A total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53. 7 percent) had a partial response, 41 patients (27. 9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4. 8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response. Early resistance to imatinib was noted in 20 patients (13. 6 percent).
Therapy was well tolerated, although mild-to-moderate edema, diarrhea, and fatigue were common. Gastrointestinal or intra-abdominal hemorrhage occurred in approximately 5 percent of patients. There were no significant differences in toxic effects or response between the two doses. Imatinib was well absorbed, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia. Conclusions: Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor.
Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy. Commentary: Gastrointestinal stromal tumors are cancers that are closely related the Cajal interstitial cells that are present in the myentetric plexus. They have several cancer markers with the cajal interstitial cells. The GI stromal tumors produce the receptor KIT. KIT signaling occurs uncontrollable in gastrointestinal stromal tumors leading to uncontrolled growth and multiplication of the tumor cells.
GI stromal tumors are even resistant to anticancer therapy with drugs and have a fatal outcome. Even if the mutational status of KIT is not significant, activation of KIT occurs. The cancer may respond to surgery during the early stages, but in the later stages the condition is terminal. Only 5% of the cases reported positive to doxorubicin and the tumor is not responsive to radiotherapy. With metastatic disease, the survival rate is 20 months.
One of the drugs that seems to be promising in the treatment of GI Stromal tumors is imatinib mesylate (ST1571 or Gleevec and Glivic) works by selectively obstructing the activity of tyrosine kinase (including ABL kinase, BCR-ABL fusion oncoprotein, KIT receptor and growth factors derived from platelets). The KIT receptor has tyrosine kinase activity. Several leukemia (Philadelphia chromosome associated and CML), have been controlled using imatinib as it lowers the tyrosine kinase activity and prevents the action of the BCR-ABL fusion oncoprotein.
Before the study was conducted there was evidence that imitanib may block the activity of the KIT receptor and tyrosine kinase in the gastrointestinal stromal cells. Several cells lines obtained that were cancerous demonstrated that it could respond to imitanib. When imitanib was used in the tumor cell lines, they prevented the activity of the tyrosine kinase in the KIT dependent cells, prevented the cells from multiplying and caused cell death by apoptosis. Studies have shown that patients treated for GO stromal cancers that are unresponsive to chemotherapy would respond fast and substantially.
The study conducted by Demetri et al (2002) aims a larger trial involving several enterprises to determine the efficacy and safety of imtinib for inoperable and metastatic spread of GI stromal cancers. The study included adults suffering from unresectable or metastatic spread of GI stromal cancers that produced CD 117 (KIT receptor tyrosine kinase marker). Patients who were previously not treated for tumors with recent radiotherapy or embolisation were included in the study, and the patients had appropriate functioning of the heart, liver, platelets and the kidneys.
The ECOG performance scores of 3 or less was acceptable to be included in the study. Patients who had received previous radiotherapy, chemotherapy, surgery, combination, etc, were included if they were conducted before the study. The study was a randomized, open-label, multi-clinical trial to determine the effect and safety in imitanib in unresectable and metastatic forms of GI stromal cancers. The study was done with randomization without any stratification.
The primary aim was to determine the efficacy of the drug, whereas the secondary objectives included determining the pharmacokinetics, safety, survival rate, failures, etc associated with the drug use. CT scanning was used to monitor the treatment, whereas in some patients PET scanning was utilized to determine changes in the metabolic profile in the tumor, and in some biopsy was taken for determining the histopathological changes. The patients were given either 400 mg or 600 mg imitanib in the form of tablet taken once daily with meals.
When the patients had a progressive tumor but a good clinical condition were given 600 mg of the drug. The other tests that were conducted regularly included physical examination, urine tests, blood tests, etc. Overall 4 centers were involved in the study. The plasma concentration of imitanib was done using liquid chromatography and mass spectrometry. The study was conducted during the July 2000 to April 2001 period and included 147 patients spread over 4 centers. 10 cases of the 147 did not produce the biopsy for review and hence they were excluded from the study.
Out of the 137 cases, 2 did not have the expression of CD-117 in their blood and hence were excluded from the study. Out of the 147 patients, 114 underwent previous surgeries, 75 patients for chemotherapy and 22 for radiotherapy. Most of these patients did not respond positively to previous treatment. Imitanib administered has a half life of 20 hours. After the period of 9 months, 120 patients of the original 147 remained in the study. There was no patient with a complete response and about 53.
7 had a partial response, evident through imaging techniques such as CT, MRI and PET scans. There was a reduction in the tumor in about 50 to 96 % of the patients to varying extents. In about 27. 9 % of the patients, the disease was stable and in about 13. 6 % the condition progressed following one to three months of initiating the treatment. On an average, response to the drug was evident 13 weeks following initiation. The responses were obvious and remained for about 46 weeks. There were no differences between the doses of imitanib administered and the response.
The drug was usually well-absorbed and tolerated in the body, and the pharmacokinetics was similar to those patients suffering from CML. The drug was tolerated and some patients had moderate to mild side-effects such as peri-orbital edema, diarrhea, muscle pain, fatigue, skin rashes, headache, nausea, abdominal pain, etc. About 21. 1 % of the patients had significant side-effects such as GI bleeding (with large tumors). Some patients in whom a biopsy was taken demonstrated a decrease in the number of cancer cells and lower atypical nuclei.
A sustained objective response was produced in more than half the patients suffering from unresectable and metastatic form of GI stromal cancer. Obstruction of the KIT tyrosine kinase pathway does seem to be promising in treating GI stromal cancers. Newer studies should look at determining the long-term effect of the drug and also combining with other therapies. Pros and Cons of the study The study was not a long-term study which demonstrated the 5-year survival rate or the average period survival following administration of imatinib in patients suffering from advanced, unresectable and metastatic GI stromal tumors.
The study is a very primitive study, aimed at seeking basic data regarding the safety and efficacy of imitinib in the management of GI stromal tumors. It gives results in terms of partial response, complete response, no response and stable disease. Huse et al (2007), clearly demonstrates the average life-expectancy in patients treated with imitinib with GI stromal tumors. The study conducted by Demetri et al (2002) regarding the safety and efficacy of imitinib is not a long-term study.
It was conducted through the period July 2000 to April 2001 (10 month period). Hence, the long-term effect and the safety of the drug cannot be assessed. Besides, the only other hypothesis developed before this study was based on tumor-cell lines and not human subjects, and hence the study could not demonstrate a consistent pattern. The study was also conducted in 4 –centers and involved about 147 subjects. A much larger segment of the population, spread over several centers and involving several hospitals would have demonstrated better results.
The trial tried to determine the benefit of greater dose administration of imitinib by using greater doses of imitinib for patients suffering from fast progressing tumors and whose general condition permitted increase of dosage. This permitted greater efficiency of the drug and ensured safety of the subjects. The patients were also closely monitored through several other means including CT scans, MRI scans, PET scans, physical examinations, urine tests, blood tests, etc. The adverse effects caused by the drugs were also closely monitored for mild, moderate, and serious side-effects.
The study is a randomized open-label study, in which all the subjects are receiving the same treatment, there is no blinding involved and both the patients and the healthcare providers have an idea which drug is being administered. There are chances of bias playing a role in the results obtained, as there was no blinding. This to a certain extent compromised the quality of the trial. As one type of drug was administered to all the patients, there was no control group and hence, the effects and safety of the drug could not be compared.
The author recognized that there were deficits as no control group was used. Hence, they tried to provide grades of response of the patients. To ensure better results from the use of imitinib in patients with GI stromal tumors, a long term trial, conducted over a greater number of patients is required. Besides, the patients have to be divided in the case group and control group, in order to compare the effect of the drug. References: Huse, D. M. (2007). Cost Effectiveness of Imatinib Mesylate in the Treatment of Advanced Gastrointestinal Stromal Tumours. Medscape , http://www. medscape. com/viewarticle/551610