Caimiao Wei

Optimizing Treatment of Desmoid Tumors

PURPOSE This study compared a large series of desmoid patients treated at a single institution to a previously published series from the same institution to determine if patient population characteristics, treatment approaches, and clinical outcomes had undergone change over the two study periods. MATERIALS AND METHODS Data from a prospective soft tissue tumor database was used to analyze clinical courses of 189 desmoid patients treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) from 1995 to 2005 as compared with 189 UTMDACC desmoid patients treated between 1965 and 1994. RESULTS A nearly three-fold increase in annualized UTMDACC desmoid referral volume with significantly higher percentages and numbers of primary desmoid tumor referrals to UTMDACC was observed in the most recent study period. Significantly increased systemic therapy use and decreased reliance on surgery alone was observed more recently. While the recent series patients had higher rates of macroscopic residual disease and equivalent rates of positive microscopic margins after definitive surgery, the estimated 5-year local recurrence rate of 20% was improved compared with the 30% rate observed in the earlier series. CONCLUSION Increased awareness of the complex multidisciplinary management needed for desmoid tumor control may underlie significantly increased numbers of referrals to UTMDACC, especially primary untreated desmoids. Increased neoadjuvant treatments may be associated with improved desmoid patient outcomes. These trends should be supported, particularly if personalized molecular-based therapies are to be rapidly and effectively deployed for the benefit of those afflicted by this rare and potentially debilitating disease.

Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas

Objective:We conducted a prospective trial to define the local recurrence rates for selected patients with T1 soft tissue sarcomas (STS) treated by surgery alone. Summary Background Data:Retrospective data suggest that some patients with small STS can be safely treated by surgery alone. There are no defined criteria to select patients for such treatment. Methods:Patients with T1 primary STS were treated with function-preserving surgery and microscopic assessment of surgical margins. Postoperative external-beam radiation was employed selectively for patients with microscopically positive (R1) final surgical margins. Patients who underwent resection with microscopically negative (R0) final margins did not receive radiotherapy. Results:Eighty-eight eligible and evaluable patients were entered on this protocol between March 1996 and April 2002. Tumor sites included the extremities (n = 60), and trunk (n = 26). Fifty-one patients (58%) had high-grade STS; 60 (68%) had superficial (T1a) disease. Fourteen patients (16%) underwent R1 resection and were treated with postoperative radiation; 74 (84%) underwent R0 resection and were treated by surgery alone. The median follow-up was 75 months. Isolated local recurrences were observed in 11 patients (13%; 6 in R1 arm, 5 in R0 arm). In the R0 surgery-alone arm, the cumulative incidence rates of local recurrence at 5 and 10 years were 7.9% and 10.6%, respectively; and the 5- and 10-year sarcoma-specific death rates were 3.2% and 3.2%. Conclusion:Selected patients with primary T1 STS of the extremity and trunk can be treated by R0 surgery alone with acceptable local control and excellent long-term survival.

Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma

Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.

Ursolic Acid Inhibits Growth and Metastasis of Human Colorectal Cancer in an Orthotopic Nude Mouse Model by Targeting Multiple Cell Signaling Pathways: Chemosensitization with Capecitabine

Purpose: Development of chemoresistance, poor prognosis, and metastasis often renders the current treatments for colorectal cancer (CRC) ineffective. Whether ursolic acid, a component of numerous medicinal plants, either alone or in combination with capecitabine, can inhibit the growth and metastasis of human CRC was investigated. Experimental design: The effect of ursolic acid on proliferation of CRC cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and protein expression by Western blot. The effect of ursolic acid on the growth and chemosensitization was also examined in orthotopically implanted CRC in nude mice. Results: We found that ursolic acid inhibited the proliferation of different colon cancer cell lines. This is correlated with inhibition of constitutive NF-κB activation and downregulation of cell survival (Bcl-xL, Bcl-2, cFLIP, and survivin), proliferative (cyclin D1), and metastatic (MMP-9, VEGF, and ICAM-1) proteins. When examined in an orthotopic nude mouse model, ursolic acid significantly inhibited tumor volume, ascites formation, and distant organ metastasis, and this effect was enhanced with capecitabine. Immunohistochemistry of tumor tissue indicated that ursolic acid downregulated biomarkers of proliferation (Ki-67) and microvessel density (CD31). This effect was accompanied by suppression of NF-κB, STAT3, and β-catenin. In addition, ursolic acid suppressed EGF receptor (EGFR) and induced p53 and p21 expression. We also observed bioavailability of ursolic acid in the serum and tissue of animals. Conclusion: Overall, our results show that ursolic acid can inhibit the growth and metastasis of CRC and further enhance the therapeutic effects of capecitabine through the suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis. Clin Cancer Res; 18(18); 4942–53. ©2012 AACR.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)-targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor-negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor-negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.

Risk of Thromboembolic Disease in Patients Undergoing Laparoscopic Gynecologic Surgery

OBJECTIVE: To estimate the incidence of venous thromboembolism among patients undergoing gynecologic laparoscopy and characterize the risk of venous thromboembolism among patients with gynecologic malignancy. METHODS: Data were collected for patients who underwent laparoscopic gynecologic surgery from January 2000 to January 2009. Incidence of deep vein thrombosis (DVT) or pulmonary embolism diagnosed within 6 weeks of surgery was estimated. Fishers exact test was used to estimate the association between the presence of perioperative venous thromboembolism and categorical variables. RESULTS: Six (of 849) patients developed symptomatic venous thromboembolism (0.7%, 95% confidence interval: 0.024–1.44%). The median time to diagnosis of venous thromboembolism was postoperative day 15.5 (range, 1–41 days), median body mass index was 25.4 kg/m2 (range, 18.4–50 kg/m2), median operative time was 176 minutes (range, 53–358 minutes), and median estimated blood loss was 125 mL (range, 10–250 mL). Five of 430 (1.2%) patients with a history of gynecologic malignancy developed postoperative thromboembolic events. Venous thromboembolism was diagnosed in three of 662 (0.5%) patients undergoing intermediate complexity procedures and three of 106 (2.8%) patients undergoing high-complexity procedures. Three patients with venous thromboembolism (50%) had a history of at least one previous modality of cancer treatment before laparoscopy. One patient (17%) had DVT only, four (67%) had pulmonary emboli without an identified DVT, and one (17%) had both. There were no associated mortalities. CONCLUSION: The incidence of thromboembolism in patients undergoing low- and intermediate-complexity, minimally invasive surgery was low, even among patients with a gynecologic malignancy. Patients undergoing high-complexity, minimally invasive procedures may benefit from postoperative anticoagulation. LEVEL OF EVIDENCE: II

Epidermal growth factor receptor blockade in combination with conventional chemotherapy inhibits soft tissue sarcoma cell growth in vitro and in vivo

Purpose: The epidermal growth factor receptor (EGFR) is highly expressed in many human soft tissue sarcomas (STS). However, EGFR blockade has not apparently been used for human STS therapy; therefore, we examined the in vitro and in vivo effects and the underlying mechanisms before considering EGFR blockade as a therapy for STS patients. Experimental Design: Human STS tissues and cell lines were used to study EGFR expression and activation. Western blot analysis was used to evaluate effects of EGFR activation on downstream signaling. Cell culture assays were used to assess the effect of EGF stimulation as well as EGFR blockade (using an EGFR tyrosine kinase inhibitor, Iressa; AstraZeneca) on STS cell growth, apoptosis, and chemosensitivity. An in vivo study (HT1080 human fibrosarcoma cell line in nude/nude mice: Iressa, doxorubicin, Iressa + doxorubicin, vehicle) was used to examine tumor growth; pEGFR, proliferating cell nuclear antigen, and terminal deoxyribonucleotide transferase–mediated nick-end labeling staining helped assess the effect of therapy in vivo on STS EGFR activation, proliferation, and apoptosis. Results: EGFR was expressed and activated in STS cell lines and tumors, probably due to ligand binding rather than EGFR mutation. Stimulation caused activation of AKT and mitogen-activated protein kinase pathways. EGFR blockade inhibited these effects and also caused increased apoptosis, a p53-independent G0-G1 cell cycle arrest, and decreased cyclin D1 expression. In vivo, Iressa + doxorubicin had markedly synergistic anti-STS effects. Conclusion: EGFR blockade combined with conventional chemotherapy results in anti-human STS activity in vitro and in vivo, suggesting the possibility that combining these synergistic treatments will improve anti-STS therapy.

Phase 1 study of dose escalation in hypofractionated proton beam therapy for non-small cell lung cancer.

BACKGROUND Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control. METHODS AND MATERIALS Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectiveness [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment. RESULTS The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT. CONCLUSION Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC.

The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. PATIENTS AND METHODS Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. RESULTS Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). CONCLUSION Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.

Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non-small cell lung cancer

BackgroundWhile conventionally fractionated radiation therapy alone is an acceptable option for poor prognostic patients with unresectable stage III NSCLC, we hypothesized that accelerated hypofractionated radiotherapy will have similar efficacy without increasing toxicity.MethodsThis is a retrospective analysis of 300 patients diagnosed with stage III NSCLC treated between 1993 and 2009. Patients included in the study were medically or surgically inoperable, were free of metastatic disease at initial workup and did not receive concurrent chemotherapy. Patients were categorized into three groups. Group 1 received 45 Gy in 15 fractions over 3 weeks (Accelerated Radiotherapy (ACRT)) while group 2 received 60-63 Gy (Standard Radiation Therapy 1 (STRT1)) and group 3 received > 63 Gy (Standard Radiation Therapy (STRT2)).ResultsThere were 119 (39.7%) patients in the ACRT group, 90 (30.0%) in STRT1 and 91 (30.3%) in STRT2. More patients in the ACRT group had KPS ≤ 60 (p < 0.001), more commonly presented with weight loss > 5% (p = 0.002), and had stage 3B disease (p < 0.001). After adjusting for clinical variables, there were no differences in the radiation groups in terms of the patterns of local or distant tumor control or overall survival. Some benefit in relapse free survival was seen in the STRT1 group as compared to ACRT (HR = 0.65, p = 0.011). Acute toxicity profiles in the ACRT were significantly lower for grade ≥ 2 radiation dermatitis (p = 0.002), nausea/vomiting (p = 0.022), and weight loss during treatment (p = 0.020).ConclusionsDespite the limitations of a retrospective analysis, our experience of accelerated hypofractionated radiation therapy with 45 Gy in 15 fractions appears to be an acceptable treatment option for poor performance status patients with stage III inoperable tumors. Such a treatment regimen (or higher doses in 15 fractions) should be prospectively evaluated using modern radiation technologies with the addition of sequential high dose chemotherapy in stage III NSCLC.