five-year follow up of patients with gastrointestinal stromal tumor: recurrence-free survival by...

ORIGINAL ARTICLE

Five-year follow up of patients with gastrointestinal stromaltumor: Recurrence-free survival by risk groupajco_1494 1..7

Rakesh KAPOOR, Divya KHOSLA, Pankaj KUMAR, Narendra KUMAR andAnjan BERADepartment of Radiotherapy and Oncology, Post-graduate Institute of Medical Education and Research, Regional CancerCentre, Chandigarh, India

Abstract

Aim: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointes-tinal tract. There is limited published data on GIST from the Indian subcontinent. This 5-year retrospectiveanalysis of 49 patients treated for GIST reports clinical and pathological features and survival outcome byrisk stratification.

Methods: We reviewed 49 cases of GIST from January 2004 to December 2008. Imatinib was administeredafter surgery in patients with either high-risk, residual or metastatic disease and at onset of recurrence ormetastatic disease in patients with intermediate risk.

Results: The mean age was 50 years (range, 17–80 years). Patients with localized tumor were classified aslow (n = 2), intermediate (n = 4) and high risk (n = 32), based on the primary tumor and mitotic index. Ata median follow up of 21 months, 2-year and 3-year recurrence or progression-free survival rates were 61and 39%, respectively, for all patients. The median recurrence-free survival rate in the intermediate-risk andhigh-risk groups were 7 and 49 months, respectively. The median progression-free survival in the residual(n = 4) and metastatic disease group (n = 7) was 10 and 29 months, respectively.

Conclusion: This study demonstrates the role of imatinib in adjuvant and therapeutic settings. Responseshave been durable and most patients tolerate the drug well at clinically effective doses. In view of highrecurrence rates in the intermediate-risk group in our study, it would be better to keep these patients on strictfollow up to detect recurrence at the earliest opportunity.

Key words: gastrointestinal stromal tumor, imatinib, sunitinib, surgery, survival.

INTRODUCTION

Gastrointestinal stromal tumors (GIST) are the mostcommon mesenchymal neoplasms of the gastrointestinaltract in adults.1 Overall, GIST are rare (the third mostprevalent) among histological types of gastrointestinaltract tumors. The term GIST was introduced by Mazurand Clark in 1983; however, in 1998, Kindblom et al.

reported the actual cell origin of GIST as a pluripotentmesenchymal stem cell programmed to differentiateinto the interstitial cells of Cajal that also act asgastrointestinal pacemaker cells.2

Perhaps the most critical development that distin-guished GIST as a unique clinical entity was the discov-ery of c-kit proto-oncogene mutations in these tumorsby Hirota et al. in 1998.3 Identifying c-KIT (CD117,a marker of KIT receptor tyrosine kinase [TK]) is key tomaking a diagnosis of GIST in 95% of patients.

The three most important characteristics for pre-dicting how GIST will behave are size, mitotic rateand location.4 However, the significance of size is site-dependent. Specifically, gastric tumors tend to be less

Correspondence: Dr Rakesh Kapoor MBBS MD, Departmentof Radiotherapy and Oncology, Post-graduate Institute ofMedical Education and Research, Regional Cancer Centre,Chandigarh, India 160012. Email: [email protected]

Accepted for publication 15 October 2011.

Asia–Pacific Journal of Clinical Oncology 2012 doi:10.1111/j.1743-7563.2011.01494.x

© 2012 Blackwell Publishing Asia Pty Ltd

aggressive than intestinal tumors, even those >5 cm insize, provided their mitotic activity is low (no more thanfive mitoses per 50 high-power fields [HPF]).5–7 Tumorswith low mitotic counts (less than five per 50 HPF)and diameter <2 cm generally exhibit benign behavior,while tumors with diameter >10 cm and high mitoticcounts (greater than five per 50 HPFs) are associatedwith malignant behavior. Importantly, neither small sizenor low mitotic rate excludes the potential for malignantbehavior.8,9

Complete surgical resection is the primary treatmentmodality for GIST. Total excision of the tumor is themost significant factor for outcome and can be accom-plished in 40 to 60% of all GIST patients and in >70%of those with primary, non-metastatic disease.10 Never-theless, around 50% of patients tend to develop tumorrecurrence and the reported 5-year survival is appro-ximately 50%.10 The median survival of recurrentGIST after surgical resection was 15 months in thepre-imatinib era.11

Conventional chemotherapy for the treatment ofGIST has a response rate of 5%.12 The development ofimatinib mesylate (Gleevec; Novartis Pharmaceuticals,Basel, Switzerland) advanced the treatment of GIST.Imatinib is a selective inhibitor of specific TK, includ-ing KIT, platelet-derived growth factor receptor alpha(PDGFR-a), ARG, c-FMS, ABL and BCR-ABL, and iscurrently the standard first-line treatment for patientswith KIT-positive unresectable or metastatic GIST, orboth.13–15

A number of additional, targeted, small-moleculetherapies have been shown to be effective for the treat-ment of GIST. These include sunitinib malate (Sutent;Pfizer, Sydney, Australia), which is available worldwideas a second-line treatment for GIST. Sunitinib is apotent, oral, multi-targeted TK inhibitor of vascularendothelial growth factor receptors (VEGFR-1, -2, -3),PDGFR-a and PDGFR-b, stem-cell factor receptors(KIT), FMS-like TK 3 (FLT3), colony-stimulating factor1 receptor, and glial cell line-derived neutropenic factorreceptor rearranged during transfection16,17 and ithas been demonstrated to be active in patients withimatinib-resistant or intolerant GIST.18–20 Recent studieshave also demonstrated efficacy for both oral masitiniband nilotinib in patients with GIST.21–23

This article reviews the clinical and pathologicalfeatures and survival outcome of 49 patients withGIST who were treated with surgery, imatinib orboth over the course of 5 years at a center in India.Some patients also received second-line treatment withsunitinib.

METHODS

Patients and study design

The records of patients treated for GIST from January2004 to December 2008 at the Department of Radio-therapy and Oncology, Regional Cancer Centre, Chan-digarh, India, were reviewed. Patients aged 17 years orolder with histologically confirmed GIST were followedup every 3 months for 5 years. The diagnosis of GISTwas based on light microscopy features and membranepositivity for CD117 (cKIT) by immunohistochemi-stry. Immunohistochemical stains including CD34,SMA, S-100 were also performed. Three cKIT-negativepatients were diagnosed on basis of morphological fea-tures, CD34 and negativity of SMA and S-100 stain. Thecase records of 49 patients were retrospectively reviewedand data on the following parameters were collected:age, sex, site of primary tumor, clinical presentation,surgical details, histopathology and markers, treatmenthistory, response to imatinib and AE. All patients werereferred for surgical assessment. Based on the size of theprimary tumor, mitotic index and Fletcher’s criteria, thetumors were classified as low, intermediate and high-riskgroups (Table 1).24

Fletcher’s criteria for risk assessment have beenfurther modified by the work of Miettinen and Lasota,who have adapted the effect of size, mitotic activity andanatomical location. However, we could not followMiettinen and Lasota’s risk classification as ours was aretrospective analysis. Hence Fletcher’s criteria, whichwere already published at that time were used for riskclassification.

Treatment

Patients with high-risk disease after curative surgery,and those with residual disease and metastatic diseasewere started treatment with oral imatinib 400 mg once

Table 1 Proposed approach for defining risk of aggressivebehavior in gastrointestinal stromal tumor

Risk level Size Mitotic count

Very low <2 cm <5/50 HPFLow 2–5 cm <5/50 HPFIntermediate <5 cm 6–10/50 HPF

5–10 cm <5/50 HPFHigh >5 cm >5/50 HPF

>10 cm Any mitotic rateAny size >10/50 HPF

Data from Fletcher.24

2 R Kapoor et al.

© 2012 Blackwell Publishing Asia Pty Ltd Asia–Pac J Clin Oncol 2012

daily (OD). Intermediate-risk patients were not startedon adjuvant imatinib after surgery but received thera-peutic imatinib 400 mg OD at the first sign of recur-rence. The patients were evaluated every 3 months,including a clinical examination and ultrasonography orcontrast-enhanced computed tomography scan. Routineblood tests were performed for patients on imatinib.

For patients who experienced disease progressionon imatinib 400 mg the dose was increased to 600 mgOD and the patients continued to be evaluated every3 months. Upon further progression, either the dose ofimatinib was increased to 600 mg or sunitinib 50 mgOD, 4 weeks on/2 weeks off treatment.

Definitions and criteria

Patients, clinical and pathological features, and survivaloutcome in terms of recurrence-free survival (RFS),progression-free survival (PFS) and response rates wereassessed. Only patients who had completed at least6 months of therapy at the time of analysis were eligiblefor analysis. RFS was defined as the time from surgery tothe time of clinical or radiological evidence of diseaserelapse. PFS in patients who had residual and metastaticdisease was defined as the period from the initiationof imatinib therapy to clinical or radiological evidenceof progression or death. Clinical evidence was defined aspalpable mass or lump warranting further radiologicalinvestigation. Differences in median RFS between theintermediate-risk and high-risk groups were evaluatedby the log – rank test. Kaplan – Meier curves for RFSwere plotted using SPSS version 12 (SPSS, Chicago, IL,USA).

Response to imatinib was defined as follows: com-plete response (CR), complete disappearance at all sitesand no new lesions; partial response (PR), decrease of30% in the sum of the single largest diameters of allmeasurable lesions; progressive disease (PD), an increasein the sum of the single largest diameters by 20%; stabledisease (SD), neither PR nor PD criteria met.25 Adverseevents (AE) were recorded in patients treated withimatinib. Follow up was continued until death or lasthospital visit.

RESULTS

Clinical and pathological characteristics

Overall, 49 patients diagnosed as GIST were included.Their clinical and pathological features are summa-rized in Table 2. Their mean age was 50 years (range,17–80 years); 34 (69%) were male. Abdominal pain was

the most common initial presenting symptom (74%),followed by gastrointestinal bleeding (40%), loss ofappetite and loss of weight (37%) and abdominal mass(33%). Four patients had a perforation at presentation.The mean duration of symptoms before presenta-tion was 5 months (range, 0.5–36 months). The mostcommon site of primary tumor was the stomach (49%),followed by the small (27%) and large bowel (18%).A laparotomy was performed in 45 patients (92%).Complete surgery was performed in 38 (78%) patients,while four (8%) patients had biopsies only. Tumor sizeranged from 2 to 35 cm (mean, 12 cm). In total 46(94%) of the GIST were positive for CD117.

Survival outcome/response

Of the 49 patients, two (4%) were classified as being atlow risk, four were (8%) at intermediate risk and 32[66%]) were at high risk. Seven (14%) patients had

Table 2 Characteristics of patients

Age (years)Mean 50Range 17–80

Sex, N (%)Male 34 (69)Female 15 (31)

Site of tumor at diagnosis, N (%)Stomach 24 (49)Small bowel 13 (27)Large bowel 9 (18)Anorectum 1 (2)Rectosigmoid 1 (2)Mesentery 1 (2)

Immunohistochemistry, N (%)CD117 46 (94)CD34 35 (71)SMA 14 (29)S-100 3 (6)

Histopathological subtype, N (%)Spindle cell 34 (69)Epithelioid 12 (25)Mixed 3 (6)

Symptoms (%)Abdominal pain 74Gastrointestinal bleeding 40Appetite and weight loss 37Abdominal mass 33

Surgical treatment, N (%)Laparotomy 45 (92)Complete surgery 38 (78)Biopsies only 4 (8)

Five-year follow-up of GIST patients 3

© 2012 Blackwell Publishing Asia Pty LtdAsia–Pac J Clin Oncol 2012

metastatic disease and four (8%) had macroscopicresidual disease (R2 resection). Out of the 49 patients,four were lost to follow up and could not be contacted.Table 3 shows the median follow up, number of recur-rences or progression and 2-year and 3-year RFS andPFS for each risk group. Low-risk patients did notreceive any treatment and were all disease free at thelast follow-up. In the two patients at low risk, medianfollow up was 22 months (range, 10.0–35 months).Four patients (8%) with intermediate-risk tumors hadRFS of 6, 7.3, 10.3 and 27 months, respectively, withmedian RFS of 7 months. Three out of four patients(75%) who experienced recurrence had colonic GIST,which may have led to a poor outcome (two developedlocal recurrence with liver metastases and one experi-enced recurrence in the peritoneum). One out of fourintermediate-risk patients was of stomach GIST whohad a survival of 27 months, hence the range is from6–27 months with median of 7 months.

There were 32 patients who were classified ashigh risk. The median duration of adjuvant imatinibwas 19.6 months (range, 7–30 months). Recurrenceoccurred in eight (25%) patients (local recurrence[n = 2], liver [n = 3], peritoneum [n = 2]); one patientdeveloped both local recurrence and liver metastases;one patient had operable disease and was started onimatinib 600 mg after surgery; one patient was startedon sunitinib and had SD after a median follow-up of24 months. The median RFS for patients in the high-riskgroup was 49 months (range, 9–61 months).

All patients with residual disease (n = 4) were startedon imatinib 400 mg OD. All four patients progressedbetween 9 and 14 months. Three patients had imatinibdose increased to 600 mg/day of which two had SD andone had PD. In our study, patients with residual diseasehad a R2 resection (one anorectum, one rectosigmoid,two small bowel) and had gross residual disease whichprogressed despite treatment and hence these patientshad poor outcome.

Of the patients with metastatic disease (n = 7), three(43%) experienced SD and four progressed on imatinibat a median of 29 months (range, 2–36 months). Threeof these patients had their imatinib dose increased to600 mg/day with further PD after 5, 6.5 and 8 months,respectively. One had sunitinib with stable disease after8 months.

RFS/PFS was also calculated for different sites ofpresentation. The 1-year, 2-year and 3-year RFS/PFS ofgastric, small bowel and colon were 84, 61 and 38%;83, 49 and 25; and 60, 45 and 18%, respectively.

At a median follow-up of 21 months (range,4–68 months), 2-year and 3-year RFS/PFS were 61 and39%, respectively, for all patients (Table 3). OS wasnot calculated as all patients were alive at the time ofanalysis.

Adverse events

The most common imatinib-related AE included edema(n = 12), which was most frequently periorbital, nausea(n = 11), drug rash (n = 5), diarrhea (n = 4), musclecramps (n = 3) and alteration in liver biochemistries(n = 1). Most of these AE were mild to moderate inseverity. The dose was increased in 13 patients and sideeffects were mild; the most common side effects seenwith dose escalation were edema (n = 7), nausea (n = 5)and diarrhea (n = 2). Only in one patient treatment wastemporarily discontinued for 2 months due to diarrhea,periorbital edema and skin rash. In this patient, treat-ment interruption was done for 2 months and the doseof imatinib was reduced to 400 mg.

DISCUSSION

GIST represent about 5% of all sarcomas and arethe most common mesenchymal neoplasm of the gas-trointestinal tract.26 Morphological risk assessment inGIST provides the basis for clinical management andoptimal patient care. Most studies of GIST suggest that

Table 3 Recurrence/progression and survival outcome by risk group

GroupsPatients

(n)Median FU,

monthsRecurrence/

progression (n)2-year

RFS/PFS (%)3-year

RFS/PFS (%)Median RFS/PFS,

months

All 49 21 11/8 61 39 37.0Low 2 22 0 100 100 Not reachedIntermediate 4 24 3 25 0 7High 32 24 8 71 64 49Residual 4 18 4 0 0 10.0Metastatic 7 7 4 57 0 29

FU, follow up; PFR, progression-free survival; RFS, recurrence-free survival.

4 R Kapoor et al.


the two most important prognostic features to assess therisk of aggressive behavior in a primary GIST are mitoticactivity and tumor size. These two features were thefoundation of the consensus approach for risk assess-ment in GIST.24 The present study consisted of hetero-geneous groups of patients with localized, residual andmetastatic disease. The mean age of the patients was50 years, which is a decade lower than that reportedin other studies.1,27–29 The present study showed a malepreponderance, which is comparable to other stud-ies,27,30 although in most published data there is no clearsex predilection. The most common location of GIST isthe stomach (50–60%) followed by the small bowel(30–40%).27,31 In our study, also, the most common siteof presentation was the stomach in 49% of patients,which is consistent with findings from a 2003 study.32

The four patients with intermediate-risk diseasecharacteristics in this study were not dissimilar fromother published reports, with median PFS of 7 monthsversus 12 months.29 Variations are likely due to thesmall cohort size and heterogeneous groups.

Because patients were treated at a tertiary care hos-pital, most were high risk (32/49), presenting withcomplex and large disease; this suggests late presenta-tion and the aggressive behavior of the disease. Thistrend is well-documented in the literature.27,28 All high-risk patients were started on adjuvant imatinib 400 mgOD. At a median follow up of 24 months, the 2-yearand 3-year RFS of the high-risk group were 71 and64%, respectively. Similar results were shown in theAmerican College of Surgeons Oncology Group Z9001phase 3 trial. In patients with kit-positive GIST witha tumor 3 cm or larger receiving adjuvant imatinib400 mg OD or placebo for 1 year after macroscopi-cally complete resection with a median follow up of19.7 months, the estimated 1-year RFS was 98% withimatinib compared to 83% with placebo.33 These resultsdemonstrate that adjuvant imatinib increases RFS inintermediate-risk to high-risk groups. In a phase 2 trialby US Intergroup, patients with a high risk of recurrence(tumor size >10 cm, tumor rupture, or <5 peritonealmetastases) had 1-year, 2-year and 3-year OS rates of99, 97 and 97%, respectively; at a median follow up of4 years, the 1-year, 2-year and 3-year RFS rates were 94,73 and 61%, respectively.33

In the present study, seven patients who had meta-static disease at presentation were started on imatinib.Three patients (43%) with metastatic disease treatedwith imatinib showed SD and four (57%) progressed. Asimilar pattern of response was shown by the USA –Finland trial, which reported a response rate of 54%

among 147 patients with inoperable or metastatic GISTtreated with imatinib 400 mg or 600 mg OD withfollow up of at least 6 months.34

Among the patients who progressed on imatinib, 75%required dose escalation to 600 mg. AE for thesepatients were mild to moderate in severity. Edema,nausea, and diarrhea were the most common AEobserved with dose escalation. One patient temporarilydiscontinued treatment due to diarrhea, periorbitaledema and skin rash.

Sunitinib has demonstrated efficacy in GIST inpatients progressing after imatinib in a number ofstudies.18,35 Our one patient is typical. A randomized,placebo-controlled, phase 3 study by Demetri et al.tested the efficacy and safety of sunitinib after failure ofimatinib. The trial was unblinded early due to highlysignificant benefit in PFS, which led to the licensing ofsunitinib for this indication.35 An open-label phase 2study that included 61 patients with imatinib-resistantor imatinib-intolerant GIST who received sunitinib indi-cated a clinical benefit rate of 53% at 24 weeks. Themedian PFS was 34 weeks and the median OS was107 weeks.18

Incomplete tumor excision is associated with a signifi-cantly reduced rate and duration of survival, comparedwith complete resection. Five-year survival rates of42% and 8 to 9% have been reported for patients whohad complete and incomplete GIST resections, respec-tively.36,37 In an analysis of 17 patients with primarygastric stromal sarcomas, median OS was 19 months,compared with a median survival of 39 months aftercomplete removal of the tumor.38 In our study, patientswith residual disease had a median PFS of 10 months.The three factors most strongly predictive of risk ofaggressive tumor behavior and adverse outcome aretumor site, size and mitotic rate. Based on long-termfollow up of more than 1600 patients, Miettinen et al.39

suggested guidelines for the risk stratification of primaryGIST based on mitotic index, size and site. According tothese guidelines, gastric GIST that are 2 cm or smallerwith a mitotic index of five or less per 50 HPF can beregarded as essentially benign, but lesions larger than2 cm with the same mitotic index have a risk for recur-rence. Miettinen and Lasota39 also evaluated the prog-nosis of gastric and small intestinal GIST in a largeseries. Their findings confirmed the results of earlier,smaller studies indicating that anatomic location affectsthe risk for disease recurrence and progression: smallintestinal GIST are more aggressive than gastric GIST ofequal size and this should be factored into the riskassessment of a primary tumor.



Nakamura et al.40 followed 80 patients with GISTand found that 4.5% of intermediate-risk casesrecurred, compared to 38.5% of high-risk categorycases.

The most interesting clinicopathological finding inour study was the high incidence of colonic GISTs. Outof four, three patients at intermediate risk had colonicGIST and all three developed recurrences despite theintermediate grade, size and mitotic rate characteristicsand complete macroscopic resection. Thus, the behaviorof colonic GIST is more akin to rectal GIST, thuswarranting a high-risk categorization in Miettinen andLasota system. In addition, in light of higher recurrencerates in intermediate-risk patients in our patient group,it would be better to keep these patients on regularfollow up so as to detect recurrence at the earliest oppor-tunity. The NCCN guidelines were not published whenthis study was started and the treatment protocol cannotbe retrospectively altered, so the Fletcher’s criteria forrisk assessment have been used. Fletcher’s criteria forrisk assessment have been further modified by Miettinenand Lasota. Therefore, the Miettinen and Lasota criteriaare considered to represent the best current method forpredicting GIST risk of recurrence.

In conclusion, with the advent of new molecularmarkers, tumors of the gastrointestinal tract have beenreclassified, as in the present study. With the recognitionof GIST as a new entity, effective management in theform of targeted tyrosine kinase inhibitor has led toimproved local control and RFS in patients with GIST.Although the duration of treatment is not yet defined,published data and our results support continuing ima-tinib for at least 2 years in high-risk patients: however,large, randomized prospective trials are needed toaddress the issue of duration of imatinib therapy.For patients who do not respond to escalated doses ofimatinib (600 mg), sunitinib has demonstrated a goodresponse with acceptable tolerability. Hence, it is alsoworthwhile to consider sunitinib as salvage after first-line failure with imatinib.

ACKNOWLEDGMENTS

Medical writing support was provided by Emily HSeidman at Acumed (New York, USA) and drug supportwas funded by Pfizer.

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