Abstract
Introduction
Radiotherapy is not commonly used for the treatment of gastric cancer in Japan, where surgery is the standard local treatment. We report the results of chemoradiotherapy in patients with advanced or recurrent gastric cancer which was deemed difficult to treat surgically.
Methods
Twenty-one patients with gastric cancer (including sixteen with advanced/recurrent gastric cancer and five with poor general condition) underwent chemo-radiotherapy, for whom the therapeutic efficacy, toxicity and survival period were analysed.
Results
The tumour response to chemoradiotherapy was categorised as complete, partial, stable or progressive in 5, 9, 3, and 4 patients, respectively, with an overall response rate of 67%. No serious complications such as gastrointestinal perforation or bleeding occurred, and no cardiac, hepatic or renal dysfunction developed during the follow-up period. The mean survival time was 19.8 months (range, 3–51 months). One patient died of another disease, 18 died of primary cancer and the cause of death was unknown in 2 patients.
Conclusions
Chemoradiotherapy appears to be an effective treatment for localised gastric cancer without distant metastases, but further studies are needed to determine the indications for chemoradiotherapy and late adverse effects, as well as the chemotherapy regimens to be used.
Keywords: Non-curative resection, Advanced gastric cancer, Recurrent gastric cancer, Chemo-radiation therapy
Introduction
In Japan, advanced or recurrent gastric cancer is usually treated by palliative surgery and/or chemotherapy.1–3 The development of new anticancer drugs has led to improved survival in patients with advanced or recurrent gastric cancer, and has increased the chances of surgical treatment as a part of a combined modality therapy. However, the oncological benefit of aggressive resection and tumour reduction therapy for advanced or recurrent gastric cancer remains unclear. Radiotherapy is not commonly used for the treatment of gastric cancer in Japan, where surgery is the standard local treatment,1–3 and adenocarcinoma is not generally regarded as radiosensitive. Furthermore, radiotherapy is associated with adverse effects. Among gastrointestinal cancers, squamous cell carcinomas such as oesophageal and anal cancers are often treated with radiotherapy but adenocarcinomas are generally treated with surgery and/or chemotherapy. However, recent reports from Europe and the Unites States have demonstrated the usefulness of radiotherapy as a local treatment for gastric cancer, and adjuvant and neoadjuvant chemoradiotherapy have attracted attention.4–7
Methods
We examined the characteristics of 21 patients with gastric cancer who underwent chemoradiotherapy as a first-line treatment between January 2005 and May 2013, and evaluated the safety, feasibility, response rate, toxicity and survival rate in comparison with chemotherapy alone. Patient characteristics are shown in Table 1. Gastric carcinoma was diagnosed by endoscopy and biopsy. Endoscopic ultrasound and contrast-enhanced computed tomography (CE-CT) were operated for clinical TNM stages. The indications for chemoradiotherapy consisted of extensive invasion of the surrounding organs in 16 patients with unresectable primary advanced (2 patients) and recurrent (14 patients) gastric cancer with no distant metastases or carcinomatous peritonitis, and because of advanced age and poor general condition in the other 5 patients. Gastrojejunostomy was performed to the 2 patients with primary advanced gastric cancer before chemo-radiotherapy; 9 of 14 patients with recurrent advanced gastric cancer were included after distal gastrectomy and 5 patients after total gastrectomy. All cases of residual stomach cancer were treated as recurrent gastric cancer.
Table 1.
Patient characteristics
| Characteristic | Tumour stage | Value | ||||
| I | II | III | IV | Unknown | ||
| Age (years) | 76.1 ± 7.1 | |||||
| Sex (male : female) | 15 : 6 | |||||
| Stage: | 1 | 2 | 1 | 16 | 1 | |
| Reason for selecting CR1: | ||||||
| Unresectable | 0 | 0 | 0 | 16 | 0 | |
| Poor general condition | 1 | 2 | 1 | 0 | 1 | |
| Hystological type: | ||||||
| Well | 3 | |||||
| Mod | 7 | |||||
| Por | 5 | |||||
| Sig | 3 | |||||
| NEC2 | 1 | |||||
| Unknown | 2 | |||||
| Chemotherapy regimen: | ||||||
| TS-1 | 15 | |||||
| 5-FU+Low-dose cisplatin | 5 | |||||
| None | 1 | |||||
| Mean irradiation dose (Gy) | 50.4 ± 4.5 | |||||
1CR, chemo-radiotherapy; 2NEC, neuroendocrine carcinoma
In this study, the patients had no distant metastases or carcinomatous peritonitis on preoperative imaging and lesions were confined to the intended radiation field. The chemotherapy regimen for patients who tolerated oral intake consisted of TS-1 (80mg/m2 of body surface area) given orally every day for 4 weeks followed by a 2-week rest. The regimen for those who had difficulty with oral intake consisted of 5-fluorouracil (5-FU; 250mg/m2 of body surface area) plus cisplatin (5mg/m2 of body surface area) given for 4 weeks. 5-FU was administered intravenously as a 24-hour continuous infusion on days 1–5, 8–12, 15–19 and 22–26. Cisplatin was administered intravenously as a bolus infusion at least 1 hour prior to starting irradiation on days 1–5, 8–12, 15–19 and 22–26.
Patients underwent CT simulation (Aquilion LB, Toshiba Medical Systems) from lower thorax to lower abdomen. The primary lesion was contoured on axial slices of the planning CT images (slice thickness 2mm) to define as the gross tumour volume (GTV). Typically, a 5-mm margin was added to the GTV to form clinical target volume (CTV) including micro-invasion. A 5–10mm margin was also added to the CTV to form the planning target volume (PTV) for internal movement and/or set up error. For compensation of the beam penumbra, a 5-mm leaf margin was added to the PTV. Treatment planning goals included covering the PTV with more than 95% of the prescription dose, with placement of the normalised point within the GTV.
As illustrated by the patient treatment planning examples in Figure 1 by XiO (Elekta), treatment was delivered using a 6-MeV photon beam (Primus, Toshiba). Treatments were usually delivered using three-dimensional conformal therapy from four field portals and a total of 50 Gy was given in 25 fractions over 5 weeks.
Figure 1.
Target volume of primary and lymph node and dose-volume histogram of patient with local advanced gastric cancer
After chemo-radiotherapy, tumour response was evaluated based on the findings of CE-CT, endoscopy and endoscopic ultrasound according to Response Evaluation Criteria in Solid Tumours (version 1.1) criteria.8 Overall survival was defined as the interval in months measured between the starts of the treatment and death from any cause, or the last examination of the patient. The analysis of overall survival was calculated using the Kaplan-Meier method. Each patient enrolled in the study provided written informed consent.
Results
The regimen for chemotherapy was TS-1 (15 patients), 5-FU plus low-dose cisplatin (5 patients) and radiotherapy alone (1 patient.) Mean irradiation dose was 50.4 ± 4.5 Gy (Table 1). Tumour response to chemoradiotherapy was as follows: complete response (5 patients; Fig 2), partial response (9 patients), stable disease (3 patients) and progressive disease (4 patients), with an overall response rate of 67%. Eighteen patients resumed an oral diet and were discharged. No serious complications such as gastrointestinal perforation or bleeding were encountered, and no cardiac, hepatic or renal dysfunction developed during the follow-up period. Chemotherapy was discontinued in nine patients because of grade 1 leucopoenia, but radiotherapy was continued. The mean survival time was 19.8 months (range 3–51 months); for patients with unresectable disease survival was 22.3 ± 14.6 months (range 5–51 months); and for patients in poor general condition it was 12 ± 7.68 months (range 3–23 months); 1 patient died of aspiration pneumonia, 18 died of primary cancer and the cause of death is unknown in 2 patients (Table 2). The main cause of death due to the primary disease is peritoneal dissemination and distant metastasis out of the radiation field. The survival curve is depicted in Figure 3.
Figure 2(a, b).
A type 3 lesion involving 4/5 of the circumference on the lesser curvature side of the gastric antrum; (c, d): the tumour has disappeared, with only mild residual erosions
Figure 3.
Overall survival of patients with gastric cancer who underwent chemoradiotherapy (n = 21)
Table 2.
Summary of the treatment results
| Over all response rate | 67% |
| CR/PR/SD/PD | 5/9/3/4 |
| Serious side effects (gastrointestinal perforation and bleeding) | None |
| Chemotherapy discontinued due to leukopenia (radiotherapy could be completed in all patients) | 9 (all grade 1) |
| Mean survival period | 19.8 (3–51) months |
| Unresectable | 22.3±14.6 (5–51) months |
| Poor general condition | 12±7.68 (3–23) months |
CR= complete response; PR= partial response; SD= stable diseasel; PD= progressive disease
Discussion
According to the Japanese gastric cancer treatment guidelines, gastric cancer has a low sensitivity to radiotherapy and cannot be cured by radiotherapy alone, although it is effective in relieving pain and other symptoms due to cancer invasion and bone metastasis.9–11 In Japan, therefore, radiotherapy is not commonly used to prolong life in patients with gastric cancer. However, in the United States, MacDonald et al.,11,12 reported that the 3-year survival rate was significantly higher in patients with gastric cancer treated with postoperative chemotherapy (5-FU + leucovorin) and radiotherapy than in those treated by surgery alone (50% vs. 41%, respectively).
In the present study, chemoradiotherapy for localised, invasive gastric cancer with no distant metastases or peritoneal dissemination caused only mild adverse effects during short-term follow-up and achieved a good response rate. Mean survival period for patients with unresectable advanced and recurrent gastric cancer was 22.3 ± 14.6 months (range 5–51 months).
The SPIRITS trial concluded that overall survival was better in patients treated with advanced gastric cancer treated with S-1 plus cisplatin over S-1 alone.13 The background of patients in this trial is different from this study, so a comparison of both groups would not be accurate. However, the mean survival time in the current study was longer than that found in the SPIRITS trial (n = 148, survival time 13 months) and the response rate of this study was better than that of the SPIRITS trial (n = 87 target tumours 54%).
These results suggest that chemoradiotherapy deserves serious consideration in patients with gastric cancer who are not amenable to curative resection or are difficult to treat by surgery because of advanced age or poor general condition.14–17 Accurate identification of the lesions involved, including peritoneal dissemination and the setting of the radiation field, is important to avoid recurrence after chemo-radiotherapy. Reported serious adverse effects of chemoradiotherapy for gastric cancer include gastrointestinal perforation and bleeding,18–20 which did not occur in this study. In addition, no cardiac, hepatic or renal dysfunction developed during the follow-up period. However, these advese effects may cause problems in the future if long-term survival is achieved.21–24 Moreover, for patients with advanced or recurrent gastric cancer which was deemed difficult to treat surgically, we believe that the survival benefit is greater than any long-term adverse effects.
Mean survival period of patients with poor general condition was 12 ± 7.68 months (range 3–23 months) and the adverse effects of chemoradiotherapy and the progression of the cancer was not a cause of death. We were therefore able to avoid unnecessary surgery for patients with poor general condition.
In conclusion, chemoradiotherapy for patients with inoperable gastric cancer was successful with no serious short-term adverse effects, and yielded a response rate of as high as 67%. Chemoradiotherapy appears to be effective in the treatment of localised lesions with no distant metastases. However, further robust clinical studies and the collection of large-scale data are still required to determine the indications for chemoradiotherapy for gastric cancer and late-onset adverse effects, as well as the chemotherapy regimens to be used. Moreover, it is our opinion that a prospective study would be useful to compare chemoradiotherapy with chemotherapy looking at patients with unresectable advanced and recurrent gastric cancer without distant metastasis.
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