|Ahead of print publication
Clinical impact of adjuvant chemotherapy and radiation for carcinoma stomach: Experience from a tertiary care center
Jomon Raphael Chalissery1, T Anilkumar Jose2, Sreekumar Pillai3, Harikumar Unni4, K Mathew Varghese1, G Paul Gopu1, K Venkatesan1
1 Department of Radiation Oncology, Amala Institute of Medical Sciences, Thrissur, Kerala, India
2 Department of Medical Oncology, Amala Institute of Medical Sciences, Thrissur, Kerala, India
3 Department of Surgical Oncology, Jubilee Mission Medical College, Thrissur, Kerala, India
4 Department of Surgical Oncology, Amala Institute of Medical Sciences, Thrissur, Kerala, India
Jomon Raphael Chalissery,
Department of Radiation Oncology, Amala Institute of Medical Sciences, Thrissur, Kerala
Source of Support: None, Conflict of Interest: None
Objectives: The main objectives of this study are (1) To assess the patient compliance for adjuvant radiotherapy and chemotherapy for carcinoma stomach, (2) Tolerance of adjuvant radiotherapy with the use of conformal techniques, and (3) Disease-free and overall survival benefits of adjuvant chemotherapy and radiation in carcinoma stomach.
Materials and Methods: Carcinoma stomach patients who registered in the institution during the period of December 2011–2014 were taken for the analysis. Treatment details of patients who received the planned adjuvant treatments, radiotherapy, and chemotherapy were collected. The treatment protocol was made as per the institutional multidisciplinary meeting decisions. The radiotherapy dose given was 45 Gy in 25 fractions using an intensity-modulated radiotherapy technique and concurrent chemotherapy offered with capecitabine 825 mg/m2 twice daily. Adjuvant chemotherapy protocol was selected from the major clinical trial information.
Results: A total of 61 patients who satisfied the inclusion criteria were selected. Males 52 (85%) and females (15%). The median age of the patients was 57 years. Stage II patients were 52%, and 48% were stage III. All patients tolerated the planned dose of radiotherapy 45 Gy in 25 fractions, and 74% of patients tolerated six or more cycles of adjuvant chemotherapy. Mean follow-up period was 48 months, and the Kaplan–Meier survival analysis shows 3 and 5 years survival percentages were 57% and 48%, respectively.
Conclusion: Adjuvant chemotherapy and radiation using conformal technique are well-tolerated. These were reflected in the overall outcome and survival of the patients. Based on the surgical pathology findings, an individualized approach of adjuvant treatment protocol can improve the outcome.
Keywords: Adjuvant treatment, carcinoma stomach, chemotherapy, and radiotherapy
|How to cite this URL:|
Chalissery JR, Jose T A, Pillai S, Unni H, Varghese K M, Gopu G P, Venkatesan K. Clinical impact of adjuvant chemotherapy and radiation for carcinoma stomach: Experience from a tertiary care center. J Can Res Ther [Epub ahead of print] [cited 2020 Sep 18]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=264697
| > Introduction|| |
Management of carcinoma stomach is a widely discussed area. Surgery remains the definitive treatment of carcinoma stomach. The locoregional relapse after surgery and systemic failure raise the need for adequate adjuvant treatment., Chemotherapy and radiation therapy mainly work in adjuvant or neoadjuvant situations. The standard of care for the management of carcinoma stomach mainly evolved from the randomized clinical trials.,, The benefits of these adjuvant therapy depend on the various factors, which includes adequacy of surgery, tolerance of patients for adjuvant treatments, maintenance of nutritional status, and the quality of life. Hence, the evidences from the clinical trials helped us to plan the treatments to produce optimum results. Sequencing of chemotherapy and radiation therapy was made as per the evidence. Perioperative chemotherapy or surgery followed by adjuvant chemotherapy or adjuvant chemo-irradiation are the most popular methods.,, Mostly, decisions regarding the treatment plans are taken according to the surgical feasibility. In a tertiary care center, patients were referred after the diagnosis of carcinoma stomach from an endoscopic biopsy or after completing the surgical management or even after giving chemotherapy. Those patients reaching after the endoscopy biopsy will require a detailed evaluation due to the associated comorbidities and nutritional status. In all kinds of situations, a multidisciplinary team discussion is needed to plan their treatment accordingly. If the patient is an ideal candidate for preoperative chemotherapy, it can be offered initially or surgery can be offered. However, many patients reach the tertiary care centers after surgical management. The extent of surgical resection in these patients always varies widely. The decision regarding further adjuvant treatment options such as chemotherapy or chemoradiation is often a difficult one. The evidence for the best treatment protocol are not very clear. Adequacy of surgical procedure performed will be the major factor in making such decisions. Available literature and the clinical practice guidelines and publications from various parts of the world shows that there are clear variations in the standard of care in different parts of the world. In the West, the preferences are more toward either preoperative chemotherapy followed by surgery or surgery followed by adjuvant chemotherapy and chemo-irradiation., Asian countries surgical resection preferably D2 lymphadenectomy followed by chemotherapy is the more popular option., The best surgical option for a locally advanced carcinoma stomach is still not clear. Whether all patients really required D2 lymphadenectomy is a debatable topic and how many of the patients are really undergoing R0 resection is also a dilemma. While dealing with such kind of clinical situations with intent to produce the best results, we must have to offer both locoregional and systemic treatments. The questions such as which clinical trial information to be followed, what regime to be offered, and what will be the sequencing of adjuvant radiation and chemotherapy also will be a difficult decision. Many institutions will follow their multidisciplinary team decisions for treating those patients. We have focused on such patients who underwent surgery for carcinoma stomach in peripheral centers and also in our own center and analyzed the tolerance and benefits of adjuvant chemotherapy and radiation treatments regarding the disease-free survival (DFS) and overall survival (OS).
| > Materials and Methods|| |
Carcinoma stomach patients who registered in the institution during the period from December 2011 to January 2015 were taken for the analysis. The patients who had surgery followed by adjuvant chemotherapy and radiation were grouped, and their treatment details, the tolerance to the planned treatment schedule, and toxicities were evaluated with the help of the CTCAE version 4.0, (U.S Department of Health and Human Services) and follow-up details were analyzed. All decisions regarding the adjuvant treatments were discussed in the institutional multidisciplinary meeting. Clinical indications for offering adjuvant treatments were as follows: (1) Patients having Stage IIA–Stage IIIB carcinoma stomach. (2) Positive surgical margins or inadequate nodal dissections. Sequencing of chemotherapy and chemo-irradiation was decided according to the surgical biopsy report and operative findings.
Chemotherapy regimens followed in the department were five fluorouracil/leucovorin six cycles or oxaliplatin/capecitabine (CAPOX) eight cycles, or epirubicin/oxaliplatin and capecitabine six cycles. External radiotherapy was delivered using intensity-modulated radiotherapy (IMRT) technique. The dose given was 45 Gy in 25 fractions to all patients, and an additional boost dose of 5.4 Gy in three fractions was offered to surgical margin positive patients. The technique used was IMRT for all patients. Concurrent chemotherapy was offered with capecitabine 825 mg/m 2 twice daily from day 1 to last day of radiotherapy.
Conformal radiation therapy treatment plans were generated for all patients. Computed tomography (CT) simulation was conducted initially for all patients; intravenous contrast was given for all and bowel contrast not used. Free breathing scans were acquired and transferred to the treatment planning system Varian Eclipse version 11. The clinical target volume (CTV) was contoured as per INT-0116 trial recommendations. It included the entire stomach/stomach bed, area of resected perigastric local tumor extension, anastomosis, distal duodenum limb that had undergone deafferentation, and the following draining nodes: gastric, gastroepiploic, celiac, porta hepatis, subpyloric, gastroduodenal, splenic, suprapancreatic, and retro-pancreaticoduodenal. For proximal T3–T4 lesions, the medial two-thirds to three-fourths of the left hemidiaphragm were included in the CTV. For proximal lesions involving the cardia or gastroesophageal junction with any positive nodes, and the lower para-esophageal nodes were included in the CTV. The planning target volume (PTV) was defined by the institutional policy and typically included the CTV with a 0.5–1 cm margin for setup variation and organ motion. At the discretion of the physician, PTV margins of up to 2 cm were sometimes used anteriorly and superiorly because of marked diaphragmatic breathing motion as assessed at the cone-beam CT acquired before the treatment. In dose volume histogram, 100% of the prescribed dose was specified to 95% of the PTV.
A normal tissue dose constraint for conformal planning was used as per the recommendations from the published literature. Normal tissue dose limitations included the following: Dose to 10% of the spinal cord volume within the treatment region not to exceed 4500 cGy, and no part of the spinal cord could receive 5000 cGy; 60% of the liver could not receive 3000 cGy; 33% of one kidney could not receive 2250 cGy (if possible, the dose to the second kidney should be kept to this limit); and 30% of the heart could not receive 4000 cGy. Toxicities and tolerance information was collected from the weekly assessment chart.
Follow-up assessment was done once in 3 monthly for the first 2 years and 6 monthly thereafter. Suspicious disease recurrences were evaluated with CT scans and endoscopy. Biopsy confirmation was done for all relapsed patients and surgery or chemotherapy was offered according to the nature of relapse. Relapsed patients with poor performance status were offered only supportive care.
Statistical analysis was done by entering the data in an Excel sheet, and the survival assessment done with the help of Sigma plot software version 14 (Systat Software, Inc. San Jose, CA 95131 USA). Kaplan–Meier survival curve was prepared for the analysis.
| > Results|| |
The demographic data [Table 1] shows a total of 61 patients were evaluated and of which majority (85%) were male patients. The median age of patients was 57 years. Stage grouping of patients shows Stage II 52% and Stage III 48%. Tumors located at the gastroesophageal junction, cardia, and fundus were grouped as proximal tumors, and at pyloric region were grouped as distal tumors. Poorly differentiated adenocarcinoma was the most common histological subgroup noticed. Detailed analysis of surgical notes and review of histopathology of patients referred from various peripheral hospitals and general surgery departments were conducted before deciding adjuvant treatment. It was found that the negative surgical margins (R0) were obtained in 33 patients (54%) and the positive margin (R1) in 26 patients (43%). Margin status was unknown in two patients. Nodal dissection status was not mentioned in majority of the referral and <15 lymph nodes dissection performed in 43 (70%) patients. Fifteen or more lymph node dissection noticed in 18 (30%) patients.
All patients were offered adjuvant treatment. Sequencing of the treatments was done according to the multidisciplinary meeting decisions. According to the treatment sequence, there were three sets of patients. (1) Concurrent chemo-irradiation followed by six or eight cycles of adjuvant chemotherapy, (2) Adjuvant chemotherapy complete cycles followed by radiotherapy alone, and (3) Three or four cycles of adjuvant chemotherapy followed by concurrent chemo radiotherapy and then remaining cycles of chemotherapy. All patients tolerated the initially planned dose of radiotherapy 45 Gy in 25 fractions. A gap of 2–3 days in the treatment was observed in five patients (8%). The major reason for the break was vomiting (Grade 2). Toxicities due to radiotherapy were very minimal. The notable toxicity observed was vomiting. Grade 1 vomiting observed in 18 patients (30%) during the first 2 weeks of treatment, and Grade 2 vomiting was observed in five patients (8%) during the 5th week of treatment. No other significant toxicities observed related to radiation treatment.
Regarding chemotherapy, concurrent chemotherapy was taken by 37 patients (60%). Adjuvant chemotherapy was offered to patients with a performance score of 0–1. Nearly, 45 patients (74%) received six or more cycles of adjuvant chemotherapy. Seven patients (11%) did not take any adjuvant chemotherapy. Major reasons for not offering adjuvant chemotherapy were poor general condition (six patients) and high-cardiac risk (one patient). Neutropenia was the major dose-limiting toxicity observed. Fifteen patients (27%) developed Grade 3 or above neutropenia. Since multiple chemotherapy protocols were used, a comparative analysis of adjuvant chemotherapy tolerance was not performed.
Follow-up assessment of all patients was done in 3–6 months interval. Patients were followed-up until their last hospital visit and those not coming for regular visits were contacted and their information collected. The maximum period of follow-up obtained is 72 months and the minimum is 36 months. A Kaplan–Meier probability curve for DFS and OS was prepared. Mean follow-up is 48 months. DFS at the end of 3 years and 5 years were 40% and 36%, respectively [Graph 1]. OS curve shows a 3-year survival of 57% and 48% for 5 years [Graph 2]. Our 5 years follow-up data are available for nearly 60% of patients. Hence, the Kaplan–Meier predicted survival curve percentage for 5 years may not be completely reliable. Survival analysis among various subgroups according to the presence of nodal metastases [Graph 3], Stage II and III [Graph 4], surgical margin positivity [Graph 5], and histopathological grading [Graph 6] were prepared. Since the number of patients in each subgroup is small, a statistically significant comparison is not feasible.
Three relapsed patients had only local recurrence (4%) and all of them undergone re-surgery and chemotherapy. All local recurrences were noticed between 12 and 18 months period. Both local and systemic relapse occurred in eight patients (13%). Seven patients (12%) had systemic relapse alone was noticed. Palliative chemotherapy was offered to systemic recurrent patients.
| > Discussion|| |
Management of carcinoma stomach has been studied in major clinical trials.,, A direct comparison of our data with other major clinical trials is not possible. However, the treatment decisions and protocols for each patient are based on the clinical trial data. We looked mainly the applicability and feasibility of these evidence-based regimes in our routine clinical practice. We also analyzed the benefits regarding the disease-free and OS of our patients at the intervals of 3 years and 5 years. Our data show the feasibility of concurrent chemo-irradiation using the conformal technique for delivering radiotherapy to be a very good option. The successful completion of all patients is based on the desired dose of radiotherapy and low levels of toxicities are strong evidence for it. The benefits regarding DFS and OS were comparable or better than the percentages described in major clinical trials.
Intergroup trial 0116 is one of the first major clinical trials published for adjuvant management of carcinoma stomach. This study looked at the benefits of concurrent chemo-irradiation and adjuvant chemotherapy for carcinoma stomach patients. Their results showed a 50% OS at 3 years and recurrence-free survival of 41%. OS in our data at 3 years is 57% and 40% is the DFS, which is comparatively better than the trial data. The major criticism against this trial was the type of lymph node dissection done in the patients. Fifty-four percentages of the patients not even undergone D1 dissection. In our group, also we found a significant number of patients with an inadequate surgical margin and partial nodal dissection. Regarding the tolerance of adjuvant treatment regime in the trial, 64% of the patients completed the planned course of treatment. In our data, 74% of the patients completed the planned course of treatment.
The MAGIC trial  is an important one followed in many institutions. This trial looked only the importance of chemotherapy in the management of carcinoma stomach using perioperative chemotherapy (three preoperative and three postoperative cycles of epirubicin cisplatin, and 5-FU) and surgery or surgery alone. With a median follow-up of 4 years, the 5-year survival rate was 36% in the perioperative chemotherapy group versus 23% in the surgery alone group. The tolerance for the complete course of chemotherapy in the MAGIC trial is 42% only. Our results are better than this trial data. This trial has recruited more nodes of negative patients in the study and 66% of patients undergone curative resection. These factors might have helped in the overall outcome.
Two clinical trials from Asia ACTS GC trial  and CLASSIC trial  randomized nearly 1000 patients with stage II and III carcinoma stomach to D2 gastrectomy versus D2 gastrectomy followed by adjuvant chemotherapy. The CLASSIC trial which is more popular in Asian countries shows a 3-year DFS of 74% and OS of 83% which is better than our data. However, the study says their regime of surgery followed by adjuvant chemotherapy eight cycles with CAPOX were tolerated by less than half of the patients only. Another issue regarding the routine clinical practice in a community-based center is the percentage of D2 gastrectomies performed is less and the percentage of margin-positive resection was more. In such situations, the locoregional treatment will be suboptimal if adjuvant radiotherapy being not offered.
The most recent clinical trials regarding the adjuvant treatment of carcinoma stomach are ARTIST 1 and ARTIST 2 trial (clinical trial data not yet published). These trials, particularly evaluated the benefit of adjuvant chemotherapy versus chemoradiotherapy in the treatment of carcinoma stomach. Regarding ARTIST 1, a Phase III trial randomized 458 patients following D2 gastrectomy to adjuvant chemotherapy alone with six cycles of capecitabine and cisplatin (XP) versus adjuvant CRT comprising two cycles of XP, then 45 Gy CRT with capecitabine, followed by two further cycles of XP. The 3-year DFS showed no statistically significant difference (74% for XP vs. 78% for XP peri-radiation [XPRT]; P = 0.0862). There was a trend toward improved DFS following the use of chemoradiotherapy (hazard ratio, 0.74; P = 0.09), which was the primary endpoint of the trial. Post-hoc analyses revealed a statistically significant DFS benefits for those patients with either node-positive disease or intestinal-type histology. The planned six cycles of XP chemotherapy and XPRT chemoradiotherapy were completed in 75% and 82% of patients, respectively. The tolerance percentages of our data are almost similar to ARTIST trial. However, the DFS and OS percentages are inferior in our study group. This may be due to the lower number of D2 gastrectomies and more number of advanced stage disease patients in our study group.
Since the management of gastric cancer trying to improve in terms of tolerance and survival, the ideal regime for optimum results yet to be evolved. The feasibility of each regime outside the clinical trial settings or in a community-based oncology practice needs to be analyzed. We have found the practice of adjuvant chemotherapy and radiotherapy after gastrectomy with curative intent is well-tolerated. The use of conformal radiotherapy technique such as IMRT is very well-tolerated and the chemotherapy regime to be individualized according to the patients' performance status.
| > Conclusion|| |
Clinical management of carcinoma stomach in a community-based tertiary care oncology center largely depends upon the expertise of physicians and the effective use of resources. To achieve optimal results as per clinical trial settings is always a challenge. By collecting and applying all the information from the available evidence and generating an individualized treatment plan will help to produce a better clinical outcome.
The authors would like to thank Mrs. Neethu Babu, Tutor, Department of Microbiology, Amala Institute of Medical Sciences, Thrissur, Kerala. They were helped in the manuscript proof reading and grammar corrections.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Gunderson LL, Sosin H. Adenocarcinoma of the stomach: Areas of failure in a re-operation series (second or symptomatic look) clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1982;8:1-11.
Gunderson LL. Gastric cancer – Patterns of relapse after surgical resection. Semin Radiat Oncol 2002;12:150-61.
Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al.
Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725-30.
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al.
Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20.
Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, et al.
Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: The ARTIST trial. J Clin Oncol 2012;30:268-73.
Knight G, Earle CC, Cosby R, Coburn N, Youssef Y, Malthaner R, et al.
Neoadjuvant or adjuvant therapy for resectable gastric cancer: A systematic review and practice guideline for North America. Gastric Cancer 2013;16:28-40.
Ohri N, Garg MK, Aparo S, Kaubisch A, Tome W, Kennedy TJ, et al.
Who benefits from adjuvant radiation therapy for gastric cancer? A meta-analysis. Int J Radiat Oncol Biol Phys 2013;86:330-5.
Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, et al.
Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol 2014;40:584-91.
Foo M, Leong T. Adjuvant therapy for gastric cancer: Current and future directions. World J Gastroenterol 2014;20:13718-27.
Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, et al.
Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 2011;29:4387-93.
Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, et al.
Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): A phase 3 open-label, randomised controlled trial. Lancet 2012;379:315-21.
Seevaratnam R, Bocicariu A, Cardoso R, Mahar A, Kiss A, Helyer L, et al.
A meta-analysis of D1 versus D2 lymph node dissection. Gastric Cancer 2012;15 Suppl 1:S60-9.
National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. National Institutes of Health; 2010.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. American Joint Committee on Cancer Staging Manual. 7th
ed. New York: Springer; 2010.
Ringash J, Perkins G, Brierley J, Lockwood G, Islam M, Catton P, et al.
IMRT for adjuvant radiation in gastric cancer: A preferred plan? Int J Radiat Oncol Biol Phys 2005;63:732-8.