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]

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Overview

The optimal therapy for stomach cancer depends on the stage at diagnosis.

Medical therapy

• The current goal of chemotherapy is to delay the manifestation of disease-related symptoms and to prolong survival. Some patients with advanced disease survive more than 5 years by chemotherapy alone.
• Chemotherapy is the treatmentof choice for unresectable/ recurrent gastric cancer.
• The median survival time achieved by chemotherapy for unresectable/ 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 in mSolid Tumors (RECIST) to decide on whether or not to continue with the treatment.

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 by 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

• Fluorouracil (5FU)
• Tegafur-gimestat-otastat potassium (S-1)
• Capecitabine
• Cisplatin
• Irinotecan
• DocetaxelPaclitaxel
• Trastuzumab
• Ramucirumab and oxaliplatin

Postoperative adjuvant chemotherapy

Postoperative adjuvant chemotherapy is delivered with an intention to reduce recurrence by controlling residual tumor cells following curative resection.

Various regimens had been tested in numerous clinical trials in Japan without producing solid evidence in support of adjuvant chemotherapy until the efficacy of S-1 was proven in the ACTS-GC trial [29, 30], a study that secured the place of postoperative chemotherapy with S-1 as a standard of care (recommendation category 1).

After this, the feasibility of several combinations of anticancer drug with S-1 was explored in the postoperative setting [31, 32], and some of the combinations are currently under evaluation in phase III trials. On the other hand, other phase III evidence in support of postoperative chemotherapy was established in 2012 by the CLASSIC trial conducted mainly in Korea [33], in which significant prolongation of recurrence-free survival was shown with a combination of capecitabine and oxaliplatin.

Survival benefit of postoperative adjuvant chemotherapy by combination of S-1 and another cytotoxic drug, including oxaliplatin, will have to be proven by a randomized trial with S-1 monotherapy as a control.

• AJCC staging system considers observation is more appropriate for T2N0 stage IB patients as long as they have undergone an adequate lymph node dissection (for most patients, a D2 rather than D1 lymphadenectomy
• However, adjuvant treatment would be recommended for any T stage with N1 disease.

Indications

• 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 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.
• 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 the INT0116 and the MAGIC trials.
• The available data have not conclusively resolved the issue of which approach is best; the radiochemotherapy or the chemotherapy alone Most of trials did not show significant importance of radiotherapy above the chemoptherapy alone.

Patients with potientially resectable diseae not yet resected

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

Neoadjuvant/perioperative chemotherapy 

• Neoadjuvant chemotherapy may be administered as a means of "downstaging" a locally advanced tumor prior to an attempt at curative resection.
• 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.

Choice of regimen and patient selection

• The best chemotherapy regimen for use in the neoadjuvant setting has not been conclusively established.
• FLOT regimen (docetaxel plus oxaliplatin and LV plus short-term infusional FU) rather than an epirubicin-containing regimen (such as ECF or ECX [epirubicin plus cisplatin and capecitabine]),

• Whether the FLOT regimen is superior to FU plus cisplatin alone, oxaliplatin plus leucovorin and short-term infusional FU (FOLFOX), or oxaliplatin plus capecitabine is not established, and these are also

ECF/ECX

• One option is to administer three cycles prior to resection and then three cycles after surgery, as was actually done in the MAGIC trial; however, some clinicians attempt to administer all six courses preoperatively because several trials indicate that the chance of delivering all planned postoperative therapy is only approximately 37 to 60%.

FLOT

A regimen that includes docetaxel (50 mg/m²) plus oxaliplatin (85 mg/m²) and LV (200 mg/m²) with short-term infusional FU (2600 mg/m² as a 24-hour infusion), all on day 1 and administered every two weeks (the FLOT regimen), is also active in the neoadjuvant setting.

The phase II/III FLOT4-AIO trial compared the docetaxel-based triplet FLOT regimen described above (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 day 1, and either FU 200 mg/m² daily as a continuous infusion days 1 to 21 [ECF] or capecitabine 1250 mg/m²orally, daily days 1 to 21 [ECX]) [58]. In a report of the 300 patients with gastric or EGJ adenocarcinoma who were enrolled in the open-label phase II part of the trial, The FLOT regimen was associated with a higher pathologic complete response rate (16 versus 8 percent), and toxicity appeared generally more favorable. At least one serious adverse event involving a perioperative medical or surgical complication developed in 25 versus 40 percent of the patients in the FLOT and ECF/ECX groups, respectively, and there was less grade 3 or 4 nausea (9 versus 17 percent), fatigue (9 versus 14 percent), and vomiting (3 versus 10 percent). However, rates of grade 3 or 4 neutropenia were higher with FLOT (52 versus 38 percent).  

Preoperative combined chemotherapy and radiation therapy (RT) is more commonly used for esophageal, EGJ, and gastric cardia cancers than for potentially resectable noncardia gastric adenocarcinomas

There are no randomized trials addressing the benefit of preoperative chemoradiotherapy for noncardia gastric cancers. In three separate phase II studies using different chemoradiotherapy protocols, 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 [60-62]. Whether these results are better than could be achieved with surgery alone, neoadjuvant chemotherapy, or surgery followed by adjuvant chemoradiotherapy is unclear.

The use of induction chemoradiotherapy for patients with initially unresectable gastric cancer is discussed below.

Locally unresectable metastatic disease

• The best way to manage locally advanced, initially unresectable disease is not established. Options for anticancer therapy include chemotherapy alone or chemoradiotherapy:
• Unresectable locally advanced gastric cancer is often treated primarily with chemotherapy, using the same regimens as are used for metastatic disease.
• Initial chemotherapy treatment may render some patients resectable.
• Use of preoperative chemotherapy for patients with locally advanced gastric cancer without distant metastases
• response rates are low, between 5 and 15%
• preoperative combined modality therapy (chemoradiotherapy with or without induction chemotherapy), approximately 70 percent of patients with localized but initially unresectable gastric cancer can undergo potentially curative resection

locally advanced unresectable and metastatic

First-line chemotherapy

Goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival.

There is no consensus as to the best agent or regimen.

Combination chemotherapy regimens provide higher response rates than do single agents

Patients with advanced gastric or esophageal adenocarcinoma who are potential candidates for trastuzumab should have their tumors assayed for the presence of human epidermal growth factor receptor 2 (HER2) overexpression utilizing tumor-specific criteria and/or gene amplification.

Ineligibility criteria to adjuvant trastuzumab trials:

Angina pectoris requiring antianginal medication

Arrhythmia requiring medication

Severe conduction abnormality

Clinically significant valvular heart disease

Cardiomegaly on chest radiography

Left ventricular hypertrophy on echocardiogram (NSABP B-31 only)

Poorly controlled hypertension

Clinically significant pericardial effusion (NCCTG trial N9831 only)

History of myocardial infarction, heart failure, or cardiomyopathy

LVEF below the lower limit of normal

• Acceptable option include cisplatin plus fluorouracil (FU) cisplatin plus capecitabine, oxaliplatin plus leucovorin and short-term infusional FU (FOLFOX), or oxaliplatin plus capecitabine (XELOX/CAPOX
• 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.

the choice of chemotherapy regimen is empiric.

fluoropyrimidine-containing doublet combination regimen, rather than a triplet regimen

For most patients, we prefer a fluoropyrimidine plus oxaliplatin.

Another option is the triplet combination of a fluoropyrimidine plus oxaliplatin and docetaxel

Later lines of therapy

Suggest ramucirumab plus paclitaxel (Grade 2A).

For patients with squamous cell cancer (SCC) who have disease progression on or after prior treatment with fluoropyrimidine or platinum-containing chemotherapy,

for those for whom limiting treatment-related toxicity is an important goal, we suggest monotherapy rather than combination chemotherapy (Grade 2C).

irinotecan

 weekly paclitaxel

weekly nanoparticle albumin-bound paclitaxel nabpaclitaxel

ramucirumab monotherapy

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibody therapy is a type of targeted therapy used in the treatment of gastric cancer.

Monoclonal antibody therapy uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. For stage IV gastric cancer and gastric cancer that has recurred, a monoclonal antibody such as trastuzumab may be given to block the effect of the growth factor protein HER2, which sends growth signals to gastric cancer cells.