Neoadjuvant chemotherapy-specific and overall treatment outcomes in patients with cutaneous angiosarcoma of the face with periorbital involvement.

BACKGROUND: Recent isolated case reports have suggested a potential role for neoadjuvant chemotherapy in patients with angiosarcoma. The goal of this report was to investigate the overall treatment outcomes and the neoadjuvant chemotherapy-specific outcomes in patients with cutaneous angiosarcoma of the face with periorbital involvement. METHODS: Our tumor database was searched for patients with angiosarcoma and periorbital involvement seen at our institution between 1981 and 2005. RESULTS: Twenty-one patients were identified,15 of whom had neoadjuvant chemotherapy and 6 of whom had a traditional approach of surgery followed by adjuvant therapy. Fourteen of 15 patients who had neoadjuvant chemotherapy had complete clinical response. Neoadjuvant chemotherapy made definitive surgery unnecessary for 9 patients. The median disease-free interval for the neoadjuvant chemotherapy group was 11.8 months (mean, 38.1 months; range, 2.4-239.6 months). Nine of the 15 patients had recurrences. The time from end of treatment to recurrence ranged from 2.6 to 24.5 months (median, 12.7 months). Five of the 6 patients who had primary surgical resection followed by adjuvant radiotherapy and/or chemotherapy had a complete clinical response, and the median disease-free interval was 31.8 months (mean, 35.9 months; range, 2.7-85 months). Two later developed recurrences, one at 2.7 months and the other at 31.8 months after the end of treatment. CONCLUSION: On the basis of this series, the authors conclude that neoadjuvant chemotherapy for periorbital angiosarcoma is a potentially attractive option and in some patients may obviate the need for major surgery, thereby preserving the eye and/or ocular adnexal structures. Given the propensity for recurrence and poor survival, the authors strongly recommend that these patients receive multidisciplinary evaluation and treatment at a major cancer center.

Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria.

PURPOSE: Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating gastrointestinal stromal tumors (GISTs) treated with imatinib. This study evaluates whether computed tomography (CT) findings of GIST after imatinib treatment correlate with tumor responses by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and develops reliable, quantitative, CT response criteria. PATIENTS AND METHODS: A total of 172 lesions selected by RECIST were evaluated in 40 patients with metastatic GISTs treated with imatinib. All patients had pretreatment and 2-month follow-up CTs and FDG-PETs. Multivariate analysis was performed using tumor size and density (Hounsfield unit [HU]) on CT and maximum standardized uptake value (SUVmax) on FDG-PET. Patients were observed up to 28 months. RESULTS: Mean baseline tumor size and density on CT were 5.3 cm and 72.8 HU, respectively, and mean baseline SUVmax on FDG-PET was 5.8. Thirty-three patients had good response on FDG-PET. A decrease in tumor size of more than 10% or a decrease in tumor density of more than 15% on CT had a sensitivity of 97% and a specificity of 100% in identifying PET responders versus 52% and 100% by RECIST. Good responders on CT at 2 months had significantly longer time to progression than those who did not respond (P = .01). CONCLUSION: Small changes in tumor size or density on CT are sensitive and specific methods of assessing the response of GISTs. If the prognostic value of our proposed CT response criteria can be confirmed prospectively, the criteria should be employed in future studies of patients with GIST.

We should desist using RECIST, at least in GIST.

PURPOSE: Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating imatinib-treated gastrointestinal stromal tumors (GISTs). Response by Choi criteria, a 10% decrease in size or a 15% decrease in density on contrast-enhanced CT, correlated well in a small training set of patients who showed response as measured by positron emission tomography, and was more predictive of time to tumor progression (TTP) than response by RECIST. This study was designed to validate these observations in an independent data set. PATIENTS AND METHODS: Fifty-eight patients with imatinib-treated GISTs were evaluated by RECIST and Choi criteria. TTP was compared with TTP in the training set. Patients were analyzed initially with follow-up to 28 months, extended to 60 months for survival analysis. RESULTS: Patients who met Choi response criteria on CT at 2 months had significantly better TTP than those who did not (P = .0002), whereas response group by RECIST was not significantly correlated with TTP. Even when the 98 patients from both sets were analyzed together, the response group by RECIST did not correlate significantly with TTP, whereas response group by Choi criteria did correlate significantly with TTP. Disease-specific survival (DSS) was also significantly correlated with response group by Choi criteria (P = .04), but not with response group by RECIST. CONCLUSION: Choi response criteria are reproducible, more sensitive, and more precise than RECIST in assessing the response of GISTs to imatinib mesylate. Response by Choi criteria, unlike response by RECIST, correlates significantly with TTP and DSS. Response by Choi criteria should be incorporated routinely into future studies of GIST therapy. We should desist using RECIST, at least in GIST.

Surgical resection of gastrointestinal stromal tumors after treatment with imatinib.

BACKGROUND: Surgical resection of gastrointestinal stromal tumors (GISTs) has been the most effective therapy for these rare tumors. Imatinib has been introduced as systemic therapy for locally advanced and metastatic GIST. In this study, the surgical resection rates and long-term outcomes of patients treated with preoperative imatinib for locally advanced primary, recurrent, or metastatic GISTs were evaluated. METHODS: Patients were retrospectively assessed for completeness of surgical resection and for disease-free and overall survival after resection. RESULTS: Forty-six patients underwent surgery after treatment with imatinib. Eleven were treated for locally advanced primary GISTs for a median of 11.9 months, followed by complete surgical resection. All eleven were alive at a median of 19.5 months, and ten were free of disease. Thirty-five patients were treated for recurrent or metastatic GIST. Of these, eleven underwent complete resection. Six of the eleven patients had recurrent disease at a median of 15.1 months. All eleven patients were alive at a median of 30.7 months. Patients with a partial radiographic tumor response to imatinib had significantly higher complete resection rates than patients with progressive disease (91% vs. 4%; P < .001). Of the 24 patients with incomplete resection, 18 initially responded to imatinib but were unable to undergo complete resection after they progressed before surgery. CONCLUSIONS: Preoperative imatinib can decrease tumor volume and is associated with complete surgical resection in locally advanced primary GISTs. Early surgical intervention should be considered for imatinib-responsive recurrent or metastatic GIST, since complete resection is rarely achieved once tumor progression occurs.

A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors.

KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T-->C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.

Phase I trial of preoperative doxorubicin-based concurrent chemoradiation and surgical resection for localized extremity and body wall soft tissue sarcomas.

PURPOSE: The primary objective of this phase I trial was to define the maximum-tolerated dose of continuous-infusion doxorubicin administered with standard preoperative radiation for patients with localized, potentially resectable soft tissue sarcomas of the extremities or body wall. PATIENTS AND METHODS: Twenty-seven patients with radiographically resectable intermediate- or high-grade soft tissue sarcomas were treated. Preoperative external-beam radiation was administered in 25 2-Gy fractions (total dose, 50 Gy). Concurrent continuous-infusion doxorubicin was administered by an initial bolus (4 mg/m(2)) and subsequent 4-day continuous infusion (12.5, 15.0, 17.5, or 20.0 mg/m(2)/wk). Radiographic restaging was performed 4 to 7 weeks after chemoradiation, and patients with localized disease underwent surgical resection. RESULTS: Chemoradiation was completed as an outpatient procedure in 25 patients (93%). The maximum-tolerated dose of continuous-infusion doxorubicin combined with standard preoperative radiation was 17.5 mg/m(2)/wk; at this dose level, seven (30%) of 23 patients had grade 3 dermatologic toxicity. Macroscopically complete resection (R0 or R1) was performed in all 26 patients who underwent surgery. Among 22 patients who were treated with doxorubicin 17.5/mg/m(2)/wk with concurrent radiation and subsequent surgery, 11 patients (50%) had 90% or greater tumor necrosis, including two patients who had complete pathologic responses. CONCLUSION: Preoperative doxorubicin-based chemoradiation appears safe and feasible. The maximum-tolerated dose of continuous-infusion doxorubicin with standard preoperative radiation was 17.5 mg/m(2)/wk. Pathologic response rates with this regimen are encouraging.

A two-arm phase II study of temozolomide in patients with advanced gastrointestinal stromal tumors and other soft tissue sarcomas.

BACKGROUND: The authors conducted a two-arm Phase II study of temozolomide to determine its efficacy and toxicity in patients with soft tissue sarcomas (STSs) who had received, had refused, or were not eligible for standard chemotherapy with doxorubicin and ifosfamide (Arm 1) and in patients with gastrointestinal stromal tumors (GISTs; Arm 2). Patients with GIST were eligible regardless of prior therapy before imatinib was available. METHODS: Sixty patients were enrolled in the current study, 19 of whom had GISTs and 41 of whom had other STSs. The patients received temozolomide at a dose of 85 mg/m2 orally for 21 days followed by 7 days without treatment. Standard radiographic imaging after every two cycles was used to assess the treatment response. RESULTS: Of the 39 patients in Arm 1, there was 1 complete response and 1 partial response of 39 evaluable patients, for a total response rate of 5% (95% confidence interval, 0-12%). The responses lasted 7 months and 8 months, respectively. In Arm 2, there was no response in 17 patients. The disease was stable in 22% of the patients with GISTs and 33% of the patients with other STSs. The median overall survival time was 26.4 months in patients with GISTs and 11 months in patients with other STSs. The median time to disease progression was 2.3 months in patients with GISTs and 3.3 months in patients with other STSs. Grade 3 and Grade 4 adverse effects (according to National Cancer Institute Common Toxicity Criteria) were rare and included fatigue (eight patients), anemia (six patients), constipation (four patients), neutropenia (four patients), and thrombocytopenia (four patients). CONCLUSIONS: The data from the current study suggest that temozolomide is well tolerated but has only minimal efficacy and a limited role in the treatment of patients with STSs.

Is there a role for surgery in patients with "unresectable" cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate?

BACKGROUND: Imatinib mesylate (Gleevec) is being studied as adjuvant chemotherapy for the treatment of cKIT+ gastrointestinal stromal tumors (GISTs). Early reports using Gleevec for the treatment of unresectable GISTs have shown 50% to 60% partial response rates based on radiographic evaluation alone. No study has yet correlated radiographic response with pathologic findings. This retrospective review of patients with cKIT+ GISTs who received Gleevec prior to surgical resection examines the pathologic response to therapy and the feasibility of surgical resection after treatment. METHODS: Patients with cKIT+ GISTs were identified from the institutional sarcoma database. Patients were included if they had pathologic confirmation of cKIT mutation and therapy with Gleevec. The pretreatment and preoperative radiographs, surgeons' operative notes, and pathology reports were reviewed for documentation of the extent of disease. RESULTS: Between January 2001 and Octorber 2002, 126 patients with unresectable cKIT + GISTs treated with Gleevec were identified. Of these 126 patients, 17 have subsequently undergone surgical resection after a median of 10 months (range 2 to 16) of treatment with Gleevec. Based on computed tomographic (CT) scanning, 1 (6%) patient had evidence of a complete tumor response, 12 (70%) patients had a partial response, 3 (24%) patients had stable disease, and 1 (6%) patient had progressive disease. Posttreatment/preoperative CT imaging documented an overall response rate of 76%. The pathologic review of the operative specimens showed that 2 (12%) patients had a complete response to therapy, 11 (65%) had a partial response to therapy, 3 (18%) patients had no evidence of treatment effect on the excised tumor, 1 patient had progressive disease. Sixteen patients (94%) underwent complete surgical resection of disease, including 3 patients with no pathologic evidence of response to therapy. One patient had progression of disease and was unresectable at surgical exploration. CONCLUSIONS: This series is the first to present pathologic data after the treatment of cKIT+ GISTs with Gleevec. In this series, the majority of responses were limited to partial responses, indicating that surgical resection remains a vital component of the treatment plan for patients with cKIT+ GISTs. This series is consistent with previous reports indicating that complete responses are extremely rare in response to treatment with Gleevec. Patients with advanced disease may benefit from a course of neoadjuvant therapy with Gleevec followed by resection, even when there is evidence of multifocal disease. A prospective evaluation of neoadjuvant Gleevec therapy for advanced cKIT+ GISTs is warranted.

Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma.

PURPOSE: The primary objective of this phase I trial was to define the maximum-tolerated dose of external-beam radiation with concurrent fixed-dose continuous-infusion doxorubicin followed by surgical resection and electron-beam intraoperative radiation therapy (EB-IORT) for patients with localized, potentially resectable retroperitoneal sarcomas (RPS). PATIENTS AND METHODS: Thirty-five patients with radiographically resectable primary or recurrent intermediate- or high-grade RPS were treated. Doxorubicin was administered each week for 4 or 5 weeks as an initial bolus (4 mg/m2) followed by a 4-day continuous infusion (4 mg/m2/d). Concurrent radiation therapy was administered in escalating doses of 18.0, 30.6, 36.0, 41.4, 46.8, or 50.4 Gy in 1.8-Gy fractions. Radiographic restaging was performed 4 to 8 weeks after chemoradiation, and patients with localized disease underwent surgical resection with EB-IORT (15 Gy). RESULTS: Chemoradiation was completed as outpatient therapy in 31 patients (89%); four patients required hospital admission during chemoradiation or in the postchemoradiation preoperative period. At the highest radiation dose of 50.4 Gy, two (18%) of 11 patients had grade 3 or 4 nausea. Twenty-nine patients (83%) underwent laparotomy; six patients had interval disease progression and did not undergo surgery. Grossly complete resection (R0 or R1) was performed in 26 (90%) of 29 patients who had surgery. EB-IORT was feasible and successfully administered to 22 patients who had R0 or R1 resections. CONCLUSION: Preoperative chemoradiation, surgical resection, and EB-IORT are feasible for patients with RPS. Preoperative external-beam radiation can be administered to a total dose of 50.4 Gy with continuous-infusion doxorubicin.

Radiographic response to neoadjuvant chemotherapy is a predictor of local control and survival in soft tissue sarcomas.

BACKGROUND: Downstaging of large soft tissue sarcomas can be accomplished by the use of neoadjuvant chemotherapy (NeoCT). The authors tested the hypothesis that radiographic response to NeoCT predicts improved local control and survival. METHODS: The authors reviewed the medical records of 65 patients with Stage II or III soft tissue sarcoma (42 extremity, 23 retroperitoneal) who were treated with doxorubicin or ifosfamide-based NeoCT from January 1991 to December 1996. Radiographic response and impact on surgical therapy were determined retrospectively by comparing imaging studies obtained before and after chemotherapy. RESULTS: The radiographic responses observed were partial response (PR; 22 patients [34%]); minor response (MR; 6 patients [9%]); stable disease (20 patients [31%]); and progressive disease (17 patients [26%]). Downstaging sufficient to decrease the scope of the operation occurred in 13% of the patients, 78% had no change, and 9% had disease progression sufficient to increase the scope of the operation. Patients having any radiographic response (PR or MR) had a higher margin-negative resection rate, a better local recurrence-free survival rate, and a better overall survival rate than did nonresponders. CONCLUSIONS: The NeoCT regimens used in this study resulted in tumor shrinkage sufficient to impact surgical therapy in a few patients. However, radiographic response predicted improved local control and overall survival rate.

Tumor volume as a prognostic factor for sarcomatosis.

BACKGROUND: The appropriate therapeutic interventions for sarcomatosis, or sarcoma characterized by intraabdominal dissemination, remain unclear. The authors performed a retrospective analysis of their recent experience with patients diagnosed with sarcomatosis to determine the overall survival and the effects of clinicopathologic features on survival rates at two and four years. METHODS: A query of the authors' prospective soft tissue sarcoma database identified 51 patients with a diagnosis of sarcomatosis who were evaluated at the authors' institution between June 1996 and June 1999. Clinical and pathologic factors were evaluated, and survival was calculated using a Kaplan-Meier survival analysis. Disease was categorized as low or high volume based on findings at surgical exploration or computed tomography scan evaluation. Disease was classified as low/intermediate grade or high grade based upon histologic examination. RESULTS: Twenty five patients were male and 26 were female. The median time from the initial diagnosis of sarcoma to the development of sarcomatosis was 0.9 years (range, 0-26 years). Thirty nine patients were treated with surgery, whereas 32 received primarily nonsurgical treatment. Histology revealed gastrointestinal stromal tumor (GIST) in 33 patients and other histologies in 18 patients. The two year overall survival rate of patients with GIST was similar to that of patients with other types of sarcoma (38% versus 42%, respectively, P = 0.77). Patients with low volume disease had an overall two year survival rate of 82%, compared with only 24% for patients with high volume disease (P = 0.008). There was no difference in the overall survival rates of patients with low grade (n = 18) versus high grade tumors (n = 33, P = 0.29). With a median followup of 2.7 years (range, 0.5-26.4 years), the median time from sarcomatosis to death was 13 months (range, 4-42 months). CONCLUSIONS: Evaluating volume of disease at the time of diagnosis permits stratification of patients into prognosis based subsets. We found no significant difference in two or four year survival rates in patients with GIST and those with non-GIST sarcomatosis.