Learn what novel patterns of GIST progression look like and mean. The majority of GIST patients treated with imatinib achieve clinical benefit, as assessed by durable complete or partial remissions or prolonged stabilization of their disease. However, in most populations of patients receiving antineoplastic therapy, a subgroup will experience progression of their cancer. Disease progression occurred in 11% to 14% of patients in the European Organization for Research and Treatment of Cancer (EORTC) and US-Finland phase II studies of imatinib treatment for metastatic or unresectable GIST, with follow-up of at least 9 to 13 months. Figure 3 shows overall survival and time to treatment failure in the US-Finland trial. Since resumption of malignant cell growth or the appearance of new lesions generally requires prompt reevaluation of the treatment plan, it is important to accurately identify signs of progressive disease as early as possible.


Nodule within a mass

Jayesh Desai, MD, of the Dana-Farber Cancer Institute (DFCI) in Boston, Massachusetts, USA, reported the results of a study by their team in which the objective was to evaluate the patterns of GIST progression following an initial positive response to imatinib, defined by conventional bidimensional radiographic criteria (see “GIST Nodule Within a Mass: A Conversation With Jayesh Desai, MD,”). As Dr. Desai explained in Barcelona, the investigators prospectively monitored 89 imatinib-treated patients with metastatic GIST for a period of up to 36 months (median, 29 months). The evaluations were based on standard anatomic measurements obtained by CT and, in some cases, MRI scanning. FDG-PET functional imaging was also performed in the majority of patients. In 42 of the 89 patients, a confirmed partial response (n = 34) or minor response (>25% tumor reduction, n = 8) to imatinib—demonstrated by reduced tumor size, with marked decrease in attenuation values, and concomitant loss of FDG uptake—was followed by evidence of progressive disease.

The key finding was a novel pattern of clonal evolution in certain GIST lesions, which was termed the “nodule within a mass.” This pattern was noted in approximately 50% of patients (22/42) with progressive GIST and was not predicted for by standard tumor response criteria. This is a new enhancing focus enclosed within a preexisting tumor mass that is nonenhancing or hypoenhancing (Figure 4), indicating loss of malignant cell activity in response to imatinib therapy. Multiple small nodules developed in some patients over a period of months. In most patients, the nodule arose from the edge of the mass, whereas both the mural surface and the tumor matrix were involved in a subset of patients.


Overall survival and duration of treatment response in the US-Finland phase II
trial of imatinib therapy for advanced GIST. (Reproduced with permission from Demetri, 2002.2)


Evaluating progression

Of particular note was the observation that the enhancing nodule often appeared before the development of progressive disease as defined by conventional tumor-size criteria, such as RECIST.

Conventional tumor measurements will not detect this type of progression unless expansion of the nodule causes a very significant increase in the size of the surrounding mass. The nodule within a mass is a subtle but important early marker of GIST progression, according to Desai and coworkers, constituting the first progressing site in the majority of patients who exhibited this pattern. Additionally, the subtle nodule within a mass is the only progressing site in more than half of the patients with this sign. The nodules appear to be independent of imatinib starting dose. The nodule within a mass probably represents clonal evolution within the tumor mass. Further study will help determine whether the nodule within a mass is specific for GIST or is perhaps associated with the use of molecularly targeted therapies in general.


Figure 4. GIST Nodule Within a Mass:
A Conversation With Jayesh Desai, MD
treat_fig4_A treat_fig4_B
treat_fig4_C treat_fig4_D
Computed tomography scans of a GIST at baseline (A); after 3 months of imatinib therapy, showing interval response characterized by greater tumor homogeneity, decreased contrast uptake, and reduction in size (B); after 15 months of therapy, showing overall stable disease but also the appearance of multiple small “nodules” within the tumor mass (C); and after 18 months of therapy, showing an increase in the size of the nodules but not in the dimensions of the encompassing mass (D).
(Courtesy of Jayesh Desai, MD.)


Question: The nodule-within-a-mass pattern was frequently the first sign of progression in your study. What is the best way of finding these nodules as early as possible?

Dr. Desai: The keys are education and awareness of this pattern. Most of our patients undergo spiral CT scans as part of their staging, and I certainly would not suggest changing this approach. However, it is important, in view of our findings, to be very vigilant in looking for these nodules. Have a high index of suspicion for subtle changes like these that may develop on imaging studies.

Question: Is FDG-PET preferable to CT for early detection of the nodule within a mass?

Dr. Desai: I do not have enough specific data to answer that question. If nodules were seen on CT scans, then in most cases they were also seen on PET scans when both happen to have been obtained concurrently. I do not think there is a reason to change what we do with respect to imaging studies based on the results of this research.

Question: A clinician might ask, “If I am seeing something new, should I be doing something new?” How would you respond?

Dr. Desai: Again, I do not think we have enough data or sufficient follow-up to know the answer to that question. In the limited set of patients I described, our management approach was generally the same as what we followed previously, before we conducted this study. For example, patients’ imatinib dose was adjusted if they had conventional indications of GIST progression, such as a new site of disease. However, dose escalation did not seem to affect these specific nodules, which clinically, at least, appear to represent new clones of resistant disease. If local treatments can be utilized, such as radiofrequency ablation or surgical resection of the limited resistant clone, I would give consideration to that approach. Continuation of the imatinib to maintain control of the remainder of the sensitive disease is also critical. These nodules appear to be indicative of a very limited and focal progression of disease; therefore, I would manage such individual cases following the same principles as I would a limited clonal mass that arose de novo elsewhere.

1 Novel Pattern of GIST Progression: What It Looks Like, What It Means
Clinical Management of GIST
Helsinki and Barcelona 2003-Conference Highlights
2. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.
N Engl J Med. 2002;347:472-480.
3. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours:
A phase I study. Lancet. 2001;358:1421-1423.
4. Verweij J, van Oosterom A, Blay J-Y, et al. Imatinib mesylate (STI-571, Glivec, Gleevec) is an active agent for gastrointestinal stromal tum ours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study.
Eur J Cancer. 2003;39:2006-2011.
5. Desai J, Shankar S, Heinrich MC, et al. The “nodule within a mass”: a unique pattern of disease progression seen in patients with metastatic gastrointestinal stromal tumors (GIST) not predicted for by standard tumor response criteria [abstract]. Program of the Connective Tissue Oncology Society 9th Annual Scientific Meeting.
2003:38. Abstract 123.

Jerry Call
Author: Jerry Call