Jamshed Ali  ( Department of Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan )
Nuzhat Humayun  ( Department of Pharmaceutical Services, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan )
Shameen Ikram  ( Department of Pharmaceutical Services, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan )
Muhammad Abu Bakar  ( Department of Cancer Registry and Clinical Data Management, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan. )
Umm-e-Kulsoom  ( Department of Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan )
Rizwan Masood Sheikh  ( Department of Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan )

Objective: To compare the overall survival and disease-free survival rates with perioperative or adjuvant chemotherapy regimens in operable gastric cancer cases.

 

Method: The retrospective, observational study was conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised date from January 2015 to December 2020 of operable gastric cancer patients who had perioperative or adjuvant chemotherapy. Overall survival and disease-free survival were evaluated. Data was analysed using SPSS 23.

 

Results: Of the 108 patients in the aga range 27-80 years, 71(65.74%) were males. The overall median age was 49.50 years (interquartile range: 28 years). There were 69(63.88%) patients on perioperative and 39(36.12%) on adjuvant chemotherapy. The probability of 2- and 3-year overall survival was 68.20% and 57.32% in the perioperative group, and 51.09% and 45.43%, respectively, in the adjuvant group. The probability of 2- and 3-year disease-free survival was 55.45% and 49.30% in the perioperative group, while 2-year disease-free survival was 38.39% in the adjuvant group which had no patient reaching the 3-year mark. The median overall survival for the perioperative group was 49.29 months (interquartile range: 44.50 months) and for the adjuvant group it was 28.23 months (interquartile range: 25.00months) (p=0.07). The median disease-free survival was 35.46 months (interquartile range: 38.50 months) for the perioperative group and 10.19 months (interquartile range: 14.00months) for adjuvant group (p=0.16). The difference between the groups was not significant (p>0.05), but there was a trend suggestive of the superiority of perioperative chemotherapy over adjuvant chemotherapy.

 

Conclusion: In operable gastric cancer cases, the difference between the groups was not significant, but there was a trend suggestive of the superiority of perioperative chemotherapy over adjuvant chemotherapy with respect to overall survival and disease-free survival.

 

Keywords: Gastric cancer, Outcomes, Pakistan, Adjuvant chemotherapy, Perioperative chemotherapy, Survival. (JPMA 73: 812; 2023)

 

DOI: https://doi.org/10.47391/JPMA.6390

 

Submission completion date: 18-03-2022 - Acceptance date: 12-11-2022

 

Introduction

 

Gastric cancer is one of the leading causes of cancer death worldwide.¹ A lot of variations in incidence rate exists globally, and there is low prevalence in southern Asia compared to other parts of Asia.² Nonetheless, gastric cancer generally has poor prognosis with overall 5-year overall survival (OS) rate <20%.³ The prognostic factors for poor outcomes are not only related to difficulty in making an early diagnosis, but also with frequent recurrences and metastasis.⁴ In gastric cancer, the cornerstone for treatment is surgical resection along with lymph node (LN) dissection.⁵ In Japan and South Korea, an extended LN dissection, which is commonly known as a D2 dissection for gastric cancer, is considered a standard surgical procedure. The D2 dissection consists of removing the stomach, the greater and lesser omentum, along with stage node 1 (N1) and N2 LN groups.⁶ In the Western world, the standard procedure is partial gastrectomy or total gastrectomy with D1 LN dissection, in which peri-gastric LNs are removed.⁷ To improve the prognosis besides curative surgery, perioperative chemotherapy and adjuvant chemotherapy have shown encouraging results.⁸ In perioperative chemotherapy, patient receives preoperative chemotherapy followed by surgery and then postoperative chemotherapy. Perioperative chemotherapy for gastric cancer is given with the intention to downstage the disease, increase the rate of curative surgery, and eradicate the undetectable micro-metastases.⁹ On the other hand, the goal of adjuvant systemic chemotherapy is to target residual micro-metastases after surgical resection. Both the modalities intend to increase disease-free survival (DFS) and OS.

Perioperative chemotherapy in the West, and post-surgery adjuvant chemotherapy in southeast Asia are established options for gastric cancer treatment. A trial showed better survival with perioperative chemotherapy compared to surgery alone.¹⁰ Another trial demonstrated improved survival with adjuvant chemotherapy over surgery alone.¹¹ However, the matter of chemotherapy mode (perioperative vs adjuvant) in gastric cancer is still open for debate.

The current study was planned to compare OS and DFS rates with perioperative and adjuvant chemotherapy regimens in operable gastric cancer cases.

 

Materials and Methods

 

The retrospective, observational study was conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised data from January 2015 to December 2020 of operable gastric cancer patients who had perioperative or adjuvant chemotherapy. After approval from the institutional ethics review committee, a research registry number (NCT04989764) was acquired, and medical records were retrieved related to patients with histologically proven gastric adenocarcinoma with operable disease status who had completed their prescribed perioperative or adjuvant chemotherapy cycles. Patients with early disease, asses by Tumour-Node-Metastasis (TNM) stage Tis or T1, node-negative, inoperable or metastatic disease, were excluded, and so were those who did not undergo adequate lymphadenectomy (

Adjuvant chemotherapy had been offered to patients who had been referred from elsewhere within 8 weeks’ post-surgery with adequate D2 lymphadenectomy. Patients who presented with tumour bleeding or perforation were also offered adjuvant chemotherapy after upfront gastric surgery. Similarly, to distal gastric cancer patients who presented with gastric outlet obstruction, upfront surgery was advised with adjuvant chemotherapy. All remaining patients were offered perioperative chemotherapy.

Regarding chemotherapy options, the patients in perioperative group A received Epirubicin, Cisplatin, Fluorouracil (ECF) or Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel (FLOT), while those in adjuvant chemotherapy group B received Capecitabine and Oxaliplatin (CAPOX) regimen. ECF[10], FLOT,¹² CAPOX¹¹ regimens were in line with literature.

The primary outcomes were OS and DFS. The OS was defined as the length of time from the date of diagnosis till the last follow-up or death, and DFS as the length of time from the date of last treatment to tumour relapse or death. The median OS or DFS was defined as the point at which 50% of the population had not encountered the event, which was death in case of OS and progression in that of DFS.

Data was analysed using SPSS 23. Since the data was skewed, continuous data was expressed as median and interquartile range (IQR), while categorical data was expressed as frequencies and percentages. Survival data was calculated using Kaplan-Meier survival to determine differences between the two groups. The end points of interest were death and progression for OS and DFS, respectively.  Survival plot and Log rank test were employed using the Kaplan-Meier analysis. P<0.05 was considered statistically significant.

 

Results

 

Of the 520 cases of gastric cancer, 108(20.7%) formed the sample for the current study; 71(65.74%) being male subjects. The aga range was 27-80 years. The overall median age was 49.50 years (IQR: 28 years). There were 69(63.88%) patients in perioperative chemotherapy group A and 39(36.12%) in adjuvant chemotherapy group B (Table 1). At the time of analysis, in September 2021, the median follow-up for both groups was 28 months (IQR: 27.50 months).

 

 

There were 48(44.4%) patients who died; 17(35.41%) in group B, and 31(64.58%) in group A. Disease progression was found in 55(51%) cases; 23(41.81%) in group B and 32(58.18%) in group A. The probability of 2- and 3-year OS was 68.20% and 57.32% in group A, and 51.09% and 45.43%, respectively, in group B. The probability of 2- and 3-year DFS was 55.45% and 49.30% in group A, while 2-year DFS was 38.39% in group B which had no patient reaching the 3-year mark. The median OS for group A was 49.29 months (IQR: 44.50 months) and for group B it was 28.23 months (IQR: 25.00 months) (p=0.07). The median DFS was 35.46 months (IQR: 38.50 months) for group A and 10.19 months (IQR: 14.00 months) for group B (p=0.16) (Table 2).

 

 

Kaplan-Meier survival curve for OS (Figure 1) and DFS (Figure 2) expressed similar data.

 

 

 

Discussion

 

Gastric surgery is the only curative treatment for locoregional gastric cancer.¹³ Patients with resectable gastric adenocarcinoma are treated with perioperative chemotherapy or adjuvant chemotherapy to achieve downstaging and elimination of micro-metastasis, respectively. To the best of our knowledge, the current study is the first presenting local retrospective comparative data of perioperative and adjuvant chemotherapy in operable gastric cancer.

The findings demonstrated a trend towards better OS and DFS with perioperative chemotherapy, though it was not statistically significant. This goes well with data from Europe and North America.¹⁴

In a study, ECF and FLOT were compared and the median OS was 50 months, while 2- and 3-year OS was 59% and 48%, respectively, and the median DFS was 30 months.¹² The corresponding data in the current study was 49.29 months, 68.20%, 57.32% and 35.46 months. The difference could be due to younger age group in the current study and a smaller sample size compared to the earlier study.¹² Gastric cancer is a disease of younger age in Asia.¹⁵

Another study¹⁰ showed superior results with perioperative ECF chemotherapy compared to the current study. Again, age of the subjects and the size of the sample could be the important variants.¹⁶

A meta-analysis reported statistically significant adjuvant chemotherapy benefits with respect to OS and DFS.¹⁷ Another meta-analysis favoured perioperative group compared to the adjuvant chemotherapy group even though there was no difference in 1- and 2-year survival between the groups.¹⁸

One study reported better response in DFS terms when patients were given adjuvant chemotherapy along with surgery compared to those who had surgery alone.¹¹ The 3-year DFS for the adjuvant chemotherapy patients was 65%, while in the current study no patient in the adjuvant therapy group was able to reach the 3-year DFS point. The variance can be due to the difference between the sample sizes, as other study had 520 subjects¹¹ compared to 39 in adjuvant arm of the current study.

Another study compared perioperative chemotherapy with adjuvant chemotherapy,¹⁹ with those in the perioperative group showing significant increase in OS and DFS compared to the adjuvant group, which is a finding similar to that of the current study.

There are limitations in the current study as the two groups were not equal in number and the sample size was limited. Also, the retrospective data has an inherent risk of bias. Ethnicity is a critical factor in this regard, but no comparable data could be found related to south Asian population. Moreover, treatment-related adverse events and dose reduction due to toxicity in both the arms of treatment were not documented in the current study.

A prospective, comparative study is recommended to further enhance understanding and improve the care of gastric cancer patients.

 

Conclusion

 

In operable gastric cancer cases, the difference between the groups was not significant, but there was a trend suggestive of the superiority of perioperative chemotherapy over adjuvant chemotherapy with respect to OS and DFS.

 

Disclaimer: None.

 

Conflict of Interest: None.

 

Source of Funding: None.

 

References

 

1.      Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006; 24: 2137-50.

2.      Rahman R, Asombang AW, Ibdah JA. Characteristics of gastric cancer in Asia. World J Gastroenterol 2014; 20: 4483-90.

3.      Asplund J, Kauppila JH, Mattsson F, Lagergren J. Survival Trends in Gastric Adenocarcinoma: A Population-Based Study in Sweden. Ann Surg Oncol 2018; 25: 2693-702.

4.      Park J, Ryu W, Kim J, Park S, Kim S, Kim C, et al. Prognostic factors for advanced gastric cancer: stage-stratified analysis of patients who underwent curative resection. Cancer Res Treat 2006; 38: 13-8.

5.      Kanhere H, Goel R, Finlay B, Trochsler M, Maddern G. Radical Gastrectomy: Still the Cornerstone of Curative Treatment for Gastric Cancer in the Perioperative Chemotherapy Era-A Single Institute Experience over a Decade. Int J Surg Oncol 2018; 2018: 9371492.

6.      Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27(suppl 5): 38-49.

7.      Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010; 11: 439-49.

8.      Elimova E, Shiozaki H, Wadhwa R, Sudo K, Chen Q, Estrella JS, et al. Medical management of gastric cancer: a 2014 update. World J Gastroenterol 2014; 20: 13637-47.

9.      Yang Y, Yin X, Sheng L, Xu S, Dong L, Liu L. Perioperative chemotherapy more of a benefit for overall survival than adjuvant chemotherapy for operable gastric cancer: an updated Meta-analysis. Sci rep 2015; 5: 12850.

10.    Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde, Cornelis JH, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11-20.

11.    Bang Y, Kim Y, Yang H, Chung HC, Park Y, 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.

12.    Al-Batran S, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019; 393: 1948-57.

13.    Schirren R, Reim D, Novotny AR. Adjuvant and/or neoadjuvant therapy for gastric cancer? A perspective review. Ther Adv Med Oncol 2015; 7: 39-48.

14.    Tokunaga M, Sato Y, Nakagawa M, Aburatani T, Matsuyama T, Nakajima Y, et al. Perioperative chemotherapy for locally advanced gastric cancer in Japan: current and future perspectives. Surg Today 2020; 50: 30-7.

15.    Alidina A, Gaffar A, Hussain F, Islam M, Vaziri I, Burney I, et al. Survival data and prognostic factors seen in Pakistani patients with esophageal cancer. Ann Oncol 2004; 15: 118-22.

16.     Li X, Wang W, Ruan C, Wang Y, Wang H, Liang X, et al. Age-specific impact on the survival of gastric cancer patients with distant metastasis: An analysis of SEER database. Oncotarget 2017; 8: 97090- 100.

17.    GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group; Paoletti X, Oba K, Burzykowski T, Michiels S, Ohashi Y, Pignon JP, et al. Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA 2010; 303: 1729-37.

18.    Zhao J, Gao P, Song Y, Sun J, Chen X, Ma B, et al. Which is better for gastric cancer patients, perioperative or adjuvant chemotherapy: a meta-analysis. BMC Cancer 2016; 16: 631.

19.    Yonemura Y, Sawa T, Kinoshita K, Matsuki N, Fushida S, Tanaka S, et al. Neoadjuvant chemotherapy for high-grade advanced gastric cancer. World J Surg 1993; 17: 256-61; discussion 261-2.