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Pharmacotherapy Overview in Gastroesophageal Cancers

Oncology
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Fluoropyrimidines

Fluoropyrimidines are the backbone of many chemotherapy regimens for the management of esophagogastric cancer. 5-Fluorouracil (5-FU) and its oral form, capecitabine, can be used interchangeably and as monotherapy or in combination with other chemotherapy agents to treat both early and advanced diseases.
They are also radiosensitizers and can enhance the activity of radiation when given concurrently. 5-FU or capecitabine are usually combined with a platinum or taxane because of known synergistic activity. Examples of these chemotherapy doublets include fluoropyrimidine plus oxaliplatin (FOLFOX, CapeOX) or fluoropyrimidine plus cisplatin (CF). FLOT, which consists of 5-FU, oxaliplatin, and docetaxel, is an option for perioperative or preoperative chemotherapy for the treatment of thoracic, esophagus, or certain gastroesophageal junction (GEJ) type adenocarcinomas.
It is also a first-line regimen for advanced esophagogastric cancer. However, its use is limited in practice due to a higher risk of toxicities. This regimen is reserved for patients with excellent performance status and in cases where the benefits outweigh the risks.
The preferred first-line chemotherapy regimen for advanced disease is a doublet of fluoropyrimidines plus platinum (FOLFOX, CapeOX, CF) with or without a targeted therapy (i.e. human epidermal growth factor receptor-2 (HER-2) or programmed death-1 (PD-1) inhibitors) depending on the tumor’s molecular profile.
For patients with a borderline performance status and unable to tolerate combination chemotherapy, 5-FU or capecitabine alone are options. Fluorouracil is also used in the second-line or advanced setting as monotherapy or in combination with irinotecan (FOLFIRI). Due to higher risks of toxicity with capecitabine, only 5-FU should be given with irinotecan [1,2].
These drugs work in the S phase of the cell cycle and interrupt DNA and RNA synthesis. Capecitabine is a prodrug that undergoes enzymatic activation to 5-FU in the liver. Activation of 5-FU forms several metabolites including fluorodeoxyuridylate (FdUMP), fluorouridine triphosphate (FUTP), and fluorodeoxyuridine triphosphate (FdUTP).
The cytotoxicity of capecitabine and 5-FU is dependent on these active metabolites. FdUMP binds to thymidylate synthase (TS) and inhibits thymidylate synthesis. Consequently, DNA replication is interrupted. Other metabolites have a more direct effect. FUTP and FdUTP can incorporate into DNA and RNA, respectively, and result in DNA strands breaks and apoptosis.[2-4]
Dosage of fluoropyrimidines varies widely depending on the agent and the regimen. 5-FU is administered intravenously (IV) as a bolus or a continuous infusion. For esophagogastric cancer, the standard starting dose ranges from 200-1200 mg/m2/day. When given concurrently with radiation, the most common dose is 200-300 mg/m2/day on days of radiation.
Some 5-FU-based doublet regimens contain both a bolus and continuous infusion. Depending on the regimen, the typical range for IV bolus is 200- 400 mg/m2 and for continuous infusion is 800-1200 mg/m2/day on days 1 and 2, every 14 days.
In contrast, capecitabine is an oral tablet. The recommended dose with concurrent radiation for esophagogastric cancer is 625-800 mg/m2 twice daily on days of radiation. In contrast, the capecitabine dose for systemic treatment alone is 750-1000 mg/m2 twice daily for 14 consecutive days every 21-day cycle.
There are two capecitabine tablet strengths: 150 mg and 500 mg. Rounding the calculated dose to the nearest number of tablets and using one strength for the entire regimen are good practices to improve compliance, safety, and patient cost.
Patients should take capecitabine 30 minutes after eating with a full glass of water. At the initiation of therapy and during treatment, prescribing information should be consulted to determine dosing adjustment for organ dysfunction particularly for renal impairment and severe toxicity. It is also advisable to initiate therapy at a lower dose for patients with borderline performance status who may not able to tolerate the full dose and for treatment with a palliative intent.[1,3,4]
Common side effects of fluoropyrimidines include hand-foot syndrome (HFS), mucositis, photosensitivity, diarrhea, and myelosuppression.
Recommended strategies for the prevention of HFS and mucositis include applying fragrant-free moisturizers to palms and soles and using baking soda mouthwash several times a day, respectively. These agents have a low emetogenic potential. Patients should be given an as-needed antiemetic agents.
To reduce the risk of infection, patients should practice good hand hygiene, monitor their temperature, and seek emergent care for fever or severe chills. It is also important to advise patients to report any chest pain while on therapy as this could be fluorouracil-induced coronary spasm. While most cases are mild, there have been a few cases of cardiomyopathy associated with fluoropyrimidines.
The frequency of these side effects can vary depending on the drug, route of administration, and schedule. For example, the risk of cardiotoxicity is higher with continuous infusion compared to bolus administration of fluorouracil.
For HFS, the risk is higher with capecitabine compared to 5-FU. When given as a bolus, 5-FU is more likely to cause myelosuppression. In general, the first step to managing mild side effects is to optimize supportive care. For moderate to severe side effects, interruption of therapy is recommended. Once symptoms have significantly decreased or resolved, a reduced dose should be considered to improve tolerance and prevent further interruption of therapy.[3,4]
In some cases, increased toxicity may be due to a deficiency in dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-FU. Testing for DPD deficiency is not standard across institutions but can be considered prior to starting or when toxicity occurs early in the treatment and/or unusually severe toxicity occurs. Patients with known complete DPD deficiency should not receive treatment with fluoropyrimidine. For other degrees of DPD deficiency, a dose reduction is required.
In case of an emergency overdose, uridine triacetate is an antidote that can reverse the toxicity of 5-FU when given immediately after an overdose or within 96 hours of fluoropyrimidine administration. The recommended dose of uridine triacetate for adults is 10 grams every 6 hours for a total of 20 doses. [3-5]
Trifluridine-tipiracil (TAS-102)
TAS-102 is an oral antitumor agent consisting of trifluridine and tipiracil. The cytotoxic component, trifluridine, is a thymidine analog. Once activated, it incorporates into DNA and prevents cell proliferation. Tipiracil inhibits thymidine phosphorylase, an enzyme that breaks down trifluridine.
TAS-102 is indicated as a monotherapy for the third-line treatment of advanced gastric or GEJ adenocarcinoma. The recommended dose is 35 mg/m2 BID on days 1 – 5 and days 8 – 12 every 28-day cycle. Given the complicated schedule, a patient calendar may be warranted to help with adherence.
Two tablet strengths are available and it is advised to prescribe rounding to the nearest number of tablets using one strength for the entire regimen. Patients with moderate hepatic function at baseline should not receive TAS-102 given a lack of study.
There are recommended dose adjustments for renal dysfunction and severe toxicities. TAS-102 does not cause HFS but may cause nausea, vomiting, diarrhea, mucositis, fatigue, and myelosuppression. Supportive medications for patients on TAS-102 should include an antiemetic regimen for moderate emetic risk and antidiarrheal medications.[6,7]

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) are changing the treatment landscape for esophagogastric cancer. The following ICIs have been added to standard treatment: nivolumab, ipilimumab, and pembrolizumab.
Nivolumab is an adjuvant treatment option given for one year for patients with esophageal or EGJ cancer who had preoperative chemoradiation and pathologic residual disease after complete resection.
All three agents have indications in the first-line treatment of advanced disease based on results from recent data showing an improved survival benefit compared to chemotherapy. Nivolumab plus chemotherapy is indicated for the first-line treatment of adenocarcinoma. Although all patients benefited from the addition of nivolumab, the largest effect was in patients with a combined positive score (CPS) score of 5 or greater.
Nivolumab can also be combined with chemotherapy for the first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). The largest benefit for this group was seen in the subgroup with a tumor propensity score (TPS) score of 1 or greater.
Nivolumab plus ipilimumab, a chemotherapy-free regimen, is also indicated for untreated advanced ESCC. The benefit of this regimen may be delayed, making it a less-than-ideal option for patients with a high symptom burden at presentation.
Similarly, pembrolizumab plus chemotherapy is indicated as a first-line treatment option for patients with untreated advanced esophagogastric cancer. The largest benefit seen in this population was in the subgroup with a CPS of 10 or greater. Additionally, pembrolizumab may be added to first-line chemotherapy for patients with HER-2-positive advanced gastric or EGJ adenocarcinoma. For previously treated patients, pembrolizumab is indicated for ESCC with a CPS of 10 or greater and MSI-H or dMMR tumors or TMB-high tumors regardless of histology if these agents were not utilized in the front-line setting. Nivolumab is also indicated for previously treated ESCC again if not given front-line. [1,8-12]
While all three drugs are ICI, these monoclonal antibodies bind to different checkpoints. Nivolumab and pembrolizumab bind to programmed cell death-1 (PD-1), and ipilimumab binds to cytotoxic T-lymphocyte associated antigen-4 (CTLA-4). The binding of ICIs to their target promotes T-cell activation and proliferation, increasing the antitumor immunologic response.
Dosages for these agents vary. The fixed dose of nivolumab is 240 mg IV every 14 days or 480 mg every 28 days. When combined with ipilimumab, the dose of nivolumab is 3 mg/kg IV every two weeks, and the dose of ipilimumab is 1 mg/kg every six weeks.
Other dosing variations of this doublet are available but may be harder to tolerate. Pembrolizumab also has a fixed dose of 200 mg IV every three weeks or 400 mg IV every six weeks. There are no recommended dose adjustments for ICIs.[13-15]
ICIs can induce immune-related toxicities that can affect any organ system. Common side effects include:
  • pruritus,
  • skin rash,
  • thyroid dysfunction,
  • pneumonitis,
  • hepatitis,
  • colitis.
Timely diagnosis and management are crucial to reducing the risk of severe complications. Evidence-based guidelines on the management of immune-related adverse events (irAEs) are available and should be consulted for specific symptoms. Thyroid hormone replacement therapy is generally enough to manage endocrine toxicities without requiring ICI treatment interruption.
For non-endocrine toxicities, treatment interruption and initiation of a high-dose corticosteroid regimen are necessary for moderate to severe symptoms. Once symptoms have improved, the steroid regimen should be slowly tapered down over approximately four to six weeks. For steroid-refractory irAEs, escalation to an appropriate immunosuppressive agent and consultation with a specialist are recommended.
Rechanging ICI is reasonable when symptoms have resolved and if the benefits outweigh the risks. For life-threatening irAE, the ICI should be discontinued permanently.[13-16]

Taxanes

Taxanes, including docetaxel and paclitaxel, work by disruption of the microtubules. These are utilized in many settings in gastroesophageal cancers. Docetaxel can be given as perioperative therapy with FLOT in early-stage gastric adenocarcinoma patients. FLOT is oxaliplatin 85 mg/m2, docetaxel 50 mg/m2, leucovorin 200 mg/m2, and 5-Fluorouracil 2600 mg/m2 continuous infusion for 24 hours repeated every 14 days.[1]
Unfortunately, many patients in the FLOT-AIO trial did not complete all planned allotted cycles[17] stressing the importance of patient selection for this approach and monitoring/management of adverse events.
Docetaxel and paclitaxel are also options in the advanced setting.[1,18] Paclitaxel at 80 mg/m2 days 1, 8, and 15 +/- ramucirumab 8 mg/kg on days 1 and 15 of a 28-day cycle is an option for gastroesophageal adenocarcinoma patients who have progressed on front-line therapy. Cumulative neuropathy from front-line platinum treatment can sometimes hinder this regimen’s utilization in the second-line setting. Docetaxel and paclitaxel are also options in the advanced squamous cancer setting.[1]
These agents have a hypersensitivity risk (particularly with the first cycle of therapy) and premedication per prescribing information should be followed to prevent such reactions.[19-20] These agents can cause myalgias, alopecia, neuropathy, and have a low emetogenic risk.

Platinums

Platinum agents work by integrating platinum DNA crosslinks. Platinums like the fluoropyrimidines and taxanes are a backbone of gastroesophageal cancer management.[1] Oxaliplatin and cisplatin are recommended front-line agents given in combination with a fluoropyrimidine for advanced unresectable gastroesophageal cancers.[1,18]
Oxaliplatin is included in FLOT regimen which as mentioned is a perioperative option for early-stage gastric adenocarcinoma patients. Carboplatin can be utilized in early-stage esophageal cancer in combination with paclitaxel as a radiation sensitizer given results of the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial.[21] Oxaliplatin or cisplatin given with a fluoropyrimidine are also radiation sensitizer regimens that can be used as alternatives to the CROSS regimen.[1]
Toxicity across platinum agents include the risk for delayed hypersensitivity, peripheral neuropathy, myelosuppression, and nausea/vomiting[22-24]. These agents are considered moderate or highly emetogenic therapies dependent on agent and dose and prevention of nausea is an important management with these agents.
Toxicity specific to each agent include oxaliplatin cold induced dysesthesia, carboplatin induced thrombocytopenia, and cisplatin induced nephrotoxicity. Dosing strategies vary for these agents given the indications.

Targeted Therapy

Targeted therapy success in gastroesophageal cancers has lagged other solid tumors. Advanced gastroesophageal adenocarcinoma patients can overexpress HER-2 (~15-20%).[18] These patients can be candidates for anti-HER-2 agents.
Trastuzumab, an anti-HER-2 monoclonal antibody, was the first targeted therapy approved. Trastuzumab was approved based on the 2010 Trastuzumab for Gastric Cancer (ToGA) trial results.[25]
ToGA examined trastuzumab in combination with chemotherapy (a fluoropyrimidine + platinum) compared to chemotherapy alone in patients with advanced unresectable HER-2 overexpressed gastric or GEJ adenocarcinoma. An improvement in outcomes was evident with the addition of trastuzumab. Trastuzumab is recommended to be given upfront in combination with a fluoropyrimidine and platinum (oxaliplatin or cisplatin).
Toxicities with trastuzumab are well known and include cardiotoxicity and infusion related reactions.[26] Dosing ranges from 2 -6 mg/kg dependent on how often this is being prescribed. Routine left ventricular heart function should be assessed. A left ventricular ejection fraction (LVEF) 10% drop from baseline or if LVEF drops below 50% should warrant review of risk vs. benefit of continuing therapy.
Unfortunately, progress in the HER-2 investigation after the approval of trastuzumab. Until recently, fam-trastuzumab deruxtecan, an antibody drug conjugate of trastuzumab in combination with a topoisomerase inhibitor, was approved in the refractory HER-2 expressed advanced unresectable gastroesophageal adenocarcinoma setting.[27] This approval was based on phase 2 promising outcomes.[28]
Fam-trastuzumab deruxtecan, given the cytotoxic component, has additional adverse effects including moderate emetogenic level, myelosuppression, and alopecia. An additional adverse effect requiring monitoring is interstitial lung disease. Fam-trastuzumab deruxtecan is approved at a dose of 6.4 mg/kg IV every three weeks.
Ramucirumab, anti-vascular endothelial growth factor receptor (VEGF) monoclonal antibody, was approved in 2014. [29] It is recommended for patients in the refractory setting alone or in combination with paclitaxel. This approval was based on results of the REGARD and RAINBOW studies.[30-31]
Ramucirumab is given at a dose of 8 mg/kg IV every 2 weeks. Adverse effect monitoring is like that of other anti-VEGF agents including hypertension, proteinuria, bleeding, and avoidance in those at risk for perforation. [29] A histamine-1 antagonist is recommended to avoid infusion related reactions with ramucirumab.

References

  1. National Comprehensive Cancer Network I. NCCN Guidelines® for Esophageal and Esophagogastric Junction Cancers (Version 4.2022). https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. Accessed October 1, 2022.
  2. Ryan DP, Grem, J., Chabner, B. A. . 5-Fluoropyrimidines. In: B. A. Chabner DLL, ed. Cancer Chemotherapy, Immunotherapy and Biotherapy: Principles and Practice. 6 ed.: Lippincott Williams & Wilkins.; 2019:114-135.
  3. Adrucil (fluorouracil injection) [prescribing information]. North Wales, PA: Teva Pharmaceuticals Inc; October 2017.
  4. Xeloda (capecitabine) [prescribing information]. South San Francisco, CA: Genentech USA Inc; May 2021.
  5. Vistogard (uridine triacetate) [prescribing information]. Rockville, MD: Wellstat Therapeutics Corporation; February 2017.
  6. Lonsurf (trifluridine and tipiracil) [prescribing information]. Princeton, NJ: Taiho Oncology; December 2019.
  7. Shitara K, Doi T, Dvorkin M, 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. 2018;19(11):1437-1448.
  8. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021;384(13):1191-1203.
  9. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40.
  10. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022;386(5):449-462.
  11. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-771.
  12. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600(7890):727-730.
  13. Opdivo (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; May 2022.
  14. Yervoy (ipilimumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; May 2022.
  15. Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; August 2022.
  16. Medina P, Jeffers KD, Trinh VA, Harvey RD. The Role of Pharmacists in Managing Adverse Events Related to Immune Checkpoint Inhibitor Therapy. J Pharm Pract. 2020;33(3):338-349.
  17. Al-Batran SE, Homann N, Pauligk C, 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(10184):1948–1957.
  18. National Comprehensive Cancer Network I. NCCN Guidelines® for Gastric Cancer (Version 2.2022). https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed October 1, 2022.
  19. Docetaxel [prescribing information]. Lake forest, IL: Hospira Inc; June 2021.
  20. Paclitaxel [prescribing information]. Lake forest, IL: Hospira Inc; April 2021. 
  21. Van Hagen P, Hulshof MCCM, van Lanschot JJB, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366 (22): 2074-2084. 
  22. Oxaliplatin [prescribing information]. Lake forest, IL: Hospira Inc; April 2021.
  23. Cisplatin [prescribing information]. Paramus, NJ: WG Critical Care, LLC. February 2019. 
  24. Carboplatin [prescribing information]. Lake forest, IL: Hospira Inc; April 2018.
  25. Bang YJ, Van Cutsem E, Feyereislova A, et al. 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. Lancet. 2010;376(9742):687–697.
  26. Herceptin (trastuzumab) [prescribing information]. South San Francisco, CA: Genetech, Inc. February 2021. 
  27. Enhertu (fam-trastuzumab deruxtecan) [prescribing information].  Basking Ridge, NJ: Daiichi Sankyo, Inc. August 2022. 
  28. Shitara K, Bang, YJ, Iwasa, S et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382(25):2419–2430.
  29. Cyramza (ramucirumab) [prescribing information]. Indianapolis, IN: Eli Lilly and Company. March 2022. 
  30. Wilke H, Muro, K, Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–1235.
  31. Fuchs CS, Tomasek, J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–39.