Stomach cancer medical therapy
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. It is indicated for; patients with unresectable or recurrent disease, after non-curative R2 resection, 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 that may include CT, endoscopy and contrast radiography. Adjuvant therapy includes one cycle of fluorouracil (425 mg/m2) + leucovorin calcium (20 mg/m2) 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 diseae not yet resected, neoadjuvant therapy 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, and gastric cardia cancers 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
- The goal of chemotherapy is to delay the disease-related symptoms and to prolong survival.
- Some patients with advanced disease survive more than 5 years by chemotherapy alone.
- The median survival time of chemotherapy for recurrent gastric cancer is 6–13 months.
- Indications:
- Patients with unresectable or recurrent disease
- After non-curative R2 resection
- 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 that may include CT, 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[1]
- Fluorouracil (5FU)
- Tegafur-gimestat-otastat potassium (S-1)
- Capecitabine
- Cisplatin
- Irinotecan
- Docetaxel
- Paclitaxel
- Trastuzumab
- Ramucirumab and oxaliplatin
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 considers observation is more appropriate 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]
- Combination of S-1 and another cytotoxic drug is still under trial.[4]
- 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
- Adjuvant chemoradiotherapy, rather than surgery alone, is recommended for these patients.[5]
- For patients with T2N0 disease, observation or adjuvant treatment is acceptable and the decision is based on the patient general condition ans risk factors.
The standard protocol:
- One cycle of fluorouracil (425 mg/m2) + leucovorin calcium (20 mg/m2) 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.[6]
- Two more five-day cycles of chemotherapy are given at monthly intervals beginning one month after completion of radiation.
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)
- Five-year overall survival rates are significantly better with S-1 than the five-year survival rates for other trials.[9]
- Most of trials did not show significant importance of radiotherapy above the chemoptherapy alone.[10]
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
- Neoadjuvant chemotherapy may be administered in locally advanced tumors before surgery.
- This approach has been applied to patients thought to have resectable disease as well as to those with apparently unresectable but nonmetastatic disease.
- 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, EGJ, and gastric cardia cancers than for potentially resectable adenocarcinomas
- The pathologic complete response rates ranged from 20 to 30 percent, and 70 to 78 percent were able to undergo an R0 resection after chemoradiotherapy.[11]
Choice of regimen and patient selection
- The best chemotherapy regimen for use in the neoadjuvant setting has not been conclusively established.
- FLOT regimen is indicated for neoadjuvant therapy, rather than an epirubicin-containing regimen such as ECF or ECX.
FLOT regimen
- A regimen includes docetaxel and leucovirin with short-term infusional FU, administered every two weeks.
- Four preoperative and four postoperative two-week cycles with epirubicin-based triplet therapy (three preoperative and three postoperative three-week cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2], both on day1.[12]
- The FLOT regimen was associated with a higher pathologic complete response rate (16 versus 8 percent), and toxicity appeared generally 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
- CBC and platelet count on day before every treatment cycle
- Creatinine and liver function tests once before treatment cycles
- Monitor hearing loss prior to each dose of cisplatin
- Monitor epirubicin dose
- Reassess left ventricular ejection fraction
Locally unresectable metastatic disease
- Options for anticancer therapy include chemotherapy alone or chemoradiotherapy. Also, the best way to manage it is not established.
- Unresectable locally advanced gastric cancer is treated primarily with chemotherapy, using the same regimens as are used for metastatic disease.
- Initial chemotherapy treatment may render some patients resectable.
- Almost 70 percent of patients with localized but initially unresectable gastric cancer can undergo potentially curative resection with preoperative chemotherapy for patients with locally advanced gastric cancer without distant metastases.[15][16]
- Response rates are low between 5 and 15%.[17]
locally advanced unresectable and metastatic
First-line chemotherapy
- Goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival.
- Combination chemotherapy regimens provide higher response rates than do single agents.
- Patients with the presence of human epidermal growth factor receptor 2 (HER2) overexpression are potential candidates for trastuzumab.
Ineligibility criteria to adjuvant trastuzumab:
- Angina pectoris requiring antianginal medication
- Clinically significant arrhythmia
- Clinical significant cardiac conductive disease
- Clinically significant valvular heart disease
- Cardiomegaly on chest radiography
- Left ventricular hypertrophy on echocardiogram
- Poorly controlled hypertension
- Clinically significant pericardial effusion
- History of cardiac disease such as myocardial infarction, heart failure, or cardiomyopathy
- Left ventricular ejection fraction below than normal limits
Acceptable other option include:
- Cisplatin plus fluorouracil (FU), cisplatin plus capecitabine, oxaliplatin plus leucovorin and short-term infusional FU
- Oxaliplatin plus capecitabine
- Patients who are receiving a capecitabine-containing regimen should probably not take proton pump inhibitors concurrently.
- Concerns have been raised that higher gastric pH levels may inhibit dissolution and absorption of capecitabine, adversely impacting efficacy.
Later lines of therapy
- Ramucirumab plus paclitaxel is the preferred second line.
- Monotherapy rather than combination chemotherapy is pereferd for patients with bad general conditions such as:
- Irinotecan
- Weekly paclitaxel
- Weekly nanoparticle albumin-bound paclitaxel
- Ramucirumab
References
- ↑ http://www.cancer.gov/types/stomach/patient/stomach-treatment-pdq#section/_50
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.