Local Tumor Response Research Articles

Abstract B29: High tumor PI3K signaling in resistance to chemoradiotherapy and metastatic dissemination of locally advanced rectal cancer

Abstract Hypoxia is an important hallmark of the tumor microenvironment and a main mechanism in tumor resistance to cytotoxic therapy, local recurrence, and metastatic progression. Locally advanced rectal cancer (LARC) comprises heterogeneous tumors with predominant hypoxic components, growing with locally advanced disease manifestations within the pelvic cavity. Despite the introduction of multimodal therapy, primarily the combination of surgery and radiation that frequently results in local control, a substantial number of patients will experience metastatic dissemination. A rational integration of molecularly targeted therapies in combined-modality regimens might cause both improvement of local control in remaining poor-responding patients and reduction in metastasis risk. This strategy, however, will require a clear definition of functional biomarkers for risk assessment and treatment stratification, and technologies comprising the resultant condition of interacting tumor signaling effects may be particularly advantageous. Within this frame of reference, kinase substrate array technologies are tools for global profiling of kinase activities in tissue samples without prior knowledge of which signaling pathways are activated, theoretically portraying the state of composite information flow through signaling cascades. The present work summarizes our experiences from a prospective study of LARC patients given neoadjuvant chemotherapy and radiation followed by surgery and no further treatment (NCT00278694). Using kinase substrate arrays to analyze study patients' tumor biopsies sampled at the time of diagnosis, we hypothesized that the approach might enable identification of potentially actionable therapy targets implicated in hypoxic tumor signaling. At first, tumor phosphorylation of array substrates was correlated to histologic tumor response to the neoadjuvant treatment. Essentially, patients with poor response had significantly elevated tumor kinase activity, representing signaling mediated by VEGFR, EGFR, and PI3K, compared to good-responding patients. Next, it appeared that phosphorylation of array substrates representing PDGFR was strongly inhibited by the addition of the anti-angiogenic agent sunitinib to tumor samples from patients without detectable tumor cells in the bone marrow at the time of diagnosis. The recognition that PDGFR-mediated signaling is central for maturation of pericytes during angiogenesis makes it tempting to speculate that intact pericytic signaling of the tumor vasculature is associated with low likelihood of early systemic tumor dissemination in LARC. Finally, unsupervised clustering analysis of the array phosphosubstrate data separated the tumor samples into two phenotypic populations. The smaller of the patient groups, displaying high tumor activities within the PI3K signaling network, showed a particularly aggressive disease course as almost a half of cases had developed metastatic disease by less than one year of follow-up, suggesting a functional biomarker for rapid failure of metastatic disease control following radical treatment of the pelvic cavity. Given our findings that PI3K may be a key signaling orchestrator both of poor local tumor response to neoadjuvant treatment and importantly, of metastatic development, therapeutic targeting of components of the PI3K complex might be rational to integrate into combined-modality treatment regimens in LARC with hypoxic tumor features. Citation Format: Anne Hansen Ree, Kjersti Flatmark, Marie Gron Saelen, Sigurd Folkvord, Svein Dueland, Jurgen Geisler, Kathrine Roe. High tumor PI3K signaling in resistance to chemoradiotherapy and metastatic dissemination of locally advanced rectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B29.

A novel strategy of radiofrequency hyperthermia (neothermia) in combination with preoperative chemoradiotherapy for the treatment of advanced rectal cancer: a pilot study.

The safety of weekly regional hyperthermia performed with 8 MHz radiofrequency (RF) capacitive heating equipment has been established in rectal cancer. We aimed to standardize hyperthermia treatment for scientific evaluation and for assessing local tumor response to RF hyperthermia in rectal cancer. Forty-nine patients diagnosed with rectal adenocarcinoma were included in the study. All patients received chemoradiation with intensity-modulated radiation therapy 5 days/week (dose, 50 Gy/25 times) concomitant with 5 days/week for five times of capecitabine (1700 mg/m2 per day) and once a week for five times of 50 min irradiations by an 8 MHz RF capacitive heating device. Thirty-three patients underwent surgery 8 weeks after treatment. Three patients did not undergo surgery because of progressive disease (PD) and 13 refused. Eight (16.3%) patients had a pathological complete response (ypCR) after surgery. Among patients without surgery, 3 (6.1%) had clinical complete response (CR) and 3 (6.1%) had local CR but distant PD (CRPD). Ninety percent of ypCR + CR patients were shown in 6.21 W min−1 m−2/treatment or higher group of average total accumulated irradiation output with 429°C min−1 m−2 or higher group of total accumulated thermal output. However, a patient with CRPD was in the higher total accumulated thermal output group. We propose a new quantitative parameter for the hyperthermia and demonstrated that patients can benefit from mild irradiation with mild temperature. Using these parameters, the exact output, optimal thermal treatment, and contraindications or indications of this modality could be determined in a multi-institutional, future study.

Comparison of Combination Therapies in the Management of Hepatocellular Carcinoma: Transarterial Chemoembolization with Radiofrequency Ablation versus Microwave Ablation

PurposeTo compare retrospectively the outcomes and complications of transcatheter arterial chemoembolization with drug-eluting embolic agents combined with radiofrequency (RF) ablation or microwave (MW) ablation in treatment of hepatocellular carcinoma (HCC). Materials and MethodsFrom 2003–2011, 89 patients with HCC received a combination therapy—transcatheter arterial chemoembolization plus RF ablation in 38 patients and transcatheter arterial chemoembolization plus MW ablation in 51 patients. Local tumor response, tumor progression-free survival (PFS), overall PFS, overall survival (OS), and complications were compared. Overall PFS and OS were compared between the two treatment groups in multivariate analysis controlling for Child-Pugh class, Barcelona Clinic Liver Classification stage, and index tumor size. ResultsComplete local tumor response was achieved in 37 (80.4%) of the tumors treated with transcatheter arterial chemoembolization plus RF ablation and 49 (76.6%) of the tumors treated with transcatheter arterial chemoembolization plus MW ablation (P = .67). The median tumor PFS and overall PFS were 20.8 months and 9.3 months (P = .72) for transarterial chemoembolization plus RF ablation and 21.8 months and 9.2 months for transarterial chemoembolization plus MW ablation (P = .32). The median OS of the transcatheter arterial chemoembolization plus RF ablation group was 23.3 months, and the median OS of the transcatheter arterial chemoembolization plus MW ablation group was 42.6 months, with no significant difference in the survival experience between the two groups (log-rank test, P = .10). In the multivariate analysis, Barcelona Clinic Liver Classification stage was the only factor associated with overall PFS and OS. One patient in the transcatheter arterial chemoembolization plus RF ablation cohort (3%) and two patients in the transcatheter arterial chemoembolization plus MW ablation cohort (4%) required prolonged hospitalization (< 48 h) for pain management after the procedure (P = 1.00). ConclusionsBased on similar safety and efficacy outcomes, both combination therapies, transcatheter arterial chemoembolization plus RF ablation and transcatheter arterial chemoembolization plus MW ablation, are effective treatments for HCC.

Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma.

Background:Transcatheter arterial chemoembolisation (TACE) is the treatment of choice for intermediate stage hepatocellular carcinoma (HCC). Doxorubicin-loaded drug-eluting beads (DEB)-TACE is expected to improve the performance of conventional TACE (cTACE). The aim of this study was to compare DEB-TACE with cTACE in terms of time-to-tumour progression (TTP), adverse events (AEs), and 2-year survival.Methods:Patients were randomised one-to-one to undergo cTACE or DEB-TACE and followed-up for at least 2 years or until death. Transcatheter arterial chemoembolisation was repeated ‘on-demand'.Results:We enrolled 177 patients: 89 underwent DEB-TACE and 88 cTACE. The median number of procedures was 2 in each arm, and the in-hospital stay was 3 and 4 days, respectively (P=0.323). No differences were found in local and overall tumour response. The median TTP was 9 months in both arms. The AE incidence and severity did not differ between the arms, except for post-procedural pain, more frequent and severe after cTACE (P<0.001). The 1- and 2-year survival rates were 86.2% and 56.8% after DEB-TACE and 83.5% and 55.4% after cTACE (P=0.949). Eastern Cooperative Oncology Group (ECOG), serum albumin, and tumour number independently predicted survival (P<0.05).Conclusions:The DEB-TACE and the cTACE are equally effective and safe, with the only advantage of DEB-TACE being less post-procedural abdominal pain.

Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis.

The aim of the present study was to evaluate the effect of bevacizumab on local tumor response and lung metastatic potential during boron neutron capture therapy (BNCT) and in particular, the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously administered bromodeoxyuridine (BrdU) to label all proliferating (P) tumor cells. The tumors were irradiated with thermal neutron beams following the administration of a 10B-carrier [L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)], with or without the administration of bevacizumab. This was further combined with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH, 40°C for 60 min). Immediately following the irradiation, cells from certain tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q cells and the total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days following irradiation, lung metastases were enumerated. Three days following bevacizumab administration, the sensitivity of the total tumor cell population following BPA-BNCT had increased more than that following BSH-BNCT. The combination with MTH, but not with nicotinamide, further enhanced total tumor cell population sensitivity. Regardless of the presence of a 10B-carrier, MTH enhanced the sensitivity of the Q cell population. Regardless of irradiation, the administration of bevacizumab, as well as nicotinamide treatment, demonstrated certain potential in reducing the number of lung metastases especially in BPA-BNCT compared with BSH-BNCT. Thus, the current study revealed that BNCT combined with bevacizumab has the potential to sensitize total tumor cells and cause a reduction in the number of lung metastases to a similar level as nicotinamide.

Significance of Fractionated Administration of Thalidomide Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis.

BackgroundThe aim of this study was to evaluate the significance of fractionated administration of thalidomide combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.MethodsB16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2’-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after thalidomide treatment through a single or two consecutive daily intraperitoneal administrations up to a total dose of 400 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated.ResultsThalidomide raised the sensitivity of the total cell population more remarkably than Q cells in both single and daily administrations. Daily administration of thalidomide elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases.ConclusionDaily fractionated administration of thalidomide in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential.

Primary peritoneal clear cell carcinoma treated with IMRT and interstitial HDR brachytherapy: a case report

Primary peritoneal clear cell carcinoma (PP‐CCC), which is a rare tumor with poor prognosis, is typically managed with surgery and/or chemotherapy. We present a unique treatment approach for a patient with a pelvic PP‐CCC, consisting of postchemotherapy intensity‐modulated radiation therapy (IMRT) followed by interstitial high‐dose–rate (HDR) brachytherapy. A 54‐year‐old female with an inoperable pelvic‐supravaginal 5.6 cm T3N0M0 PP‐CCC tumor underwent treatment with 6 cycles of carboplatin and taxol chemotherapy. Postchemotherapy PET/CT scan revealed a residual 3.3 cm tumor. The patient underwent CT and MR planning simulation, and was treated with 50 Gy to the primary tumor and 45 Gy to the pelvis including the pelvic lymph nodes, using IMRT to spare bowel. Subsequently, the patient was treated with an interstitial HDR brachytherapy implant, planned using both CT and MR scans. A total dose of 15 Gy in 5 Gy fractions over two days was delivered with Ir‐192 HDR brachytherapy. The total prescribed equivalent 2 Gy dose (EQD2) to the HDR planning target volume (PTV) from both the EBRT and HDR treatments ranged between 63 and 68.8Gy2 due to differential dosing of the primary and pelvic targets. The patient tolerated radiotherapy well, except for mild diarrhea not requiring medication. There was no patient‐reported acute toxicity one month following the radiotherapy course. At four months following adjuvant radiation therapy, the patient had near complete resolution of local tumor on PET/CT without any radiation‐associated toxicity. However, the patient was noted to have metastatic disease outside of the radiation field, specifically lesions in the liver and bone. This case report illustrates the feasibility of the treatment of a pelvic PP‐CCC with IMRT followed by interstitial HDR brachytherapy boost, which resulted in near complete local tumor response without significant morbidity.PACS number: 87.55.‐x

Intratumoral Mistletoe (Viscum album L) Therapy in Patients With Unresectable Pancreas Carcinoma

Pancreatic carcinoma remains one of the main causes for cancer-related death. Intratumoral application of anticancer agents is discussed as a promising method for solid tumors such as pancreatic cancer. Endoscopic ultrasound provides a good tool to examine and treat the pancreas. European mistletoe (Viscum album L) is a phytotherapeutic commonly used in integrative oncology in Central Europe. Its complementary use seeks to induce immunostimulation and antitumoral effects as well as alleviate chemotherapeutic side effects. Intratumoral mistletoe application has induced local tumor response in various cancer entities. This off-label use needs to be validated carefully in terms of safety and benefits. Here we report on 39 patients with advanced, inoperable pancreatic cancer, who received in total 223 intratumoral applications of mistletoe, endoscopic ultrasound guided or under transabdominal ultrasound control. No severe procedure-related events were reported. Adverse drug reactions were mainly increased body temperature or fever in 14% and 11% of the applications, respectively. Other adverse drug reactions, such as pain or nausea, occurred in less than 7% of the procedures. No severe adverse drug reaction was recorded. Patients received standard first- and second-line chemotherapy and underwent adequate palliative surgical interventions as well as additive subcutaneous and partly intravenous mistletoe application. A median survival of 11 months was observed for all patients, or 11.8 and 8.3 months for stages III and IV, respectively. Due to the multimodal therapeutic setting and the lack of a control group, the effect of intratumoral mistletoe administration alone remains unclear. This retrospective analysis suggests that intratumoral-applicated mistletoe might contribute to improve survival of patients with pancreatic cancer. In conclusion, the application is feasible and safe, and its efficacy should be evaluated in a randomized controlled trial.

Abstract OT2-1-02: Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases

Abstract Background/Rationale: To assess the immune and systemic anti-tumor effects of the novel combination of local radiotherapy combined with imiquimod applied topically to breast cancer metastatic to skin. Breast cancer is the most common tumor, excluding melanoma, to metastasize to the skin in women. Chest wall recurrence is debilitating for patients, substantially affecting quality of life. Current treatment modalities for unresectable lesions are rarely curative and patients ultimately die of visceral metastases, indicating the need for more effective therapies. Imiquimod (IMQ), a synthetic TLR-7 agonist has immunomodulatory activity with profound effects on the tumor environment and can lead to tumor regression of cutaneous breast cancer metastases (Adams et al, Clin Ca Res, Dec 15, 2012). Accumulating evidence indicates that the potential of local radiotherapy to convert the tumor into an in-situ vaccine can be enhanced by combination with immunotherapy to achieve a therapeutic synergy. We have previously shown in a mouse model of cutaneous breast cancer that topical IMQ synergizes with local RT to induce complete tumor regression (REF). Importantly, this approach used a local treatment to generate anti-tumor immune responses with ability to control the tumor systemically (Dewan et al, Clin Ca Res Dec 15, 2012). This trial was designed to test the feasibility of translating this therapeutic synergy in the clinic (clinicaltrials.gov NCT01421017). Methods: Eligibility includes patients with biopsy-confirmed breast cancer, measurable disease and skin metastases, ECOG PS 0-2 and adequate organ/marrow function. Radiation therapy is delivered to one area of skin metastases in five fractions of 6 Gy (days 1,3,5,8,10). IMQ 5% cream is applied topically to skin metastases overnight for 5 days/week for 8 weeks, beginning the evening of the first radiotherapy. Continuous imiquimod to all skin metastases even after completion of RT is based on our preclinical evidence of an improved effector phase of the immune response. Additional treatment cycles with IMQ/RT are permitted. Following a brief phase I portion to allow dose optimization in the event of unanticipated adverse events (3-3 design), the phase II study evaluates efficacy with a planned additional 25 patients. Primary endpoint is the response rate in untreated metastases, assessed by immune-related response criteria. Furthermore, the local tumor responses and safety of the combination will be determined; tumor FNA biopsies will be obtained to investigate signatures of immune-mediated rejection as recently described with IMQ mediated rejection of basal cell carcinomas; and peripheral lymphocytes will be examined for the induction/boosting of selected tumor antigen-specific T and B cell responses. The phase I portion has been successfully completed with 6 patients without DLT. Enrollment into the phase II portion has begun. At present, a total of 11 patients have been enrolled. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-1-02.

Degradable Starch Microspheres versus Ethiodol and Doxorubicin in Transarterial Chemoembolization of Hepatocellular Carcinoma

PurposeTo compare outcomes of transarterial chemoembolization with degradable starch microspheres (DSMs) and conventional transarterial chemoembolization with doxorubicin and Ethiodol in patients with unresectable intermediate-stage hepatocellular carcinoma (HCC). Materials and MethodsA total of 69 patients underwent 169 chemoembolization procedures with Ethiodol (n = 35) or DSMs (n = 34) as the embolic agent. The same chemotherapeutic agent was used for all patients (50 mg doxorubicin). The primary endpoint was patient survival, and secondary endpoints were local tumor response and incidence of therapy-associated complications with conventional or DSM chemoembolization. Tumor response was evaluated by consensus reading by two radiologists in accordance with modified Response Evaluation Criteria In Solid Tumors. Mean survival was calculated according to Kaplan–Meier analysis, and differences in survival curves were assessed by univariate log-rank test. The statistical significance of quantitative variables was determined by parameter-free Wilcoxon–Mann–Whitney U test. ResultsThe study groups were similar with regard to demographic data and disease stage. For the DSM chemoembolization group, the objective response rate (ie, complete or partial response) was 44.1%, and the rate of stable disease was 38.2%. The respective rates for the conventional chemoembolization group were 48.6% and 31.4%. Mean survival (P = .337) and complications did not significantly differ between groups (P = .907; P = 1.000). ConclusionsDSM chemoembolization represents an alternative method of HCC treatment with a safety profile similar to that of conventional transarterial chemoembolization. Regarding local tumor response and overall survival, results of DSM chemoembolization were similar to those of conventional chemoembolization.

Significance of Daily Fractionated Administration of Wortmannin Combined With Gamma-Ray Irradiation in Terms of Local Tumor Response and Lung Metastatic Potential

To evaluate the usefulness of fractionated administration of wortmannin combined with gamma-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.

Automated Cosegmentation of Tumor Volume and Metabolic Activity Using PET-CT in Non-Small Cell Lung Cancer (NSCLC)

Purpose/Objective(s): This study presents a novel computer-aided, automatic contouring (co-segmentation) gross target volume (GTV) that integrates tumor boundaries on both PET and CT through a globally optimal graph-based algorithm. Metabolic TV (MTV) was developed by integration of co-segmented tumor boundaries and metabolic activities as a tumor response metric. Materials/Methods: Records of 649 lung cancer patients were reviewed. Patients with stage III/IV NSCLC who received chemotherapy and lung radiation and had PET-CT imaging for simulation and PET-CT/CT at 2-4 months follow-up post-radiation were included. A total of 19 patients fulfilled the criteria. Post-treatment residual GTV (post-GTV) was retrospectively contoured by physician. A co-segmented GTV was generated on pretreatment PET-CT. MTV was defined as co-segmented GTV times mean SUV. As tumor response metrics, co-segmented GTV, co-segmented MTV, and mean SUV were generated on pretreatment dataset and tested for correlation with a pre-treatment, physician contoured GTV (pre-GTV) that was used as a ground truth for comparison. Their correlations with physician’s contour were measured using spearman’s correlation coefficient. Linear regression was used to evaluate if the different metric was predictive of post-GTV. Tumor response after chemoradiation therapy was measured using preand post-GTV. Results: Co-segmented GTV and MTV significantly correlated with pre-GTV (p < 0.001). Co-segmented GTV (p < 0.0001), co-segmented MTV (p Z 0.0009), pre-GTV (p < 0.0001) significantly correlated with post-GTV. No significant correlation was found in mean SUV (p Z 0.74). The overall averaged tumor response rate after chemoradiation therapy in 2-4 months is 69.5% +/-19.2%. Squamous cell histology responded better by 20% compared to adenocarcinoma. Tumor response pattern was modeled as post-GTV Z 10.0 + 0.4*pre-GTV (R Z 0.68). Conclusions: Co-segmented GTV and MTV present significant correlations with physician’s manual contouring, showing potential as a tumor response evaluation tool for large scale clinical trials and daily clinical practice. Average local tumor response in 2-4 months for advanced stage NSCLC after chemoradiation therapy was 69.5%. Author Disclosure: H. Li: None. J. Bai: None. T. Abu Hejle: None. X. Wu: None. S. Bhatia: None. Y. Kim: None.

PET/CT-based metabolic tumour volume for response prediction of neoadjuvant chemoradiotherapy in oesophageal carcinoma

Neoadjuvant chemoradiotherapy is increasingly used in oesophageal cancer patients. In general, small tumours are associated with a survival benefit compared to large tumours. Little is known, however, about the relationship between initial tumour volume and response to chemoradiotherapy. Therefore, the aim of this study was to determine whether the pretherapy metabolic tumour volume (MTV) on diagnostic PET/CT in oesophageal cancer patients is correlated with response to chemoradiotherapy in the resection specimen. A consecutive series of patients underwent diagnostic PET/CT scanning prior to chemoradiotherapy and oesophagectomy. MTVs were determined on PET/CT and an automated tumour contour was generated using specified standard uptake value thresholds. Response to chemoradiotherapy was determined in the resection specimen according to the scoring system developed by Mandard et al. Patients were divided into different groups according to response to chemoradiotherapy. Between January 2008 and May 2011 a total of 115 patients underwent an oesophagectomy. The MTV determined on diagnostic PET/CT scans was available in 79 patients. Of these 79 patients, 30 (38 %) showed no residual tumour cells at the location of the primary tumour. Three of these patients presented with residual tumour cells in the lymph nodes; 27 patients (34 %) had a complete pathological response. There was a trend towards a better response in patients with a smaller MTV (p = 0.084). This study demonstrated a trend towards a correlation between response to chemoradiotherapy in oesophageal cancer patients and smaller MTVs as determined on diagnostic PET/CT prior to neoadjuvant chemoradiotherapy. However, tumour volumes overlapped between groups, indicating the need for multifactorial parameters as predictors. In addition, a complete local tumour response may be accompanied by residual disease in the regional lymph nodes.

Photodynamic therapy for hilar bile duct cancer: clinical evidence for improved tumoricidal tissue penetration by temoporfin

Photodynamic therapy (PDT) has been established for palliation of non-resectable hilar bile duct cancer (hBDC). Ablation of hBDC using porfimer (P-PDT) improves cholestasis and survival. However, the tumoricidal effect is confined to the inner 4 mm of the tumor wall. Here, we have studied whether temoporfin PDT (T-PDT) shows an efficient local response and an increased tumoricidal penetration depth. In the first stage of a phase-II trial (NCT01016002), eleven patients with hBDC (Bismuth III-IV) were treated with T-PDT plus stenting and 10 could be analyzed for local tumor response. T-PDT resulted in complete local response in n = 1 of 10 patients, partial response in n = 8 and no response in one patient (occluded right hepatic duct re-opened but positive for residual tumor cells) - indicating a tumoricidal efficacy of 90%. Four patients showed a tumoricidal depth of ≥7.5 mm. Cholestasis and palliation improved in 8 patients with an overall median survival of 18 (4.4-32.0) months after the first T-PDT. Adverse events were phototoxic skin reaction (n = 4), cholangitis (n = 3), and liver abscess (n = 3). T-PDT doubles the depth of the local tumor-ablative effect of P-PDT, is highly tumoricidal and is associated with similar rates of infectious complications and grade I and II skin phototoxicity.

Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases.

TPS3122 Background: To assess the local and systemic effects of the novel combination of local radiotherapy (RT) with imiquimod (IMQ) applied topically to breast cancer metastatic to skin, and measure immunologic correlates (clinicaltrials.gov NCT01421017). Breast cancer is the 2nd most common tumor to metastasize to the skin. Current therapies for unresectable skin lesions are rarely curative. Patients ultimately die of visceral metastases, necessitating more effective therapies. IMQ, a synthetic TLR-7 agonist has profound effects on the tumor immune microenvironment and can lead to regression of cutaneous breast cancer metastases (Adams, Clin Ca Res, 2012). The trial was designed based on accumulated data supporting the synergy of combined RT/immunotherapy (Formenti, JNCI, 2013), and pre-clinical data demonstrating the synergy of topical IMQ and local RT in a mouse model of mammary adenocarcinoma which ulcerates through the skin, and mimics a chest wall recurrence. In the mouse model, the combination was superior with complete regressions of the treated tumors, responses at untreated sites and improved survival (Dewan, Clin Ca Res, 2012). Methods: Eligibility: patients with biopsy-confirmed breast cancer, measurable disease and skin metastases, ECOG PS 0-2 and adequate organ/marrow function. RT is delivered to 1 area of skin metastases in 5 fractions of 6 Gy (days 1, 3, 5, 8, 10). IMQ cream is applied topically 5 nights/week for 8 weeks, beginning on day 1. Following a brief phase I portion to allow dose optimization in the event of unanticipated adverse events (3-3 design), the phase II study evaluates efficacy with 25 additional patients planned. Primary endpoint is the response rate in untreated distant metastases, assessed by immune-related response criteria. The local tumor responses and safety of the combination will also be determined; tumor biopsies will be studied for immune-mediated rejection signatures and peripheral lymphocytes for antigen-specific T and B cell responses. To date, 10 patients have been enrolled. The phase I portion has been successfully completed with 6 patients without DLT. Phase II enrollment has begun. Clinical trial information: NCT01421017.

Repetitive Chemoembolization of Hypovascular Liver Metastases from the Most Common Primary Sites

To evaluate tumor response in patients with hypovascular liver metastases from the most common primary sites treated with chemoembolization. Chemoembolization was performed in 190 patients (five groups) who had hypovascular liver metastases from the colon (n = 66), breast (n = 40), uveal malignant melanoma (n = 20), pancreas (n = 48) and stomach (n = 16). Surgical resection of primary sites had been performed for all included patients. Tumor response, survival statistics from the first chemoembolization using Kaplan-Meier method and progression rate of embolized lesions were evaluated by analysis of variance with Tukey's post hoc test. Multiple comparison between the groups showed no statistical significant difference in local tumor response (H: 9.23; p > 0.05). Survival indices of the patients, including survival rate, progression-free survival rate, median survival time and time to progression, demonstrated significant difference between the groups during the follow-up period (H: 9.7; p = 0.045). The progression rate of treated liver metastases from colon, breast, uvea, pancreas and stomach were 16.6, 17.5, 30.0, 25.0 and 32.0%, respectively (p = 0.002). Hypovascular liver metastases treated with chemoembolization may demonstrate equal local response, but are significantly different in rate of progression and survival.

Usefulness of Daily Fractionated Administration of Wortmannin Combined With gamma-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis

Background: To evaluate the usefulness of fractionated administration of wortmannin combined with gamma-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. Methods: B16-BL6 melanoma tumor-bearing C57BL / 6 mice were continuously given 5-bromo-2 ' -deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received gamma -ray irradiation after wortmannin treatment through a single or 4 consecutive daily intraperitoneal administrations up to a total dose of 4 mg / kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total ( = P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Results: Wortmannin raised the sensitivity of Q cells more remarkably than the total cell population in both single and daily administrations. Daily administration of wortmannin elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. Conclusion: Daily fractionated administration of wortmannin in combination with gamma -ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential. World J Oncol. 2013;4(1):26-36 doi: https://doi.org/10.4021/wjon640w

Transcatheter Arterial Embolization With Spherical Embolic Agent for Pulmonary Metastases From Renal Cell Carcinoma

This retrospective study aimed to evaluate the safety and local efficacy of transcatheter arterial embolization (TAE) with superabsorbent polymer microspheres (SAP-MS) in patients with pulmonary metastases from renal cell carcinoma (RCC). Sixteen patients with unresectable pulmonary metastases from RCC refractory to standard therapy were enrolled to undergo TAE with the purpose of mass reduction and/or palliation. The prepared SAP-MS swell to approximately two times larger than their dry-state size (100-150 μm [n = 14], 50-100 μm [n = 2]). Forty-nine pulmonary nodules (lung n = 22, mediastinal lymph node n = 17, and hilar lymph node n = 10) were selected as target lesions for evaluation. Local tumor response was evaluated 3 months after TAE according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The relationship between tumor enhancement ratio by CT during selective angiography and local tumor response was evaluated. The number of TAE sessions per patient ranged from 1 to 5 (median 2.9). Embolized arteries at initial TAE were bronchial arteries in 14 patients (87.5 %) and nonbronchial systemic arteries in 11 patients (68.8 %). Nodule-based evaluation showed that 5 (10.2 %) nodules had complete response, 17 (34.7 %) had partial response, 15 (30.6 %) had stable disease, and 12 (24.5 %) had progressive disease. The response rate was significantly greater in 22 lesions that had a high tumor enhancement ratio than in 27 lesions that had a slight or moderate ratio (90.9 vs. 7.4 %, p = 0.01). Severe TAE-related adverse events did not occur. TAE with SAP-MS might be a well-tolerated and locally efficacious palliative option for patients with pulmonary metastases from RCC.

Usefulness of FDG-PET in the evaluation of tumor response to proton beam therapy for locally advanced pancreatic ductal adenocarcinoma.

271 Background: Evaluation of tumor response to radiation therapy in pancreatic ductal adenocarcinoma (PDA) using conventional radiological tests is difficult due to generally small size and inflammatory or fibrotic changes of radiated tissue. Although increasing evidence has shown that 18-F-fluorodeoxyglucose-positoron emission tomography (FDG-PET) can assess functional changes in various tumors, available data in PDA with radiation therapy is scarce. In this study, we investigated the role of FDG-PET in long-term monitoring tumor response to proton beam therapy (PBT) for PDA. Methods: Thirty-four locally advanced PDA patients with pre- and post-PBT FDG-PET data were included in this study. Local tumor responses by computed tomography (CT) and FDG-PET were defined as below: response group in CT (complete response: CR, partial response: PR, stable disease: SD, progressive disease: PD) was defined according to Response Evaluation Criteria in Solid Tumors, but only evaluation of primary tumor; and in FDG-PET, CR was defined as disappearance of FDG uptake, PR as decrease, SD as unchange, and PD as increase, compared to pre-PBT data. We evaluated tumor response at three different time points: 0-3, 3-6, and 6-12 months after PBT. Also serum CA19-9 values were evaluated. Results: Radiation doses were 50.4-70.2 GyE and 28 (82%) patients received concomitant chemotherapy. During the follow-up period (median 19 months), a total of 90 FDG-PET tests were performed. At the first time point, SD was noted in 90% (9/10) of patients by CT, whereas CR or PR in all by FDG-PET. At the second point, 39% (7/18) of patients demonstrated PR by CT, whereas 91% CR or PR by FDG-PET. Two patients with PD by FDG-PET were diagnosed as SD by CT, while one patient with PD by CT was diagnosed as PR by FDG-PET. At the third point, four patients with PD by FDG-PET were diagnosed as PR or SD by CT. Serum CA19-9 values supported FDG-PET findings. In four of 14 patients with serial FDG-PET, the maximum effects were noted at the second point. Conclusions: Serial FDG-PET can detect changes in local tumor response to PBT for PDA earlier and more sensitively than CT. Of note, there is the risk for false positive in early post-PBT FDG-PET.

Mature results of a randomized trial comparing two fractionation schedules of high dose rate endoluminal brachytherapy for the treatment of endobronchial tumors

PurposeTo determine the efficacy of high dose rate endobronchial brachytherapy (HDR-BT) for the treatment of centrally located lung tumors, two different fractionation schedules were compared regarding local tumor response, side effects and survival. Mature retrospective results with longer follow-up and more patients were analyzed. Initial results were published by Huber et al. in 1995.Methods and materials142 patients with advanced, centrally located malignant tumors with preferential endoluminal growth were randomized to receive 4 fractions of 3.8 Gy (time interval: 1 week, n = 60, group I) or 2 fractions of 7.2 Gy (time interval: 3 weeks, n = 82, group II) endobronchial HDR-BT.Age, gender, tumor stage, Karnofsky Performance Score and histology were equally distributed between both groups.ResultsLocal tumor response with 2 fractions of 7.2 Gy was significantly higher as compared to 4 fractions of 3.8 Gy (median 12 vs. 6 weeks; p ≤ 0.015). Median survival was similar in both groups (19 weeks in the 4 fractions group vs. 18 weeks in the 2 fractions group). Fatal hemoptysis was less frequent following irradiation with 2 × 7.2 Gy than with 4 × 3.8 Gy, although the difference did not achieve statistical significance (12.2% vs. 18.3%, respectively. p = 0,345). Patients presenting with squamous cell carcinoma were at higher risk of bleeding compared to other histology (21.9% vs. 9%, p = 0,035).Multivariate analysis with regard to overall survival, revealed histology (p = 0.02), Karnofsky Performance Score (p < 0.0001) and response to therapy (p < 0.0001) as significant prognostic factors. For patients showing complete response the median survival was 57 weeks, while for patients with progressive disease median survival time was 8 weeks, p < 0.0001.The KPS at the start of the treatment was significantly correlated with survival. Patients presenting with a KPS ≤ 60 at the start had a significantly (p = 0,032) shorter survival time (10 weeks) than patients with a KPS > 60 (29 weeks).Moreover, the Karnofsky Performance Score of most patients improved during therapy (p = 0,001), suggesting successful palliation of cancer associated symptoms.Multivariate analysis with regard to local tumor control found no significant factors.ConclusionEndobronchial HDR-BT is an effective local treatment for advanced centrally located malignant tumors with endoluminal tumor growth. Local tumor response was significantly higher after HDR-BT with 2 × 7.2 Gy.