogastric Cancers Enters a New Era
Management of Locally Advanced Gastroesophageal Cancer
Management of Metastatic Gastric Cancer
The Evolving Role of Checkpoint Inhibitors in the Management of Gastroesophageal Cancer
Antiangiogenic Therapy in Gastroesophageal Cancer
Emerging Novel Therapeutic Agents in the Treatment of Patients with Gastroesophageal and Gastric Adenocarcinoma
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