Japanese Journal of Clinical Oncology Advance Access originally published online on January 17, 2006
Japanese Journal of Clinical Oncology 2006 36(1):17-24; doi:10.1093/jjco/hyi212
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© 2006 Foundation for Promotion of Cancer Research
Patterns of Progression in Gastrointestinal Stromal Tumor Treated with Imatinib Mesylate
Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
For reprints and all correspondence: Yoon-Koo Kang, Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1, Poongnap-dong, Songpa-gu, Seoul, Korea. E-mail: ykkang{at}amc.seoul.kr
Received August 17, 2005; accepted November 29, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Although most patients with gastrointestinal stromal tumor (GIST) treated with imatinib mesylate achieve remission or disease stabilization, a significant proportion show progressive disease (PD) with or without initial favorable responses. We evaluated and categorized the patterns of progression of metastatic or unresectable GIST treated with imatinib to identify the prognostic significance and contribution to further treatment decision-making.
Methods: We prospectively gathered clinical data from 62 GIST patients treated with imatinib mesylate (400 mg/day) over a median period of 26 months. Twenty-one of these patients showed evidence of PD based on Response Evaluation Criteria in Solid Tumor criteria.
Results: Four patterns of PD were defined: focal progression (FP, N = 4), general progression (GP, N = 6), new cystic lesion (NCL, N = 6) and new solid lesion (NSL, N = 5). The groups were found to differ in terms of time to progression and prior response to imatinib. The proportion of patients who responded to escalated doses of imatinib (600–800 mg/day) was significantly higher in NCL patients (P = 0.04). Overall survival and survival from the confirmation of PD were significantly better in NCL or FP patients compared with NSL or GP patients (P = 0.0157, P = 0.0013).
Conclusions: We identified four patterns of disease progression based on radiographic criteria with different clinical characteristics and impact on survival. Knowledge of these patterns was relevant for early detection and may be helpful in further treatment decision-making.
Key Words: gastrointestinal stromal tumor • imatinib • disease progression • sarcoma • tomography • spiral computed • prognosis
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Imatinib mesylate revolutionized the care of patients with gastrointestinal stromal tumor (GIST) and created a new paradigm in targeted cancer chemotherapy. In phase II and III clinical trials of imatinib mesylate, 45–67% of patients achieved a partial response (PR) based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria during 9–24 months of follow-up. An additional 4–6% of patients showed a complete response (CR), and 18–32% displayed stable disease (SD) (1–4). In total, up to 85% of GIST patients benefited from imatinib mesylate, which also increased overall survival.
Despite these encouraging results, a significant proportion of GIST patients administered imatinib will experience disease progression, and primary or secondary imatinib resistance has begun to emerge. A phase III study of imatinib mesylate treatment for metastatic or unresectable GIST, which had a median follow-up of 2 years, showed that disease progression occurred in 44–53% of patients, and this included a primary imatinib resistance rate of 9–13% (3).
Although the efficacy and safety of imatinib mesylate have been examined in large GIST studies, few studies have focused on the pattern of progression and the response to increasing doses of imatinib mesylate. Improved knowledge of the various patterns of disease progression is important in order to adequately manage patients and to interpret clinical trials employing new tyrosine kinase inhibitors (TKI).
The purpose of the present study was to evaluate and categorize the patterns of disease progression of metastatic or unresectable GIST treated with imatinib mesylate. In addition, the study sought to determine the prognostic significance associated with the different patterns of disease progression.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PATIENTS AND TREATMENT
From July 2001 to December 2004, we prospectively gathered clinical data from 62 consecutive patients with metastatic or unresectable GIST diagnosed and treated at our institution, 12 of whom were also enrolled in the recently closed Korean multicenter phase II clinical trial of imatinib mesylate. All patients had histological confirmation of GIST with positive KIT expression on the basis of CD117 immunohistochemical staining (A4502, DAKO) and at least one measurable lesion.
Patients received 400 mg imatinib mesylate p.o. per day until disease progression, unacceptable toxicity or patient refusal. In cases of disease progression, the dose of imatinib mesylate was escalated to 600 or 800 mg per day. The median patient age was 57 years (range 33–73 years), with a male to female ratio of 1.6:1. The primary tumor sites were the stomach (44%) and small bowel (47%). At enrolment, 12 patients (19%) had initial metastatic disease, 45 (73%) had recurrent disease and 5 (8%) had unresectable locally advanced disease.
The best overall responses to imatinib mesylate were CR in 4 patients (7%), PR in 33 (53%), SD in 16 (26%) and progressive disease (PD) in 9 (15%) patients. Including 9 patients with initial PD, 21 of 62 patients (34%) demonstrated evidence of PD based on RECIST (5), with a median follow-up of 25.6 months (range 8.8–42.6 months). The institutional review board of the Asan Medical Center granted permission for this analytic study.
KIT AND PDGFRA MUTATIONAL ANALYSIS
From formalin-fixed and paraffin-embedded tissue sample, 10 µm thick sections were taken. Tissue samples were obtained from the non-necrotic region of the solid tumor in order to avoid sampling error, and tumor histology was confirmed using H&E staining and light microscopy. Genomic DNA was extracted from three sections using a DEXPAT kit (TaKaRa, Kyoto, Japan). Exons 9, 11, 13 and 17 of KIT, and exons 12 and 18 of PDGFRA, were amplified using PCR (6,7). The PCR products were subcloned using a TOPO TA cloning kit (K4500-01; Invitrogen, Carlsbad, CA) and sequenced twice using an ABI 3700 DNA analyzer (Applied Biosystems, Foster City, CA).
ASSESSMENT OF RESPONSE AND PROGRESSION
The objective tumor response was measured using contrast-enhanced spiral computed tomography (CT) scans. Target lesions were prospectively evaluated 1–2 months after the start of treatment and every 2–3 months thereafter. CT scans were performed earlier if tumor progression was suspected. CT scans both before (with the exception of patients who underwent scans at other hospitals before treatment) and after treatment were obtained using one of three commercially available helical CT scanners (Somatom Plus-S, Siemens, Erlangen, Germany; Somatom Plus 4, Siemens; Hispeed, GE Medical Systems, Milwaukee, WI). A monophasic bolus of 100–125 ml iopromide (Ultravist 300 or Ultravist 370; Schering, Berlin, Germany) was administered at a rate of 2.5–3.0 ml/s, and scanning began 65–70 s after injection to coincide with the portal venous phase. Images were obtained using 1 s scans in 5 mm thick sections in the high-quality mode. Hardcopy archived CT images were evaluated by three non-blinded oncologists (M.-H.R. and J.-L.L. separately but in consensus with Y.-K.K.) for the analysis of disease progression according to RECIST and to identify the representative pattern of the tumor progression. Consistent with the Southwest Oncology Group (SWOG) criteria, an increase in the sum of the longest diameters of target lesions was not regarded as disease progression if it was accompanied by definite cystic change in the tumor suggesting necrosis (8), and lesions having typical features of ‘nodule within a mass’ described by Desai et al. were also regarded as DP (9). In some cases, 18FDG-PET (Scanditronix PC4096-16WB, Uppsala, Sweden) was performed.
PATTERNS OF PROGRESSION
Patterns of progression were categorized into four types.
- Focal progression (FP) was defined as a single-site progression, which was either an increase in size (Fig. 1) or the development of a new enhancing focus enclosed within a preexisting tumor mass that was low density and non-enhancing indicating loss of malignant cell activity in response to imatinib therapy (Fig. 2), described as ‘nodule within a mass’ (9).
- General progression (GP) was defined as an increase in tumor size, tumor density and heterogeneous enhancing pattern in two or more tumor masses, which may have been either initially responding or progressive with imatinib treatment (Fig. 3).
- A new cystic lesion (NCL) was defined as the appearance of one or more new lesions that were relatively well defined, low density and homogeneous, cyst-like and round in shape without enhancing nodules or boundaries (Fig. 4).
- A new solid lesion (NSL) with or without a cystic component was defined as the appearance of one or more new lesions that were solid with or without a cystic component and had thick enhancing walls (Fig. 5).
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STATISTICAL ANALYSIS
Fisher's exact test was used to assess associations between patterns of progression and overall responses to initial imatinib therapy and to the escalated dose of imatinib. Kruskal–Wallis test was used to assess the differences in time-to-progression (TTP) between the progression patterns. Survival distributions were estimated using the Kaplan–Meier method, and comparisons between the patterns of progression were made using log-rank tests. P-values <0.05 were considered to indicate a significant difference between groups.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PATIENT CHARACTERISTICS
The final study population numbered 21 patients (15 men and 6 women) with a median age of 55 years (range 33–70) (Table 1). Primary tumor sites were the small bowel in 12 patients (57%), stomach in 8 (38%), and colon in 1 (5%). The sites of active disease were the liver in 15 patients (71%), peritoneum in 12 (57%), bowel in 2 (10%), kidney in 1 (5%), spleen in 1 (5%), esophagodiaphragmatic recess and lung in 1 (5%), and subcutaneous tissue in relation to a laparotomy scar in 1 (5%). Four patients (19%) had initial metastatic disease and 17 (81%) patients had recurrence after surgical resection. Among 21 patients, c-kit and PDGFRA mutational status were available in 19 patients; exon 11 of c-kit mutation was found in 16 patients (84%) while 2 patients (11%) had exon 9 of c-kit mutation. There was no patient who had either exon 13 or 17 of c-kit, or exon 12 or 18 of PDGFRA mutations.
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FOUR PATTERNS OF DISEASE PROGRESSION
PROGRESSION IN THE PREEXISTING LESION
FP was detected in four patients (19%). One FP lesion occurred in the liver, one in the esophagodiaphragmatic recess and two in the peritoneum. All FP sites had shown prior response to imatinib mesylate. The best overall response prior to PD was CR in one patient, PR in two and SD in one. The two peritoneum FPs had a typical ‘nodule within a mass’ appearance. Median time to FP was 17.9 months (range 13.5–21.1). GP was observed in six patients (29%). All GP lesions were found in peritoneal masses, with one patient having both peritoneal and liver masses. The majority of GP patterns developed as an initial response to imatinib and the median time to GP was 1.4 months (range 0.7–33.5). However, two patients showed GP after an initial PR or prolonged SD.
DEVELOPMENT OF NEW LESIONS
NCL was observed in 6 of the 21 patients (29%). Interestingly, NCL developed exclusively in the liver, and were mostly <2 cm in the longest diameter. Median time to PD manifestation as NCL was 1.4 months (range 0.8–5.3). The best overall response to imatinib in the majority of NCL patients was PD (with the exception of one PR), which reflects that NCL developed early in the course of imatinib treatment. NSL was detected in five patients (24%). Three NSL developed in the peritoneum and two in the liver. The best overall response to imatinib was PR in two patients and SD in three. Four NSL were detected within 10 months after the start of imatinib, and the median time to NSL was 6.3 months (range 2.9–21.3). In our study, we did not find any patients with NCL or NSL who fitted the definition of two or more patterns of progression.
TIME TO PROGRESSION AND INITIAL RESPONSE TO IMATINIB ACCORDING TO PATTERNS OF DISEASE PROGRESSION
The median TTP for the different progression patterns was compared. NCL and GP showed a similar TTP and were observed during the early follow-up period (median 1.4 months, range 0.7–33.5 months), whereas FP and NSL were recognized later and in a wider range (median 13.5 months, range 2.9–21.3 months, P = 0.033). Best overall responses to imatinib therapy also differed between progression patterns. GP was more common in patients with initial responses as PD. While FP and NSL appeared to occur more commonly in patients who had shown prior responses to imatinib (P = 0.04).
RESPONSE TO INCREASED IMATINIB DOSE AND OVERALL SURVIVAL ACCORDING TO PATTERNS OF DISEASE PROGRESSION
Among the 21 patients with PD, 14 were treated with increased doses of imatinib to a maximum of 800 mg/day. There was neither response nor SD in patients who had FP or GP patterns. In contrast, three of the four patients displaying the NCL pattern showed SD or better in response to elevated doses of imatinib (P = 0.04, NCL versus non-NCL progression). Only one NSL patient showed PR in response to escalated doses of imatinib, while all patients in the non-NCL group showed PD.
Curative or palliative surgical resection of the progressing lesion was undertaken in 7 patients (Table 1); 2 FP, 1 GP, 1 NCL and 3 NSL. One such FP patient (UPN 1) was alive 4+ months after surgical resection without any evidence of disease progression, while the other FP patient (UPN 3) was again found to have PD 3 months after surgery. One NCL patient (UPN 16) and one NSL patient (UPN 20) were alive 10+ and 8+ months after surgery, respectively, without any signs of disease progression. Two NSL patients, UPN17 and UPN19, were dead 10 and 12 months after surgery, respectively. One GP patient (UPN 5) underwent repeated surgery on progressive lesions and was dead 23 months after the first salvage operation. With a median follow-up duration of 25 months (range 10–40), the median overall survival was 26.8 months (95% CI, 19.5–34.2), with the 1 year survival rate being 75%. Overall survival was better in FP or NCL patients compared with GP or NSL patients (Fig. 6A, P = 0.0157). In addition, overall survival from the confirmation of disease progression was better in FP or NCL patients (Fig. 6B, P = 0.0013).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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GIST was once considered a poorly defined oddity by pathologists, and was a chemoresistant sarcoma often neglected by oncologists because of the absence of effective treatment until recently. With the advent of imatinib, GIST has emerged as a distinct pathogenetic entity that has reinforced the concept of molecular targeted therapy (10). While most GIST patients treated with imatinib experience and continue to enjoy remission or disease stabilization, a small percentage does not respond to imatinib. In addition, some patients who show initial favorable responses subsequently show disease progression, such as emergence of new liver lesions or rapidly progressing imatinib-resistant implants. A recent study reported that PD occurred in 44–53% of GIST patients treated with either standard or high dose imatinib with a median follow-up of 2 years (3). Despite a high progression rate, little attention has been given to the pattern of progression and the eventual outcome after the development of PD in such patients. In the present study, 34% of patients demonstrated evidence of PD, with a median follow-up of 25.6 months.
In the present study we categorized disease progression as one of four patterns: two related to progression in preexisting lesions and two to development of new lesions. Four patients showed the FP pattern, which represented PD in a single site manifested as an increase in size or ‘nodule within a mass’ (9) while the other peritoneal implants and liver metastases responded to imatinib. While increasing the dose of imatinib did not improve FP lesion responses, surgery on the progressing lesion was able to control two such cases. Since an increased imatinib dose did not control the disease in the FP cases, yet a survival benefit was found in FP patients, two of whom received surgery, we propose that a surgical approach when feasible is a reasonable option for FP patients. However, we feel that further research is required before this approach can be fully recommended.
Development of NCLs, which indicated PD according to RECIST criteria, did not deteriorate patient clinical benefit. It has been observed that hepatic metastases from GISTs that responded to imatinib exhibited cyst-like changes and resembled simple cysts with well-defined borders according to contrast-enhanced CT (11,12). As NCL developed exclusively in the liver and did not negatively affect overall survival, it might be speculated that NCL represent preexisting subtle solid hepatic lesions with iso-density with liver parenchyma on enhancing and acquire a cyst-like appearance consisting of hyaline degeneration upon imatinib treatment (13). Favorable responses to escalated imatinib doses and no further increases in size after NCL development also support our hypothesis that liver NCL represent the appearance of responding minute hepatic lesions that were not visible at the initial imaging study. Indeed, one patient with an initially unresectable gastric GIST who had a remarkable response at the primary site following imatinib administration had accompanying NCL scattered in the liver. Total gastrectomy and hepatic metastatectomy was undertaken and only necrotic debris was found in the hepatic NCL.
It has been suggested that RECIST might not be optimal for response assessment in GIST patients (14). Owing to the cystic changes in responding lesions without significant reduction in size, RECIST may significantly underestimate GIST response and fail to discriminate between good and poor responders, especially in the early treatment phase (14). Furthermore, in some patients, tumor size actually increases with cystic change despite clinical improvement and metabolic response (i.e. decreased FDG uptake) due to intratumoral hemorrhage and extensive necrosis (15). Considering cystic change, SWOG criteria may be better than RECIST since the former excludes the definition of PD when the lesion is cystic in nature. These observations lead to questioning of the usefulness and accuracy of RECIST in assessing tumor progression. The present study revealed that RECIST was suboptimal for early detection of FP and may overestimate DP in NCL cases. The first evidence of FP often appeared before the development of RECIST-defined DP. Conventional tumor response criteria, such as WHO, RECIST and SWOG criteria, will not detect FP unless expansion of the focal progressive nodule causes a very significant increase in the sum of size of the surrounding or other implanted target masses, which are still responding to imatinib mesylate (9).
In general practice, contrast-enhanced CT is the most common modality used to detect postoperative recurrence and to assess response and eventual progression in GISTs (15). In regard to contrast-enhancement, imaging during the portal venous phase alone might be inadequate, and the addition of arterial phase imaging may be helpful for evaluating some GISTs that appear hyperintense compared with normal liver parenchyma on arterial phase and isointense on venous phase. Routine triphasic CT scanning in NCL patients may be able to detect invisible lesions on venous phase which would become NCL after imatinib therapy. 18FDG-PET was recently suggested as an early and sensitive method to evaluate GIST response to imatinib treatment (16). However, 18FDG-PET is costly and available at relatively few institutions. In addition, some GISTs are not FDG avid, making pretreatment PET mandatory, and no other effective drugs are available at this time if GIST does not respond to imatinib. It is important to accurately identify signs of PD, such as FP or NSL, as early as possible and prior to their becoming RECIST-defined PD, which is usually unresectable. Although it has not been tested, 18FDG-PET may have the ability to detect FP or NSL earlier or more accurately than CT, especially in patients with ambiguous CT change, which could prompt us to re-evaluate the treatment plan and give patients the opportunity to enjoy long-term disease control if local treatments can be utilized.
In this study, curatively unresectable GP and NSL lesions resulted in progression to end-stage disease. As there were no differences in KIT mutational status between the groups, poor prognosis of GP and NSL cannot be attributable to inherent genetic change. With the exception of one patient who showed PR in response to escalated doses of imatinib, disease progressed relentlessly resulting in death in a median of 5.8 months. Therefore, GP or unresectable NSL patients should be enrolled as a priority in clinical trials investigating novel TKIs or other experimental agents.
Each pattern of disease progression may correlate with a specific molecular event resulting in imatinib resistance. FP or NSL with residual quiescent-responding GIST is consistent with the concept that each individual peritoneal implant or hepatic metastatic tumor in GIST can be viewed as a single clone growing in vivo (17), and additional c-kit mutations or KIT overexpression develop in some clones leading to imatinib resistance (17,18). In contrast, GP, which occurred without prior response to imatinib in the majority of patients, is the main pattern of progression in early imatinib resistance, and c-kit or PDGFRA mutations outside the juxtamembrane hotspot lesion without secondary mutation may underlie the mechanism of imatinib resistance (18). In the present study, analysis of progressive lesion specimens from six patients showed three had additional c-kit exon 17 mutations (one in FP, GP, and NSL, respectively, data not shown).
The present study has several limitations. First, a relatively small number of patients were enrolled and the follow-up durations after the documentation of PD were relatively short, which made statistical analysis difficult calling for cautious interpretation of the results. Second, we were unable to analyze PET and pathological correlations in terms of the pattern of PD. In particular, no NCL patients underwent PET imaging. Unfortunately such imaging is costly and is not reimbursed by the national health insurance system.
In summary, recognition of the pattern of progression after imatinib mesylate treatment is relevant in clinical practice. Improving the prognosis for progressive GIST treated with imatinib mesylate appears to require regular follow-up of patients with initially responding tumors and early detection of FP or NSL. In such cases, locoregional treatment such as radiofrequency ablation or surgical resection can be employed or may be repeated to prolong patient survival while responding GIST implants are controlled by imatinib. It is also important for clinicians to realize that NCL might not represent progression, especially if it occurs in the early phase of treatment. The present findings showing the pattern of progression has prognostic value, indicating that further study using a larger number of patients is warranted to confirm these potentially important clinical observations. In addition, further study needs to be undertaken in order to identify the biological principles governing each of the four progression patterns.
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Notes |
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The first two authors contributed equally to this work.
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REFERENCES |
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