Case Report, Clin Oncol Case Rep Vol: 5 Issue: 3

Treatment Care Pathways of Four Patients with Metastatic Gastro-Oesophageal Cancer in the United Kingdom (UK), Utilising Trifluridine/Tiparicil

V Kunene^1,2*, and D Fackrell^1,2

¹University Hospitals of Birmingham NHS Foundation Trust, United Kingdom

²Walsall Manor Hospital NHS Trust, United Kingdom

*Corresponding Author:

V Kunene
Cancer Centre, Queen Elizabeth Hospital,
Mindelsohn Road, Birmingham, United Kingdom
E-mail: victoriakunene@nhs.net

Received: February 28, 2022, Manuscript No: COCR-22-55803;
Editor assigned: March 02, 2022, PreQC No: P-55803;
Reviewed: March 24, 2022; QC No: Q-55803;
Revised: March 29, 2022, Manuscript No: R-55803;
Published: April 03, 2022, DOI: 10.4172/cocr.5(3).222

Citation: Kunene V, Fackrell D (2022) Treatment Care Pathways of Four Patients with Metastatic Gastro-Oesophageal Cancer in the United Kingdom (UK), Utilising Trifluridine/Tiparicil. Clin Oncol Case Rep 5:3

Abstract

Keywords: Trifluridine/Tiparicil; Metastatic; Gastric cancer; Esophageal cancer; Gastro-oeosphageal junction cancer; Prognosis; Prognostic score

Introduction

Metastatic gastric and gastro-oesophageal junction cancers outcomes remain poor, despite advances in treatment. Five years survival for stage 4 disease is less than 10%, in most parts of the world [1]. Although histopathological classification has little clinical impact, there is evidence to suggest that diffuse type and signet ring tumours do worse [2]. Molecular classification has characterised gastric cancer further, demonstrating different principal driver pathways and prognosis for each subtype [3,4].

Systemic chemotherapy remains mainstay of care in metastatic disease. Choice of first line treatment depends on patient fitness and molecular profile. In first line setting, backbone chemotherapy for most patients comprises of platinum doublet in combination with Trastuzumab in the presence of HER-2 receptor amplification [5,6]. Recently, Pembrolizumab and Nivolumab received approval in first line setting in combination with platinum doublet for tumours with combined positive score (CPS) of ≥10 and CPS ≥5 respectively [7,8]. So far, only Pembrolizumab has received approval in the United Kingdom and Nivolumab is awaiting Medicines and Healthcare products Regulatory Agency (MHRA) approval. Second line treatment options include taxanes, ramucirumab (single agent or in combination with taxanes), or irinotecan [9]. However, amucirumab is not available within the National Health service (NHS). Patients with mismatch repair protein deficiency can still receive immune check point inhibitors in 2nd line (2L) setting onwards, if not already given in first line (1L) [10]. Clinical Prognostic scores in both 1L and 2L settings have been published, to help guide treatment strategy in clinical setting and patient stratification for clinical trials [11-13].  

In 2019, Food and Drug Administration (FDA) and European Medicine Agency (EMA) approved trifluridine tipiracil (Lonsurf) for metastatic gastric cancer in 3rd line setting following the TAGS clinical trial. This showed improved overall survival with trifluridine/tipiracil compared with placebo (5.7 vs. 3.6 months respectively) [14,15]. Other approved drugs in 3rd line setting include Nivolumab and Apatinib, licenced in Asia and other countries, but not the UK or Europe [16,17]. Here we present cases of patients who received chemotherapy beyond 2^nd line and challenges encountered.

Case Presentation

Patient A

Patient A is a 79-year-old patient, with T4N1M1 metastatic adenocarcinoma of the proximal stomach. He was commenced on trifluridine/tipiracil at 35mg/m², twice daily on days 1-5 and 8-12 of each 28-day cycle after 2 lines of therapy. Baseline ECOG Performance status was 1 prior to 3^rd line treatment. He tolerated the first 2 cycles well with no side effects. He remained clinically well and treatment was paused due to the 1^st wave of the COVID virus pandemic and at this time access to imaging was unfortunately limited to emergencies. Computerised Tomography of Thorax Abdomen and Pelvis (CT TAP) at 5 months (including the 3 months break) from the start of trifluridine/tipiracil showed a mixed response with stable and progressive disease. As the patient was clinically well and performance status maintained, he was re-exposed to trifluridine/tipiracil at the same dose. After further 3 cycles, he had another CT TAP, which showed stable disease. The main side effect from treatment was neutropenia which started after cycle 3. This was managed with Pegfilgrastim 6 mg, subcutaneously and dose intensity maintained. The next CT TAP was delayed due to the 2^nd wave of COVID. As he was continuing to get clinical benefit, he continued treatment. CT Scan after cycle 10 showed disease progression. Performance status was still 1. As there were no locally available clinical trials and patient was unwilling to travel out of the region, he was re-exposed to weekly Paclitaxel based on previous good response. Unfortunately, after 2 cycles, CT scan showed disease progression and treatment was stopped. He was then put onto Best Supportive Care pathway.

Patient B

Patient B is a 67-year-old patient with metastatic Her-2+ Gastro-Oesophageal Junction (GOJ) adenocarcinoma. He was commenced on trifluridine/tipiracil 35mg/m², twice daily on days 1-5 and 8-12 of each 28-day cycle after 3 lines of chemotherapy (refer to table 1). Baseline ECOG Performance status was 0. Side effects after the first 2 cycles were grade 1 nausea, grade 1 fatigue and reduced appetite. On week 2 of cycle 3, he was admitted to hospital unwell. He was treated for neutropenic sepsis as per local treatment protocol. CT scan on cycle 3 showed disease progression. He recovered from the sepsis and was discharged home 4 days later. At this point performance status had deteriorated to 3 and clinical condition continued to decline. Treatment was stopped and unfortunately the patient passed away at home 4 weeks following hospital discharge.

Patient C

Patient C is a 58-year-old patient with metastatic HER-2 negative Type-1 GOJ adenocarcinoma. He was commenced on trifluridine/tipiracil after 2 lines of therapy. Baseline ECOG Performance status was 1. During cycle 1, he presented to hospital with hematemesis and low haemoglobin of 76 (130 g/L-180 g/L). Platelets were within normal range. He was on enoxaparin for pulmonary embolism. Gastroscopy did not show any active bleeding and Enoxaparin stopped. He had the 2^nd cycle of treatment but developed further intermittent hematemesis with drop in haemoglobin, requiring blood transfusions. Repeat gastroscopy showed friable tumour, with bleeding on contact with the scope. He was referred for radiotherapy and commenced on Tranexamic Acid. By the time he was reviewed for radiotherapy, bleeding was controlled as evidenced by increase in haemoglobin level, thus decision made not to proceed. He was not able to go back on trifluridine/tipiracil due to clinical deterioration and radiological evidence of disease progression.

Patient D

Patient D was an 80-year-old gentleman with metastatic gastric adenocarcinoma. He was consented for trifluridine/tipiracil after 2 lines of therapy. Just prior to starting treatment he was admitted to his local hospital with E.coli sepsis as a result of cholangitis. Unfortunately, his clinical condition deteriorated rapidly and could not be started on treatment. He was then put on Best Supportive Care (BSC) pathway.

In all four patients, retrospective prognostic scores were done in both 1st and 2nd line settings. (Table 2 and 3). Unfortunately, in the 2nd line setting, none of the patients had been tested for AST and LDH as these do not form part of the routine blood tests panel.

Discussion

All patients presented with metastatic disease and received at least 2 lines of treatment before they were considered for 3^rd line trifluridine/tipiracil. All patients received first line platinum doublets and Herceptin in the case of patient B. Although patient A had radiological evidence of disease progression on first lien treatment, ECOG performance status improved from 2 to 1. Second line treatment was either taxanes, or irinotecan based. Patient B was re-challenged with platinum as he had had >3 years good disease control. He achieved stable disease. Three of four patients managed to start on trifluridine/tipiracil at full dose (35mg/m²) twice daily on days 1-5 and 8-12 of each 28-day cycle.

Patient A received most benefit from trifluridine/tipiracil despite treatment interruptions due to COVID, with survival of 20 months from start of trifluridine/tipiracil until death. In the TAGS trial, over 50% of patients had received at least 3 lines of treatment [15]. The trial protocol included patients whose disease had progressed within 3 months of the last dose of therapy or were unable to tolerate their previous therapy. Over 50% of the whole study population had 3 or more metastatic sites. Post study systemic therapy was given to 25% of patients in both treatment arms. Partial response was 4% with disease control rate of 44% in the trifluridine/tipiracil arm. Time to deterioration of performance status was 4.3 months vs. 2.3 months in the trifluridine/tipiracil and placebo arms respectively. Treatment was well tolerated, with grade 3 or worse adverse events reported in 80% vs. 58%, in trifluridine/tipiracil and placebo arms respectively. The most common grade 3 adverse events were neutropenia (34%), anaemia (19%) and leucopenia (9%). Neutropenia was seen in both patient A and B but not in patient C. The tags and recourse study reported febrile neutropenia in 2% and 4.5% of patients respectively. Neutropenia was associated with treatment benefit in recourse study [18]. Response to treatment and disease control with other 3rd line agents like Apatinib and Nivolumab are comparable to trifluridine/tipiracil, reflecting disease resistance at this stage of the treatment pathway [16,17]. Increasingly, patients who are still fit after 3^rd line treatment are referred for further lines of treatment including clinical trials, as observed in the TAGS study.

Although patient B, had the longest survival, he also did not respond to trifluridine/tipiracil. Unfortunately, he died at about 3 months from start of trifluridine/tipiracil despite baseline ECOG performance status of 1 and good response to previous lines of treatment. 16%-20% of patients in the tags study were HER-2 positive. Both HER-2 positive and HER-2 negative patients benefited from trifluridine/tipiracil compared with placebo [15]. Patient C had radiological evidence of disease progression following 2 cycles. He also had intermittent upper gastrointestinal bleeding likely to have been due to combination of disease progression and anticoagulation. Patient D was unable to start treatment due to rapid clinical deterioration following a septic episode.

Patient fitness and disease burden affect outcome in most cancers. The Royal Marsden Hospital prognostic index score (RMHI) which was subsequently validated in the REAL 2 study cohort, reported  that  presence of peritoneal disease, liver metastasis, and ECOG performance status were significant prognostic factors [11,12]. Pooled analysis of 1,721 patients, showed median survival times for good, moderate, and poor risk groups to be 12.7 months, 8.6 months, and 4.3 months, respectively [11]. One-year survival for good, moderate, and poor risk groups were 48.5%, 25.7%, and 11%, respectively. In addition, patients in the good risk group who achieved good radiological response had better survival in contrast to non-responders, highlighting importance of early disease response. Slightly different Japanese Clinical Oncology Group (JCOG) prognostic index (JCOG index), also showed that ECOG PS ≥1, ≥2 metastatic sites, no prior gastrectomy, and elevated serum Alkaline Phosphatase (ALP), were significant prognostic markers [19]. One year survival in good, moderate and poor prognostic groups were 70%, 40.2% and 19.3% respectively, which was comparable to the RMHI score. Our retrospective analysis of prognostic indices showed that prior to 1^st line treatment, Patient A was classified as moderate risk whilst the rest were in the good prognostic groups (Table 2). In 2nd line setting, Fuchs et al identified 12 independent prognostic factors of survival (Rainbow/Regard index score) and came up with a 4-tier prognostic index score (low risk 0-2; medium risk 3-4; moderate risk 5-6; high risk 7-13) [13]. Survival for low, medium, moderate and high risk groups were 14.46 months, 9.92 months, 6.41 months, 3.35 months respectively [13]. Although patient A, is classified as high risk group prior to 2^nd line weekly paclitaxel, response to treatment and availability of 3^rd line treatment had a positive impact on outcome (Table 3). Patients B and C classified as low to medium risk group prior to 2^nd line treatment did not respond to trifluridine/tipiracil. Unfortunately, at present we do not have clinically meaningful predictive markers to chemotherapy agents.

Choi et al, reported prognostic factors in patients who received 3^rd line treatment [20]. Age, chemotherapy regimen and gender were not significant factors for survival. Median time interval of ≥9.5 months from 1L line therapy to 3L was a significant prognostic factor. These patients had better overall survival compared with those with interval of ≤9.5 months. In the post study subgroup exploratory analysis, Tabernero et al, looked for clinicopathological predictive factors to trifluridine/tipiracil [21]. None of the baseline clinicopathological factors analysed on multivariate cox regression analysis, were predictive of overall survival and to date there are no published predictive biomarkers to trifluridine/tipiracil. Nevertheless, superior benefit to trifluridine/tipiracil was observed in 3L compared with 4L setting and beyond. Median survival in 3L setting in the trifluridine/tipiracil  group, was 6.8 months compared to 5.2 months in 4+ line; indicating that perhaps trifluridine/tipiracil should be considered earlier in the treatment pathway than later. This is in contrast to what was seen in the RECOURSE study in chemo-refractory colorectal cancers [22,23].

Median overall survival was 5.7 months vs. 4.0 in the trifluridine/tipiracil and placebo arms respectively [22]. Exploratory analysis by prognostic factors showed that patients with low tumour burden, with at least 3 lines of treatment and responses to previous treatment, had better survival than their counterparts [23]. In addition, those in the trifluridine/tipiracil arm without liver metastasis had overall survival of 16.4 months compared to 7.7 months with liver metastasis in the same group.

Uncontrolled symptoms and poor quality of life can interfere with treatment and ultimately survival. Chau et al reported that pre-treatment general wellbeing, role functioning, and global quality of life affect survival [11]. Fuchs et al, also reported that disease related symptoms can adversely affect outcome [13]. Improvements in fatigue, nausea/vomiting, dysphagia and pain have been reported in patients receiving radiotherapy [24]. Most of the data available is retrospective with variable results, thus optimal dose of radiotherapy for symptom control remains unclear [25]. Early involvement of palliative care services is also important for ongoing supportive care.

Conclusion

Trifluridine/tipiracil is effective in 3^rd line setting compared with placebo. Absence of predictive biomarkers, like it is the case with other chemotherapy agents makes it difficult to select patients who will receive the most benefit from Trifluridine/tiparicil. Although presence of adverse clinicopathological factors can be predictive of survival outcome, they are not necessarily predictive of treatment response. Disease heterogeneity due to complex underlying molecular landscape, has significant impact on disease response and survival. Therefore, prognostic indices combining molecular markers, host immune factors, gut microbiome and clinicopathological factors are required to properly stratify patients and guide treatment. Further studies are required to help identify patients who might benefit from re-exposure to past treatments.

Disclosures

Honorarium received from Servier laboratories Ltd for the writing and submission of this publication but has had no input to the content of the publication.

References

1. American cancer Society (2021) Stomach cancer survival rates. Amer Canc Soc.
2. Petrelli F, Berenato R, Turati L, Mennitto A, Steccanella F, et al. (2017) Prognostic value of diffuse versus intestinal histotype in patients with gastric cancer: A systematic review and meta-analysis. J Gastro Oncol 8: 148-163.
   Google Scholar                            Cross Ref
3. Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513: 202-209
   Cross Ref
4. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, et al. (2015) Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 21: 449-456.
   Google Scholar
5. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, et al. (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358: 36-46.
   Google Scholar                            Cross Ref
6. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, et al. (2010) Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. The Lancet 376: 687-697.
   Google Scholar                            Cross Ref
7. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, et al. (2021) Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer: A randomised, placebo-controlled, phase 3 study. Lancet 398: 759-771.
   Google Scholar                            Cross Ref
8. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, et al. (2021) First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma: A randomised, open-label, phase 3 trial. Lancet 398: 27-40.
   Google Scholar                            Cross Ref
9. Smyth E, Moehler M (2019) Late-line treatment in metastatic gastric cancer: Today and tomorrow. Ther Adv Med Oncol 11: 175883591986752.
   Google Scholar                            Cross Ref
10. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, et al. (2019) Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II keynote-158 study. J Clin Oncol 38: 1-10.
    Google Scholar                            Cross Ref
11. Chau I, Norman AR, Cunningham D, et al. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer--pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 22: 2395-2403.
    Google Scholar                            Cross Ref
12. Chau I, Ashley S, Cunningham D (2009) Validation of the Royal Marsden hospital prognostic index in advanced esophagogastric cancer using individual patient data from the REAL 2 study. J Clin Oncol 27: e3-e4.
    Google Scholar                            Cross Ref
13. Fuchs CS, Muro K, Tomasek J, Van Cutsem E, Cho JY, et al. (2017) Prognostic factor analysis of overall survival in gastric cancer from two phase iii studies of second-line ramucirumab (regard and rainbow) using pooled patient data. J Gastric Cancer 17: 132-144.
    Google Scholar                            Cross Ref
14. USFD (2021) FDA approves Lonsurf for recurrent, metastatic gastric and gastroesophageal junction adenocarcinoma. USFD.
15. Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 19: 1437-1448.
    Google Scholar                            Cross Ref
16. Li J, Qin S, Xu J, Xiong J, Wu C, et al. (2016) Randomized, double-blind, placebo-controlled phase iii trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 34: 1448-1454.
    Google Scholar                            Cross Ref
17. Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, et al. (2017) Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double- blind, placebo-controlled, phase 3 trial. Lancet 390: 2461-2471.
    Google Scholar                            Cross Ref
18. Ohtsu A, Yoshino T, Falcone A, Garcia-Carbonero R, Argiles G, et al. (2017) Onset of neutropenia as an indicator of treatment response in the phase 3 RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo in patients with metastatic colorectal cancer. J Clin Oncol 35: 775.
    Google Scholar                            Cross Ref
19. Takahari D, Boku N, Mizusawa J (2014) Determination of prognostic factors in Japanese patients with advanced gastric cancer using the data from a randomized controlled trial, Japan clinical oncology group 9912. Oncologist 19: 358-366.
    Google Scholar                            Cross Ref
20. Choi IS, Choi M, Lee JH (2018) Treatment patterns and outcomes in patients with metastatic gastric cancer receiving third-line chemotherapy: A population-based outcomes study. PLoS One 13: e0198544.
    Google Scholar                            Cross Ref
21. Tabernero J, Shitara K, Zaanan A, Doi T, Lorenzen S, et al. (2021) Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: An exploratory subgroup analysis from the TAGS study. ESMO Open 6: 100200.
    Google Scholar                            Cross Ref
22. Mayer RJ, Van Cutsem E, Falcone A (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372: 1909-1919.
    Google Scholar                            Cross Ref
23. Tabernero J, Argiles G, Sobrero AF, Borg C, Ohtsu A, et al. (2020) Effect of trifluridine/tipiracil in patients treated in RECOURSE by prognostic factors at baseline: an exploratory analysis. ESMO Open 5: e000752.
    Google Scholar                            Cross Ref
24. Kawabata H, Hitomi M, Motoi S (2019) Management of bleeding from unresectable gastric cancer. Biomedicines 7: 54.
    Google Scholar                            Cross Ref
25. Tey J, Soon Y, Koh W, Leong C, Choo B, et al. (2017) Palliative radiotherapy for gastric cancer: A systematic review and meta-analysis. Oncotarget 8: 25797-25805.
    Google Scholar                    Cross Ref