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. 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

• 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 (macroscopic removal of primary tumor margins)
  • Patients with unresectable T4b disease
  • Extensive nodal disease
  • Hepatic metastases
  • Peritoneal dissemination or other M1 disease (metastatic disease)

• 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:

• 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 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.

• Another trial in Korea showed significant prolongation of recurrence-free survival with a combination of capecitabine and oxaliplatin.

• Combination of S-1 and another cytotoxic drug is still under trial.

• 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.
• For patients with T2N0 disease, observation or adjuvant treatment is acceptable and the decision is based on the general condition of the patient and risk factors.

Preferred regimen (standard protocol):

• One cycle of fluorouracil (425 mg/m2 of body surface area) + 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.
• 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.
• S-1 is an oral fluoropyrimidine that includes three different agents:
• 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.
• Most of trials do not show increased benefit of radiotherapy over chemoptherapy alone.

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 non-metastatic 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, esophagogastric junction cancers, and cancer affecting the gastric cardia rather than for potentially resectable adenocarcinomas
• The response rates ranging from 20 percent to 30 percent, and 70 percent to 78 percent were able to undergo an R0 resection after chemoradiotherapy.

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.

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.
• 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.

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.

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 one day before every treatment cycle
• Creatinine and liver function tests once before treatment cycles
• Monitor for 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.
• Unresectable locally advanced gastric cancer is treated primarily with chemotherapy, using the same regimens as are used for metastatic disease.
• Initial chemotherapy treatment may transform a previously unresectale tumor to a resectable tumor.
• 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.
• Response rates are low between 5 and 15%.

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.

Contraindications 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 not take proton pump inhibitors concurrently.
• Concerns have been raised that higher gastric pH levels may inhibit dissolution and absorption of capecitabine, leading to decreased efficacy.

Alternative regimens:

• Ramucirumab plus paclitaxel is the preferred second line.

• Monotherapy rather than combination chemotherapy is pereferred for patients with bad general conditions such as:?

• Irinotecan
• Weekly paclitaxel
• Weekly nanoparticle albumin-bound paclitaxel
• Ramucirumab