Stomach cancer medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2] Mohammed Abdelwahed M.D[3]

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Overview

The optimal therapy for stomach cancer depends on the stage at diagnosis. Medical therapy is indicated for patients with unresectable or recurrent disease, after non-curative R2 resection (macroscopic tumor removal), patients with unresectable T4b disease, extensive nodal disease, hepatic metastases, peritoneal dissemination or other M1 disease. Response to the treatment should be evaluated by examinations such as CT scan, endoscopy and contrast radiography. Adjuvant therapy includes one cycle of fluorouracil (425 mg/m2 of body surface area) plus leucovorin calcium (20 mg/m2 of body surface area) for five days followed by radiation therapy for one month given with the same chemotherapy regimen on days 1 through 4 and the last three days of the month. For patients with potientially resectable disease not yet resected, neoadjuvant chemotherapy is preferred over initial surgery. Another benefit of neoadjuvant chemotherapy is that patients who are at high risk of developing distant metastases may be spared the morbidity of unnecessary gastrectomy if evidence of distant metastases emerges after chemotherapy. Preoperative combined chemotherapy and radiation therapy is more commonly used for esophageal, esophagogastric junction cancers, and cancer affecting the gastric cardia rather than for potentially resectable adenocarcinomas. For locally advanced unresectable and metastatic tumors, goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival. Patients with the presence of human epidermal growth factor receptor 2 (HER2) overexpression are potential candidates for trastuzumab

Medical Therapy

  • Response to the treatment should be evaluated by examinations such as CT scan, endoscopy and contrast radiography, followed by comparison with the baseline data.
  • Tumor shrinkage should be evaluated by response criteria of the Japanese Classification of Gastric Carcinoma or Response Evaluation Criteria to decide to continue with the treatment or not.
  • When continuation of the treatment is deemed oncologically feasible, the drug dosage and administration schedule should be reconsidered taking into account the adverse events observed in the previous cycle of treatment.
  • Attention should also be paid to cumulative adverse events such as skin manifestations, taste disturbance and neurotoxicity.
  • Chemotherapy for individuals exposed or infected with hepatitis B virus should be screened, monitored, and treated.
  • These drugs are to be used alone or in combination, adhering to the dose and schedule employed when being evaluated in clinical trials.

Drugs used in chemotherapy for gastric cancer

The following drugs may be used as chemotherapy for the treatment of gastric cancer:[1]

Postoperative Adjuvant Chemotherapy

  • Postoperative adjuvant chemotherapy is indicated to reduce recurrence by controlling residual tumor cells following curative resection.
  • Adjuvant treatment would be recommended for any T stage with N1 disease. However, AJCC staging system recommends observation for T2N0 stage IB patients as long as they have undergone an adequate lymph node dissection.
  • S-1 efficay was proven in the ACTS-GC trial, a study that secured the place of postoperative chemotherapy with S-1 as a standard of care.[2]
  • Another trial in Korea showed significant prolongation of recurrence-free survival with a combination of capecitabine and oxaliplatin.[3]
  • The patients eligible for the ACTS-GC trial were those with a tumor of pathological stage II, IIIA or IIIB, excluding those classified as stage II due to T1, N2, N3 status.

Patients Who Have Already Undergone Potentially Curative Resection

Preferred regimen (standard protocol):

Japanese S-1 trial:

  • S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric cancer.[7]
  • S-1 is an oral fluoropyrimidine that includes three different agents:[8]
  • Ftorafur
  • Gimeracil
  • Oteracil (responsible for treatment-related diarrhea)

Patients With Potentially Resectable Disease Not yet Resected

For most patients with potentially resectable gastric cancer, neoadjuvant therapy is preferred over initial surgery.

Neoadjuvant/perioperative chemotherapy 

Choice of regimen and patient selection

FLOT regimen

  • A regimen includes docetaxel and leucovorin with short-term infusional fluorouracil, administered every two weeks.
  • Four preoperative and four postoperative cycles (each lasting two weeks) with epirubicin-based triplet therapy (three preoperative and three postoperative cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2], both on day1.[12]
  • The FLOT regimen is associated with a higher response rate (16 percent versus 8 percent), and has less toxicity which generally makes it more favorable.[13]
Drug Dose
Oxaliplatin 85 mg/m2 IV
Leucovorin 400 mg/m2 IV
Fluorouracil 2600 mg/m2 as a 24-hour infusion
Docetaxel  50 mg/m2

ECF/ECX regimens

  • One option is to administer three cycles prior to resection and then three cycles after surgery.
  • Some clinicians attempt to administer all six courses preoperatively.[14]

Epirubicin, cisplatin, and capecitabine (ECX) regimen

Drug Dose
Epirubicin 50 mg/m2 IV
Cisplatin 60 mg/m2 IV
Capecitabine 625 mg/m2 per dose by mouth.

Epirubicin, cisplatin, and fluorouracil (ECF) regimen

Drug Dose
Epirubicin 50 mg/m2 IV
Cisplatin 60 mg/m2 IV
Fluorouracil (FU) 200 mg/m2 per day IV

Patients monitoring

Locally Unresectable Metastatic Disease

Locally Advanced Unresectable And Metastatic

First-line chemotherapy

References

  1. http://www.cancer.gov/types/stomach/patient/stomach-treatment-pdq#section/_50
  2. Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A; et al. (2007). "Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine". N Engl J Med. 357 (18): 1810–20. doi:10.1056/NEJMoa072252. PMID 17978289.
  3. Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW; et al. (2014). "Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial". Lancet Oncol. 15 (12): 1389–96. doi:10.1016/S1470-2045(14)70473-5. PMID 25439693.
  4. Kodera Y, Ishiyama A, Yoshikawa T, Kinoshita T, Ito S, Yokoyama H; et al. (2010). "A feasibility study of postoperative chemotherapy with S-1 and cisplatin (CDDP) for gastric carcinoma (CCOG0703)". Gastric Cancer. 13 (3): 197–203. doi:10.1007/s10120-010-0559-y. PMID 20820990.
  5. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN; et al. (2001). "Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction". N Engl J Med. 345 (10): 725–30. doi:10.1056/NEJMoa010187. PMID 11547741.
  6. O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG; et al. (1994). "Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery". N Engl J Med. 331 (8): 502–7. doi:10.1056/NEJM199408253310803. PMID 8041415.
  7. Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC; et al. (2017). "Chemotherapy for advanced gastric cancer". Cochrane Database Syst Rev. 8: CD004064. doi:10.1002/14651858.CD004064.pub4. PMID 28850174.
  8. Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T; et al. (2011). "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. 29 (33): 4387–93. doi:10.1200/JCO.2011.36.5908. PMID 22010012.
  9. Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA; et al. (2012). "Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection". J Clin Oncol. 30 (19): 2327–33. doi:10.1200/JCO.2011.36.7136. PMC 4517071. PMID 22585691.
  10. Ilson DH (2017). "Current Progress in the Adjuvant Treatment of Gastric Cancer". Surg Oncol Clin N Am. 26 (2): 225–239. doi:10.1016/j.soc.2016.10.008. PMID 28279466.
  11. Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM; et al. (2004). "Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma". J Clin Oncol. 22 (14): 2774–80. doi:10.1200/JCO.2004.01.015. PMID 15254045.
  12. Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB; et al. (2016). "Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial". Lancet Oncol. 17 (12): 1697–1708. doi:10.1016/S1470-2045(16)30531-9. PMID 27776843.
  13. Anter AH, Abdel-Latif RM (2013). "The safety and efficacy of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) combination in the front-line treatment for patients with advanced gastric or gastroesophageal adenocarcinoma: phase II trial". Med Oncol. 30 (1): 451. doi:10.1007/s12032-012-0451-1. PMID 23307258.
  14. Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH; et al. (2012). "Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial". Lancet. 379 (9813): 315–21. doi:10.1016/S0140-6736(11)61873-4. PMID 22226517.
  15. Gallardo-Rincón D, Oñate-Ocaña LF, Calderillo-Ruiz G (2000). "Neoadjuvant chemotherapy with P-ELF (cisplatin, etoposide, leucovorin, 5-fluorouracil) followed by radical resection in patients with initially unresectable gastric adenocarcinoma: a phase II study". Ann Surg Oncol. 7 (1): 45–50. PMID 10674448.
  16. Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM; et al. (2004). "Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma". J Clin Oncol. 22 (14): 2774–80. doi:10.1200/JCO.2004.01.015. PMID 15254045.
  17. 17.0 17.1 Yoshikawa T, Sasako M, Yamamoto S, Sano T, Imamura H, Fujitani K; et al. (2009). "Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer". Br J Surg. 96 (9): 1015–22. doi:10.1002/bjs.6665. PMID 19644974.
  18. Nakajima T, Ota K, Ishihara S, Oyama S, Nishi M, Ohashi Y, Yanagisawa A (1997). "Combined intensive chemotherapy and radical surgery for incurable gastric cancer". Ann. Surg. Oncol. 4 (3): 203–8. PMID 9142380.



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