Trends in perioperative treatment of gastric cancer 2004–2017: An NCDB analysis

There will be 27,600 new diagnoses of gastric cancer and 11,010 gastric cancer-related deaths in the U.S. in 2020. Most patients with gastric cancer will succumb to their disease, and only those few patients diagnosed at an early stage can expect to be cured.¹ Gastric cancer occurs with significantly higher incidence in eastern countries, which screen for gastric cancer as a result. This difference has called into question the applicability of some data from eastern studies to western populations and has led to reliance on data generated in European and North American populations for treatment recommendations in those populations.² Resection has the greatest impact on survival and has curative potential, yet in western countries where disease incidence has not justified screening programs,³ even with perioperative treatment, five-year overall survival is less than 50 percent after surgery.⁴

An important issue for investigators in recent decades has been the absolute benefit of systemic treatment, as well as its appropriate timing (adjuvant versus neoadjuvant). For much of the last two decades, fluorouracil and cisplatin or capecitabine have been the mainstay of treatment, and current National Comprehensive Cancer Network (NCCN) guidelines suggest perioperative (neoadjuvant and adjuvant) systemic treatment when possible. Only recently has there been significant improvement in systemic regimens.⁵

The appropriate extent of lymph node dissection also has been a subject that has generated some controversy. While more extensive dissection may remove more cancer—containing nodes, potentially increasing survival, and providing more sensitive staging—there is associated concern over increased postoperative complications in patients who undergo more extensive lymph node dissections. Based on a number of recent studies, current guidelines suggest an intermediate extent of dissection by experienced surgeons.⁶

Also of interest to researchers has been the potential benefit of chemoradiation. Due to findings of limited benefit, recommendations are to consider chemoradiation based on tumor location at the gastroesophageal junction or after positive margin resection, but chemoradiation is not definitively recommended, with NCCN guidelines assigning only class 2B evidence for chemoradiation in gastric cancer.⁶

Twenty years of data

In the last 20 years, a series of studies highlighted the importance of adjuvant and perioperative systemic treatment in resectable patients in western countries. Published in 2001, the SWOG (formerly known as the Southwest Oncology Group)– Directed Intergroup Study 0116 trial (556 patients over 83 months) compared surgery alone with adjuvant 5-fluorouracil and chemoradiation therapy and showed improved overall and recurrence-free survival in the adjuvant therapy group.⁷ However, a high proportion of patients in this study underwent minimal lymphadenectomy, calling into question the applicability of these findings in patients with the more complete, D2 lymphadenectomy and citing the possibility that the observed survival benefit may have been driven by inadequate surgery.⁷

The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (503 patients over 93 months), published in 2006, compared a perioperative chemotherapy regimen, epirubicin, cisplatin, and fluorouracil before and after surgery with surgery alone. Five-year survival was significantly improved (36 percent versus 23 percent) in the systemic therapy group.⁸ A few years later, the results of the Fédération Nationale des Centres de Lutte contre le Cancer/Fédération Francophone de Cancérologie Digestive (also known as the FNCLCC/FFCD) study were published and confirmed the results of the MAGIC trial.⁹ The Japanese Adjuvant Chemotherapy for Gastric Cancer with S-1 (also known as ACTS-GC) (D2 resection +/- oral S-1 treatment)¹⁰ and Korean Adjuvant Capacitabine plus Oxaliplatin for Gastric Cancer after D2 gastrectomy (also known as CLASSIC) (D2 surgery +/- capecitabine and oxaliplatin) also showed survival benefit for patients who received adjuvant chemotherapy.¹¹

The value of the chemoradiotherapy was further addressed in the Adjuvant ChemoraditionTherapy in Stomach Cancer(ARTIST) and the Phase III comparison of preoperative chemotherapy compared with chemoradiotherapyin patients with locally advanced adenocarcinoma of the esophagogastricjunction (POET) studies in South Korean and German populations, respectively.^12,13 ARTIST compared surgery and chemotherapy with surgery and chemoradiation in patients having undergone D2 lymphadenectomy. In ARTIST, only in the subgroup of patients with node-positive disease was there a moderate disease-free survival advantage in the chemoradiation group.¹² In POET, which included only gastroesophageal junction (GEJ) tumors, data suggested that neoadjuvant chemoradiation improves survival over neoadjuvant chemotherapy, but failed to meet accrual goals.¹³

In 2017, the Multicenter Randomized Phase III Trial of Neoadjuvant Chemotherapy Followed by Surgery and Chemotherapy or by Surgery and Chemoradiotherapy in Resectable Gastric Cancer (also known as CRITICS) trial showed no outcome improvement with postoperative chemoradiation over postoperative chemotherapy.¹⁴ Based on these equivocal findings, chemoradiation therapy is recommended as level 2B evidence, and generally reserved for those with GEJ tumors.⁶

Historically, North American and European surgeons removed only those lymph nodes along the lesser and greater curvature of the stomach (D1 dissection), whereas eastern surgeons have routinely performed a more extensive lymphadenectomy. Initially, the Dutch Gastric Cancer Group (DGCG) 1999 trial showed that D2-lymphadenectomy had higher operative mortality and surgical complication rate with no statistically significant increase in five-year overall survival.¹⁵ However, after a median follow-up of 15 years, D2-lymphadenectomy was associated with lower local recurrence, regional recurrence, and gastric cancer-related deaths.¹⁶ The DGCG study and other trials have recommended lymphadenectomy of intermediate extension (D2 dissection), which removes all nodes along the celiac vessels from the splenic hilum to and including the gastrohepatic ligament, but does not include removal of the spleen (D3 dissection).¹⁶

In spite of data supporting the benefit of perioperative and adjuvant chemotherapy treatment and lymphadenectomy of 16 lymph nodes or more and the related changes to national guidelines,⁶ studies demonstrate that compliance with guidelines is lacking. In an analysis of National Cancer Database (NCDB) data from diagnosis years 1998–2005, 60 percent of patients who underwent gastrectomy received no systemic therapy.¹⁷ An analysis of the Surveillance, Epidemiology, and End Results Medicare database found only 19.1 percent of surgical gastric cancer patients between 1991 and 2009 received postoperative chemotherapy, 1.9 percent received perioperative chemotherapy, while 60.9 percent underwent surgery alone.¹⁸

Our analysis

Methods

In the current analysis of NCDB data from diagnosis years 2004– 2017, we reported trends among 28,465 patients who underwent surgery for stage I–IV(M0) gastric cancer. Specifically, we focused on the percent of patients receiving neoadjuvant and adjuvant chemotherapy and radiation therapy, and the extent of lymph node dissection. We analyzed patients who were 18 years old or older at diagnosis, were treated for their first or only malignant or in situ primary, with a primary site of C16.0-C16.6, C16.8, and C16.9, and histology of 8000-8152, 8154-8231, 8243-8245, 8247-8248, 8250-8576, 8940-8950 and 8980-8990. Any case with clinical or pathologic M as M1, cM1, cM1a, cM1b, pM1, or pM1a was excluded.

For this analysis the categories of chemotherapy, lymph node dissection, radiation therapy, and GEJ versus other locations within the stomach were defined as follows:

• Chemotherapy was broken down into none given, administered, considered but not administered, and other/unknown, with treatment timing consisting of neoadjuvant, adjuvant, or other/ unknown.

• Lymph node dissection was based on the number of regional lymph nodes examined and was grouped as 0–15 nodes examined, and 16 or more nodes examined. Cases with other/unknown number of nodes examined were excluded from this portion of the analysis.

•Radiation therapy also was broken down into none given, administered, considered but not administered, and other/ unknown with treatment timing consisting of neoadjuvant, adjuvant or other/unknown.

• GEJ was classified as any patient with C16.0 as his/her primary site, and other locations within the stomach were classified as any patient with C16.1-C16.6, C16.8, or C16.9 as his/her primary site.

Results

From 2004 to 2017, rates of chemotherapy administration increased from 46 percent (421 patients in 2004) to 74 percent (1,722 patients in 2017). The use of neoadjuvant chemotherapy increased from 15 percent (135 patients in 2004) to 60 percent (1,393 patients in 2017) (see Figure 1).

Whether a D1 or D2 lymphadenectomy was intended in each reported case is not addressed in the NCDB data. Lymph node yield increased over time (see Figure 2). However, even in the last years analyzed, only approximately 60 percent of patients had 16 or more lymph nodes removed.

Figure 1. Neoadjuvant versus adjuvant chemotherapy treatment, 2004 to 2017

Though the current study included only patients who underwent surgery, those with tumors at the GEJ may be more likely to receive radiation. NCBD data do not delineate GEJ tumors according to Seiwert classification, which describes three categories of tumor location near the GEJ, as follows:

• Seiwert I and II tumors (1–5 cm above the GEJ and 1 cm above to 2 cm below the GEJ, respectively),¹⁹ in accordance with guidelines for patients with esophageal cancer, should in most cases best be treated with esophagectomy and partial gastrectomy after neoadjuvant chemoradiation.
• Seiwert III tumors are located greater than 2 cm below the GEJ and are best treated with perioperative or adjuvant chemotherapy, with radiation therapy having a lower level of evidence for benefit.⁷

With such a large cohort of patients, some patients may have had GEJ tumors, but still have received surgery with or without radiation. In an attempt to determine whether a GEJ tumor might encourage a greater use of radiation therapy, we have reported rates of adjuvant and perioperative radiation therapy with reference to anatomic location near the GEJ versus other locations within the stomach. Over the study period, the use of neoadjuvant radiation therapy increased in the GEJ tumor group from 32 percent (109 patients in 2004) to 59 percent (645 patients in 2017). Very few patients in the non-GEJ group received neoadjuvant radiation therapy. During the same time period, the use of adjuvant radiation therapy in the non-GEJ group decreased from 25 percent (141 patients  in 2004) to 13 percent (165 patients in 2017). The use of adjuvant radiation therapy in the GEJ tumor group decreased from 19 percent (63 patients in 2004) to 5 percent (58 patients in 2017) (see Figure 3).

Figure 2. Lymph nodes examined, 2004 to 2017

Figure 3. Radiation therapy neoadjuvant versus adjuvant treatment for GEJ and other locations within the stomach tumors, 2004 to 2017

Discussion

Based on our review of literature, data proving survival benefit have had a positive impact on the proportion of patients who receive systemic chemotherapy. Over the period studied (2004–2017), the proportion of patients receiving chemotherapy or radiation therapy increased, 28 percent for chemotherapy, 45 percent for neoadjuvant chemotherapy, and 4 percent for radiation (324 [36 percent]) in 2004, and 931 (40 percent) in 2017). However, the obstacles that prevented 48 percent of patients in 2004 and 23 percent of patients in 2017 from receiving chemotherapy are unknown. Certainly, some proportion of patients may refuse systemic therapy or be unable to receive treatment because of operative complications. However, given the steady rise in administration of chemotherapy over the time period studied, we must question whether a plateau has yet been achieved.

The literature, which evolved during the years studied, showed efficacy of neoadjuvant chemoradiation for esophageal/GEJ cancer, but limited or no benefit for gastric cancer. Our results showed the use of neoadjuvant radiation for GEJ cancers increased while being given less often in the adjuvant setting for non-GEJ gastric cancers.

Low rates of adequate lymph node retrieval may suggest that the technical difficulty of the recommended dissection is limiting for surgeons who do not frequently perform periceliac dissections.

Acknowledgment

Statistical support for this column was provided by Amanda E. Browner, MS, Statistician, NCDB.

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