Microscopic Residual Disease Research Articles

P53-autoantibody may be more sensitive than CA-125 in monitoring microscopic and macroscopic residual disease after primary therapy for epithelial ovarian cancer

To evaluate the use of p53-autoantibodies (p53-aab) for monitoring minimal disease after standard therapy of advanced epithelial ovarian cancer (EOC). Retrospective analysis of p53-aab in preoperative and long-term follow-up serum samples from 10 patients selected for representing three relevant EOC subgroups: platinum-sensitive disease after macroscopic complete debulking (n = 4) and platinum-sensitive (n = 3) or platinum-resistant disease (n = 3), both after suboptimal debulking with residual tumor of <1 cm diameter. p53-aab levels were quantified by a sandwich ELISA in two independent experiments. CA-125 values of all samples and clinical information were retrieved from medical records. Patients with early relapse (median PFS 7 months, n = 8) had high p53-aab levels throughout follow-up while CA-125 values had dropped below the cut-off after primary surgery during or after chemotherapy in these cases. Patients with seroconversion to p53-aab negativity experienced prolonged PFS (n = 2; #1: 50 months, #2: no evidence of disease for 36 months until last follow-up). Continued p53-aab positivity was not related to the resection status or platinum sensitivity. p53-autoantibodies may be a highly sensitive marker for minimal residual tumor mass after surgery and/or chemotherapy rather than standard CA-125, possibly due to the different nature of these markers. CA-125 released by cancer cells is related to tumor mass, whereas p53-aab levels can indicate the presence of few tumor cells due to amplification by the immune system. Seroconversion of p53-aab could be associated with long-term survival.

Outcomes and patterns of secondary relapse in platinum-sensitive ovarian cancer: Implications for tertiary cytoreductive surgery

To evaluate the outcomes and patterns of patients with secondary relapsed ovarian cancer. A retrospective study was conducted. The cases comprised 83 patients who underwent tertiary cytoreductive surgery (TCS) followed by chemotherapy, whereas the controls consisted of 76 patients who received chemotherapy alone. The median survival was 20 months in 159 patients. Patients with microscopic residual disease after TCS had a median survival of 32.9 months compared with 14.6 months in those with macroscopic residual disease [hazard ratio (HR), 2.82; P = 0.001) and 15.0 months in patients with chemotherapy alone (HR, 2.23; P = 0.001). When stratified by a progression-free interval (PFI) after secondary cytoreduction (SCR), TCS showed no benefit in patients with a PFI ≤12 months or a PFI >12 months compared with those with chemotherapy alone. TCS improved survival in patients with recurrent disease in the pelvis compared with those with recurrent disease in the middle or upper abdomen, with a median survival of 34.9 months and 14.6 months, respectively (HR, 2.94; P = 0.010). However, TCS was not a survival determinant by multivariate analysis. A multivariate analysis identified a PFI after SCR (≤12 mos vs. >12 mos; HR, 2.34; 95% CI, 1.29-4.24; P = 0.005), mesenteric lymph node metastasis at SCR (yes vs. no; HR, 4.18; 95% CI, 1.93-9.03; P < 0.001) and treatment arms at secondary relapse (chemotherapy alone vs. TCS; HR, 1.56; 95% CI, 1.03-2.38; P = 0.037) as independent predictors of survival. Limited survival benefit from tertiary cytoreductive surgery was observed in patients with platinum-sensitive secondary relapsed ovarian cancer.

Clinicopathologic Findings Predictive of Relapse in Children With Stage III Favorable-Histology Wilms Tumor

Stage III designation in NWTS-5 (National Wilms Tumor Study-5) was determined by four pathologic criteria: positive lymph nodes (LNs), peritoneal implants, residual disease, and tumor rupture. The objective of this study was to determine the prognostic significance of each of the stage III criteria. Children with stage III Wilms tumor (WT) treated in NWTS-5 were assessed for event-free (EFS) and overall survival (OS). Sites of relapse and molecular status of tumors are reported. EFS and OS are reported 8 years after diagnosis. There were 569 patients with local stage III favorable-histology (FH) WT in this analysis, of whom 109 had overall stage IV disease. LN involvement alone was the most frequent criterion for stage III designation (38%), followed by microscopic residual disease alone (20%), microscopic residual disease and LN involvement (14%), and spill or soilage alone (9%). The 8-year EFS and OS estimates for all patients with local stage III FHWT were 82% and 91%, respectively. Multivariate analysis demonstrated that both LN involvement (relative risk, 1.89; P = .005) and microscopic residual disease (relative risk, 1.87; P = .007) were predictive of EFS, and OS results were similar. There was no apparent difference in pattern of relapse according to stage III subtype. The rate of loss of heterozygosity was higher (6%) for those with positive LNs than for those without (2%; P = .05). LN involvement and microscopic residual are the stage III criteria highly predictive of EFS and OS for patients with stage III FHWT. It is possible that in future studies, patients with different stage III criteria may receive different therapies.

A phase II trial of combination oxaliplatin, capecitabine, and celecoxib with concurrent radiation for patients with newly diagnosed resectable rectal cancer.

487 Background: The goal of preoperative chemoradiation in rectal cancer is complete surgical resection without impairing sphincter function and to decrease local recurrence. The primary objective of the study was to determine complete pathological response rate (pCR) with capecitabine, oxaliplatin and celecoxib with concurrent radiation therapy. The secondary objectives were down staging rate, sphincter preservation rate, incidence and severity of adverse events. Methods: A total 37 out of 55 planned patients (pts) were enrolled by New Mexico cancer center consortium from 2005 to 2012. Inclusion criteria were: Resectable adenocarcinoma of the rectum within 12 cm of the anal verge, biopsy proven T3-4 N1-2 M0 based on endoscopic ultrasound, performance status of 0-2, adequate bone marrow reserve and liver functions. The neoadjuvant chemoradiation treatment was: capecitabine 850 mg/m2 bid Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 IV, celecoxib 200 mg bid with concurrent 45 gray radiation therapy in 25 fractions over 5 weeks. Results: Only 21 of 37 pathology reports were assessable for the primary objective of pCR. 7/21 pts (33%, 95% CI, 0.14-0.56) had pCR and 4 had only microscopic residual disease. Thus, 11/21 pts (52%, 95% CI, 0.30-0.74) had an excellent response following chemoradiation. The secondary outcome analysis showed 19/21 pts (90%, 95% CI, 0.69-0.98) were down staged. Sphincter preservation rate was 71% (15/21) (95% CI, 0.47-0.88). Grade 3 and 4 toxicities were observed in 23% and included nausea, vomiting, diarrhea, dehydration, hypokalemia, lymphopenia and fatigue. Conclusions: We report the highest pathological CR so far in stage III rectal cancer with these early results. This could be due to anti-inflammatory activity of celecoxib leading to better tolerance of radiation therapy and possible synergistic anti-tumor activity. Final results will be reported upon completion of the trial. Clinical trial information: NCT00250835.

A phase I study of hyperfractionated low-dose radiotherapy (RT) as a chemotherapy sensitizer in combination with gemcitabine (G) and erlobtinib (E) in advanced pancreatic cancer.

268 Background: G can sensitize pancreatic cancer (PC) to radiotherapy (RT). However, this approach requires lower doses of G and thus delays aggressive systemic treatment, which may lead to distant failure. In preclinical models, hyperfractionated low-dose RT sensitizes PC cells to G and erlotinib. We thus initiated a Phase I trial combining hyperfractionated low-dose RT combined with full dose G and a tyrosine kinase inhibitor, E, in the treatment of patients with advanced PC. Methods: Patients (pts) with locally advanced or metastatic PC confined to the abdomen and an ECOG performance status (PS) of 0-1, who had received 0-1 prior regimens (without G or E) and no prior RT were enrolled to successive cohorts in a 3+3 design. Patients were treated in 21 day cycles with G IV days 1 &amp; 8, E once PO QD, and twice daily RT fractions separated by at least 4 hours on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Dosing cohorts were as follows (G in mg per m2, E in mg, XRT/fraction in cGy): 1 (1,000, 100, 40), 2 (1,000, 100, 50), 3 (1,000, 100, 60), 4 (1,000, 150, 60). Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Results: A total of 27 pts, (median age 64 yrs and 15 male), were enrolled between 11/24/08 and 4/12/12. 17 patients had a PS of 1. The majority of patients were stage IV. Seven pts were enrolled in dose level 1, with 1 pt experiencing a DLT of grade 3 ileus, 3 pts enrolled each in dose levels 2-4 without DLT and 11 pts enrolled in the expanded portion of level 4. Best response by RECIST in 24 evaluable pts and was as follows: partial response 8, stable disease 15 and progressive disease 1. One pt initially found to be unresectable at surgery was subsequently resected with only minimal microscopic residual disease. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Conclusions: This phase I study combining low-dose hyperfractionated RT as a sensitizer to full dose G plus E was well tolerated with the majority of pts experiencing either a partial response or stable disease. This represents a novel strategy worthy of further investigation in pts with advanced PC. Clinical trial information: NCT00761345.

Is there a survival advantage of incomplete resection of non-small-cell lung cancer that is found to be unresectable at thoracotomy?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: in patients with non-small-cell lung cancer that is found to be unresectable at thoracotomy, is incomplete resection superior for achieving survival advantage? Altogether more than 400 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. In total, data from an estimated 1083 patients were analysed. Three-year survival rates varied from 0 to 22% in incomplete resection and from 0 to 10% in exploratory thoracotomy. Median survival ranged from 6.5 to 19.1 months in incomplete resection and from 5.3 to 17 months in exploratory thoracotomy. The majority of studies (8/9) found survival in incomplete resection to be superior. However, only 3/9 studies presented statistical analysis of results. The largest of these found superior postoperative survival in incomplete resection (including residual nodal disease), one study showed a significant survival difference for R1 but not R2 resection and another with small patient numbers (n = 29) found no significant difference. We conclude that the best evidence suggests that there may be a survival advantage from incomplete resection of non-small-cell lung cancer when there is microscopic (R1) or nodal residual disease, but not when macroscopic residual (R2) disease remains.

The Impact of Preradiation Residual Disease Volume on Time to Locoregional Failure in Cutaneous Merkel Cell Carcinoma—A TROG Substudy

This study evaluated the impact of margin status and gross residual disease in patients treated with chemoradiation therapy for high-risk stage I and II Merkel cell cancer (MCC). Data were pooled from 3 prospective trials in which patients were treated with 50 Gy in 25 fractions to the primary lesion and draining lymph nodes and 2 schedules of carboplatin based chemotherapy. Time to locoregional failure was analyzed according to the burden of disease at the time of radiation therapy, comparing patients with negative margins, involved margins, or macroscopic disease. Analysis was performed on 88 patients, of whom 9 had microscopically positive resection margins and 26 had macroscopic residual disease. The majority of gross disease was confined to nodal regions. The 5-year time to locoregional failure, time to distant failure, time to progression, and disease-specific survival rates for the whole group were 73%, 69%, 62%, and 66% respectively. The hazard ratio for macroscopic disease at the primary site or the nodes was 1.25 (95% confidence interval 0.57-2.77), P=.58. No statistically significant differences in time to locoregional failure were identified between patients with negative margins and those with microscopic or gross residual disease. These results must, however, be interpreted with caution because of the limited sample size.

Revisiting the Role of Radiation Treatment for Non-serous Subtypes of Epithelial Ovarian Cancer

Except for its palliative use, radiation has been largely abandoned in the management of ovarian cancers because of the recognized efficacy of chemotherapy agents. Whole abdominal irradiation (WAR), however, has been shown to be of adjuvant and curative value in ovarian cancer with microscopic or minimal residual disease in the pelvis, the so-called "intermediate risk group." Recent hypothesis generating data from the use of adjuvant radiation following adjuvant chemotherapy in ovarian cancer has shown an incremental survival benefit for the rarer non-serous ovarian subtypes including clear cell, endometrioid, and mucinous. No incremental benefit was observed for the more common serous subtype. A retrospective examination of early trials using WAR as the sole postoperative treatment in ovarian cancer has determined that the majority of patients in these studies and cured by radiation actually had the non-serous subtypes. The recognition that the non-serous subtypes differ from the serous cancers in their stage of presentation, their molecular characteristics, their response to classic chemotherapy, and their outcomes suggest the non-serous subtypes should be treated as rare and different cancers. In addition to specific targeting therapies that may be developed, radiation should be reconsidered as part of the treatment armamentarium for these diseases.

Abstract P5-16-04: A phase I study of a DNA plasmid based vaccine encoding the HER-2/neu intracellular domain in subjects with HER2+ breast cancer.

Abstract HER2+ breast cancer (BC) is associated with early disease relapse, usually to distant sites. This would suggest relapse is due to residual microscopic disease. Generation of vaccine-induced HER2-specific CD4+ T helper immunity (Th1) may result in immunologic eradication of residual HER2+ tumor cells and subsequent development of immunologic memory and epitope spreading (ES), which has been associated with a survival benefit in vaccinated BC patients. We have shown HER2 peptide-based vaccines can generate immunity in BC however, more recently we developed a plasmid DNA based vaccine (pNGVL3-hICD) which may have additional advantages over synthetic peptides. DNA vaccines offer a strategy to immunize against multiple tumor antigens and are able to elicit both CTL and Th1 immunity. Plasmid DNA can also remain at the vaccine site, providing a constant source of antigen. Intradermal (i.d.) delivery of DNA vaccines with GM-CSF as adjuvant may enhance immunogenicity due to local influx of dermal Langerhans cells. We have recently completed a phase I trial utilizing pNGVL3-hICD in optimally treated stage III and IV HER2+ BC patients and have defined vaccine safety profile, optimal dose and schedule; and demonstrated vaccine biologic activity. Methods: A total of 66 subjects with stage III and IV HER2+ BC in complete remission were enrolled sequentially into 1 of 3 pNGVL3-hICD dose arms (22 subjects/arm): Arm 1=10µg, Arm 2=100 µg, and Arm 3 = 500µg. All vaccines were admixed with 100µg GM-CSF and given i.d. monthly for a total of 3 vaccines. Toxicity was assessed at baseline, during vaccination and at follow-up. Immune responses to HER ICD and ECD were assessed with IFN-γ ELISPOT at baseline and serially through week 60 post-vaccination. Linear regression analysis was used to compare differences in immune responses from baseline over the whole study period between dose arms. Vaccine site skin biopsies and peripheral lymphocytes were serially analyzed for plasmid persistence via RT-PCR. Results: 64 subjects (20 in Arm 1; 22 in Arm 2; 22 in Arm 3) completed 3 vaccines. Age, stage/status, number of previous chemotherapy regimens, and use of bisphosphonate and trastuzumab therapies was similar across dose arms. Vaccine-related toxicity was primarily Grade 1/2 injection site reactions, myalgias, arthralgias and not significantly different between arms; no cardiac or grade IV toxicity was observed. Immune responses to HER2 ICD were significantly better in Arms 2 and 3 vs Arm 1 (p = 0.001 and 0.002, respectively) but not statistically different between Arms 2 and 3. 38 patients had DNA plasmid persistence at the vaccination site with no difference between arms. There has been no detection of DNA plasmid in lymphocytes from patients in all arms. Analyses of survival and ES (HER ECD immune responses) are on-going and will be presented. Conclusions: pNGVL3-hICD was safe and effectively induced persistent HER2 ICD specific Th1 immunity without increased cardiac toxicity. Moreover, immunity was present more than 1 year after end of vaccination, indicative of vaccine-induced immunologic memory. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-04.

Intraoperative EBRT and resection for renal cell carcinoma

We report the outcomes of a multimodality treatment approach combining maximal surgical resection and intraoperative electron radiotherapy (IOERT) with or without external beam radiation therapy (EBRT) in patients with locoregionally (LR) recurrent renal cell carcinoma (RCC) after radical nephrectomy or LR advanced primary RCC. From 1983 to 2008, 25 patients with LR recurrent (n = 10) or LR advanced primary (n = 15) RCC were treated with this approach. Median patient age was 60 years (range, 16-79 years). Fifteen patients (60%) received perioperative EBRT (median dose, 44 Gy). Surgical resection was R0 (negative margins) in 6 patients (24%) and R1 (residual microscopic disease) in 19 patients (76%). The median dose of IOERT was 14 Gy (range, 9-15). Overall survival (OS) and relapse patterns were calculated using the Kaplan-Meier method. Median follow-up for surviving patients was 22.2 years (range, 3.6-26 years). OS and DFS at 5 and 10 years were 38% and 18% and 19% and 14%, respectively. LR control (tumor bed or regional lymph nodes) and distant metastases-free survival rates at 5 years were 80% and 22%, respectively. The death rate within 30 days of surgery and IOERT was 4% (n = 1). Six patients (24%) experienced acute or late toxicities of grade 3 or higher according to the National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) v4. In patients with LR recurrent or LR advanced primary RCC, a multimodality approach consisting of maximal surgical resection and IOERT with or without adjuvant EBRT yielded encouraging local control results, justifying further evaluation.

Intraoperative high-dose-rate brachytherapy using dose painting technique: Evaluation of safety and preliminary clinical outcomes

Intraoperative radiation therapy (IORT) allows delivery of tumoricidal doses of radiation to areas of potential residual microscopic disease while minimizing doses to normal tissues. IORT using high-dose-rate (HDR) brachytherapy allows dose modulation and delivery of concomitant boosts to high-risk areas. This study describes a novel technique of HDR-IORT with dose painting (DP) (HDR-IORT-DP) and evaluates the clinical outcomes. Sixteen patients with recurrent cancers received HDR-IORT-DP at the time of radical resection. Of these patients, 13 had colorectal cancer, 2 had head and neck cancer, and 1 had a gynecologic malignancy. All received external beam radiation previously. Negative margin (R0) was obtained in 12 patients (75%) and microscopically positive margins (R1) in 4 patients (25%). The median total target and boost area were 45 and 8.5cm(2), and HDR-IORT and boost dose were 1500 and 1750cGy, respectively. Median followup was 14.9 months. The 2-year local control and overall survival were 80% and 20%, respectively. Eleven patients (69%) developed distant metastasis and were deceased at the time of the last followup. A total of 13 patients (19%) developed Grade 3 toxicity related to HDR-IORT; no grade 4+ toxicities were observed. HDR-IORT-DP technique is feasible, safe, and allows for dose escalation in locally advanced or recurrent previously irradiated tumors. To our knowledge, this is the first clinical report on HDR-IORT-DP. Further studies are warranted to evaluate efficacy in a larger patient cohort. Local control was encouraging in our patients.

Results of Second-Look Laparotomy in Advanced Ovarian Cancer: One Single Center Experience

Objective. The goal of the study was to analyse the results of 85 cases of second-look laparotomy (SLL) and explore the influence of this procedure on survival. Patients and Methods. We reviewed retrospectively 85 cases of SLL collected and treated in our institute between 1994 and 2003. Results. Complete pathologic response (CPR) was 25.8%, microscopic disease (Rmicro) was 38.8%, and macroscopic disease (Rmacro) was 35.4%. In patients with negative SLL results, disease recurrence was diagnosed in 41%. The 3- and 5-year overall survival rates for the entire population were 91% and 87%, respectively. The 3- and 5-year disease-free survivals were, respectively, 76.3% and 58.5% in negative SLL versus 55.7% and 16% in positive SLL. The difference between the group of patients with complete response (76%) and the patients with residual microscopic disease (72%) was not significant. The tumoral residuum after initial surgery was the only prognostic factor influencing significantly the disease-free survival. On Cox regression model analysis, only initial tumoral residuum (P = 0.04) and tumoral residuum after SLL (P = 0.02) were independent prognostic factors for survival. Conclusions. The most important advantage of SLL is the early detection of recurrence and thus the early administration of consolidation treatment resulting in a better prognosis.

Tissue Tolerable Plasma (TTP) induces apoptosis in pancreatic cancer cells in vitro and in vivo

BackgroundThe rate of microscopic incomplete resections of gastrointestinal cancers including pancreatic cancer has not changed considerably over the past years. Future intra-operative applications of tissue tolerable plasmas (TTP) could help to address this problem. Plasma is generated by feeding energy, like electrical discharges, to gases. The development of non-thermal atmospheric plasmas displaying spectra of temperature within or just above physiological ranges allows biological or medical applications of plasmas.MethodsWe have investigated the effects of tissue tolerable plasmas (TTP) on the human pancreatic cancer cell line Colo-357 and PaTu8988T and the murine cell line 6606PDA in vitro (Annexin-V-FITC/DAPI-Assay and propidium iodide DNA staining assay) as well as in the in vivo tumour chorio-allantoic membrane (TUM-CAM) assay using Colo-357.ResultsTTP of 20 seconds (s) induced a mild elevation of an experimental surface temperature of 23.7 degree Celsius up to 26.63+/−0.40 degree Celsius. In vitro TTP significantly (p=0.0003) decreased cell viability showing the strongest effects after 20s TTP. Also, TTP effects increased over time levelling off after 72 hours (30.1+/−4.4% of dead cells (untreated control) versus 78.0+/−9.6% (20s TTP)). However, analyzing these cells for apoptosis 10s TTP revealed the largest proportion of apoptotic cells (34.8+/−7.2%, p=0.0009 versus 12.3+/−6.6%, 20s TTP) suggesting non-apoptotic cell death in the majority of cells after 20s TTP. Using solid Colo-357 tumours in the TUM-CAM model TUNEL-staining showed TTP-induced apoptosis up to a depth of tissue penetration (DETiP) of 48.8+/−12.3μm (20s TTP, p<0.0001). This was mirrored by a significant (p<0.0001) reduction of Ki-67+ proliferating cells (80.9+/−13.2% versus 37.7+/−14.6%, p<0.0001) in the top cell layers as well as typical changes on HE specimens. The bottom cell layers were not affected by TTP.ConclusionsOur data suggest possible future intra-operative applications of TTP to reduce microscopic residual disease in pancreatic cancer resections. Further promising applications include other malignancies (central liver/lung tumours) as well as synergistic effects combining TTP with chemotherapies. Yet, adaptations of plasma sources as well as of the composition of effective components of TTP are required to optimize their synergistic apoptotic actions.

P7. A multidisciplinary onco-plastic approach for management of chest wall tumours

P7. A multidisciplinary onco-plastic approach for management of chest wall tumours

MIS3-5 - Fluorodeoxyglucose Positron Emission Tomography for Evaluating Early Response During Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma

ABSTRACT Background To determine whether fluorodeoxyglucose positron emission tomography (FDG-PET) could differentiate between responding and non-responding locally advanced esophageal squamous cell carcinoma (ESCC) early in the course of neoadjuvant chemoradiotherapy (CRT). Methods Patients with T3 or N1M0-1a (AJCC, 6th ed.) ESCC first received a 21-day cycle of induction CT with paclitaxel, cisplatin, 5-FU/leucovorin D 1, 8). This was followed by concurrent paclitaxel, cisplatin CRT (Lin CC et al. Ann Oncol 18: 93; 2007). When the accumulated RT dose reached 40 Gy, the feasibility of esophagectomy was evaluated. In patients for whom esophagectomy was not feasible, CCRT was continued to a dose of 60 Gy. Serial FDG-PETs were carried out before and 14 days after the start of induction CT. Pathologic response (PR) was defined as no or microscopic residual disease. PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic (ROC) analysis was used to evaluate the SUV ability in distinguishing between PR and non-PR. Results Of 65 patients (M:F = 60:5, median age 55, range 39–71) with locally advanced (M0:M1a = 58:7) ESCC enrolled from March 2008 to December 2011, 40 patients underwent esophagectomy and 26 patients were pathologic responders. The median SUV decrease 140 days after the start of therapy was 75.8% for pathologic responders and 30.1% for non-responders (P Conclusions A 35% SUV decrease 14 days after the start of induction CT is significantly associated with PR, but its accuracy in detecting non-responders is too low to justify the clinical use of FDG-PET for early discontinuation of neoadjuvant CRT in patients with locally advanced ESCC.

Accelerated Partial Breast Irradiation: A Review and Description of an Early North American Surgical Experience with the Intrabeam Delivery System

Targeted intraoperative radiation therapy (IORT) as an alternative to whole breast irradiation (WBI) has been described for patients with early-stage breast cancer. The randomized phase III TARGiT trial demonstrated similar recurrence rates to WBI and a lower overall toxicity profile on short-term follow-up. We report on our early North American surgical experience using the Intrabeam radiotherapy delivery system and review the current literature. Prospectively gathered estrogen receptor-positive, clinically node-negative patients with invasive breast cancer < 3 cm receiving IORT using the Intrabeam system were reviewed. IORT-related effects and early postoperative outcome were assessed. A literature review was also performed. Forty-two patients (median age 71 years) underwent lumpectomy, sentinel lymph node (SLN) biopsy, and concurrent IORT from January 2011 to July 2011. Ninety-one percent of patients had invasive ductal histology with a median tumor size of 1.0 cm. This review highlights the patient selection criteria, describes commercially available accelerated partial breast irradiation (APBI) treatment options, and discusses outcomes for the variety of APBI techniques currently utilized in clinical practice as well as an institutional review of our early surgical experience using the Intrabeam radiotherapy delivery system. While a variety of APBI techniques are currently available for clinical use, our early North American operative experience with IORT shows it is well tolerated with low morbidity. Delivery of IORT adds moderate operative time and may require creating subcutaneous tissue fl aps. The addition of WBI may be necessary in situations for positive residual margins or microscopic nodal disease in patients who do not undergo additional surgery.

Towards an integrated molecular and clinical strategy to predict early recurrence in surgically resected non-functional pituitary adenomas

Pituitary adenomas (PA) are histologically benign tumors of the sella that are capable of recurrence following resection. No mechanism exists to predict accurately the risk of recurrence in patients with PA following successful gross total surgical resection. We used microarray-based gene expression profiling to search for genotypically distinct subgroups of non-functional PA associated with the early recurrent phenotype. Rigorous phenotypic controls were used to select four patients with PA with early (<12months) recurrence and seven patients with non-recurrent PA for comparative molecular analysis. Seventy genes with differential expression patterns between the phenotypic groups were identified, although this required some relaxation of rigid multiple-testing corrections. While some of these genes may therefore represent statistical false discoveries attributable to limited sample size, the CHL1 gene has a differential expression patterns that suggests a potential role as a predictor of recurrence phenotype. Transcriptome-level differences between early recurrent and non-recurrent non-functional PA appear to be subtle, although CHL1 expression may be a candidate for further study as a class discriminator. This suggests two possibilities with regard to recurrence; (i) that microscopic residual disease unidentifiable either by the surgeon or by current neuroimaging strategies may serve as a focus for early recurrence or that biological differences in recurrence phenotypes may occur outside of the transcriptome. These findings are useful for focusing future investigations into the clinical and biological mechanisms of PA recurrence as well as for development of strategies designed to predict prospectively these recurrence phenotypes.

Gastrointestinal stromal tumor: Our experience

Gastrointestinal stromal tumor: Our experience

Imaging Cutaneous Head and Neck Cancer with Panitumumab‐IRDye

Objective: To determine if intraoperative, real-time fluorescence imaging hardware (SPY System, Novadaq, Toronto, Canada) and lab-based fluorescence optical imaging of histological sections (Odyssey scanner, LiCor) are capable of detecting micrometastatic cutaneous squamous cell carcinoma (SCC) in preclinical models. Method: An NIR fluorescent probe (IRDye800) was covalently linked to a monoclonal antibody targeting EGFR (panitumumab) or non-specific IgG and injected into mice bearing flank xenografts derived from a cutaneous SCC cell line (SCC-13). The primary tumor and regional lymph nodes were imaged and dissected using fluorescence guidance with the SPY system and verified with a charge-coupled NIR system (Pearl). An NIR charged-coupled device (Odyssey) was used to measure fluorescence intensity of cut sections of tumor and were confirmed with immunohistochemical staining (cytokeratin, CD147). Results: Tumors were clearly delineated from normal tissue with tumor-to-background ratios of 4.5 (Pearl) and 3.4 (SPY). Disease detection was significantly improved with panitumumab-IRDye compared to IgG-IRDye800 ( P &lt; .05). Tissue biopsies positive for fluorescence were confirmed for pathologic disease by histology and immunohistochemistry (n = 10/10); while biopsies of non-fluorescent tissue were proven to be negative for malignancy (n = 12/12). The SPY system was able to detect regional lymph node metastasis (&lt;1.0 mm) and microscopic areas of disease as small as 200 micrometers in diameter. Additionally, the Odyssey successfully detected residual microscopic disease in both frozen and paraffin-embedded histologic specimens. Conclusion: These data suggest that panitumumab-IRDye800 may have clinical utility in detection and removal of cutaneous SCC using existing optical imaging hardware. This technique may prove useful in the detection of microscopic disease grossly and in histological sections.

The Timing of Salvage Radiotherapy After Radical Prostatectomy: A Systematic Review

Salvage radiotherapy (SRT) after radical prostatectomy can potentially eradicate residual microscopic disease. Defining the optimal patient and treatment factors is essential and is particularly relevant within the context of adjuvant vs early vs delayed postoperative radiotherapy (RT). A systematic review of all published SRT studies was performed to identify the pathologic, clinical, and treatment factors associated with relapse-free survival (RFS) after SRT. A total of 41 studies encompassing 5597 patients satisfied the study entry criteria. Radiobiologic interpretation of biochemical tumor control was used to provide the framework for the observed relationships. Prostate-specific antigen (PSA) level before SRT (P<.0001) and RT dose (P=.0052) had a significant and independent association with RFS. There was an average 2.6% loss of RFS for each incremental 0.1 ng/mL PSA at the time of SRT (95% CI, ∼2.2-3.1). With a PSA level of 0.2 ng/mL or less before SRT, the RFS approached 64%. The dose for salvage RT in the range of 60-70 Gy seemed to be on the steep part of the sigmoidal dose-response curve, with a dose of 70 Gy achieving 54% RFS compared with only 34% for 60 Gy. There was a 2% improvement in RFS for each additional Gy (95% CI, ∼0.9-3.2). The observed dose-response was less robust on sensitivity analysis. This study provides Level 2a evidence for initiating SRT at the lowest possible PSA. Dose escalation is also suggested by the data. Progressively better tumor control rates with SRT after radical prostatectomy are achieved with a lower PSA at initiation and with a higher RT dose. Early salvage RT may be an equivalent strategy to adjuvant RT.