Dose painting for re-irradiation of head and neck cancer.

BACKGROUND: For patients with recurrent or second primary disease, re-irradiation can be challenging due to overlap with previously irradiated volumes. Dose painting may be attractive for these patients, as the focus is on delivering maximal dose to areas of high tumor activity. Here, we compare dose painting by contours (DPBC) treatment plans based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with conventional plans. MATERIAL AND METHODS: We included 10 patients with recurrent or second primary head and neck cancer (HNC) eligible for re-irradiation. Our conventional re-irradiation regimen is hyperfractionated radiotherapy 1.5 Gy twice daily over 4 weeks, giving a total dose of 60 Gy. For DPBC, we defined two prescription volumes, PV33 and PV66, corresponding to 33 and 66% of the highest FDG uptake in the tumor. The clinical target volume (CTV) prescription dose was 60 Gy, PV33; 65-67 Gy and PV66; 70-73 Gy. The DPBC plan is to be given the first 20 fractions and the conventional plan the last 20 fractions. Dose to organs at risk (OARs) were compared for DPBC and conventional treatment. By summation of the initial curative plan and the re-irradiation plan, we also evaluated differences in dose to the 2 ccm hot spot (D2cc). RESULTS: We achieved DPBC plans with adequate target coverage for all 10 patients. There were no significant differences in OAR doses between the standard plans and the DPBC plans (p=.7). Summation of the initial curative plan and the re-irradiation plan showed that the median D2cc increased from 130 Gy (range 113-132 Gy; conventional) to 140 Gy (range 115-145 Gy; DPBC). CONCLUSIONS: Our proposed DPBC could be straightforwardly implemented and all plans met the objectives. Re-irradiation of HNC with DPBC may increase tumor control without more side effects compared to conventional radiotherapy.

Patterns of local-regional recurrence after conformal and intensity-modulated radiotherapy for head and neck cancer.

AIM: To evaluate the patterns of loco-regional recurrences in head and neck cancer patients METHODS: Twenty-six out of 112 patients treated with primary or postoperative 3D CRT or IMRT for their primary and recurrent disease between 2007 and 2013 were included. The CT images of recurrent disease were rigidly registered with the primary CT images for each patient. To assess overlaps and overlap localization, the recurrence volume overlapping with the primary target volume was identified. For relapses occurring in the regional lymph nodes, the epicenter distance in recurrences and primary volumes and dose in recurrences were also identified. The recurrences were defined as in-field, marginal or out-of-field. RESULTS: The majority of the failures occurred within 1 year after completed primary treatment. The dose differences in recurrence volume were not statistically significant when patients were treated with IMRT or 3D CRT. Recurrence in 15/26 of the included patients occurred in the regional lymph nodes located fully or partly inside the primary target volume or the elective lymph node region. The majority of recurrences were recognized as in-field, independent of the primary treatment. CONCLUSION: Recurrence in the majority of the patients occurred in the regional lymph nodes located in high dose area. The cause of recurrence may be due to inadequate total dose in the primary treatment and/or lack of optimal primary diagnosis leading to inadequate primary target delineation.

Hormonal dysfunction is frequent in cancer survivors treated with radiotherapy to the head and neck region.

PURPOSE: Cancer treatment may lead to hormonal dysfunction. Therefore, we assessed the prevalence of dysfunction in four hormonal axes among long-term cancer survivors who received radiotherapy to the head and neck region and analyzed associations between hormonal status and clinical variables. METHODS: We included 140 cancer survivors who received radiotherapy to the head and neck region, either locally or through total body irradiation after a diagnosis of lymphoma, plasmacytoma/multiple myeloma, or carcinoma of the epipharynx. Radiation doses to the pituitary gland and thyroid gland were estimated, and blood samples were collected to analyze hormonal levels. RESULTS: At a median of 16 years after their cancer diagnosis, 46% of cancer survivors showed dysfunction in one hormonal axis, 24% had dysfunction in two axes, and 3% had dysfunction in three axes. Twenty cancer survivors (14%) had hormone levels consistent with pituitary dysfunction. Cancer survivors who had received an estimated 30 Gray (Gy) or more to the pituitary gland had an increased risk for pituitary dysfunction in one of the hormonal axes (odds ratio [OR] 3.16, confidence interval [CI] 1.02-9.87, p = 0.047) and for growth hormone dysfunction alone (OR 2.96, CI 1.02-8.55, p = 0.045). CONCLUSIONS: Abnormal hormone values are frequent after radiotherapy to the head and neck region. IMPLICATIONS FOR CANCER SURVIVORS: Screening for hormonal dysfunction during follow-up might be indicated.

Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma.

BACKGROUND: The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. METHODS: Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. RESULTS: Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. CONCLUSIONS: Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials.

Radiosensitization by SAHA in experimental colorectal carcinoma models-in vivo effects and relevance of histone acetylation status.

PURPOSE: Histone deacetylase inhibitors are being evaluated as antitumor agents in ongoing clinical trials, and promising preclinical results, combined with favorable toxicity profiles, have rendered the drugs as interesting candidates for combination with other treatment modalities, such as radiotherapy. The aim of the present study was to evaluate the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) and the possible requirement of histone hyperacetylation at radiation exposure. METHODS AND MATERIALS: Radiosensitization by SAHA was assessed in a colorectal carcinoma cell line and in two colorectal xenograft models by analysis of clonogenic survival and tumor growth delay, respectively. Histone acetylation status at radiation exposure was evaluated by Western blot. RESULTS: In vitro, radiosensitization was demonstrated when cells were preincubated with SAHA, and, in the xenografts, tumor growth was delayed when the mice were treated with fractionated radiation combined with daily SAHA injections compared with radiation alone. Surprisingly, the SAHA-dependent growth delay was still present when radiation was delivered at restored baseline acetylation levels compared with maximal histone hyperacetylation. CONCLUSION: SAHA was an effective radiosensitizer in experimental colorectal carcinoma models, suggesting that histone deacetylase inhibition might constitute a valuable supplement to current multimodal treatment strategies in rectal cancer. The presence of histone hyperacetylation at radiation was not required to obtain an increased radiation response, questioning the validity of using histone hyperacetylation as a molecular marker for radiosensitivity.

Radiobiological responses for two cell lines following continuous low dose-rate (CLDR) and pulsed dose rate (PDR) brachytherapy.

The iso-effective irradiation of continuous low-dose-rate (CLDR) irradiation was compared with that of various schedules of pulsed dose rate (PDR) irradiation for cells of two established human lines, T-47D and NHIK 3025. Complete single-dose response curves were obtained for determination of parameters alpha and beta by fitting of the linear quadratic formula. Sublethal damage repair constants micro and T(1/2) were determined by split-dose recovery experiments. On basis of the acquired parameters of each cell type the relative effectiveness of the two regimens of irradiation (CLDR and PDR) was calculated by use of Fowler's radiobiological model for iso-effect irradiation for repeated fractions of dose delivered at medium dose rates. For both cell types the predicted and observed relative effectiveness was compared at low and high iso-effect levels. The results indicate that the effect of PDR irradiation predicted by Fowlers model is equal to that of CLDR irradiation for both small and large doses with T-47D cells. With NHIK 3025 cells PDR irradiation induces a larger effect than predicted by the model for small doses, while it induces the predicted effect for high doses. The underlying cause of this difference is unclear, but cell-cycle parameters, like G2-accumulation is tested and found to be the same for the two cell lines.

Differential expression of steroid receptors in prostate tissues before and after radiation therapy for prostatic adenocarcinoma.

The expression, distribution and the role of steroid receptors in benign and malignant untreated prostate tissues is well recognized, however, the status of steroid receptors in prostate after radiotherapy (RT) for adenocarcinoma has not yet been studied fully. Immunohistochemical evaluation of androgen receptor (AR), estrogen receptor-alpha (ER-alpha), estrogen receptor-beta (ER-beta), and progesterone receptor (PR) was carried out in prostate needle biopsies obtained before and after radiotherapy from 60 patients with adenocarcinoma. The ER-beta transcripts were also studied by RT-PCR in LNCaP prostate carcinoma cell line before and 24 hr after gamma-irradiation at 0.5 Gy and 8.0 Gy. Significantly higher level of ER-beta expression was found in post-radiation samples of prostate adenocarcinoma and benign epithelium. After RT, all steroid receptors were upregulated in prostatic stroma. Tumor AR expression did not change significantly. Although a positive association between AR and ER-beta expression was observed in pre-treatment prostate adenocarcinoma, it was lost after RT suggesting that these 2 steroid receptors respond differently to RT. High levels of pretreatment tumor ER-beta were associated with local recurrence after RT and decreased biochemical recurrence-free survival (p = 0.028). LNCaP cell line that expressed no ER-beta mRNA before gamma-irradiation, clearly expressed ER-beta mRNA 24 hr after 0.5 Gy and 8.0 Gy. Upregulation of all steroid receptors in the prostate stroma and upregulation of ER-beta in the tumor epithelium after RT, may represent a protective tissue response to radiation-induced tissue injury. Although stromal AR was doubled after RT, the tumor and benign epithelium expression of AR seemed resistant to change by RT.