Treatment of Gastrointestinal Stromal Tumor (GIST)

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GISTs arise from the interstitial cells of Cajal (ICC) in the gastrointestinal (GI) tract. The ICC are a part of the autonomous nervous system that regulate the smooth muscles in the GI tract. Thus, they are sometimes referred to as pacemaker of the GI tract.

GISTs may occur anywhere in the GI tract with the stomach being the most common site, followed by the small intestine. They may even start outside of the GI tract, such as the tissue in the vicinity of the digestive system, e.g. the omentum or peritoneum. They are rare and mostly affect old-aged individuals. They show variable behavior in different individuals, and may spread to nearby and distant body parts.

TNM Staging of Gastrointestinal Stromal Tumor (GIST)

TNM is the most commonly used system for staging GISTs by the medical community. “T” stands for “Tumor Size”, “N” for “Lymph Nodes”, and “M” for “Metastasis”. Numbers and/or letters after T (1, 2, 3, and 4), N (0 and 1), and M (0 and 1) provide more details about each of these factors.

Additionally, GIST is graded to assess the aggressiveness of the disease. The grading of GIST is based on the mitotic activity (the rate of cancerous cell division). The grade is assigned as Low or High, where Low grade means low rate of cell division.

T Staging

T0 – No evidence of tumor

T1 – Tumor is 2 cm or less

T2 – Tumor is more than 2 cm but not more than 5 cm

T3 – Tumor is more than 5 cm but not more than 10 cm

T4 – Tumor is more than 10 cm

N Staging

N0 – No regional lymph nodes involved by tumor

N1 – Tumor has spread to regional lymph nodes

M Staging

M0 – No spread to distant sites

M1 – Spread to tumor to distant sites

Grading

G1 – Low grade, Mitotic rate </= 5/50 hpf

G2 – High grade, Mitotic rate > 5/50 hpf

Once T, N, and M categories and the grade of a tumor are determined, this information is combined to assign an overall stage (from 0 to IV) to the disease.

4 Stages of Gastrointestinal Stromal Tumor (GIST)

For Stomach and Omental GIST

Stage IA

T1-2 N0 M0 Low Grade The primary tumor is </=5 cm in size. No spread to nearby lymph nodes or distant body parts. The assigned grade is Low.

Stage IB

T3 N0 M0 Low Grade The primary tumor size is >5 cm but </=10 cm. No spread to nearby lymph nodes or distant body parts. The assigned grade is Low.

Stage II

T1-2 N0 M0 High Grade The primary tumor is </=5 cm in size. No spread to nearby lymph nodes or distant body parts. The assigned grade is High. T4 N0 M0 Low Grade The primary tumor size is >10 cm. No spread to nearby lymph nodes or distant body parts. The assigned grade is Low.

Stage IIIA

T3 N0 M0 High Grade The primary tumor is >5 cm but </=10 cm in size. No spread to nearby lymph nodes or distant body parts. The assigned grade is High.

Stage IIIB

T4 N0 M0 High Grade The primary tumor size is >10 cm. No spread to nearby lymph nodes or distant body parts. The assigned grade is High.

Stage IV

Any T N1 M0 Any G The primary tumor of any size. The disease has spread to nearby lymph nodes. No spread to distant body parts. The assigned grade may have any value. Any T Any N M1 Any G The primary tumor of any size that might or might not have spread to nearby lymph nodes. The disease has spread to distant body parts, such as the liver. The assigned grade may have any value.

For Small Intestine/ Esophagus/ Colon/ Rectum/ Peritoneum GIST

Stage I

T1-2 N0 M0 Low Grade The primary tumor is </=5 cm in size. No spread to nearby lymph nodes or distant body parts. The assigned grade is Low.

Stage II

T3 N0 M0 Low Grade The primary tumor size is >5 cm but </=10 cm. No spread to nearby lymph nodes or distant body parts. The assigned grade is Low.

Stage IIIA

T1 N0 M0 High Grade The primary tumor is </=2 cm in size. No spread to nearby lymph nodes or distant body parts. The assigned grade is High. T4 N0 M0 Low Grade The primary tumor size is >10 cm. No spread to nearby lymph nodes or distant body parts. The assigned grade is Low.

Stage IIIB

T2-4 N0 M0 High Grade The primary tumor size may range from >2 cm to >10 cm. No spread to nearby lymph nodes or distant body parts. The assigned grade is High.

Stage IV

Any T N1 M0 Any Grade The primary tumor of any size. The disease has spread to nearby lymph nodes. No spread to distant body parts. The assigned grade may have any value. Any T Any N M1 Any Grade The primary tumor of any size that might or might not have spread to nearby lymph nodes. The disease has spread to distant body parts, such as the liver. The assigned grade may have any value.

Survival/Life Expectancy according to Stage

It is calculated based on whether the disease is Localised, Regional or Distant.

Localised

  • Cancer is limited.
  • 5 year survival 94%.

Regional

  • Cancer has spread to nearby structures or lymph nodes
  • 5 year survival 82%.

Distant

  • Cancer has spread to distant body parts.
  • 5 year survival 52%.

Treatment of Gastrointestinal Stromal Tumor (GIST) based on disease extent

GIST treatment usually depends on many factors, including but not limited to stage of disease, the location of the disease, performance status of the patient, side effects associated with the treatment, patient’s preference, along with other factors.

Following is the preferred treatment approache for GIST, but the final decision is taken after clinical assessment of the patient by an oncologist.

Localized, Resectable

For small, resectable, low-grade tumors, surgical resection to remove all cancerous tissue is the preferred approach. Targeted drug (e.g. Imatinib) should be employed after surgical resection to prevent disease recurrence in case of intermediate or high risk disease.

Localized, Marginally Resectable

For localized GISTs that cannot be completely removed with surgery (marginally resectable tumors), targeted therapy should be considered as the first-line treatment. This should be continued until the cessation of clinical benefit.

In case of a good response to treatment (sufficient shrinkage to resectable disease), surgical resection to remove all cancerous should be attempted. After surgery, a continuation of the targeted drug is generally recommended to prevent disease recurrence.

In case of the cessation of clinical benefit and unresectable disease, the dose of the targeted drug should be increased or a different drug may be employed.

Disseminated, Unresectable

For disseminated GISTs that cannot be removed with surgery (unresectable tumors), targeted therapy should be considered as the first-line treatment. This should be continued until the cessation of clinical benefit.

In case of a good response to treatment (sufficient shrinkage to resectable disease), surgical resection to remove all cancerous should be attempted.

In the case of the cessation of the clinical benefit and unresectable disease, the dose of the targeted drug should be increased or a different drug may be employed.

Role of Surgery

surgery for treatment of GIST Surgery is the treatment of choice for most early-stage and some higher stage GISTs that has not spread to distant body parts and can be completely removed. The goal of surgery is to remove entire cancerous tissue along with some healthy tissue.

However, a complete resection is not always possible, such as in the case of advanced-stage disease, the disease involving a vital organ/structure, or when a surgical resection will lead to a significant functional disability. In such cases, neoadjuvant targeted therapy may be given, and surgery may be tried thereafter, if the tumor shrinks and becomes resectable.

Targeted Therapy for GIST

targeted therapy for GIST Targeted drugs works differently than chemotherapy drugs that they target a specific gene or protein characteristic of the cancer cells that help them to divide and grow indefinitely.

Mutations that are seen in GIST include-

  • KIT (c-KIT) receptor tyrosine kinase (80%)
  • platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase (5% to 10%).
  • SDH gene leading to the loss of SDHB protein expression on their surface. Such GISTs are known as wild-type GISTs or SDH-deficient GIST. GISTs lacking KIT and PDGFRA mutations should be evaluated for SDHB immunostaining for confirming SDH-deficient tumor types.

Immunohistochemical (IHC) staining technique is generally used for the detection of CD117, DOG1, SDHB, and/or CD34 protein expression. Molecular genetic testing technique is used for the detection of KIT and/or PDGFRA mutations.

In GIST, c-kit mutation may be targeted with the help of targeted therapies like Imatinib, Sunitinib or Regorafenib. GISTs are typically resistant to conventional chemotherapy but due to the presence of KIT mutations in the majority of cases, they respond well to tyrosine kinase inhibitor (TKI) therapy that has transformed the treatment landscape of GISTs. The detection of KIT or PDGFRA mutation is important because these mutations are predictive of response to TKI therapy. SDH-deficient GISTs are relatively refractory to conventional TKI therapy.

Imatinib

imatinib Imatinib is an inhibitor of the KIT protein tyrosine kinase and is associated with a durable clinical benefit in most patients with advanced-stage GIST. It has been approved by the US FDA for the treatment of patients with KIT-positive unresectable and/or metastatic GISTs and also for adjuvant treatment post-surgery in selected patients.

Efficacy of imatinib is generally seen in patients with KIT exon 11 deletions but lesser in patients with KIT exon 11 insertion/point mutation, KIT exon 9 mutation, PDGFRA exon 18 D842V mutation, or wild-type GISTs. Such resistance observed during the first 6 months of treatment is referred to as primary resistance.

Higher dose (800 mg/d) of imatinib has been reported to benefit patients who progressed on lower imatinib dose (400 mg/d) or patients who have KIT exon 9 mutations.

Although imatinib has shown clinical benefit in most patients with advanced-stage GISTs, some of the patients deriving benefit from imatinib therapy eventually progress due to the development of secondary resistance to the treatment. The most common reason for secondary resistance development is the outgrowth of tumor clones with secondary mutations in KIT. Such patients require treatment with novel targeted agents.

Sunitinib

Sunitinib Sunitinib is a small molecule multitargeted TKI that confers clinical benefit to patients with imatinib-resistant GIST, that is, SDH-deficient GIST and treatment of patients with GIST who have progressed on or have developed resistance to imatinib treatment.

Sunitinib has higher response rates in patients with KIT exon 9 mutations compared to those with KIT exon 11 mutations as opposed to imatinib. Also, it has been reported that patients with SDH-deficient, unresectable, recurrent, or metastatic GIST have a higher probability of deriving benefit from sunitinib compared to imatinib.

Apart from its proven efficacy in GISTs, sunitinib is also a preferred treatment option for first-line treatment of patients with advanced alveolar soft part sarcoma, solitary fibrous tumor (SFT or hemangiopericytoma), and clear cell sarcoma.

Regorafenib

regorafenib Regorafenib is a small molecule multitargeted TKI that can inhibit a variety of kinases including KIT, PDGFR alpha, PDGFR beta, and all three subtypes of vascular endothelial growth factor receptor (VEGFR). It has been approved by the US FDA for the treatment of patients with locally advanced, unresectable, or metastatic GIST who have previously received treatment with imatinib and sunitinib. It has also shown benefit in the treatment of patients with advanced Liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma, and some other non-GIST STS subtypes.

Role of Ablation and Embolization for Metastatic Disease

These techniques are generally employed to treat GISTs that have spread to the lungs or liver. In ablation, small secondary tumors are destroyed without actual removal from the body. High-energy radio waves are utilized in radiofrequency ablation (RFA), microwaves are used in microwave ablation (MWA) technique, while very cold gases are used in cryoablation to destroy tumors. ablation of liver metastasis In embolization, small (relatively larger than ablation) secondary cancers are destroyed by blocking the blood supply to the cancer cells with the help of some inert tiny particles (particles are loaded with drugs in chemo-embolization and with a radioactive substance in radio-embolization) that are injected directly in the artery supplying blood to cancer cells. Embolization can sometimes be employed in conjunction with ablation. Imaging techniques are utilized along with these techniques to accurately locate the target tumors. hepatic artery embolization of liver metastasis

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