Radiation Oncology/GIST

Epidemiology

Rare. 0.1-3% of all GI tumors. But 20% of small bowel tumors. Incidence is 20 per 1,000,000 people / year. Predominantly affects those in their 5th - 7th decades.

Location: 60% from stomach, 30% from small intestine

Symptoms

GI bleeding is most common. Abdominal pain, bowel obstruction.

10% present with metastatic disease. Most common site of metastasis is to the liver. May spread to peritoneal surface.

Pathology

Term GIST was coined in 1983 by Mazur and Clark (PMID 6625048). GISTs were recognized as distinct tumors in the early 1990s, but the correct diagnosis of these tumors was problematic until around 2000.

Originate from the interstitial cell of Cajal, an intestinal pacemaker cell.

Previously were classified as visceral leiomyosarcomas due to their similar appearance histologically. Much of the older data for gastrointestinal sarcomas is therefore of little value because of the mixed histologies.

Immunohistochemistry: KIT (CD-117) positive, CD34 positive, smooth muscle actin variably positive. Negative for desmin. Usually negative for S100 (distinguishes from schwannomas).

Staging

Was added as a separate classification starting with the 7th edition of the AJCC Staging Manual. GISTs were not previously classified by the AJCC.

AJCC 7th Edition (2009)
Primary Tumor

• T1 - 2 cm or less
• T2 - >2 cm and <= 5 cm
• T3 - >5 cm and <= 10 cm
• T4 - > 10 cm

Regional Lymph Nodes

• N0 - no
• N1 - yes (note: very rare in GIST)

Distant Metastasis

• M0 - none
• M1 - yes

Mitotic Rate

• low - <= 5/50 HPF
• high - > 5/50 HPF

Stage Grouping

For Gastric GISTs:

(includes omentum)

• IA - T1-T2 N0, Low mitotic rate
• IB - T3 N0, Low mitotic rate
• II - T1-T2 N0, High mitotic rate; T4 N0, Low mitotic rate
• IIIA - T3 N0, High mitotic rate
• IIIB - T4 N0, High mitotic rate
• IV - N1 or M1

For Small Intestinal GISTs:

(includes esophagus, colorectal, mesentery, and peritoneum)

• I - T1-T2 N0, Low mitotic rate
• II - T3 N0, Low mitotic rate
• IIIA - T1 N0, High mitotic rate; T4 N0, Low mitotic rate
• IIIB - T2-4 N0, High mitotic rate
• IV - N1 or M1

Prognosis

Malignant potential depends on size and number of mitoses but can be difficult to predict in some cases. Are malignant in about 10-30% of cases.

NIH scale: (based on size and mitotic count) - PMID 12094370

• Very low risk - < 2 cm, < 5/50 HPF
• Low risk - 2-5 cm, < 5/50 HPF
• Int risk - < 5 cm and 6-10/50 HPF, or 5-10 cm and < 5/50 HPF
• High risk - any size and > 10/50 HPF, or > 10 cm and any mitotic count, or > 5 cm and >5/50 HPF

Major and minor criteria: - Bucher et al - PMID 15191872

• Minor criteria: size > 5 cm, mitotic index >5 mitoses/50 HPF, necrosis, infiltration of adjacent structures, MiB1 index > 10%
• Major criteria: LN invasion, metastases
• Low risk - fewer than 4 minor criteria - 5-year survival is 95%
• High risk - 1 major or 4 or more minor criteria - 5-year survival < 20%

c-KIT and Imatinib

Approximately 90% contain a mutation in the c-kit protooncogene which encodes the KIT receptor tyrosine kinase. The ligand for KIT is known as stem cell factor, Steel factor, or KIT ligand. The c-kit mutation is a gain-of-function mutation which provides a continuous signal for cell growth without the binding of the normal ligand and creates an antiapoptotic signal.

STI-571 or Imatinib (Gleevec) is a selective inhibitor of the ABL, BCR-ABL, KIT, and PDGF receptor tyrosine kinases. Usually given at a dose of 400-600 mg/day orally.

Treatment

Primary treatment is surgical resection.

Use of Imatinib

Metastatic disease

Used in metastatic disease. Patients without c-kit mutations are less likely to respond.

Trials:

• (Pending - trial closed in 2002) North American Sarcoma Intergroup study S0033 - tests Gleevec at 800 mg/d (divided BID) vs 400 mg/d (once daily) for metastatic GIST

• EORTC trial - similar to Intergroup S0033

Duration of therapy:

• French Sarcoma Group BFR14 (2002-)
  • Pts with metastatic GIST. After 3 yrs of Imatinib therapy, pts were randomized to continual therapy (C) vs interrupted therapy (I) with Imatinib. Pts on interrupted arm could resume Imatinib if progressive disease detected.
  • 2007 ASCO Abstract #10005 — "Continuous versus interruption of imatinib (IM) in responding patients with advanced GIST after three years of treatment: A prospective randomized phase III trial of the French Sarcoma Group."
    • 35 pts enrolled (19 interrupted vs 16 continuous). Median f/u 5.3 mos.
    • Higher rate of progressive disease in I pts. Reintroduction of Imatinib in the I arm after progression allowed tumor response (stable disease or overall response) in all pts.
  • Conclusion: high risk of rapid progression when treatment is interrupted.

Adjuvant therapy

• Multicenter; 2012 PMID 22453568 Full Text -- "One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial." (Joensuu, JAMA. 2012 Mar 28;307(12):1265-72.)
  • 400 high risk patients, defined by having at least 1 modified NIH Consensus Criteria
    • The longest tumor diameter >10.0 cm
    • Mitotic count >10 mitoses per 50 HPF
    • Tumor diameter >5.0 cm and mitotic count over 5
    • Tumor rupture before surgery or at surgery
  • Median follow-up 54 months.
  • 5yr RFS: 36-month group 65.6% vs 12-month group 47.9%
    • HR 0.46; 95% CI, 0.32-0.65; p < .001
  • 5yr OS 36-month group 92.0% vs 12-month group 81.7%
    • HR 0.45; 95% CI, 0.22-0.89; p = .02
  • Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence.
  • Conclusion: Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence.

• ACOSOG - adjuvant 400 mg/d x 1 yr after complete resection for high-risk (10 cm, tumor rupture, or multifocal). Compared with historical controls.

• ACOSOG - Phase III, high-risk and moderate-risk (>3 cm). Randomized to placebo vs Imatinib x 1 yr.

Neoadjuvant

• RTOG / American College of Radiology Imaging Network (ACRIN) - serial PET scans.

Radiotherapy

Poor response rate to RT. Only very scanty reports in literature. There have been case reports of RT being used as adjuvant therapy for positive margins and as primary therapy when combined with chemo and immunotherapy.

RT's role may be restricted to palliation: palliation for bleeding, pain

Review

• 2007 PMID 17512858 -- "Gastrointestinal stromal tumour." (Rubin BP, Lancet. 2007 May 19;369(9574):1731-41.)

• 2002 PMID 12094371 - Dematteo RP et al - Clinical management of gastrointestinal stromal tumors: before and after STI-571. 2002.