Gastric Cancer Management

Evaluation

The Eastern Cooperative Oncology Group (ECOG) performance status scale and Karnofsky performance status may be used to assess the functional status of patients with cancer. Patients with an ECOG performance score ≥3 or Karnofsky performance score <60% should be offered palliative or best supportive care only. Chemoradiation for locally unresectable tumors without previous therapy or systemic therapy in addition to palliative or best supportive care may be offered to patients with an ECOG performance score ≤2 or Karnofsky performance score ≥60%.

ECOG Performance Status

0 - Fully active; no performance without restriction
1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg office work, light household chores)
2 - Ambulatory and capable of all self-care but unable to carry out any work activities; up and about >50% of waking hours
3 - Capable of only limited self-care; confined to bed or chair >50% of waking hours
4 - Completely disabled; cannot carry on any self-care; totally confined to bed or chair

Karnofsky Performance Status

100 - Normal, no complaints, no evidence of disease
90 - Able to carry on normal activity; minor signs and symptoms of disease
80 - Normal activity with effort, some signs and symptoms of disease
70 - Cares for self but is unable to carry on normal activity or to do active work
60 - Requires occasional assistance but is able to care for most personal needs
50 - Requires considerable assistance and frequent medical care
40 - Disabled; special care and assistance
30 - Severely disabled; hospitalization is indicated, although death not imminent
20 - Very ill; hospitalization and active supportive care necessary

Pharmacological therapy

Chemotherapy

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Perioperative Chemotherapy

Perioperative chemotherapy is a widely adopted standard of care throughout most of the UK and Europe. This is a means of downstaging a locally advanced tumor before an attempt at curative resection. This is the preferred approach for patients with localized resectable disease (≥T2, any N). The preferred regimens include: Fluoropyrimidine and Oxaliplatin or Cisplatin (4 cycles preoperative and 4 cycles postoperative); FOLFOX is used mostly for patients with good to moderate performance status; Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel (FLOT) (4 cycles preoperative and 4 cycles postoperative) which is recommended for select patients with good performance status; and Docetaxel, Oxaliplatin and Tegafur/Gimeracil/Oteracil (S-1) (DOS).

Other recommended regimen includes: Fluorouracil and Cisplatin (4 cycles preoperative and 4 cycles postoperative). Since Capecitabine avoids the need for an indwelling central venous access and is non-inferior to 5-fluorouracil (5-FU) in the advanced disease setting, Capecitabine-containing regimens may be used instead of 5-FU.

Neoadjuvant/Perioperative Immunotherapy

Neoadjuvant immunotherapy may be considered for patients with localized, potentially resectable disease (≥T2, any N) with MSI-H/MMR-deficient (dMMR) tumors. Nivolumab and Ipilimumab followed by Nivolumab; Pembrolizumab; and Tremelimumab and Durvalumab (for neoadjuvant therapy only).

Postoperative Chemotherapy

Postoperative chemotherapy is recommended for patients with pathologic stage T3-T4, any N and/or any T, N+ tumors after primary D2 lymph node dissection. Studies have shown that the use of postoperative chemotherapy after curative surgery with D2 lymph node dissection improved disease-free survival compared to surgery alone. The preferred regimens include: CAPOX, which has been reported to significantly improve overall and disease-free survival; and FOLFOX.

Intraperitoneal Chemotherapy (IC)/Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Intraperitoneal chemotherapy is a therapeutic alternative in select patients with peritoneal carcinoma as their only disease or those with a low burden of tumor. This is used in conjunction with cytoreductive surgery for patients with low peritoneal cancer index (PCI ≤10) who are candidates to undergo complete cytoreduction. For patients with a higher burden of peritoneal disease (PCI >10), IC/HIPEC may be considered in the setting of a clinical trial.

Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC)

Pressurized intraperitoneal aerosolized chemotherapy may be considered in the setting of a clinical trial.

Palliative Therapies

Palliative therapies should be considered in patients with stage IV disease that can improve survival compared with best supportive care alone. The co-morbidities, organ function and performance status must always be taken into consideration. The decision to offer palliative or best supportive care alone or in combination with systemic therapy is based on the patient's performance status.

Systemic Therapy

Systemic therapy provides palliation of symptoms, enhances quality of life, and improves survival of patients with locally advanced or metastatic gastric cancer.

First-line Therapy

Two-drug cytotoxic combination regimens are preferred due to lower toxicity. Three-drug cytotoxic combination regimens are reserved for medically fit patients with good performance status. Oxaliplatin is preferred over Cisplatin due to lower toxicity.

The preferred regimens for HER2 overexpression-positive adenocarcinoma include: Fluoropyrimidine (5-FU or Capecitabine) and Cisplatin and Trastuzumab; Fluoropyrimidine (5-FU or Capecitabine) and Oxaliplatin and Trastuzumab; Fluoropyrimidine (5-FU or Capecitabine) + Cisplatin + Trastuzumab + Pembrolizumab for tumors with PD-L1 expression levels by combined positive score (CPS)¹ ≥1; and Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Trastuzumab + Pembrolizumab for tumors with PD-L1 expression levels by CPS¹ ≥1.

The preferred regimens for HER2 overexpression-negative adenocarcinoma include: Fluoropyrimidine (5-FU or Capecitabine) and Cisplatin; Fluoropyrimidine (5-FU or Capecitabine) and Oxaliplatin; Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Nivolumab for tumors with PD-L1 expression levels by CPS¹ ≥5; Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Pembrolizumab for tumors with PD-L1 expression levels by CPS¹ ≥1; and Fluoropyrimidine (5-FU or Capecitabine) + Cisplatin + Pembrolizumab for tumors with PD-L1 expression levels by CPS¹ ≥1.

The preferred regimens for MSI-H/dMMR-positive tumors include: Dostarlimab-gxly; Pembrolizumab; Nivolumab and Ipilimumab; Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Nivolumab; and Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Pembrolizumab.

Other recommended regimens include: Docetaxel; Docetaxel and Cisplatin; Docetaxel, Cisplatin and Fluorouracil (DCF) that has been recommended as an alternative treatment option for the treatment of patients with advanced gastric cancer, including EGJ cancers, in patients who have not received prior chemotherapy. However, it was associated with increased myelosuppression and infectious complications; Docetaxel, Oxaliplatin and Fluorouracil; Fluoropyrimidine (Fluorouracil or Capecitabine); Fluorouracil and Irinotecan (FOLFIRI); Paclitaxel; Paclitaxel and Cisplatin or Carboplatin; Tegafur/Gimeracil/Oteracil (S-1) in combination with Cisplatin; and Zolbetuximab: For patients with PD-L1-negative or CPS <5 and CLDN18.2-positive tumors.

Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Nivolumab may be useful in HER2 overexpression negative adenocarcinoma with PD-L1 expression levels by CPS¹ <5.

Second-line or Subsequent Therapy

The choice of agents as second-line therapy depends on previous therapy and performance status.

The preferred regimens include: Docetaxel; Fam-trastuzumab deruxtecan-nxki (Trastuzumab deruxtecan) which is used for patients with HER2 overexpression-positive adenocarcinoma and received prior Trastuzumab-based therapy; FOLFIRI for patients who did not previously receive FOLFIRI; Irinotecan; Paclitaxel; Ramucirumab and Paclitaxel; and Trifluridine and Tipiracil which are indicated as third-line or subsequent therapy for select patients with low-volume gastric cancer without or minimal symptoms and with the ability to swallow pills.

Other recommended regimens include: Docetaxel and Irinotecan; FOLFIRI + Ramucirumab; Irinotecan and Cisplatin; Irinotecan and Ramucirumab; and Ramucirumab.

The agents useful in certain circumstances include: For MSI-H or dMMR tumors, Dostarlimab-gxly; Nivolumab with or without Ipilimumab; Pembrolizumab, used also for TMB high (≥10 mutations/megabase) tumors; Entrectinib, Larotrectinib or Repotrectinib for NTRK gene fusion-positive tumors; Dabrafenib and Trametinib for BRAF V600E mutated tumors; and Selpercatinib for RET gene fusion-positive tumors.

In patients of adequate performance status, second-line chemotherapy is associated with proven improvements in overall survival and quality of life compared with best supportive care.

Targeted Therapies

HER2 testing is recommended for all patients with inoperable, locally advanced, recurrent, and metastatic disease at the time of diagnosis. In HER2-positive gastric cancer, addition of Trastuzumab to a Cisplatin-fluoropyrimidine doublet showed clinically and statistically significant improvements in response rate, progression-free survival and overall survival. Trastuzumab in combination with Cisplatin and fluoropyrimidine (first-line) or with other chemotherapy agents (eg Capecitabine or 5-fluorouracil and Oxaliplatin) is the standard care regimen. Trastuzumab was limited only to patients with an immunohistochemistry score of 3+ or 2+ and FISH positive. Trastuzumab is not recommended to be continued in second-line therapy.

Pembrolizumab is a PD-1 antibody. This is another second-line or subsequent therapy for MSI-H or dMMR tumors or for TMB high (≥10 mutations/ megabase) tumors. This is also used as neoadjuvant or perioperative immunotherapy. This may be added to first-line fluoropyrimidine, platinum and Trastuzumab in the treatment of HER2 overexpression-positive adenocarcinoma. Dabrafenib is used as a second-line or subsequent therapy for BRAF V600E mutated tumors.

Dostarlimab-gxly is a PD-1 antibody. This is indicated for patients with progressive MSI-H or dMMR gastric cancer on or following prior therapy which did not include a checkpoint inhibitor such as PD-1i, PDL-1i, or CTLA4i, and without alternative therapy options. Entrectinib, Larotrectinib and Repotrectinib is recommended as second-line or subsequent therapy for NTRK gene fusion-positive tumors. Repotrectinib can be used in patients whose disease progressed on a prior NTRK targeted therapy.

Fam-trastuzumab deruxtecan-nxki (Trastuzumab deruxtecan) is an antibody-conjugate composed of Trastuzumab and a cytotoxic topoisomerase I inhibitor, which is connected by a cleavable tetrapeptide-based linker. This is a preferred second-line or subsequent therapy for patients with HER2 overexpression-positive adenocarcinoma and received prior Trastuzumab-based therapy.

Nivolumab is a monoclonal PD-1 antibody. In combination with fluoropyrimidine- and platinum-based chemotherapy, this is approved as first-line therapy for patients with HER2-negative advanced or metastatic gastric cancer with PD-L1 expression levels by CPS¹ of ≥5, may be useful in tumors with a CPS¹ <5, and can be used as neoadjuvant or perioperative immunotherapy. This is also used as third- or later-line therapy in heavily pretreated patients with unresectable advanced or recurrent disease. An addition of Nivolumab to chemotherapy resulted in significant improvements in overall survival and progression-free survival in patients with a PD-L1 CPS¹ of ≥5.

Targeting vascular endothelial growth factor receptors (VEGFR) with the anti-VEGFR-2 monoclonal antibody Ramucirumab showed promising results in patients with advanced gastric or EGJ adenocarcinoma positive for disease progression despite treatment with platinum-/fluoropyrimidine-based doublet/triplet chemotherapy. Ramucirumab may be given alone or in combination with Paclitaxel. Selpercatinib may be used as a second-line or subsequent therapy for RET gene fusion-positive tumors. Trametinib is another treatment option as a second-line or subsequent therapy for BRAF V600E mutated tumors. Tremelimumab and Durvalumab are treatment options used as neoadjuvant immunotherapy in patients with MSI-H or dMMR tumors. Zolbetuximab, a monoclonal antibody that targets the transmembrane protein CLDN18.2, may be used in combination with chemotherapy for HER2 overexpression-negative patients with PD-L1-negative or CPS <5 and CLDN18.2-positive tumors.

¹Combined positive score (CPS) is the number of PD-L1 staining cells (eg lymphocytes, macrophages, tumor cells) divided by the total number of viable tumor cells evaluated, multiplied by 100.

Surgery

Surgery with lymph node dissection is the primary treatment option in early-stage/resectable gastric cancer. Though a majority still relapse following resection, it is potentially curative. For ≥stage 1B combined modality approaches are standard. The standard goal is complete resection with negative margins. The extent of resection is determined by the preoperative stage of the cancer. Gastrectomy with D1 or a modified D2 lymph node dissection with a goal of examining at least 16 lymph nodes for patients with localized resectable cancer.

Endoscopic Therapies

Endoscopic resection is necessary to accurately stage early-stage cancers (T1a or T1b). For the treatment of patients with early-stage (Tis or T1a) gastric cancer, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been used as an alternative to surgery. Endoscopic submucosal dissection is the treatment of choice for most superficial gastric neoplasmic lesions. Endoscopic mucosal resection or endoscopic submucosal dissection of focal nodules (≤2 cm) performed during early-stage cancer can provide more information on the degree of differentiation, presence of lymphovascular invasion and depth of invasion, and can be potentially therapeutic. It has been shown that en-bloc excision by endoscopic submucosal dissection is more effective than endoscopic mucosal resection in curing early gastric cancer. For lesions >5 cm in diameter, complete resection rates were significantly better for endoscopic submucosal dissection, while in lesions <5 cm in diameter, there was no difference between endoscopic mucosal resection and endoscopic submucosal dissection rates regardless of location. T4 tumors require en bloc resection of involved structures. The indications for endoscopic mucosal resection or endoscopic submucosal dissection include: Carcinoma in situ; lesions ≤2 cm in diameter; well or moderately differentiated lesions; confined to the mucosa; with clear lateral and deep margins; not ulcerated; and without lymph node metastases or lymphovascular invasion.

Gastrectomy

Distal, subtotal or total gastrectomy is recommended for T1b-T3 tumors.

Subtotal Gastrectomy

Subtotal gastrectomy is a procedure that involves the removal of a section of the stomach, and may include part of the esophagus or the 1st part of the duodenum; the remaining section of the stomach is then reattached. This is the preferred approach for distal gastric cancers. This may be carried out if a macroscopic proximal margin of 5 cm can be achieved between the tumor and esophagogastric junction. Eating is much easier after surgery.

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Total gastrectomy is a procedure involving the surgical removal of the stomach as a whole, including adjacent lymph nodes and omentum, as well as part of the esophagus that is attached to the small intestines. This is the preferred gastrectomy for patients with stage IB-III gastric cancer. Proximal gastrectomy and total gastrectomy are both indicated for proximal gastric cancers and are typically associated with postoperative nutritional impairment. A margin of 8 cm is recommended for diffuse-type cancers.

Lymph Node Dissection

Lymph node dissection should be included in gastric resection. The classification depends on the extent of lymph nodes removed during gastrectomy: D0 refers to incomplete resection of N1 lymph nodes; D1 involves gastrectomy and removal of the involved proximal or distal part of the stomach or the entire stomach, including the greater and lesser omental lymph nodes; and D2 involves D1 with additional removal of the anterior leaf of the transverse mesocolon and all the nodes along the corresponding arteries.

Laparoscopic/Robotic Surgery

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Palliative/Best Supportive Care

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Endoscopic tumor ablation helps to stop bleeding or help relieve blockage without surgery. This is done for short-term control of bleeding. Stent placement helps keep the opening at the beginning and end of the stomach open and allows food to pass through it. Endoscopic insertion of self-expanding metal stents (SEMS) has been shown to be effective for the long-term relief of tumor obstruction at the gastric outlet or EGJ. This is preferred over gastrojejunostomy for patients with luminal obstruction secondary to advanced gastric cancer and with relatively short life expectancy. Venting gastrostomy may be performed to reduce symptoms of obstruction when bypass or alleviation is not possible. Feeding tube placement is done to help in the liquid nutrition that can be put directly into the tube.

Radiation Therapy

Chemoradiation

Chemoradiation may be an option for medically fit patients with locally unresectable tumors and no previous therapy. The preferred regimens include: Cisplatin and Fluorouracil, Cisplatin and Capecitabine, FOLFOX, and CAPOX. Other recommended regimens include: Fluoropyrimidine (Fluorouracil or Capecitabine) and Paclitaxel.

Preoperative Chemoradiation

Studies have shown that patients who received sequential preoperative induction chemotherapy followed by chemoradiation yielded substantial pathologic responses that resulted in durable survival time. Chemoradiation therapy includes radiation therapy of 45-50.4 Gy of external beam with the below preoperative chemotherapy regimens: Cisplatin and Fluorouracil; Oxaliplatin and Fluorouracil (FOLFOX); Cisplatin and Capecitabine; Oxaliplatin and Capecitabine (CAPOX); Paclitaxel and Carboplatin; Fluoropyrimidine (Fluorouracil or Capecitabine).

Postoperative Chemoradiation

Postoperative chemoradiation is the preferred treatment in patients who underwent surgery for pathologic stage T3-T4, any N or any T, N+ esophagogastric cancer with D0 and D1 lymph node dissection who have not received any preoperative therapy. For patients with pathologic stage T2, N0 tumors who underwent EMR, observation is recommended. Postoperative chemoradiation is only for patients with high-risk features (eg poorly differentiated or higher grade cancer, lymphovascular invasion, neural invasion or age <50 years old). Fluoropyrimidine (infusional 5-FU or Capecitabine) is used before and after fluoropyrimidine-based chemoradiation. Radiotherapy may be given to a total dose of 45 Gy in 25 fractions of 1.8 Gy, 5 fractions/week by 3D-conformal or intensity-modulated radiation therapy techniques. Clinical target volume encompasses the gastric bed (with stomach remnant when present), anastomoses, and draining regional lymph nodes.

Palliative/Best Supportive Care

The best supportive care is recommended for all patients with unresectable locally advanced, recurrent or metastatic gastric cancer. The goal is to prevent, reduce and relieve suffering and improve the quality of life for patients and their families.

Interventional Radiology

Angiographic embolization may be considered in patients with acute bleeding not relieved by endoscopy.

Radiotherapy   

Hypofractionated radiotherapy is an effective and well-tolerated treatment modality that may palliate bleeding, obstructive symptoms or pain in patients with symptomatic locally advanced or recurrent disease. External beam radiotherapy may be considered for patients with malignant obstruction causing pain, and acute or chronic GI bleeding.