Results of Resection for Recurrent or Residual Retroperitoneal Sarcoma After Failed Primary Treatment.

BACKGROUND: Local recurrence after resection of retroperitoneal sarcoma (RPS) is a common and difficult problem. Gross residual disease after incomplete resection is a particular challenge. The authors reviewed their experience with patients referred for management of recurrent or residual RPS. METHODS: Patients seen at the authors' center from 1996 to 2013 who had undergone resection at an outside institution were identified from a prospective database. Kaplan-Meier survival curves were generated and compared by log-rank analysis. RESULTS: A total of 45 patients were referred with recurrent (n = 33) or residual (n = 12) disease. Before initial surgery elsewhere, cross-sectional imaging (computed tomograpy/magnetic resonance imaging) had been obtained for 30 patients (67 %) and percutaneous biopsy for 8 patients (18 %). At referral to the authors' center, 15 patients were deemed inappropriate for resection, with a subsequent median overall survival (OS) period of 15 months. At the authors' center, 30 patients (22 with recurrent and 8 with residual disease) were resected. The majority received preoperative radiation (77 %). The postoperative mortality rate was 0 % in the recurrent group and 25 % (2/8) in the residual group (p = 0.015). Among the 30 resected patients, the median and 5-year OS was 53 months (50 %), and the OS was better in the recurrent group (median, 77 months) than in the residual group (median, 41 months (p = 0.027). The median time to local re-recurrence was 49 months in the recurrent group and 35 months in the residual group (p = 0.730). CONCLUSIONS: Durable disease control and prolonged survival may be achieved for selected patients with recurrent RPS. In this study, resection after previous grossly incomplete resection was associated with high postoperative mortality and inferior OS. The benefit of extensive surgery for these patients may be limited.

Toward Observation as First-line Management in Abdominal Desmoid Tumors.

BACKGROUND: Desmoid tumors (DT) occur sporadically, in familial adenomatous polyposis, or in association with pregnancy. Initial observation has been proposed in the management of DT. An advantage of this approach is to select patients who have indolent disease versus those who require intervention. Here we report our multidisciplinary experience of abdominal DT as it relates to nonoperative management. METHODS: Patients seeking care from 1980 to 2012 with pathologically confirmed DT were identified from clinical research databases. Clinicopathologic data and management strategies were collected, and statistical analyses were performed by Chi square and t tests. RESULTS: A total of 213 patients were identified; DT occurred in abdominal wall (n = 103, 48 %), intra-abdominally (n = 92, 43 %), or at both sites (n = 18, 9 %). Patients were predominantly female (72 %); disease was sporadic (48 %), associated with familial adenomatous polyposis (38 %), or associated with pregnancy (14 %). Patient presentation was stratified into 3 groups: untreated (group A; n = 176), DT resected elsewhere (group B; n = 19), or recurrent DT (group C; n = 18). In group A, 109 patients were initially observed, with 51 patients requiring intervention as a result of progression or symptoms. Of the 58 patients who underwent only observation, 93 % experienced spontaneous regression or stable disease (median follow-up 38 months). Of the 67 patients in group A who underwent resection, 28 % experienced recurrence (median 22 months). Abdominal wall DT >7 cm and intra-abdominal DT were more likely to recur (P < 0.01). CONCLUSIONS: Initial observation has been implemented for abdominal DT at our institution. Over half of patients observed required no intervention with prolonged follow-up. Tumor size and site may predict progression during observation, therefore representing higher-risk groups.

Trabectedin for inoperable or recurrent soft tissue sarcoma in adult patients: a retrospective cohort study.

BACKGROUND: Trabectedin is an antineoplastic agent used for patients with soft tissue sarcoma (STS) who fail standard-of-care treatment. Real-world data of its performance is scarce. This study evaluates the safety and effectiveness of trabectedin for patients with advanced STS who were treated at a high-volume sarcoma center. METHODS: A retrospective chart review was performed on 77 patients treated with trabectedin (24 h infusion q3w) between 01/2005 and 05/2014. Data regarding safety, objective radiological response, progression-free and overall survival were analyzed. RESULTS: Median age at treatment onset was 52y [interquartile range (IQR): 45-61y]. Tumors included leiomyosarcoma (41.6%), liposarcoma (18.2%), and synovial sarcoma (13%). Trabectedin was provided as ≥ third-line chemotherapy in 71.4%. Median number of cycles was 2 (range: 1-17). Dose reduction and treatment delays occurred in 19.5 and 40.3%, respectively. Toxicities occurred in 78%, primarily for neutropenia or elevated liver enzymes. Two patients died secondary to trabectedin-induced rhabdomyolysis. Treatment was discontinued because of disease progression (84.7%), toxicity (10%), and patient preference (5%). Partial response or stable disease occurred in 14.1 and 33.8%, respectively, while 52.1% developed progressive disease. Median progression-free survival was 1.3 m (IQR: 0.7-3.5 m) and was significantly higher in patients lacking severe toxicities or progressive disease. Median overall survival was 6.7 m (IQR: 2.3-12.7 m) and was significantly higher in patients with leiomyosarcoma or liposarcoma relative to other histologies. CONCLUSIONS: Trabectedin has an acceptable safety profile as an anti-tumor agent. Our data further suggest there may be some benefit in using trabectedin particularly in patients with leiomyo- or liposarcoma who failed standard-of-care agents.

Axial Skeletal Location Predicts Poor Outcome in Ewing's Sarcoma: A Single Institution Experience.

Introduction. Ewing's sarcomas (EWSs) of bone and soft tissue are neuroectodermal tumors that affect both axial and appendicular locations. We hypothesized that axial location predicted poor outcome in EWS patients. Materials and Methods. Sixty-seven patients (57 with bone EWS and 10 with soft tissue EWS) were identified from our database. Thirty-four (51%) had axial EWS and 33 (49%) had appendicular EWS. Statistical analyses identified predictors of poor outcome. Results and Discussion. Axial location, large size, metastases at presentation, lack of definitive treatment, and positive surgical margins all correlated with poor outcome in univariate analysis. In multivariate analysis, axial location still predicted poor outcome when adjusted for pretreatment variables. Axial location was not statistically predictive of poor outcome when adjusted for treatment variables. Conclusions. Anatomic location has a negative effect on outcome in EWS that cannot be completely explained by pretreatment or treatment factors. Additional studies are required to determine if there is a biologic difference between axial and appendicular EWS.

Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. METHODS: We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. FINDINGS: All randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. INTERPRETATION: Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. FUNDING: US National Institutes of Health and Novartis Pharmaceuticals.

Limitations of single slice dynamic contrast enhanced MR in pharmacokinetic modeling of bone sarcomas.

BACKGROUND: Single slice dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) appears to provide perfusion data about sarcomas in vivo that correlate with tumor necrosis on equivalent pathological sections. However, sarcomas are heterogeneous and therefore single slice DCE-MRI may not correlate with total tumor necrosis. PURPOSE: To determine whether changes in pharmacokinetic modeling of DCE-MRI, during chemotherapy for primary bone sarcomas correlated with histological measures of total tumor necrosis. MATERIAL AND METHODS: Twelve patients with appendicular primary bone sarcomas were included in the study. Each patient had DCE-MRI before, and after completion, of pre-operative chemotherapy. The mean arterial slope (A), endothelial permeability coefficient (K(trans)), and extravascular extracellular volume (V(e)) were derived from each data set using a modified two compartment pharmacokinetic model. Total tumor necrosis rates were compared with changes in A, K(trans), and V(e). RESULTS: Six patients had total tumor necrosis of >or=90% and six had a measure of <90%. The median percentage changes in A, K(trans), and V(e) for the >or=90% necrosis group were -52.5% (-83 to 6), -66% (-82 to 26), and 23.5% (-26 to 40), respectively. For the <90% necrosis group, A = - 35% (-75 to 132), K(trans)= - 53 (-66 to 149) and V(e)= - 14.5% (-42 to 40). One patient with >90% necrosis had increases in all three measures. Comparison of the two groups generated P-values of 0.699 for A, 0.18 for K(trans), and 0.31 for V(e). CONCLUSION: There was no statistically significant correlation between changes in pharmacokinetic perfusion parameters and total tumor necrosis. When using single slice DCE-MRI heterogeneous histology of primary bone sarcomas and repair mediated angiogenesis might both be confounding factors.

Clinical benefit of methotrexate plus vinorelbine chemotherapy for desmoid fibromatosis (DF) and correlation of treatment response with MRI.

BACKGROUND: Desmoid fibromatosis (DF) is a rare fibroblastic proliferation that was historically treated with surgery. We report (a) outcomes using low-dose chemotherapy, methotrexate (MTX), and vinorelbine (VNL) for patients with progressing disease (PD) and (b) whether tumor volume (Vtumor ) and T2 signal on magnetic resonance imaging (MRI) are more reflective of treatment response compared with maximum tumor dimension (Dmax ) defined by RECIST1.1. METHODS: Patients with biopsy-proven DF, treated with MTX/VNL from 1997 to 2015 were reviewed. MRI for a subset of patients was independently re-evaluated for response by RECIST, Vtumor , and quantitative T2 hyperintensity. RESULTS: Among 48 patients treated for a median 19 months MTX/VNL, only nine (19%) had previous surgery. RECIST-based overall response rate was complete response (CR) 20 (42%) + partial response (PR) 19 (39%), stable disease (SD) 8 (17%), for a clinical benefit rate of 98%. The median progression-free survival (PFS) was 120 months, (95%CI 84-155 months). Thirty-six (75%) patients had not progressed at a median 38 months from treatment completion. Most common grade 1/2 toxicities included nausea (n = 12, 25%) and fatigue (n = 9,19%) with no grade 3/4 toxicities. In 22 patients with serial MRIs, there was a decrease in Dmax mean by 30%, Vtumor by 76%, and in 19/22 (86%) a decrease in T2 signal intensity. CONCLUSION: Low-dose MTX/VNL for a defined duration has high efficacy with sustained benefit and minimal toxicity for treating DF. Vtumor and T2 signal might better predict treatment response than RECIST.

The challenge of conducting pharmacoeconomic evaluations in oncology using crossover trials: the example of sunitinib for gastrointestinal stromal tumour.

This paper examines the challenge of conducting economic evaluations to support patient access to cancer therapies when the cost-effectiveness estimation is hampered by crossover trial design. To demonstrate these limitations, we present the submission to the Canadian Drug Review (CDR) of a cost-effectiveness evaluation of sunitinib versus best supportive care (BSC) for the treatment of gastrointestinal stromal tumour in patients intolerant or resistant to imatinib. The economic model generated an incremental cost-effectiveness ratio for sunitinib versus BSC of dollars 79,884/quality-adjusted life-year gained. Eight months after initial submission, CDR granted a final recommendation to fund sunitinib following the manufacturer's appeal against their first recommendation. Although cost-effectiveness is an important consideration in reimbursement decisions, there is a need for improved decision-making processes for cancer drugs, as well as a better understanding of the limitations of clinical trial design.

Rectal gastrointestinal stromal tumor mimicking a primary prostatic lesion.

The interstitial cells of Cajal have been identified in locations beyond the gastrointestinal tract, including the prostate, uterus and bladder. Indeed, there are reports of primary gastrointestinal stromal tumor (GIST) arising from each of these sites. We report the case of a 72-year old male who presented with benign prostatic hypertrophy and was diagnosed on retropubic prostatectomy as having a GIST. While the initial clinical and radiologic impression was that of a primary prostatic GIST, subsequent imaging ultimately revealed a small rectal extension as the source of the lesion. The purpose of our report is to highlight the need to assiduously rule-out gastrointestinal sources of GIST prior to making the diagnosis of primary prostatic GIST.

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.

BACKGROUND: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS: 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION: We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033.

IMPORTANCE: After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients. OBECTIVE: To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes. DESIGN, SETTING, AND PARTICIPANTS: In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study. INTERVENTIONS: Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors. RESULTS: Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex. CONCLUSIONS AND RELEVANCE: A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00009906.

Analysis of incidence and prognostic factors for ipsilateral breast tumour recurrence and its impact on disease-specific survival of women with node-negative breast cancer: a prospective cohort study.

INTRODUCTION: This study had three aims: to establish the incidence of ipsilateral breast tumour recurrence (IBTR) in a community treatment setting, to evaluate known factors--in particular younger age (< 40 years)--predictive for local recurrence, and to assess the impact of local recurrence on disease-specific survival (DSS). METHODS: A consecutive series of 1,540 women with node-negative breast cancer, diagnosed between the ages of 18-75 years, were prospectively accrued between September 1987 and September 1999. All had undergone a resection of the primary breast cancer with clear margins, an axillary lymph node dissection with a minimum of four sampled nodes, and breast-conserving surgery (of any type). RESULTS: During the study follow-up period, 98 (6.4%) IBTRs and 117 (7.6%) deaths from or with breast cancer were observed. The median time to IBTR was 3.1 years and to death from or with disease was 4.3 years. In the multivariate Cox proportional hazards (PH) regression model for IBTR with adjuvant therapy factors, independent risk factors included age < 40 years (relative risk (RR) = 1.89, 95% confidence interval (CI) of 1.00 - 3.58), presence of intraductal disease (RR = 1.81, 95% CI = 1.15-2.85) and histological grade ('G2' or G3 versus G1: RR = 1.59, 95% CI = 0.87-2.94). In the multivariate Cox PH regression model for DSS with adjuvant therapy factors, independent risk factors included previous IBTR (RR = 2.58, 95% CI = 1.41-4.72), tumor size (1-2 cm versus < 1 cm: RR = 1.95, 95% CI = 1.05-3.64, > 2 cm versus < 1 cm: RR = 2.94, 95% CI = 1.56-5.56), progesterone receptor status (negative or equivocal versus positive or unknown: RR = 2.15, 95% CI = 1.36-3.39), lymphatic invasion (RR = 1.78, 95% CI = 1.17-2.72), and histological grade ('G2' or G3 versus G1: RR = 8.59, 95% CI = 2.09-35.36). The effects of competing risks could be ignored. CONCLUSION: The Cox PH analyses confirmed the importance of known risk factors for IBTR and DSS in a community treatment setting. This study also revealed that the early occurrence of an IBTR is associated with a relatively poor five-year survival rate.

Gastrointestinal stromal tumours: consensus statement on diagnosis and treatment.

In the multidisciplinary management of gastrointestinal stromal tumours (GISTs), there is a need to coordinate the efforts of pathology, radiology, surgery and oncology. Surgery is the mainstay for resectable nonmetastatic GISTs, but virtually all GISTs are associated with a risk of metastasis. Imatinib 400 mg/day with or without surgery is the recommended first-line treatment for recurrent or metastatic GIST; a higher dose may be considered in patients who progress, develop secondary resistance or present with specific genotypic characteristics. Adjuvant or neoadjuvant imatinib is not advised for resectable nonmetastatic GISTs. Neoadjuvant imatinib may be considered when surgery would result in significant morbidity or loss of organ function. Follow-up computed tomography imaging is recommended every three to six months for at least five years. Patients with metastatic disease should be continued on imatinib due to the high risk of recurrence on discontinuation of therapy. Treatment should be continued until there is progression or intolerable adverse effects. If dose escalation with imatinib fails, a clinical trial with novel agents alone or in combination may be considered. The present recommendations were developed at a surgical subcommittee meeting and a subsequent full Advisory Committee meeting held in Toronto, Ontario, in April 2005, under the sponsorship of Novartis Pharmaceuticals Canada Inc.

Histopathologic Features of Prognostic Significance in High-Grade Osteosarcoma.

Context .- In osteosarcoma treated with neoadjuvant chemotherapy the extent of tumor necrosis on resection is considered an indicator of treatment response, and this has been shown to correlate with survival in most but not all studies. Objective .- To identify additional histologic variables of prognostic significance in high-grade osteosarcoma. Design .- Slides of pretreatment biopsy and primary postneoadjuvant chemotherapy resections from 165 patients with high-grade osteosarcoma were reviewed. Univariate (Kaplan-Meier) and multivariate (Cox regression) analyses were performed to identify clinical and histomorphologic attributes associated with overall survival. Results .- Univariate analyses confirmed the prognostic significance of metastatic status on presentation, primary tumor size, anatomic site, and histologic subtype. Additionally, the identification of lymphovascular invasion, 10% or more residual viable tumor, and 10 or more mitoses per 10 high-powered fields assessed in posttreatment resections were associated with poor survival, retaining significance in multivariate analyses. Based on results from multivariate analysis, we developed a prognostic index incorporating primary tumor size and site, and significant histologic features assessed on resection (ie, lymphovascular invasion status, mitotic rate, and extent of viable tumor). This scoring system segregates patients into 3 risk categories with significant differences in overall survival and retained significance in an independent validation set of 42 cases. Conclusions .- The integration of clinical and microscopic features improves prognostication of patients with osteosarcoma.

Efficacy of denosumab in joint preservation for patients with giant cell tumour of the bone.

BACKGROUND: Giant cell tumour of the bone (GCTB) is an aggressive osteolytic primary tumour. GCTB is rich in osteoclast-like giant cells and contains mononuclear cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. The potential therapeutic effect of denosumab was investigated with special reference to its role in joint preservation. METHODS: In this prospective non-randomised study patients with GCTB received denosumab for 6-11 months preoperatively. Serial radiographs and biopsy and resection tumour specimens were used to monitor response to denosumab. RESULTS: All 20 patients experienced pain relief in the first month of treatment. All patients demonstrated a positive radiographic response with improved subchondral and cortical bone which allowed intralesional tumour resection and preservation of the joint and articular surface in 18 cases. Histological examination following denosumab revealed rarely detectable osteoclast-like giant cells. There was an obvious increase in osteoid matrix and woven bone which showed rare RANK staining amongst the mononuclear cells and only focal RANKL positivity. At median 30 months follow-up after resection, local tumour recurrence occurred in three patients. CONCLUSION: Denosumab provides favourable and consistent clinical, radiographic and pathologic responses which facilitates less aggressive surgical treatment, especially joint preservation. However, the local recurrence rate for GCTB following resection does not seem to be affected by denosumab and remains a concern.

The combination of p53 mutation and neu/erbB-2 amplification is associated with poor survival in node-negative breast cancer.

PURPOSE: Increases in neu/erbB-2 have been implicated in breast cancer prognosis, but do not predict all recurrences. On the basis of evidence that p53 mutation is involved in the development of human neoplasia, we examined the prognostic value of p53 alterations in combination with neu/erbB-2 amplification. PATIENTS AND METHODS: A consecutive series of women were observed for recurrence and death (median follow-up of 85 months) and tumors from 543 individuals were analyzed for p53 mutation status and neu/erbB-2 amplification. Exons 4 through 10 of the p53 gene were analyzed by single-stranded conformational polymorphism and mutations were confirmed by DNA sequencing. The association of p53 mutation status and neu/erbB-2 amplification with risk of recurrence and death was examined in survival analyses with traditional and histologic markers as prognostic factors. RESULTS: p53 mutations occurred in 24.5% of the axillary node-negative breast carcinomas. Mutations were more frequent in carcinomas with neu/erbB-2 amplification: 38.9% compared with only 20.9% in those without neu/erbB-2 amplification. We found elevated risks of disease recurrence and overall mortality in patients with both p53 mutation and neu/erbB-2 amplification in their tumor compared with patients with neither or only one of the alterations. This increase persisted with adjustment for other prognostic factors (relative risk, 2.32; P =.002 for recurrence; relative risk, 2.22; P =.004 for death). CONCLUSION: Evaluation of tumors for p53 mutations may be beneficial to identify women at higher risk of disease recurrence and death when the tumor has neu/erbB-2 amplification, but in the absence of neu/erbB-2 amplification, the presence of p53 mutation may not provide additional independent prognostic information.

Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage IIIA (T1-3, N2) unresectable non-small-cell lung cancer: final results of the Toronto phase II trial.

PURPOSE: This is a phase II study to assess the role of induction chemotherapy in the management of stage IIIA non-small-cell lung cancer (NSCLC). We are now reporting the long-term follow-up of the Toronto phase II trial. METHODS: Sixty five patients with mediastinoscopy proven stage IIIA NSCLC received two cycles of preoperative MVP or VLB/P followed by thoracotomy followed by two further courses of chemotherapy. RESULTS: The overall response rate was 67.7% with three complete and 41 partial responders. Forty seven patients went on to thoracotomy with 35 complete resections. Pathologically 4.6% of patients had no tumour remaining. There were three postop deaths as well as five chemotherapy related deaths. Of the 35 patients completely resected 19 have recurred including eight in brain. The median survival for the entire 65 patients is 18.6 months with a 1 year survival of 66%, 5 year survival of 29% and a 10 year survival of 22%. CONCLUSIONS: The long-term survival of induction chemotherapy is maintained. The high incidence of brain recurrences warrants assessment of the role of prophylactic cranial radiation. The role of surgery for stage IIIA NSCLC following induction chemotherapy awaits further study.

The GOLD ReGISTry: a Global, Prospective, Observational Registry Collecting Longitudinal Data on Patients with Advanced and Localised Gastrointestinal Stromal Tumours.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal sarcomas. This global, prospective registry followed patients with advanced or localised GIST (2007-2011). METHODS: Current and evolving diagnostics, treatments and outcome measures in patients with GIST were assessed. Eligible patients were diagnosed with advanced or localised GIST within 15months of registry entry. No treatment plan was prescribed, and no visit schedule was mandated. Treating physicians recorded patient information, including tumour response, diagnostic methods, medications, surgeries performed, mutation status and adverse events leading to dose/medication changes. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analysed using descriptive statistics. RESULTS: The registry included 1663 patients (advanced GIST, n=1095; localised GIST, n=537). Medications (e.g. tyrosine kinase inhibitor use and dosing), disease progression or recurrence and physician assessment of response to treatment in registry patients were consistent with controlled trials and prevailing clinical recommendations. In advanced GIST, estimated 30-month progression-free survival (PFS) (59.8%) and overall survival (OS) (82.7%) were higher than results from previously reported trials (≈40% and ≈70%, respectively). Consistent with treatment guidelines, the most common initial treatments were imatinib for advanced GIST, and complete surgical resection for localised GIST. Computed tomography scans were the most common imaging technique used at diagnosis and follow-up. Mutation analysis was performed at diagnosis in only 15.3% and 14.5% of patients with advanced and localised GIST, respectively. CONCLUSIONS: In this real-world GIST registry, patients with advanced GIST were treated with imatinib and patients with localised GIST received surgical resection, in accordance with prevailing clinical recommendations.

Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial.

PURPOSE: The ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome. PATIENTS AND METHODS: There were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis. RESULTS: RFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model-adjusted P < .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival. CONCLUSION: Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.