Diffusion-weighted MRI and ADC versus FET-PET and GdT1w-MRI for gross tumor volume (GTV) delineation in re-irradiation of recurrent glioblastoma.

BACKGROUND AND PURPOSE: GTV definition for re-irradiation treatment planning in recurrent glioblastoma (rGBM) is usually based on contrast-enhanced MRI (GdT1w-MRI) and, for an increased specificity, on amino acid PET. Diffusion-weighted (DWI) MRI and ADC maps can reveal regions of high cellularity as surrogate for active tumor. The objective of this study was to compare the localization and quality of diffusion restriction foci (GTV-ADClow) with FET-PET (GTV-PET) and GdT1w-MRI (GTV-GdT1w-MRI). MATERIAL AND METHODS: We prospectively evaluated 41 patients, who received a fractionated stereotactic re-irradiation for rGBM. GTV-PET was generated automatically (tumor-to-background ratio 1.7-1.8) and manually customized. GTV-ADClow was manually defined based on DWI data (3D diffusion gradients, b = 0, 1000 s/mm2) and parametric ADC maps. The localization of recurrence was correlated with initial GdT1w-MRI and PET data. RESULTS: In 30/41 patients, DWI-MRI showed areas with restricted diffusion (mean ADC-value 0.74 ±â€¯0.22 mm2/s). 66% of GTVs-ADClow were located outside the GdT1w-MRI volume and 76% outside increased FET uptake regions. Furthermore, GTVs-ADClow were only partially included in the high dose volume and received in mean 82% of the reference dose. An adjusted volume including GdT1w-MRI, PET-positive and restricted diffusion areas would imply a GTV increase of 48%. GTV-PET and GdT1w-MRI correlated better with the localization of re-recurrence in comparison to GTV-ADClow. CONCLUSION: Unexpectedly, GTV-ADClow overlapped only partially with FET-PET and GdT1w-MRI in rGBM. Moreover, GTV-ADClow correlated poorly with later rGBM-recurrences. Seeing as a restricted diffusion is known to correlate with hypercellularity, this imaging discrepancy could only be further explained in histopathological studies.

Outcomes of patients with squamous cell carcinoma of esophagus who did not receive surgical resection after neoadjuvant radiochemotherapy.

AIMS AND BACKGROUND: The primary objective was to assess the different reasons for refusal of surgical resection (SR) in patients with esophageal squamous cell cancer (ESCC), who were initially planned for neoadjuvant radiochemotherapy (N-RCT) + SR, but SR was not performed after N-RCT. METHODS AND STUDY DESIGN: From 1988 to 2011, 311 patients with ESCC were treated with N-RCT in a tertiary referral center for esophageal diseases. Fifty-three patients were analyzed who received RCT with 40-45 Gy and concomitant chemotherapy in neoadjuvant intention, but in whom the treatment was stopped or switched to definitive RCT due to progression, patient decision, or new findings. RESULTS: The reasons for refusal of SR for these 53 patients were as follows: (1) patients' or physicians' preference for the planned treatment was changed during the N-RCT, such that RCT was continued to a curative dose without a break (group 1, n = 23, 44%); (2) patients were restaged after 4 weeks, and the tumor board decided to continue RCT because R0 resection was unlikely and/or patients were medically unfit (group 2, n = 15, 28%); (3) patients refused continuation of any treatment (group 3, n = 15, 28%). Refusal of SR was significantly more likely in patients with longitudinal tumor dimension >8 cm and those with an Eastern Cooperative Oncology Group performance status score of 2. Median follow-up time from the start of N-RCT was 57 months (range 1-137 months). The survival rates at 2 and 5 years were 36 ± 7% and 27 ± 7%, respectively. Group 1 had significantly longer survival. CONCLUSIONS: The planned N-RCT+SR could not be completed in a considerable number of patients in a tertiary referral center. More strict selection criteria for multimodality treatment including SR could spare some of these patients an incomplete treatment and probably lead to increased utilization of definitive RCT.

Long-term outcomes of trimodality treatment for squamous cell carcinoma of the esophagus with cisplatin and/or 5-FU: more than 20 years' experience at a single institution.

PURPOSE: The purpose of this article is to report the outcome of neoadjuvant radiochemotherapy (N-RCT) + surgery in patients with squamous cell carcinoma of the esophagus at a single institution. METHODS: We retrospectively reviewed data from patients who were referred to our department for N-RCT. From 1988­2011, 103 patients were treated with N-RCT with cisplatin and/or 5-fluorouracil (5-FU). Group 1: (n = 55) from 1988­2006 with 39.6­40 Gy and 5-FU with (n = 17) or without cisplatin (n = 38). Group 2: from 2003­2010 with 44­45 Gy and 5-FU with (n = 40) or without cisplatin (n = 8). All patients underwent radical resection with reconstruction according to tumor location and 2-field lymph node dissection. The degree of histomorphologic regression was defined as grade 1a (pCR, 0 % residual tumor), grade 1b (pSTR, < 10 % residual tumor), grade 2 (10­50 % residual tumor), and grade 3 (> 50 % residual tumor). RESULTS: Median follow-up time from the start of N-RCT was 100 months (range 2­213 months). The median overall survival (OS) for the whole cohort was 42 months and the 5-year OS was 45 ± 5 %. In the multivariate analysis, worse ECOG performance status (p < 0.001), weight loss > 10 % before the start of the N-RCT (p = 0.025), higher pT category (p = 0.001), and grade 2/3 pathologic remission (p < 0.001) were significantly associated with a poor OS. PCR and pSTR rates for group 1 were 36 % and 18 % compared to 53 % and 22 % for group 2 (p = 0.011). There was a tendency for a better outcome in group 2 patients without statistical significance. The 5-year OS, disease-free survival and recurrent-free survival were 36 ± 7 %, 35 ± 6, and 36 ± 7 % for group 1 and 55 ± 7, 49 ± 7, and 53 ± 7 in group 2 (p = 0.117, p = 0.124, and p = 0.087). There was no significant difference between the two groups considering the postoperative morbidity and mortality. CONCLUSION: Higher radiation doses and more use of simultaneous cisplatin lead to higher pathologic response rates to N-RCT and may be associated with better survival outcomes. Prospective controlled trials are needed to assess the true value of intensified N-RCT regimens.

Impact of common medications on serum total prostate-specific antigen levels and risk group assignment in patients with prostate cancer.

A recent study in men without prostate cancer suggested that extended use of common medications (nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide diuretics and statins) may lower serum total prostate-specific antigen (PSA) levels by clinically relevant amounts. The present study evaluated the impact of these drugs in patients with clinically localized prostate cancer. A retrospective analysis of 177 patients was performed. The multivariate regression analyses were adjusted for age, prostate volume, Gleason score, T stage, diagnostic setting (clinical symptoms versus elevated PSA only) and presence of diabetes mellitus. Drug use increased with age, e.g. to 50% in patients ≥70 years. The most commonly used drugs were statins (32% of all patients, including those who used drug combinations), followed by NSAIDs (21%) and thiazide diuretics (13%). Drug use was associated with a statistically significant PSA reduction (12%, when comparing 104 non-users to 73 users of any of the three drug types; adjusted analysis, p=0.01). Compared to the U.S.A. National Comprehensive Cancer Network risk group assignment based on measured PSA level, reassignment after correcting for medication use resulted in 8 changes among 57 patients with low or intermediate risk (14%). No such changes can be expected in patients belonging to the high-risk group. These results support the concerns expressed previously, given that risk group assignment, which may be inaccurate in patients using concomitant medications, eventually guides choice of treatment.

Improvement, clinical course, and quality of life after palliative radiotherapy for recurrent glioblastoma.

The purpose of this review is to assess the palliative effect of re-irradiation in adult patients with recurrent supratentorial glioblastoma (GBM) previously treated with adjuvant or primary radiation therapy, with or without chemotherapy. From a comprehensive literature search, studies were identified reporting on survival, progression, and quality of life endpoints including, but not limited to, EORTC QLQ-C30 questionnaire, clinical symptoms, and ability to reduce dexamethasone. Data from more than 300 GBM patients (grade 3 anaplastic gliomas were excluded) demonstrate that re-irradiation yields 6-month PFS of 28% to 39% and 1-year overall survival of 18% to 48%, without additional chemotherapy (median value 26%). Patients with Karnofsky performance status <70 appeared to be at higher risk of early progression and apparently had lesser benefit from re-irradiation. Clinical improvement was observed in 24% to 45% of the patients. Most studies suggest that stabilization of the performance status is a realistic aim. In the studies reporting on corticosteroid usage during and after re-irradiation, 20% to 60% of the patients achieved a reduction in steroid dependency. Serious late toxicity was uncommon, especially after conventional treatment and fractionated stereotactic radiotherapy (FSRT). In light of recent technological advances such as FSRT and intensity modulated radiotherapy, which permit maximal sparing of normal brain, re-treatment seems attractive, and deserves scientific validation. Even fraction sizes of 3 to 5 Gy seem to be well tolerated in limited-volume recurrences as long as the total dose is limited to 30 to 35 Gy. Salvage chemotherapy or targeted agents should be prospectively tested against re-irradiation alone.

Current status of angiogenesis inhibitors combined with radiation therapy.

Angiogenesis inhibitors combined with cytotoxic chemotherapy have recently entered routine oncological practice. Several rationales exist for combining these agents with ionizing radiation, a primary curative cancer treatment, either in bimodal or trimodal fashion, i.e. with or without additional chemotherapy. More than 20 different anti-angiogenic agents have been studied in preclinical animal tumor models. This systematic review compares the results of preclinical studies published before February 2006. The combination of vascular endothelial growth factor (VEGF) inhibitors with irradiation consistently resulted in improved tumor growth delay (at least additive effects), despite different radiation schedules, drugs and doses, and combination regimens. Only two studies evaluated tumor control dose (TCD)50 as a measure of tumor cure (radiation dose yielding permanent local control in 50% of the tumors). While anti-VEGF receptor (VEGFR) antibody treatment improved the outcome, a VEGFR tyrosine kinase inhibitor showed negative results. For agents interfering with other pathways, the results are also not consistent, although most studies were positive. Trimodal approaches seem to improve tumor growth delay even further. Importantly, both radiotherapy schedule and sequence of the modalities in combined treatment may impact on the outcome. Hence, further preclinical studies examining these parameters need to be conducted. While preclinical research is ongoing, phase I and II clinical trials with bevacizumab, combretastatin A-4, thalidomide and different receptor tyrosine kinase inhibitors, usually combined with radio- and chemotherapy, have been designed. Early results suggest that acute toxicity is acceptable, planned surgery after such treatment is feasible, and that further evaluation of such combined modality treatment is warranted.

Potential role of growth factors in diminishing radiation therapy neural tissue injury.

Human growth factors are firmly established in treatment of cytopenias that are associated with cancer chemotherapy, and have been used successfully to reduce severe mucositis in patients receiving radiation therapy and chemotherapy in the setting of autologous bone marrow transplantation. The ability of growth factors that are involved in differentiation and proliferation of neural tissue cells to prevent or accelerate recovery from radiation injury currently is being evaluated in preclinical studies. Data from these studies indicate that brief therapeutic intervention with platelet-derived growth factor, insulin-like growth factor-1, vascular endothelial growth factor, and the combination of insulin-like growth factor-1 and basic fibroblast growth factor can prevent or delay radiation myelopathy after spinal cord irradiation. Additional investigation is required to define potentially clinically useful growth factor regimens in the clinic.