Tailored management of primary gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and can form along the entire gastrointestinal tract. Over the last 20 years, considerable advances have been made in our understanding of the biology of GISTs. The advent of tyrosine kinase inhibitors has provided effective medical therapy for the first time. In fact, given that GIST typically is driven by either a KIT or PDGFRA gene mutation, it has become a paradigm of targeted molecular therapy. In addition, diagnostic and surgical techniques have been refined. Here, the critical aspects of primary GISTs and how they are now managed with an integrated approach are summarized. Treatment plans are developed based on specific pathologic and molecular features of the tumor. The authors outline the general principles of therapy and highlight some of the nuances. Particular focus is given to diagnosis, surgical considerations, and the use of preoperative and postoperative tyrosine kinase inhibitors.     

Cytodiagnosis of soft tissue tumors

The only acceptable definitive diagnosis of a soft tissue mass is histologic or cytologic examination. In recent years, fine-needle aspiration cytology is used in more and more centers for diagnosis of soft tissue masses. We studied 196 aspiration cytologies performed on soft tissue lesions. Out of these, in 48 cases a definitive surgical procedure or open biopsy for histology and further evaluation were performed. There were 25 sarcomas and 23 benign tumors. There was one false negative cytologic result in this group; no false positive cytologies were detected. It seems that cytodiagnosis of soft tissue masses performed by an experienced pathologist is the method of choice, permitting a good diagnostic evaluation, with almost none of the traumatic and oncologic disadvantages of the other methods of biopsy.     

Strategies for care of patients with gastrointestinal stromal tumor or soft tissue sarcoma during COVID‐19 pandemic: A guide for surgical oncologists

The coronavirus disease‐2019 (COVID‐19) pandemic is deeply impacting the accessibility of cancer patients to surgery. In resource‐limited conditions, the standard of care might not be deliverable, but evidence to support alternative management strategies often exists. By revisiting available treatment options, this review provides surgical oncologists with an evidence‐based framework for treating patients with gastrointestinal stromal tumor, extremity/truncal soft tissue sarcoma, and retroperitoneal sarcoma to rapidly adapt their decision‐making to the constant evolution of the COVID‐19 pandemic.     

Clinical utility of the new American Joint Committee on Cancer staging system for gastrointestinal stromal tumors: current overall survival after primary tumor resection

BACKGROUND:

The objectives of the current study were to assess the reliability of the new revision of the American Joint Committee on Cancer (AJCC) staging system for gastrointestinal stromal tumors (GISTs) based on the National Comprehensive Cancer Network‐Armed Forces Institute of Pathology risk classification and to analyze the factors that influence after resection for primary GISTs in 2 AJCC groups: patients with GISTs originating from the stomach and omentum (G‐GISTs) and patients with other primary GISTs located mainly in the small bowel (nongastric GISTs [NG‐GISTs]).

METHODS:

The authors prospectively analyzed a group of 640 patients with primary, CD117‐positive GISTs who underwent surgery with curative intention (R0/R1 resection), including 340 G‐GISTs (55.5%) and 300 NG‐GISTs (44.5%). Factors were explored that had an effect on disease‐free survival time (DFS), which was calculated from the date of radical operation to the date of recurrence or last follow‐up. The median follow‐up was 39 months.

RESULTS:

Compared with NG‐GISTs, G‐GISTs were characterized by a significantly lower median size (5.3 cm and 8.5 cm, respectively; P < .0001) and lower mitotic activity (median, 3 in 50 high‐power fields [HPF] vs 5 in 50 HPF; P < .0001), and they were diagnosed in older patients (median age, 62 years vs 57 years; P = .002). The most commonly detected mutations in G‐GIST were those located in KIT exon 11 (60.5%) and platelet‐derived growth factor receptor alpha (PDGFRA) exon 18 (19%) versus KIT exons 11 and 9 in NG‐GISTs (72% and 17.4%, respectively). The prognosis of patients who had G‐GISTs was significantly better compared that of patients who had NG‐GISTs, with 5‐year DFS rates of 69% (median, 83 months) versus 43% (median, 33 months), respectively (P < .00001). The most significant prognostic factors that correlated with shorter DFS in both G‐GISTs and NG‐GISTs were primary tumor size >5 cm and >10 cm (P < .0001) and mitotic index >5 in 50 HPF and >10 in 50 HPF (P < .0001). The 5‐year DFS rates in G‐GISTs according to AJCC stage categories were as follows: 96% for stage IA tumors, 92% for stage IB tumors, 51% for II tumors, 22% for stage IIIA tumors, and 22% for stage IIIB tumors (P < .0001). The 5‐year DFS rates in NG‐GISTs according to AJCC categories were as follows: 92% for stage I tumors, 66% for stage II tumors, 28% for IIIA tumors, and 16% for IIIB tumors (P < .0001). The high prognostic significance of the AJCC classification also was confirmed for overall survival data, including the impact of therapy with tyrosine kinase inhibitors.

CONCLUSIONS:

The reliability of AJCC risk classification after resection of primary GIST was confirmed for DFS and overall survival. Patients with primary G‐GISTs had a better prognosis than patients with NG‐GISTs. In both groups, primary tumor size and mitotic activity were the most important prognostic factors in terms of DFS. Cancer 2011;. © 2011 American Cancer Society.     

Histology‐specific nomogram for primary retroperitoneal soft tissue sarcoma

BACKGROUND:

This study was conducted to develop a histology‐specific nomogram to predict postoperative overall survival (OS) at 5 and 10 years in primary retroperitoneal soft tissue sarcoma (STS).

METHODS:

Data registered at a single institution (National Cancer Institute, Milan, Italy) prospective sarcoma database were used. In the present analysis, patients with primary localized retroperitoneal STS resected with curative intent between 1985 and 2007 were included. A parametric piecewise exponential survival multivariate model was used for nomogram development, and internal validation was performed with standard methodologies. Known prognostic variables, such as age, tumor burden, histologic variant (as reviewed by a sarcoma pathologist), grade, and surgical margins were considered as putative predictors.

RESULTS:

Among the 192 patients analyzed, within 10 years from surgery, 114 patients were alive, with a median follow‐up time of 55 months (interquartile range, 25‐104 months). Among the investigated factors, only histologic subtype did not reach significance at the 10% level. The relative hazard increased while increasing tumor size up to about 25 cm, and decreased thereafter.

CONCLUSIONS:

A histology‐specific nomogram for retroperitoneal STS is now available. It can be used for better assessing the risk of the single patient and then making individualized decisions within the specific subset of retroperitoneal sarcomas. Cross‐check external validation should be performed. Cancer 2010. © 2010 American Cancer Society.     

Gastrointestinal stromal tumors of the esophagus: evaluation of a pooled case series regarding clinicopathological features and clinical outcome

Background and Objectives: To elucidate diagnostic criteria, clinicopathological features and clinical outcome in patients with esophageal gastrointestinal stromal tumors (GIST), representing an extremely rare subform of GIST with an estimated incidence of about 0.1 to 0.3 per million people. Patients and methods: Esophageal GIST cases from the Ulmer GIST registry consisting of 1077 cases were pooled with case reports and case series of esophageal GIST extracted from MEDLINE. Data were compared with those from 683 cases with gastric GIST from the Ulmer GIST registry. Results: In comparison to gastric GIST, esophageal GIST (n = 55) occurred significantly more frequent in men (p = 0.035) as well as in patients younger than 60 at diagnosis (p < 0.001). Primary tumor sizes were significantly larger (p < 0.001), thereby resulting more frequently in a high-risk classification (OR = 4.53, CI 95% 2.41-8.52, p < 0.001). The 5-year rates of disease-specific survival (DSS), disease-free survival (DFS), and overall survival (OS) were 50.9%, 65.3% and 48.3%, respectively. The prognosis of esophageal GIST was less favorable compared with gastric GIST (DSS: p < 0.001, HR = 0.158, 95% CI: 0.087-0.288; DFS: p = 0.023, HR 0.466, 95% CI: 0.241-0.901; OS p = 0.003, HR = 0.481, 95% CI: 0.294-0.785; univariate Cox model) after a median follow-up time of 28 months (range 1.9 to 202). Mutational analysis for KIT showed more frequently wild-type status in esophageal GIST (OR = 10.13, CI 95% 3.02-33.96, p < 0.001). Conclusions: Esophageal GIST differ significantly from gastric GIST in respect to clinicopathological features and clinical outcome. To optimize treatment options further prospective data on patients with esophageal GIST are urgently warranted.     

Local recurrence of localized soft tissue sarcoma

BACKGROUND:

The objective of this study was to examine the effect of known predictors of local recurrence of soft tissue sarcoma in a competing risk setting.

METHODS:

The outcome of interest was the cumulative probability of local recurrence per category of relevant predictors, with death as a competing event. In total, 1668 patients with a localized soft tissue sarcoma of the extremity or trunk were included.

RESULTS:

Tumor size (hazard ratio, 3.3), depth (hazard ratio, 3.2), and histologic grade (hazard ratio, 4.5) were the variables that had the most effect on the risk of metastasis and, accordingly, were the most likely to induce competition. Surgical margins (hazard ratio, 3.3), histologic grade (hazard ratio, 2.1), presentation status (hazard ratio, 2.4), and tumor depth (hazard ratio, 1.5) were the variables that had the most effect on the risk of local recurrence. The 10‐year cumulative probabilities of local recurrence were markedly different within categories for presentation status (P < .001) and surgical margin status (P < .001). However, because of the competing effect of death, there was little difference in the 10‐year cumulative probabilities of local recurrence with regard to tumor depth (12% and 11.4% for deep and superficial tumors, respectively; P = .2), tumor size (10.6% and 13.3% for large and small tumors, respectively; P = .99), or histologic tumor grade (12.6%, 10.7%, and 11.1% for high, intermediate, and low‐grade tumors, respectively; P = .17).

CONCLUSIONS:

Because of the competition between local recurrence and death, histologic tumor grade, tumor size, and tumor depth had little influence on the cumulative probability of local recurrence. The authors concluded that local management should be based on presentation status and surgical margins rather than other, previously acknowledged factors. Cancer 2012. © 2012 American Cancer Society.     

Consensus approaches to best practice management of gastrointestinal stromal tumors

Gastrointestinal stromal tumors are rare mesenchymal tumors of the gastrointestinal tract. Progress in diagnosis has led to increased recognition of this disease, and the availability of effective, molecularly targeted therapy has revolutionised its management. Treatment of metastatic gastrointestinal stromal tumors with imatinib has led to unprecedented improvements in progression free and overall survival and there are ongoing investigations into the optimal pre‐operative and adjuvant use of imatinib. Second‐line sunitinib is now available for patients who develop resistance to imatinib, and third‐ and fourth‐line therapies are being investigated in clinical trials. In this ever‐changing environment, evidence from controlled clinical trials and the authors' experience were used to comprehensively outline current best practice management of patients with gastrointestinal stromal tumors.     

Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate

BACKGROUND: The aim of the study was to analyze the surgical possibilities of unresectable and/or metastatic GIST CD117(+) patients during imatinib treatment. METHODS: We analyzed the results of surgery in 141 patients treated with imatinib for initially inoperable and/or metastatic GIST CD117(+). Median follow-up time was 12 months (range: 3-26). RESULTS: Surgery was performed as subsequent treatment in 24 patients (Group I, 17%) for resection of residual disease after complete/partial response and lack of further response to imatinib and as salvage therapy in eight patients (Group II, 6%), who progressed on initially successful imatinib therapy. In Group I, the viable GIST cells were not detected histologically in only three resection specimens. The first five patients in Group I did not receive imatinib further and we observed four recurrences. In next 19 patients, continuing imatinib after surgery, we observed only one relapse. In Group II, we continued imatinib therapy after high-risk surgical procedures, but in five patients we observed subsequent progression. CONCLUSIONS: Surgical removal of residual disease during imatinib treatment may allow for complete remission in selected GIST patients after response to therapy, theoretically prolonging durable remission, but it is necessary to continue imatinib for its maintenance.     

Cancer testis antigen expression in gastrointestinal stromal tumors: new markers for early recurrence

Cancer testis antigens (CTAs) are expressed in a variety of malignant tumors but not in any normal adult tissues except germ cells and occasionally placenta. Because of this tumor-associated pattern of expression, CTAs are regarded as potential vaccine targets. The expression of CTAs in gastrointestinal stromal tumors (GIST) has not been analyzed systematically previously. The present study was performed to analyze the expression of CTA in GIST and to determine if CTA expression correlates with prognosis. Thirty-five GIST patients were retrospectively analyzed for their expression of CTAs by immunohistochemistry using the following monoclonal antibodies (mAb/antigen): MA454/MAGE-A1, M3H67/MAGE-A3, 57B/MAGE-A4, CT7-33/MAGE-C1 and E978/NY-ESO-1. Fourteen tumors (40%) expressed 1 or more of the 5 CTAs tested. Fourteen percent (n = 5/35) were positive for MAGE-A1, MAGE-A3 or MAGE-A4, respectively. Twenty-six percent (n = 9/35) stained positive for MAGE-C1 and 20% (n = 7/35) for NY-ESO-1. A highly significant correlation between CTA expression and tumor recurrence risk was observed (71% vs. 29%; p = 0.027). In our study population, the high-risk GIST expressed CTAs more frequently than low-risk GIST (p = 0.012). High-risk GISTs which stained positive for at least 1 CTA, recurred in 100% (n = 25) of the cases. This is the first study analyzing CTA expression in GIST and its prognostic value for recurrence. The CTA staining could add information to the individual patient prognosis and represent an interesting target for future treatment strategies.     

Long-term outcome after local recurrence of soft tissue sarcoma: a retrospective analysis of factors predictive of survival in 135 patients with locally recurrent soft tissue sarcoma

Background:

The aim of this study was to identify prognostic indicators of survival in patients with locally recurrent soft tissue sarcoma (STS) through a long-term follow-up.

Methods:

We retrospectively assessed the relationship between post-recurrence survival (PRS) and potential prognostic factors in 135 patients who had experienced local recurrence, which was suitable for further surgical treatment. The median follow-up time after initial recurrence was 12.3 years (95% confidence interval (CI): 10.4–14.2 years).

Results:

The 5-year estimate of the PRS rate was 53.1% (95% CI: 44.3–61.2%) for the entire series. Patients with negative margins after the final surgery experienced improved survival compared with patients with positive margins (5-year survival: 46.7% (35.2–57.5%) vs 35.5% (23.4–47.8%); P=0.01). In a multivariate analysis, the significant prognostic indicators for PRS were histologic grade, tumour site, time to initial recurrence, the number of recurrences and the surgical margin status attained at the last resection.

Conclusions:

Complete surgical resection with microscopically clear margins is desirable in patients with locally recurrent STS. However, when achieving clear surgical margins will require major functional impairment of the extremity, a radical surgical approach should be weighed for the patient in each case.     

Five‐year follow up of patients with gastrointestinal stromal tumor: Recurrence‐free survival by risk group

Aim: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. There is limited published data on GIST from the Indian subcontinent. This 5‐year retrospective analysis of 49 patients treated for GIST reports clinical and pathological features and survival outcome by risk stratification. Methods: We reviewed 49 cases of GIST from January 2004 to December 2008. Imatinib was administered after surgery in patients with either high‐risk, residual or metastatic disease and at onset of recurrence or metastatic disease in patients with intermediate risk. Results: The mean age was 50 years (range, 17–80 years). Patients with localized tumor were classified as low (n = 2), intermediate (n = 4) and high risk (n = 32), based on the primary tumor and mitotic index. At a median follow up of 21 months, 2‐year and 3‐year recurrence or progression‐free survival rates were 61 and 39%, respectively, for all patients. The median recurrence‐free survival rate in the intermediate‐risk and high‐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. Responses have been durable and most patients tolerate the drug well at clinically effective doses. In view of high recurrence rates in the intermediate‐risk group in our study, it would be better to keep these patients on strict follow up to detect recurrence at the earliest opportunity.     

Surgical management of soft tissue sarcoma in patients over 80 years

AIMS: To report outcome on patients over 80years of age with soft tissue sarcoma (STS), with respect to surgical treatment, co-morbidity, complications and survival. METHODS: From a prospective database of 3400 patients with STS presenting over a 13-year period, all patients over 80years of age were identified and reviewed, with respect to tumour characteristics morbidity, mortality and outcome. RESULTS: 128 patients over 80years were treated for STS with 63 referred for treatment of primary disease, of whom 50 underwent resectional surgery. The remaining 65 patients were treated for recurrent or incompletely excised disease. Of the 50 patients treated primarily with surgery, 56% of tumours where high grade and 56% were greater than 10cm in diameter. The overall complication rate was 34%, with a 30-day mortality of 4%. Two- and 5-year survival rates were 56% and 46%, with a local recurrence rate of 22% at a mean follow-up of 22months. CONCLUSION: This patient group presented with poor prognosis tumours that were associated with poor outcomes in the medium to long term. Age need not be considered a contra-indication to radical surgery with curative intent.     

Primary and recurrent retroperitoneal soft tissue sarcoma: prognostic factors affecting survival

BACKGROUND AND OBJECTIVES: To analyze treatment and survival in 34 patients (28 resected) with primary or recurrent retroperitoneal sarcoma (RPS). METHODS: Between July 1994 and January 2001, 34 patients (15M, 19F; mean age: 56 years, range: 25-77) were evaluated. Complete resection was defined as removal of gross tumor with histologically confirmed clear resection margins. RESULTS: Twenty-eight out of 34 patients (82%) (15 were affected by primary RPS, and 13 by recurrent RPS), underwent surgical exploration. Twenty-three patients had a grossly and microscopically complete resection, (3 having a grossly incomplete resection and 2 patients with a grossly complete resection having histologically involved resection margins). Twenty-one out of 28 patients (75%) underwent removal of contiguous intra-abdominal organs. Preoperative mortality was nil, and morbidity occurred in six cases only (21%). High tumor grade results a significant variable for a worse survival in all 28 patients (100% 5 years survival for low grade vs. 0% for high grade; P = 0.0004). Amongst completely resected patients, only histologic grade and peroperative blood transfusions affected disease-free survival (P = 0.04 and P = 0.05, respectively). CONCLUSIONS: An aggressive surgical approach in both primary and recurrent RPS is associated with long-term survival.     

Tumor response assessment by modified Choi criteria in localized high‐risk soft tissue sarcoma treated with chemotherapy

BACKGROUND.

The objective of this study was to compare the prognostic relevance of Response Evaluation Criteria in Solid Tumors (RECIST) versus Choi criteria for the assessment of response in patients with high‐risk soft tissue sarcoma of the extremities or trunk wall who received preoperative chemotherapy with or without radiotherapy in a phase 3 trial.

METHODS.

Patients received 3 cycles of preoperative epirubicin + ifosfamide with or without radiotherapy. The diagnostic concordance between RECIST and Choi criteria and their correlation with overall survival (OS) and freedom from progression (FFP) were evaluated in a univariate Cox regression model.

RESULTS.

In 243 of 321 eligible patients, RECIST, Choi criteria, and histology were predictive for OS and FFP. In the subgroup of 69 patients who received chemotherapy alone and were evaluable by both RECIST and Choi criteria, Choi criteria were associated significantly with OS and FFP, whereas RECIST predicted only FFP, and the pattern of agreement observed between the 2 criteria was unsatisfactory. On a dichotomous scale, comparing objective response (complete and partial responses) and lack of response (stable and progressive disease) to preoperative chemotherapy according to RECIST and Choi criteria, only Choi criteria were predictive of OS and FFP, and fair agreement between RECIST and Choi criteria was observed. When lack of progression and progression were compared (complete and partial responses + stable disease vs progressive disease), both assessment criteria were significantly predictive of OS and FFP, and there was substantial agreement between the 2 criteria.

CONCLUSIONS.

Response to chemotherapy with or without radiotherapy was associated with a better outcome in patients with high‐risk soft tissue sarcoma. Choi criteria were better predictors than RECIST in patients who received preoperative chemotherapy alone. Cancer 2012. © 2012 American Cancer Society.