Tumor Chemotherapy Response Research Articles

Dedicated Breast CT: Getting Ready for Prime Time.

Dedicated breast CT is an imaging modality that provides true 3D imaging of the breast with many advantages over current conventional breast imaging modalities. The addition of intravascular contrast increases the sensitivity of breast CT substantially. As such, there are immediate potential applications in the clinical workflow. These include using breast CT to replace much of the traditional diagnostic workup when faced with indeterminate breast lesions. Contrast-enhanced breast CT may be appropriate as a supplemental screening tool for women at high risk of breast cancer, similar to breast MRI. In addition, emerging studies are demonstrating the utility of breast CT in neoadjuvant chemotherapy tumor response monitoring as well as planning for surgical treatment options. While short exam times and fully 3D imaging in a noncompressed position are advantages of this modality, limited coverage of chest wall/axilla due to prone positioning and use of ionizing radiation are drawbacks. To date, several studies have reported on the performance characteristics of this promising modality.

UGT1A1 polymorphisms with irinotecan-induced toxicities and treatment outcome in Asians with Lung Cancer: a meta-analysis.

Previous studies of irinotecan pharmacogenetics have shown that the UGT1A1*28 polymorphism has an effect on irinotecan (IRI)-induced toxicities in Caucasians. Yet compared with the UGT1A1*6 mutation, the UGT1A1*28 occurs at a much lower frequency in the Asians. Whether UGT1A1*6 and UGT1A1*28 are associated with IRI-induced neutropenia, diarrhea and IRI-based chemotherapy tumor response (TR) in Asians with lung cancer remains controversial. In this meta-analysis, we found a higher risk of neutropenia and diarrhea with IRI-based chemotherapy in Asians with lung cancer carrying the UGT1A1*6 polymorphism. However, UGT1A1*28 showed a weak correlation with diarrhea, but no significant correlation with neutropenia. Neither UGT1A1*6 nor UGT1A1*28 is associated with IRI-based chemotherapy TR. These data suggest that the UGT1A1*28 polymorphism may not be a suitable biomarker to predict IRI-induced toxicities and chemotherapy TR in Asians, while UGT1A*6 polymorphism is associated with a higher risk of IRI-induced neutropenia and diarrhea, but not IRI-based chemotherapy TR.

Survival Rates Using Individualized Bioselection Treatment Methods in Patients With Advanced Laryngeal Cancer

Use of chemoradiotherapy for advanced laryngeal cancer led to a major shift in treatment as an alternative to laryngectomy. Despite widespread adoption of chemoradiotherapy, survival rates have not improved and the original premise of matching neoadjuvant chemotherapy tumor response to determine subsequent treatment has not been followed. To determine whether improved survival could be achieved by incorporating a single cycle of neoadjuvant chemotherapy to select patients with advanced disease for either laryngectomy or concurrent chemoradiotherapy. An unselected cohort of 247 patients with laryngeal cancer in an academic institution between 2002 and 2012 was evaluated. Patients with limited disease (stages I and II) underwent endoscopic resection, radiotherapy, or chemoradiotherapy for deeply invasive T2 lesions. For patients with advanced disease (stages III and IV), neoadjuvant chemotherapy, concurrent chemoradiotherapy, or primary surgery was recommended. Overall survival (OS) and disease-specific survival (DSS) were analyzed. Median follow-up was 48 months. The study was conducted from January 1, 2002, to December 31, 2012; data analysis was completed December 1, 2015. Endoscopic resection, radiotherapy, chemoradiotherapy, neoadjuvant chemotherapy, concurrent chemoradiotherapy, and primary surgery. Overall survival and DSS. Of the 247 patients, 191 (77.3%) were male; mean (SD) age was 59.6 (10.4) years. Of 94 patients with limited disease, 33 (35.1%) underwent endoscopic resection; 50 (53.2%), radiotherapy alone; and 11 (11.7%), chemoradiotherapy for deeply invasive T2 lesions. Of 153 patients with advanced disease, 71 (46.4%) received neoadjuvant chemotherapy; 50 (32.7%), concurrent chemoradiotherapy; and 32 (20.9%), surgery. Five-year OS and DSS was 75% (95% CI, 68%-81%) and 83% (95% CI, 77%-88%), respectively, for the entire cohort. The DSS was 92% (95% CI, 83%-97%) for patients with stage I or II and 78% (95% CI, 69%-84%) for patients with stage III or IV disease. For patients with advanced disease, 5-year OS and DSS ranged from 78% (95% CI, 55%-90%) and 91% (95% CI, 67%-98%), respectively, for surgery; to 76% (95% CI, 63%-85%) and 79% (95% CI, 67%-88%), respectively, for neoadjuvant bioselection; and to 61% (95% CI, 44%-75%) and 66% (95% CI, 48%-79%), respectively, for primary chemoradiotherapy. Propensity-adjusted, multivariable controlling for known prognostic factors DSS was significantly improved in the neoadjuvant group compared with the chemoradiotherapy group (hazard ratio [HR], 0.48; 95% CI, 0.29-0.80). Superior survival rates were achieved with a bioselective treatment approach using a single cycle of neoadjuvant chemotherapy. Good survival rates were also achieved in patients selected for primary surgery, and both neoadjuvant chemotherapy and primary surgery were better than survival rates with concurrent chemoradiotherapy, suggesting that the optimal individualized treatment approach for patients with advanced laryngeal cancer has not yet been defined.

Can FDG-PET/CT predict early response to neoadjuvant chemotherapy in breast cancer?

Neoadjuvant chemotherapy (NAC) in breast cancer is currently used not only for locally advanced tumors, but also for large operable tumors when breast preservation is considered. It also provides the opportunity to evaluate chemotherapy tumor response. Our aim was to correlate the relative change in the standardized uptake value (SUV) of (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET/CT) with pathologic response after NAC. We prospectively evaluated 40 patients with invasive ductal breast carcinomas from February 2010 to December 2011. FDG-PET/CT was performed at baseline and after the second cycle of NAC. All patients underwent surgery after NAC. Pathologic response was evaluated according to Residual Cancer Burden (RCB) index. The mean age was 41.9 years. Median primary tumor size was 6 cm. Pathologic complete response (pCR) was obtained in 12 (30%) patients. The tumor baseline mean maximum SUV (SUV(max)), and after second cycle were: 8.97 (sd.4.3) and 4.07 (sd.3.2), respectively. The relative change (ΔSUV) after the second course of NAC was significantly higher for patients with pCR (-81.58%) when compared to the non-pCR patients (-40.18%) (p = 0.001). The optimal ΔSUV threshold that discriminates between pCR and non-pCR was -71.8% (83.3% sensitivity; 78.5% specificity). Moreover, the optimal ΔSUV threshold to discriminate between NAC responders and non-responders was -59.1% (68% sensitivity; 75.0% specificity). Our data suggest that the FDG-PET/CT ΔSUV after the second course of NAC can predict pathological response in ductal breast carcinomas, and potentially identify a subgroup of non-responding patients for whom ineffective chemotherapy should be avoided. Breast cancer is the most frequently diagnosed cancer in women. The indications for neoadjuvant chemotherapy are increasing. Early information on chemotherapy response is crucial and methods that predict the therapeutic effectiveness might avoid potentially ineffective chemotherapies in non-responding patients.

Triggers in the pathway from lung cell damage to malignancy: The glycans.

e22189 Background: It has been reported that carbon nanoparticles (CN) produce mesothelioma as readily as do asbestos fibers. We have studied early CN damage in experimental animals, quantifying toxicity by release from cells of the nuclear chaperone HMGB1. Damage-released HMGB1 binds to receptors (RAGE, CD24) to upregulate cytokines and produce regulatory signals that control cell homeostasis. Further, HMGB1 has recently been shown to form a complex with P53, one of the most commonly mutated genes in human cancers, and HMGB1 is the controlling factor in autophagy, an important new field in translational cancer research. Methods: One HMGB1 receptor, CD24, is the source of a whole-receptor antibody used to determine extent of malignancy during surgery. CD24 is highly glycosylated. We hypothesized that carbohydrate vs protein specificity would show differences in tumor character. Would antibodies to the CD24 carbohydrate moiety reflect a tumor glycan character, and how would this relate to the tumor profile such as metastasis? With cooperation of TMC pathology Dept, blocks (N=15 each) of lung squamous cell, adenocarcinoma, and small cell cancer were sectioned and stained with mouse monoclonals to CD24, IgM –glycan, IgG-protein fraction. Results: Small cell and adenocarcinoma lung tumors showed mostly similar staining by CD24 protein vs CD24 glycan antibodies. Squamous cell CA showed elevated carbohydrate CD24 staining with negative or low protein stain in over half of the cases, and examination of patient records are being studied to determine metastatic character, lung- damage history and tumor chemotherapy response. Conclusions: Squamous cell tumors demonstrate significantly more staining by antibody to the glycan moiety of CD24, p=0.02. There was no relationship between numbers of positive nodes and staining, although other chart information awaits analysis. Research continues into the significance of this glycan CD24 receptor for HMGB1, our marker for nanoparticle lung damage, and its relationship to malignant transformation. [Table: see text]

Preirradiation chemotherapy with methotrexate, rituximab, and temozolomide and post-irradiation temozolomide for primary central nervous system lymphoma: RTOG 0227 phase II study results.

2033 Background: This prospective phase II study tested a methotrexate (MTX), temozolomide (TMZ) and rituximab (RTX) pre-irradiation regimen with hyperfractionated whole brain radiation therapy (hWBRT) followed by post-irradiation TMZ for patients with primary CNS lymphoma (PCNSL). The primary phase II endpoint was the 2-year overall survival (OS) rate compared with the 2-year OS from RTOG 93-10 (MTX, procarbazine, vincristine, whole brain radiation therapy, cytarabine). Secondary endpoints were pre-irradiation chemotherapy tumor response rates (compared to RTOG 93-10), progression free survival (PFS), acute and late neurologic toxicities, and quality of life. Methods: 53 patients (28 women, 25 men), median age 57.5 years, median Zubrod 1 were treated with RTX 375 mg/m2 3 days prior to first cycle of MTX; 5 cycles of intravenous MTX 3.5 g/m2 with leucovorin rescue on weeks 1, 3, 5, 7, 9; TMZ 100 mg/m2 daily for 5 days weeks 4 and 8; hWBRT 1.2 Gy twice daily fractions 5 days/week on weeks 11, 12, 13 for a total of 36 Gy and TMZ 200 mg/m2 daily for 5 days on weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, 50. Results: Dosing of pre-irradiation temozolomide at 100 mg/m2 was determined in the phase I portion of the study. With a median follow-up of 3.6 years, 2-year OS and PFS rates were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG 93-10, 2-year OS and PFS were significantly improved (p = 0.006 and 0.03). The overall response rate to the pre-irradiation chemotherapy was 37.7% (complete response 11.3%, partial response 26.4%). 38% experienced grade 3 and 25% experienced grade 4 toxicities before the start of hWBRT. 33% experienced grade 3 and 21% experienced grade 4 toxicities attributable to post-hWBRT chemotherapy. Conclusions: The combination of MTX, TMZ, RTX followed by hWBRT and TMZ for PCNSL is safe with demonstrated improved 2 year OS and PFS compared with RTOG 93-10. Further investigations regarding the role of hWBRT and post-hWBRT TMZ are indicated. This project was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough. Clinical trial information: NCT00068250.

P5-11-05: Measurement of Neoadjuvant Chemotherapy Tumor Response in Locally Advanced Breast Cancer by Three Methodologies. Correlation with Overall Survival.

Abstract Background Measurement of residual disease following neoadjuvant chemotherapy that accurate predicts long-term survival in locally advanced breast cancer (LABC) is an essential requirement for new drugs efficacy evaluation. Several methods to assess neoadjuvant chemotherapy tumor response have been described. However, to our knowledge, agreement between methods and correlation with survival in independent prospective cohorts has not been reported. Patients & Methods: In this study we report neoadjuvant chemotherapy tumor response and survival in 151 consecutive LABC patients, included in a neoadjuvant clinical trial (http://www.clinicaltrials.gov; NCT00123929). Patients were randomized to either neoadjuvant docetaxel 100 mg/m2 every 21 days or neoadjuvant doxorubicin 75mg/m2, every 21 days, for 4 cycles. Following surgery, response was established according to three methodologies: the measurement of residual breast cancer burden (RBC) as described by Symman's (Symmans WF et al. J Clin Oncol. 2007;25:4414–22), Miller and Payne classification (Ogston KN et al. Breast. 2003;12:320–7) and RECIST criteria. Regarding to Symmans classification we have evaluate both RBC index, as a continuous variable, and RBC classes as a categorical variable (RBC-0,I,II,III). Kappa Cohen's coefficient (K) was used to test agreement between methods. We assessed the correlation between treatment outcome and overall survival (OS) by calculating the Harrell's C- statistic. Results: Median of follow up was 51.9 months. All three methods showed a moderate capacity to classify patients according to OS. The C-statistic to predict OS was 0.76 (IC: 0.67- 0.84) for RBC index and 0.71 (IC: 0.64−0.78) for RBC classes, 0.68 (IC: 0.58−0.78) for RECIST criteria and 0.69 (0.60−0.78) for Miller and Payne classification. Interesting, we did not encountered any death events within RCB-0 class. No significant differences were found between C-statistic when patients were stratified according to therapy. In order to assess the agreement between techniques, we grouped categories 1 and 2 of Miller and Payne classification in 1 category. The agreement between Miller and Payne classification and Symmans method was very high (K=0.87). In contrast, we found a moderate-fair agreement between Miller and Payne classification and RECIST criteria (K=0.46) and Symmans method and RECIST criteria (K=0.27). Conclusion: All three methods predicted fairly well OS. RCB-0 identified the best outcome group. The agreement between methodologies based in pathology analyses was very high. However, the agreement falls off when these methodologies were compared with RECIST criteria. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-05.