Stomach Cancer Recurrence: What to Ask

NCI's PDQ summary for health professionals puts recurrent gastric cancer in the same section as stage IV and inoperable disease. The three share one option list.

That grouping tells a patient something useful. The plan will be built the way an advanced-disease plan is built, starting with tumor testing rather than with a drug.

PDQ says patients with metastatic gastric adenocarcinoma should consider testing for a specific set of markers.

• HER2 amplification. PDQ counts a tumor as HER2-positive at 3+ on staining, or at 2+ on staining with a positive FISH test.
• Defective mismatch repair, or dMMR, which is checked by staining the tissue.
• Microsatellite instability, or MSI, which is checked by polymerase chain reaction.
• PD-L1 combined positive score, known in the United States as the CPS score.

Each of those routes to a different drug. HER2 status decides the first-line branch. dMMR or MSI-high status opens pembrolizumab in the second line. PD-L1 scoring feeds the immunotherapy decision.

There is a fifth marker further down the list. PDQ names zolbetuximab for tumors positive for CLDN18.2, also written claudin 18.2. It is given with CAPOX or with mFOLFOX6.

For HER2-negative tumors, PDQ lists palliative chemotherapy, with or without immunotherapy. It names one combination in full. Fluorouracil or capecitabine, plus oxaliplatin, plus nivolumab.

Below that come the chemotherapy tiers. Triplet regimens pair fluorouracil with two other drugs, in several combinations. Doublet regimens include a taxane with cisplatin or carboplatin. They also include fluorouracil with cisplatin, and CAPOX. Single agents are fluorouracil, capecitabine, or a taxane alone.

For HER2-positive tumors, PDQ lists three first-line approaches. Immunotherapy with chemotherapy. Nivolumab with chemotherapy. And trastuzumab with chemotherapy.

PDQ's second-line list has four entries. Palliative chemotherapy. Ramucirumab, with or without chemotherapy. Pembrolizumab, for tumors that are dMMR or MSI-high. And trastuzumab deruxtecan, for HER2-positive tumors.

Third-line, PDQ names one option: trifluridine with tipiracil.

Two approaches sit outside the standard list, still under study. One is regorafenib with nivolumab. The other pairs cytoreductive surgery with heated chemotherapy washed through the abdomen.

And one line is a clear negative. PDQ states that treatment with PARP inhibitors and hepatocyte growth factor inhibitors has not shown efficacy at this time, though combination studies are under way.

PDQ answers this directly, which is unusual and useful.

Standard chemotherapy has been tested against best supportive care in metastatic gastric cancer across several trials. PDQ says there is general agreement that patients who receive chemotherapy live for several months longer on average than patients who receive supportive care. It grades that Level of evidence A1.

It then notes what 20 years of comparisons produced. Many randomized studies set single-drug chemo against doublets and triplets. PDQ says no clear consensus emerged on the best approach. A meta-analysis of those studies gave a hazard ratio of 0.83 for overall survival, favoring combinations. The 95% confidence interval ran from 0.74 to 0.93.

PDQ adds that adding immune checkpoint inhibitors to oxaliplatin-based chemotherapy has shown further overall survival benefit.

The numbers here help set expectations, and they are modest.

PDQ describes epirubicin, cisplatin, and fluorouracil, abbreviated ECF, as often considered the reference standard in the United States and Europe.

One European trial enrolled 274 patients with metastatic esophagogastric cancer. It compared ECF against fluorouracil, doxorubicin, and methotrexate. Median survival was 8.9 months with ECF, against 5.7 months. The P value was .0009.

A second trial compared ECF against mitomycin, cisplatin, and fluorouracil. Median survival was 9.4 months against 8.7, with a P value of .315. That difference was not statistically significant.

PDQ notes that oxaliplatin or capecitabine are often swapped into the ECF regimen. The basis is the REAL-2 trial. That randomized trial used a two-by-two design. It enrolled 1,002 patients with advanced esophageal, gastroesophageal junction, or gastric cancer.

Recurrent gastric cancer often causes mechanical problems, and PDQ handles those separately.

For a blocked stomach outlet, it names three measures. Laser therapy inside the stomach. A stent placed inside it. And gastrojejunostomy, a surgical bypass joining the stomach to the small bowel.

Palliative radiation therapy, PDQ says, may relieve bleeding, pain, and obstruction.

Palliative surgery to remove tumor is described narrowly. PDQ reserves it for patients with continued bleeding or obstruction.

Those options matter at a recurrence because eating, bleeding, and blockage often drive symptoms more than tumor size does.

The structure of PDQ's list suggests the questions almost by itself.

• Has the recurrence been biopsied, and were HER2, dMMR or MSI, PD-L1 CPS, and CLDN18.2 all tested on the new tissue?
• Which first-line branch applies, HER2-positive or HER2-negative?
• Given prior treatment, which of PDQ's second-line entries remain available?
• Is a trial open for one of the combinations still under evaluation?
• If obstruction or bleeding is the main problem, is a stent, bypass, or radiation appropriate alongside systemic treatment?

PDQ's summary does not publish a follow-up schedule for gastric cancer after treatment. It does not describe testing belly fluid, or staging laparoscopy, in this section. Those are reasonable things to raise. But the answer has to come from the treating team, not from this source.

• Call 911 or go to an emergency department if you vomit blood or material that looks like coffee grounds, or pass black tarry stools or visible blood in the stool. Continued bleeding is one of the two problems PDQ names when it describes palliative surgery.
• Call 911 or go to an emergency department if belly pain becomes sudden and severe, or you feel faint, cold, and clammy.
• Call your care team the same day if you are vomiting repeatedly, or cannot keep fluids down, or food seems to stop and come back up. A tumor can block the passage into or out of the stomach, and a stent, a bypass, or laser treatment can open it.
• Call your oncology team the moment it happens, day or night, if you have a temperature of 100.4°F (38°C) or higher, or chills, while on chemotherapy. Chemotherapy lowers your white cells, and the CDC treats a fever during it as a medical emergency. Speak to a person rather than leaving a message, and if nobody answers soon, go to an emergency department and tell them you are on chemotherapy.
• Call your care team within a day or two if you have new trouble swallowing, a belly that is swelling with fluid, yellowing of the eyes or skin, or steady weight loss you cannot explain.

The disease itself is described in stomach cancer. Tumor marker testing in general is covered in biomarker testing. The general shape of a return workup is in when cancer comes back.

• NCI PDQ: gastric cancer, HP version
• NCI: stomach cancer symptoms
• NCI: Infection and Neutropenia During Cancer Treatment