Proposal for magnetic resonance imaging-guided salvage radiotherapy for prostate cancer.

BACKGROUND: A subset of patients experience a biochemical recurrence following radical prostatectomy. Radiotherapy can salvage those patients, provided that all disease is encompassed within the target volume. We hypothesized that this can be achieved more adequately with magnetic resonance imaging (MRI)-guided treatment planning. MATERIAL AND METHODS: From January 2009 to April 2014, 183 patients were referred to our department for salvage radiotherapy (SRT). According to protocol, patients received a planning computed tomography (CT) as well as an MRI in treatment position. All MRI scans were retrospectively reviewed by an experienced uro-radiologist. RESULTS: Median prostate-specific antigen (PSA) value at time of referral was 0.3 ng/ml (range 0.02-4.7 ng/ml). MRI did not show any suspected macroscopic disease in 137 patients (75%). In 46 (25%) patients, MRI did indicate a pelvic recurrence. The mean PSA level was significantly higher in patients with a suspected recurrence on MRI (0.4 vs. 1.4 ng/ml, p < .001) on a Student's t-test. The mean follow-up was 33 months (range 5-69 months). Biochemical disease-free survival (bDFS) was significantly worse in patients with suspected disease on MRI [hazard ratio (HR) 2.9, p < .0001]. bDFS was significantly worse in the subgroup where the macroscopic recurrences on MRI received a lower radiation dose (HR 3.4, p = .01). CONCLUSION: MRI detects loco-regional disease in a substantial subset of patients with a biochemical recurrence after prostatectomy, especially in a PSA above 0.5 µg/l. Lack of MRI-based dose escalation on these macroscopic recurrences could explain some of the biochemical progression observed after SRT.

A phase I dose-escalation trial of stereotactic ablative body radiotherapy for non-spine bone and lymph node metastases (DESTROY-trial).

BACKGROUND: In an oligometastatic setting, metastasis-directed treatment could render patients disease free, possibly for a protracted interval. Stereotactic ablative radiotherapy (SABR) is one of the treatment modalities that can be offered to these patients. In addition, the radiobiological qualities of SABR are promising for the use in perceived radioresistant tumours. There is also emerging evidence that SABR can stimulate the immune response, and a specific therapeutic window may exist for the optimal use of radiotherapy as an immune adjuvant. However, when SABR is considered for non-spine bone or lymph node metastases, the optimal fractionation schedule is not yet known. METHODS: The DESTROY-trial is a non-randomized prospective phase I trial determining a regimen of choice for patients with non-spine bone and lymph node metastases. A total of 90 patients will be included in three different treatment regimens. They will be offered stereotactic ablative radiotherapy in 5, 3 or 1 fractions. Dose-limiting toxicity will be recorded as primary endpoint. Acute and late toxicity, local response and local recurrence, and progression-free survival are secondary endpoints. Liquid biopsies will be collected throughout the course of this study from the second fractionation schedule on. DISCUSSION: Despite its almost universal use in (oligo-)metastatic patients, the level of evidence supporting radical local treatment in general, and stereotactic radiotherapy in particular, is low. This prospective phase I trial will evaluate different SABR regimens for metastases and the differences in immune-stimulatory effects. TRIAL REGISTRATION: The Ethics committee of the GZA Hospitals (B099201732915) approved this study on 05/07/2017. Amendment for translational research was approved on 06/02/2018. Trial registered on Clinicaltrials.gov ( NCT03486431 ) on 03/04/2018 - Retrospectively registered.

A federal audit of the Belgian radiotherapy departments in breast cancer treatment.

BACKGROUND: The Belgian Federal College of Radiotherapy carried out an external audit of breast cancer patient documentation in the 26 Belgian radiotherapy centres. The objective was to assess compliance with the recommendations regarding minimal requirements for documentation of radiotherapy prescription and administration. All centres volunteered to take part in this audit. METHODS: Two experienced radiation oncologists site-visited the departments over a 6 month period (Sept. 2003-Feb. 2004), with a list of items to be verified, including details on the surgery, the pathological report, details on systemic treatments, details on the radiotherapy prescription (and consistency with therapeutic guidelines) and delay surgery/radiotherapy. FINDINGS: Three hundred and eighty-nine patients files were reviewed, for a total of 399 breast cancers (10 patients with bilateral cancer). Mean age was 57.8 y (range 29-96). Breast conservative surgery (BCS) was used in 71%; radical mastectomy in 29%. A complete pathological report was present in all files but 2 (99.5% conformity). 5.2% were treated for DCIS, 61.6% for pT1, 28.2% for pT2 and 5% for pT3-4. Data regarding resection margins were specified to be free in 76.2%, tangential in 12% (within 2 mm) and positive for DCIS in 3.8% or invasive cancer in 1.5% (no information, on margins in 6.5%). The pT stage was always specified, and consistent with the macroscopic and microscopic findings. Hormonal receptors were routinely assessed (94.7%), as well as Her2neu (87.4%). Axillary surgery was carried out in 92%, either by sentinel node biopsy or by complete clearance, in which case the median number of nodes analysed was 12 for all centres together (7-17). All radiotherapy prescriptions were in line with evidence-based standards of therapy (i.e., irradiation of breast after BCS or after mamectomy (in case of pN+), but one. The mean delay between surgery and radiotherapy was 5.5 weeks (SD 11 days). CONCLUSION: There was a high degree of conformity of the various centres with the minimal requirements for documentation of radiotherapy prescription and administration of the Federal College of Radiotherapy. In addition, the quality of surgery (assessed by margin clearance) and of pathological reports was excellent, whatever the institution of origin (teaching vs. non-teaching, private vs. public). Belgian patients referred for radiotherapy are treated with great care. Prescriptions are based on pathological evidence, gathered through appropriate surgery. All indications were evidence-based; there was no overuse of radiotherapy in early breast cancer treatment.

Circulating tumour cells and lung microvascular tumour cell retention in patients with metastatic breast and cervical cancer.

We have shown that in up to half of the patients with metastatic breast cancer (MBC), higher numbers of circulating tumour cells (CTCs) are present in the central venous blood (CVB) compared to the peripheral venous blood (PVB), suggesting that the lungs might retain a substantial number of CTCs. Here we report the presence of tumour cell emboli (TCE) in the microvasculature of the lungs in three out of eight patients with MBC and one patient with metastatic cervical carcinoma who had markedly elevated numbers of CTCs in the blood. All these patients suffered from symptomatic dyspnoea not easily attributable to other causes. No TCE were observed in five patients with MBC and elevated CTC counts and three patients with MBC who had low CTC counts (<5/7.5 ml). To investigate whether CTCs derived from CVB or PVB exhibit different transcriptional characteristics that might explain selective CTC retention, paired CTC samples from CVB and PVB of 12 patients with advanced breast cancer were subjected to gene expression analysis of 105 genes. No significant differences in CTC gene expression were observed. Together, these data suggest that potentially clinically relevant CTC retention in the microvasculature of the lung can occur in a subset of patients with advanced metastatic breast and cervical cancer, which seems to be transcriptionally non-selectively.

Trastuzumab emtansine in breast cancer.

INTRODUCTION: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine). Administration of T-DM1 leads to limited systemic exposure of free DM1, with no evidence of DM1 accumulation after repeated dosing. AREAS COVERED: Phase I and Phase II clinical trials with T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown substantial clinical activity and a favorable safety profile. A randomized, open-label, first-line trial comparing trastuzumab and docetaxel with single agent T-DM1 showed a significant improved progression-free survival for T-DM1. EXPERT OPINION: T-DM1 has successfully completed second-line Phase III development for advanced HER2-positive breast cancer. The Phase III EMILIA study demonstrated an overall survival benefit for T-DM1 compared to the combination of lapatinib and capecitabine in taxane-trastuzumab pretreated patients. T-DM1 may offer delivery on a personalized basis of very potent cytotoxic agents in a cellular selective manner.

Circulating interleukin-6 predicts survival in patients with metastatic breast cancer.

Interleukin-6 (IL-6) is a multifunctional cytokine produced by macrophages, T cells, B cells, endothelial cells and tumour cells. Interleukin-6 is able to promote tumour growth by upregulating anti-apoptotic and angiogenic proteins in tumour cells. In murine models it has been demonstrated that antibodies against IL-6 diminish tumour growth. Several reports have highlighted the prognostic importance of IL-6 in e.g., prostate and colon cancer. We addressed prospectively the prognostic significance of serum IL-6 (sIL-6), measured at diagnosis of metastasis, in 96 unselected and consecutive patients with progressive metastatic breast cancer before the initiation of systemic therapy. The median sIL-6 value for the breast cancer population was 6.6 +/- 2.1 pg/ml. Patients with 2 or more metastatic sites had higher sIL-6 values compared to those with only 1 metastatic site (respectively 8.15 +/- 1.7 pg/ml and 3.06 +/- 6.6 pg/ml; p < 0.001). Patients with liver metastasis (8.3 +/- 2.4 pg/ml), with pleural effusions (10.65 +/- 9.9 pg/ml) and with dominant visceral disease (8.15 +/- 3.3 pg/ml) had significantly higher values compared to those without liver metastases (4.5 +/- 3.4 pg/ml; p = 0.001), without pleural effusions (5.45 +/- 1.5 pg/ml; p = 0.0077) and with dominant bone disease (4.5 +/- 1.4 pg/ml; p = 0.007) respectively. No correlation between sIL-6 and age, menopausal status, performance status, tumour grade, body-mass index, histology and hormone receptor status was found. Multivariate analysis showed that high levels of serum IL-6 have independent prognostic value. We conclude that circulating IL-6 is associated with worse survival in patients with metastatic breast cancer and is correlated with the extent of disease.