Use of neoadjuvant electrochemotherapy to treat a large metastatic lesion of the cheek in a patient with melanoma.

BACKGROUND: Approximately 200,000 new cases of melanoma are diagnosed worldwide each year. Skin metastases are a frequent event, occurring in 18.2% of cases. This can be distressing for the patient, as the number and size of cutaneous lesions increases, often worsened by ulceration, bleeding and pain. Electrochemotherapy (ECT) is a local modality for the treatment of cutaneous or subcutaneous tumors that allows delivery of low- and non-permeant drugs into cells. ECT has been used in palliative management of metastatic melanoma to improve patients' quality of life. This is, to our knowledge, the first application of ECT as neoadjuvant treatment of metastatic subcutaneous melanoma. METHODS AND RESULTS: A 44-year-old Caucasian woman underwent extensive surgical resection of a melanoma, with a Breslow thickness of 1.5 mm, located on the right side of her scalp. No further treatment was given and the woman remained well until she came to our attention with a large nodule in her right cheek. Whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) was performed for staging and treatment monitoring. Baseline FDG PET/CT showed the lesion in the cheek to have a maximal standardized uptake value (SUVmax) of 19.5 with no evidence of further disease spread. Fine needle aspiration cytology confirmed the presence of metastatic melanoma. The patient underwent two sessions of ECT with intravenous injections of bleomycin using a CliniporatorTM as neoadjuvant treatment permitting conservative surgery three months later.Follow-up PET/CT three months after the first ECT treatment showed a marked decrease in SUVmax to 5. Further monitoring was performed through monthly PET/CT studies. Multiple cytology examinations showed necrotic tissue. Conservative surgery was carried out three months after the second ECT. Reconstruction was easily achieved through a rotation flap. Pathological examination of the specimen showed necrotic tissue without residual melanoma. One year after the last ECT treatment, the patient was disease-free as determined by contrast-enhanced CT and PET/-CT scans with a good functional and aesthetic result. CONCLUSIONS: ECT represents a safe and effective therapeutic approach that is associated with clear benefits in terms of quality of life (minimal discomfort, mild post-treatment pain and short duration of hospital stay) and may, in the neoadjuvant setting as reported here, offer the option of more conservative surgery and an improved cosmetic effect with complete local tumor control

Sequential PET/CT with [18F]-FDG Predicts Pathological Tumor Response to Preoperative Short Course Radiotherapy with Delayed Surgery in Patients with Locally Advanced Rectal Cancer Using Logistic Regression Analysis.

UNLABELLED: Previous studies indicate that FDG PET/CT may predict pathological response in patients undergoing neoadjuvant chemo-radiotherapy for locally advanced rectal cancer (LARC). Aim of the current study is evaluate if pathological response can be similarly predicted in LARC patients after short course radiation therapy alone. METHODS: Thirty-three patients with cT2-3, N0-2, M0 rectal adenocarcinoma treated with hypo fractionated short course neoadjuvant RT (5x5 Gy) with delayed surgery (SCRTDS) were prospectively studied. All patients underwent 3 PET/CT studies at baseline, 10 days from RT end (early), and 53 days from RT end (delayed). Maximal standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and total lesion glycolysis (TLG) of the primary tumor were measured and recorded at each PET/CT study. We use logistic regression analysis to aggregate different measures of metabolic response to predict the pathological response in the course of SCRTDS. RESULTS: We provide straightforward formulas to classify response and estimate the probability of being a major responder (TRG1-2) or a complete responder (TRG1) for each individual. The formulas are based on the level of TLG at the early PET and on the overall proportional reduction of TLG between baseline and delayed PET studies. CONCLUSIONS: This study demonstrates that in the course of SCRTDS it is possible to estimate the probabilities of pathological tumor responses on the basis of PET/CT with FDG. Our formulas make it possible to assess the risks associated to LARC borne by a patient in the course of SCRTDS. These risk assessments can be balanced against other health risks associated with further treatments and can therefore be used to make informed therapy adjustments during SCRTDS

Standardized Index of Shape (DCE-MRI) and Standardized Uptake Value (PET/CT): Two quantitative approaches to discriminate chemo-radiotherapy locally advanced rectal cancer responders under a functional profile.

PURPOSE: To investigate dynamic contrast enhanced-MRI (DCE-MRI) in the preoperative chemo-radiotherapy (CRT) assessment for locally advanced rectal cancer (LARC) compared to18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). METHODS: 75 consecutive patients with LARC were enrolled in a prospective study. DCE-MRI analysis was performed measuring SIS: linear combination of percentage change (Δ) of maximum signal difference (MSD) and wash-out slope (WOS). 18F-FDG PET/CT analysis was performed using SUV maximum (SUVmax). Tumor regression grade (TRG) were estimated after surgery. Non-parametric tests, receiver operating characteristic were evaluated. RESULTS: 55 patients (TRG1-2) were classified as responders while 20 subjects as non responders. ΔSIS reached sensitivity of 93%, specificity of 80% and accuracy of 89% (cut-off 6%) to differentiate responders by non responders, sensitivity of 93%, specificity of 69% and accuracy of 79% (cut-off 30%) to identify pathological complete response (pCR). Therapy assessment via ΔSUVmax reached sensitivity of 67%, specificity of 75% and accuracy of 70% (cut-off 60%) to differentiate responders by non responders and sensitivity of 80%, specificity of 31% and accuracy of 51% (cut-off 44%) to identify pCR. CONCLUSIONS: CRT response assessment by DCE-MRI analysis shows a higher predictive ability than 18F-FDG PET/CT in LARC patients allowing to better discriminate significant and pCR

Hypoxia and perfusion in breast cancer: simultaneous assessment using PET/MR imaging

Funder: National Institute for Health Research (NIHR) - Cambridge Biomedical Research CentreAbstract: Objectives: Hypoxia is associated with poor prognosis and treatment resistance in breast cancer. However, the temporally variant nature of hypoxia can complicate interpretation of imaging findings. We explored the relationship between hypoxia and vascular function in breast tumours through combined 18F-fluoromisonidazole (18 F-FMISO) PET/MRI, with simultaneous assessment circumventing the effect of temporal variation in hypoxia and perfusion. Methods: Women with histologically confirmed, primary breast cancer underwent a simultaneous 18F-FMISO-PET/MR examination. Tumour hypoxia was assessed using influx rate constant Ki and hypoxic fractions (%HF), while parameters of vascular function (Ktrans, kep, ve, vp) and cellularity (ADC) were derived from dynamic contrast-enhanced (DCE) and diffusion-weighted (DW)-MRI, respectively. Additional correlates included histological subtype, grade and size. Relationships between imaging variables were assessed using Pearson correlation (r). Results: Twenty-nine women with 32 lesions were assessed. Hypoxic fractions > 1% were observed in 6/32 (19%) cancers, while 18/32 (56%) tumours showed a %HF of zero. The presence of hypoxia in lesions was independent of histological subtype or grade. Mean tumour Ktrans correlated negatively with Ki (r = − 0.38, p = 0.04) and %HF (r = − 0.33, p = 0.04), though parametric maps exhibited intratumoural heterogeneity with hypoxic regions colocalising with both hypo- and hyperperfused areas. No correlation was observed between ADC and DCE-MRI or PET parameters. %HF correlated positively with lesion size (r = 0.63, p = 0.001). Conclusion: Hypoxia measured by 18F-FMISO-PET correlated negatively with Ktrans from DCE-MRI, supporting the hypothesis of perfusion-driven hypoxia in breast cancer. Intratumoural hypoxia-perfusion relationships were heterogeneous, suggesting that combined assessment may be needed for disease characterisation, which could be achieved using simultaneous multimodality imaging. Key Points: • At the tumour level, hypoxia measured by 18F-FMISO-PET was negatively correlated with perfusion measured by DCE-MRI, which supports the hypothesis of perfusion-driven hypoxia in breast cancer. • No associations were observed between 18F-FMISO-PET parameters and tumour histology or grade, but tumour hypoxic fractions increased with lesion size. • Intratumoural hypoxia-perfusion relationships were heterogeneous, suggesting that the combined hypoxia-perfusion status of tumours may need to be considered for disease characterisation, which can be achieved via simultaneous multimodality imaging as reported here

Critical role of bevacizumab scheduling in combination with pre-surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: Results of the BRANCH trial.

BACKGROUND: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy. PATIENTS AND METHODS: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate. RESULTS: The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade ≥ 3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%-89%) and 85% (95%CI, 69%-93%), respectively, for the sequential-schedule. CONCLUSIONS: These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.The study was a no-profit trial partially supported by research grants from the Italian Ministry of Health to A. Avallone (RF-2009-1539464) and to A. Budillon (RF- 2011-02346914)

Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid--short Radiotherapy--rectum 3rd trial).

BACKGROUND: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. METHODS/DESIGN: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT. DISCUSSION: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01898104

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873

Use of neoadjuvant electrochemotherapy to treat a large metastatic lesion of the cheek in a patient with melanoma

Abstract Background Approximately 200,000 new cases of melanoma are diagnosed worldwide each year. Skin metastases are a frequent event, occurring in 18.2% of cases. This can be distressing for the patient, as the number and size of cutaneous lesions increases, often worsened by ulceration, bleeding and pain. Electrochemotherapy (ECT) is a local modality for the treatment of cutaneous or subcutaneous tumors that allows delivery of low- and non-permeant drugs into cells. ECT has been used in palliative management of metastatic melanoma to improve patients’ quality of life. This is, to our knowledge, the first application of ECT as neoadjuvant treatment of metastatic subcutaneous melanoma. Methods and results A 44-year-old Caucasian woman underwent extensive surgical resection of a melanoma, with a Breslow thickness of 1.5 mm, located on the right side of her scalp. No further treatment was given and the woman remained well until she came to our attention with a large nodule in her right cheek. Whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) was performed for staging and treatment monitoring. Baseline FDG PET/CT showed the lesion in the cheek to have a maximal standardized uptake value (SUVmax) of 19.5 with no evidence of further disease spread. Fine needle aspiration cytology confirmed the presence of metastatic melanoma. The patient underwent two sessions of ECT with intravenous injections of bleomycin using a CliniporatorTM as neoadjuvant treatment permitting conservative surgery three months later. Follow-up PET/CT three months after the first ECT treatment showed a marked decrease in SUVmax to 5. Further monitoring was performed through monthly PET/CT studies. Multiple cytology examinations showed necrotic tissue. Conservative surgery was carried out three months after the second ECT. Reconstruction was easily achieved through a rotation flap. Pathological examination of the specimen showed necrotic tissue without residual melanoma. One year after the last ECT treatment, the patient was disease-free as determined by contrast-enhanced CT and PET/-CT scans with a good functional and aesthetic result. Conclusions ECT represents a safe and effective therapeutic approach that is associated with clear benefits in terms of quality of life (minimal discomfort, mild post-treatment pain and short duration of hospital stay) and may, in the neoadjuvant setting as reported here, offer the option of more conservative surgery and an improved cosmetic effect with complete local tumor control.</p