Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: a centre-based study of 17 patients

P Bümming, J Andersson, J M Meis-Kindblom, H Klingenstierna, K Engström, U Stierner, B Wängberg, S Jansson, H Ahlman, L-G Kindblom, B Nilsson, P Bümming, J Andersson, J M Meis-Kindblom, H Klingenstierna, K Engström, U Stierner, B Wängberg, S Jansson, H Ahlman, L-G Kindblom, B Nilsson

Abstract

Malignant gastrointestinal stromal tumours (GIST) have a poor prognosis. Since these tumours are resistant to conventional radiation and chemotherapy, surgery has been the mainstay of treatment. However, surgery is usually inadequate for the treatment of malignant GIST. Imatinib, a KIT tyrosine kinase inhibitor, has recently been found to have a dramatic antitumour effect on GIST. In this centre-based study of 17 consecutive patients with high-risk or overtly malignant GIST, imatinib was used in three different settings - palliatively, adjuvantly, and neoadjuvantly. The treatment was found to be safe and particularly effective in tumours with activating mutations of exon 11 of the KIT gene. Clinical response to imatinib treatment correlated morphologically to tumour necrosis, hyalinisation, and reduced proliferative activity. The value of neoadjuvant imatinib treatment was illustrated in one case.

Figures

Figure 1
Figure 1
Case 1, neoadjuvant imatinib treatment. Positron-emission tomography examinations before (A), after 3 weeks (B), and after 12 weeks (C) of imatinib treatment. The increased uptake of the tracer [18F] fluorodeoxyglucose that was seen in a huge abdominal tumour before treatment cannot be detected at PET examinations after 3 and 12 weeks of imatinib treatment. Corresponding CT examinations before (D), after 3 weeks (E), and after 12 weeks of imatinib treatment (F). During 12 weeks of treatment, the tumour decreased from 35 to 18 cm. Corresponding sagittal gadolinium-enhanced T2-weighted and T1-weighted MRI before (G) and after 12 weeks (I) of treatment, respectively, showing tumour reduction. After 3 months of treatment, the tumour could be completely excised, leaving the rectum intact (H).
Figure 2
Figure 2
Case 1, neoadjuvant imatinib treatment. Pretreatment core needle biopsies of a huge abdominal tumour and liver metastases showing characteristic features of a malignant spindled and epithelioid GIST (A) that is immunoreactive for CD117 (B) and MIB1 (Ki67 proliferative index=10%) (C). After 3 months of imatinib treatment, the tumour shows extensive hyalinisation with scattered residual tumour cells (D), necrosis (E), cyst formation and areas of viable tumour (F) in which the proliferative index is virtually zero (only a few inflammatory cells next to a vessel are MIB1 immunoreactive, G).

References

    1. Andersson J, Sjögren H, Meis-Kindblom J, Stenman G, Åman P, Kindblom L-G (2002) The complexity of KIT gene mutations and chromosome rearrangements and their clinical correlation in gastrointestinal stromal (pacemaker cell) tumors. Am J Pathol 160: 15–22
    1. Cancer Therapy Evaluation Program 1999. Common Toxicity Criteria, version 2.0. Bethesda: National Cancer Institute
    1. DeMatteo R, Lewis J, Leung D, Mudan S, Woodruff J, Brennan M (2000) Two hundred gastrointestinal stromal tumors, recurrence patterns and prognostic factors for survival. Ann Surg 231: 51–58
    1. Demetri GD, Rankin C, Fletcher C, Benjamin RS, Blanke C, Von Mehren M, Bramwell V, Maki RG, Blum R, Antman K, Baker L, Borden E (2002) Phase III dose-randomized study of imatinib mesylate (Gleevec, STI571) for GIST: intergroup S0033 early results. Proc Am Soc Clin Oncol 21: A1651
    1. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33: 459–465
    1. Goldman JM, Melo JV (2001) Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1084–1086
    1. Heinrich MC, Blanke CD, Druker BJ, Corless CL (2002a) Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20: 1692–1703
    1. Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Von Mehren M, McGreevey CL, Wait L, Griffith D, Chen C-J, Haley A, Kiese B, Druker BJ, Roberts P, Eisenberg B, Singer S, Silberman S, Dimitrijevic S, Fletcher CDM, Fletcher JA (2002b) KIT mutational status predicts clinical response to STI571 in patients with metastatic gastrointestinal stromal tumors (GISTs). Proc Am Soc Clin Oncol 21: A6
    1. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279: 577–580
    1. Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker BJ, Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344: 1052–1056
    1. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM (1998) Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152: 1259–1269
    1. Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M (1999) Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol 154: 53–60
    1. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen CJ, Xiao S, Tuveson DA, Demetri GD, Fletcher CD, Fletcher JA (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61: 8118–8121
    1. Sakurai S, Fukasawa T, Chong JM, Tanaka A, Fukayama M (1999) C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal). Jpn J Cancer Res 90: 1321–1328
    1. Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, Matsuda H, Kitamura Y (1999) Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res 59: 4297–4300
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, Van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92: 205–216
    1. Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CDM, Fletcher JA, Demetri GD (2001) STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20: 5054–5058
    1. Van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, Van Glabbeke M, Silberman S, Nielsen OS (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358: 1421–1423

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться