Adjuvant Treatment (Preventative Gleevec)

/Adjuvant Treatment (Preventative Gleevec)
Adjuvant Treatment (Preventative Gleevec)2019-03-05T13:51:45-04:00

Many GIST patients have surgery to remove a primary tumor and do not have detectable metastases at the time of surgery. Adjuvant therapy refers to additional treatment given after a main mode of therapy (the main treatment is usually surgery). For example, Gleevec given after surgery in hopes of preventing or delaying a recurrence is called adjuvant therapy.

Gleevec is approved for adjuvant therapy in many countries. In a phase III randomized trial, one year of treatment with adjuvant Gleevec resulted in 97% of GIST patients being recurrence-free one year after surgery compared to an 83% recurrence-free rate for placebo. In this trial, there was no difference in overall survival between the two groups.

Gleevec was approved for adjuvant treatment for GIST in the United States (December 19th, 2008). In 2011, the NCCN guidelines (USA) were updated after the 1 year versus 3 year Scandinavian trial results were presented at 2011 ASCO. According to the updated guidelines; “Adjuvant imatinib (Gleevec) for at least 36 months should be considered for patients with high risk GIST.” In January, 2012, the FDA prescribing information for imatinib was updated to recommend 3 years of adjuvant imatinib (for high risk patients as defined in the Scandinavian study), but the prescribing information noted that, “The optimal treatment duration with Gleevec is not known”.

ASCO 2011 – Adjuvant Gleevec shows significant overall survival benefit when given for three years Glivec (international spelling) is also approved by the European Commission (EC) for adjuvant treatment of GIST (May 7, 2009). This approval applies to all 27 EU member states, plus Norway and Iceland and was also based on the Z9001 phase III trial results. In February 2012, the EC approved an updated prescribing label to include 36 months of treatment after surgery for adults with KIT (CD117)-positive gastrointestinal stromal tumors (GIST) who met the inclusion criteria of the Scandinavian study. This extended treatment regimen has been shown to improve recurrence-free survival and overall survival for these patients with KIT+ GIST compared to patients who received 12 months of treatment after surgery. The newly updated label also states that treatment with Glivec beyond 36 months may delay the onset of tumor recurrences further, while noting that an effect (of treatment beyond 36 months) on overall survival has not been determined.

Although early adjuvant Gleevec trials showed a clear benefit in terms of reducing recurrences, they had not shown an overall survival benefit. On June 5th, 2011, new data from a randomized phase III trial comparing one year of adjuvant Gleevec to three years of adjuvant Gleevec showed, for the first time, a significant overall survival benefit (see table 1). This data was presented by Heikki Joensuu, M.D., Ph.D., Professor, Oncology, University of Helsinki and principal investigator of the study at the plenary session of ASCO. Plenary sessions are reserved for the most important new oncology data; data that is likely to change oncologists practice. The final results of the study were published in JAMA (March 2012)7.

Table 1 – 1 year vs. 3 years Adjuvant Gleevec for High Risk GIST Patients

1 year

Adjuvant Gleevec

3 years

Adjuvant Gleevec

Five-year overall survival rates 81.7% 93.9%  P=0.02
Five-year recurrence-free rate 47.9% 65.6%  P=>0.001
SSGXVIII/AIO – A 400-patient Phase III trial, conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

“This study confirms the hypothesis that extending the duration of Glivec treatment for patients following surgery improves recurrence-free survival. For the first time, an effect on overall survival was found,” said Dr. Joensuu. “Results from this trial may positively impact clinical practice by helping physicians create the optimal treatment plan for patients with operable KIT+ GIST.”

“Over the past nine years Glivec has provided KIT+ GIST patients with the first effective drug treatment option in the metastatic setting and later in the adjuvant setting,” said Hervé Hoppenot, President, Novartis Oncology.

“Now we see exciting new data showing that by extending post-surgical treatment duration to three years, Glivec has significant impact on overall survival in patients with KIT+ GIST. This is important news for GIST patients and the GIST community.”

SSGXVIII Study Details

The SSG XVIII clinical trial was conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie (AIO). SSG XVIII is a multicenter, prospective, randomized study for the evaluation of adjuvant treatment with Glivec of histologically verified KIT+ GIST with a greater than 50% risk of GIST recurrence despite complete removal of all macroscopic GIST tissue at surgery.

The primary endpoint of the study was to compare the recurrence-free survival in GIST patients with a greater than 50% estimated risk of disease recurrence within the first five years following the diagnosis and treatment with adjuvant Glivec for 12 or 36 months. The secondary endpoints included overall survival and treatment safety.

Four hundred patients entered the study and the median follow-up was 54 months. Recurrence-free survival was longer in the 36-month group compared to the 12-month group (HR 0.46, 95% CI 0.32-0.65; p<.0001; five-year recurrence-free survival 66% vs. 48%, respectively). Patients assigned to 36 months of Gleevec had longer overall survival (HR 0.45, 95% CI 0.22-0.89; p=.019; five-year overall survival 92% vs. 82%, respectively). Gleevec was generally well tolerated. The proportion of patients who discontinued Gleevec during the assigned treatment period for reasons other than GIST recurrence was 26% in the 36-month group and 13% in the 12-month group.

Duration of Adjuvant Gleevec

In an article written by Roxanne Nelson for Medscape Today, Dr. Charles Blanke, the discussant for the ASCO presentation, noted, “These results clearly demonstrated that 3 years of imatinib are better than 1 for recurrence-free survival and, to date, overall survival.

“If you have a patient with a high risk — at least defined by the study — GIST, giving him or her 3 years of imatinib represents the new gold standard,” he said.

“For now, with the overall survival benefit demonstrated with immediate postoperative imatinib, it is no longer acceptable to withhold treatment in the adjuvant setting, hoping to ‘catch up’ when the patient has recurrent metastatic disease,” Dr. Blanke continued.

In the article, Dr. Blanke went on to add, “There are plenty of reasons to think that giving imatinib for a longer period (more than 3 years) would be better, but that theory remains unproven. For now, if I was a patient with high-risk GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatments to eternity — meaning indefinitely.”

At the 2010 GI ASCO meeting (January 2010). Dr. Blackstein (Univ. of Toronto) and colleagues reported on maturing data from the Z9001 adjuvant Gleevec trial. At this analysis, data on recurrence by risk category was given. See table below.

Table 2 – Recurrence-Free Survival by Risk Category
2 year Recurrence-Free Survival
Low Risk Tumors
Gleevec 98% P=0.92
Placebo 98%
Moderate Risk Tumors
Gleevec 98%  P=0.05
Placebo 76%
High Risk Tumors
Gleevec 77%  P<0.0001
Placebo 41%
Note: Risk determined according to the Miettinen (Sem Diagn Pathol 2006) criteria. See our section on Diagnosis for more information.

Table adapted from 2010 GI ASCO, abstract #6

Risk assessment for tumor recurrence after surgical resection of localized primary gastrointestinal stromal tumor (GIST): North American Intergroup phase III trial ACOSOG Z9001, Blackstein et al.

Table 3 – Independent Risk Factors
High Mitotic Rate (≥5/50 HPF) <0.001 11.3
Tumor Size ≥ 5 cm <0.0001 2.0
Small bowel primary = 0.02 1.7
Note: Risk factor calculations via multivariate analysis.

Some questions remain about the use of adjuvant Gleevec

  • Should patients with exon 9 tumors take higher doses of Gleevec for adjuvant therapy?
  • Are there some subsets of patients that might not benefit from adjuvant Gleevec?
  • Should patients with low-risk tumors take adjuvant Gleevec?

Readers interested in exploring these questions further are referred to the links at the bottom of this page. However, please note that these articles were written prior to the results at 2011 ASCO showing improved survival for 3 years of imatinib.

At this time, there appears to be three factors that a doctor and patient can use to determine whether or not to take preventative Gleevec.  This list is an example of important factors in decision making that might occur but are NOT intended as a replacement for discussion with your doctor.

  1. Risk of recurrence. A very low risk or low risk tumor might suggest not taking Gleevec. See the Diagnosis and Risk Assessment section for a review of the risk of recurrence.
  1. How likely a patient is to respond to Gleevec (if mutational testing is available). Patients with less responsive or non-responsive tumor types are probably less likely to receive benefit from Gleevec, especially if they are low risk. See Mutational Testing.
  1. The anxiety level of the patient. Patients with a higher level of anxiety might receive comfort from adjuvant Gleevec.

If a patient has been on preventative Gleevec for an extended time, consider this when deciding to continue or stop taking Gleevec.

  1. How well a patient is tolerating Gleevec. A patient that is low risk or has a less responsive mutation type might be more inclined to stop taking Gleevec if they were not tolerating it. A patient with a high-risk tumor and a responsive mutation type might have more incentive to keep taking the Gleevec even though they were not tolerating it well.

In practice, a doctor might consider all of these things when making a recommendation. Adjuvant Gleevec is approved (in the US) for all risk categories without any limits on duration.

In a presentation at 2008 GI ASCO, Dr. Ronald DeMatteo presented data (from the Z9000 phase II trial) that showed that GIST patients with an exon 9 mutation were especially prone to having recurrences soon after the end of the one year trial period on Gleevec.

This seems to suggest that exon 9 patients might benefit from longer periods of adjuvant Gleevec; perhaps indefinitely. The optimal dosage for adjuvant therapy for exon 9 patients remains unclear. Exon 9 patients typically require higher doses of Gleevec for treatment for metastatic disease.

In 2008, Dr. Ronald DeMatteo presented trial data that showed that GIST patients with an exon 9 mutation were especially prone to having recurrences soon after the end of the one year trial period on Gleevec. This suggests that exon 9 patients might benefit from longer periods of adjuvant Gleevec; perhaps indefinitely. The optimal dosage for adjuvant therapy for exon 9 patients remains unclear. Exon 9 patients typically require higher doses of Gleevec for treatment for metastatic disease.

Links for more information on Adjuvant and Neoadjuvant therapy

Disclaimer:  The information presented on this website has been gathered by the Life Raft Group staff and should not be used as a substitute for consultation with a medical physician who is experienced with GIST.

References

  1. Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran S-E, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P. One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor (SSGXVIII/AIO) Full text article. 
  1. Prof Ronald P DeMatteo MD, Karla V Ballman PhD b, Cristina R Antonescu MD a, Robert G Maki MD a, Prof Peter WT Pisters MD c, George D Demetri MD d, Martin E Blackstein MD e, Prof Charles D Blanke MD f, Margaret von Mehren MD g, Prof Murray F Brennan MD a, Prof Shreyaskumar Patel MD c, Martin D McCarter MD h, Jonathan A Polikoff MD i, Benjamin R Tan MD j, Kouros Owzar PhD k, on behalf of the American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.
  1. Gold JS, Gönen M, Gutiérrez A, Broto JM, García-del-Muro X, Smyrk TC, Maki RG, Singer S, Brennan MF, Antonescu CR, Donohue JH, DeMatteo RP. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis.

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