Human papillomavirus DNA load and p16INK4a expression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy.

As the detection rate of HPV-DNA in anal carcinoma commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment response following chemoradiotherapy (CRT) and long-term oncological outcome is challenging. Against this background, we aimed to assess HPV types and HPV DNA load in formalin-fixed paraffin-embedded tissue (FFPE) of 95 patients treated with standard CRT for anal cancer to correlate viral load (≤/> median) with local failure, distant metastases, cancer-specific (CSS) and overall survival (OS) rates. Various clinicopathologic parameters and the immunohistochemical marker p16(INK4a) were evaluated for any correlation with HPV16 DNA load and were included in uni- and multivariate analyses. The overall prevalence of HPV DNA was 95.8% with HPV16 monoinfection being the most commonly encountered HPV type (78.9%), followed by HPV16 and 31, 35, 39, 44, 58, 66 and 81 dual infection in 9 patients (9.5%). HPV16 DNA load was significantly associated with p16(INK4a) expression (p = 0.001). Patients with HPV16 DNA load ≤ median and low p16(INK4a) expression showed significantly worse local control (HPV16 DNA load: univariate p = 0.023, multivariate p = 0.042; p16(INK4a): univariate p = 0.021), and OS (HPV16 DNA load: univariate p = 0.02, multivariate p = 0.03). Moreover, a combined HPV16 DNA load and p16(INK4a) variable revealed a significant correlation to decreased local failure, and increased CSS and OS (p = 0.019, p = 0.04 and p = 0.031). In conclusion, these data indicate that HPV16 DNA load and p16(INK4a) expression are significant prognostic factors for local tumor control and overall survival of patients with anal SCC following CRT.

Long-term effects of chemoradiotherapy for anal cancer in patients with HIV infection: oncological outcomes, immunological status, and the clinical course of the HIV disease.

BACKGROUND: Despite the increasing evidence for chemoradiotherapy as standard treatment for anal cancer in patients with HIV infection, there is still some uncertainty regarding increased toxicity and adverse effects on the immune status. OBJECTIVE: We report the clinical outcome of 5-fluorouracil/mitomycin C-based concurrent chemoradiotherapy for anal carcinoma in patients with HIV infection with an emphasis on the long-term course of CD4 counts and the HIV-related morbidity during follow-up. DESIGN AND SETTINGS: A retrospective single-institution chart review was performed. PATIENTS: Between 1997 and 2012, 36 HIV-positive patients were treated with standard chemoradiotherapy (median tumor dose, 54 (range, 50.4-60.4) Gy at 1.8 Gy/fraction; 5-fluorouracil, 800-1000 mg/m(2), days 1-4 or 1-5; mitomycin C, 10 mg/m(2), day 1, in the first and fifth week). MAIN OUTCOME MEASURES: A retrospective analysis was performed with respect to tumor response, local control, cancer and overall survival, and toxicity. Immunological parameters, including pre- and posttreatment CD4 counts, viral load, and HIV-specific morbidity were recorded during follow-up. RESULTS: Chemoradiotherapy could be completed in all patients. Acute grade 3 toxicities occurred in 17/36 patients (47%). Complete response was achieved in 31 patients (86%). Five-year local control, colostomy-free, cancer-specific, and overall survival were 72%, 87%, 77%, and 74%. The median pretreatment CD4 count significantly decreased from 367 cells/µL to 139 cells/µL, 3 to 7 weeks after completion of chemoradiotherapy (p < 0.001). Four patients (11%) experienced opportunistic illnesses during the follow-up (median, 66; range, 10-164 months). LIMITATIONS: This study is limited by its retrospective design and its small sample size. CONCLUSIONS: Our data confirm again that, in the highly active antiretroviral therapy era, anal cancer can be treated in HIV-positive patients with standard chemoradiotherapy, with a clinical outcome similar to their HIV-negative counterparts. The chemoradiotherapy-related decline of the CD4 counts, which remain decreased up to 6 years after chemoradiotherapy, was not associated with increased HIV-related clinical morbidity.

Differences in the Course of CD4 and CD8 Cells After Chemoradiotherapy in People Living with HIV with Anal Cancer.

Incidence of anal carcinoma (AC) in people living with HIV (PLWH) is increased compared to the general population. Adverse effects of chemoradiotherapy (CRT) on the immune system are associated with a significant detrimental prognosis on overall survival in patients receiving CRT for solid tumors. The aim of this study was to evaluate immunological factors, in particular the differences in recovery of CD4+ and CD8+ cell counts before and after CRT for AC in PLWH. Retrospective single-center chart review extraction to analyze immunological data collected from PLWH with AC; descriptive statistics were used. Thirty-six PLWH with histologically proven AC were included in the analysis. Absolute CD4 cell count 60 months after CRT was 67.2% of the value at the beginning of CRT, whereas the CD8 cell count reached 82.3%. These differences were statistically significant (p = .048), whereas CD4/CD8-ratio remained stable. The findings of the presented study regarding CD4+ and CD8+ cell recovery after CRT are congruent with results from prior studies in non-HIV infected patients. Although not reaching the level of prior CRT T cell numbers, the ability to generate CD8+ cells seems to be better recovered, while CD4+ regeneration is more impaired. These observations are best explained by faster recovery of CD8+ cells via thymic-independent pathways, which are not available for regeneration of CD4+ cells. Further studies with larger numbers of patients are required to analyze the specific CD4+ and CD8+ cell subsets.

Patient- and treatment-related risk factors for nausea and emesis during concurrent chemoradiotherapy.

PURPOSE: To evaluate the prevalence of acute nausea and emesis during concurrent chemoradiotherapy (CRT) with emphasis on the influence of patient- and treatment-related risk factors and prophylactic antiemetic medication. PATIENTS AND METHODS: A total of 335 patients treated with different intravenous standard chemoradiotherapy protocols in the inpatient setting were included in this retrospective study. Acute nausea and emesis, scored according to the CTC (version 3.0) criteria, were evaluated during 821 chemotherapy cycles. Side effects were correlated with patient-, tumor-, and treatment-related parameters. RESULTS: Overall, at least one episode of acute nausea occurred in 48% of the patients and at least one episode of vomiting occurred in 25% of patients. The emetogenic level of the applied chemotherapy protocol was the most significant risk factor for developing nausea and emesis (p < 0.0001). The site of irradiation - namely the thorax (p = 0.0110) and head and neck (p = 0.0415) - was also confirmed as a risk factor. Patient-related parameters, e.g., female gender (p = 0.0003), young age (< 40 years; p = 0.0029), weight loss > 5% (p = 0.0004), and the presence of a percutaneous endoscopic gastrostomy (PEG; p = 0.0071), were associated with higher rates of nausea and emesis, while a history of alcohol abuse showed a protective effect (p = 0.0553). In high emetogenic chemotherapy protocols, prophylaxis with 5-HT3 antagonist plus dexamethasone was superior to 5-HT3 antagonist alone (p = 0.0383). CONCLUSION: Future studies should evaluate more effective prophylaxis protocols in CRT in order to reduce the high rates of nausea and emesis.

Combined-modality treatment for anal cancer: current strategies and future directions.

BACKGROUND: Concurrent chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and mitomycin C (MMC) is the treatment of choice for anal carcinoma. The most appropriate radiation (RT) dose, fractionation, techniques, and the most effective chemotherapy regimen (agents, number of neoadjuvant, concomitant, adjuvant cycles) remain to be established. MATERIAL AND METHODS: This review article focuses on recent randomized trials designed to improve standard 5-FU/MMC-based CRT through the inclusion of (induction, concurrent, maintenance) cisplatin, and describes developments in combining RT with other chemotherapeutic drugs and targeted therapies. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings. RESULTS: Based on results of three recent randomized phase III trials, neither induction chemotherapy (RTOG 98-11, ACCORD 03) or maintenance chemotherapy with 5-FU/cisplatin (ACT II) nor RT dose escalation (ACCORD 03) improved the outcome of concurrent 5-FU/MMC-CRT. A randomized phase II trial (EORTC 22011-40014) compared concurrent 5-FU/MMC-CRT with cisplatin/ MMC-CRT. The response rate of cisplatin/MMC-CRT was promising, but compliance to this regimen was limited. Current phase I/II studies are evaluating the use of capecitabine, oxalipatin, and the EGFR (epidermal growth factor receptor) inhibitor cetuximab. CONCLUSION: Concurrent 5-FU/MMC-CRT without induction or maintenance chemotherapy remains the standard of care for anal cancer patients.

Radiation therapy for early stages of morbus Ledderhose.

PURPOSE: To evaluate the efficacy of radiation therapy (RT) in the treatment of early stages of benign plantar fibromatosis (Morbus Ledderhose [ML]). PATIENTS AND METHODS: From 2003 to 2008, 24 patients (33 sites) with a mean age of 52 years received RT for symptomatic ML. Prior to RT, 19 patients complained of pain and 15 had walking difficulties. 21 patients (28 sites) were irradiated with orthovoltage X-rays and three (five sites) received electron-beam irradiation. The RT protocol consisted of five weekly fractions of 3.0 Gy (15 Gy), repeated after 6 weeks to a total dose of 30 Gy in 20 patients (28 sites). In four patients (five sites), two single fractions of 4.0 Gy were applied, repeated at intervals of 4 weeks to total doses of 24-32 Gy. Primary study endpoints were the prevention of disease progression and the avoidance of a surgical intervention. Secondary endpoints were pain relief, improvement of gait, and patients' subjective satisfaction measured with a linear analog scale (LAS). RESULTS: After a median follow-up of 22.5 months, none of the patients experienced a progression of number and size of the lesions or the clinical symptoms. In eleven sites (33.3%) complete remission of cords or nodules occurred, in 18 (54.5%) a reduced number or size was noted, and four sites (12.1%) were unchanged. Pain relief was achieved in 13/19 patients (68.4%), and an improvement of gait abnormalities was noted in 11/15 patients (73.3%). The patients' subjective satisfaction measured by means of the LAS revealed a median improvement of 3.5 points in 22/24 patients (91.6%). Skin or soft tissues toxicities RTOG grade > 2 were not noted. CONCLUSION: RT is effective for treatment of the early stages of ML and may obviate the need for a surgical intervention. Long-term follow-up studies including a larger number of patients are required to define the role of RT in the management of this disorder.

Epidermal growth factor receptor expression as prognostic marker in patients with anal carcinoma treated with concurrent chemoradiation therapy.

PURPOSE: To investigate the prognostic value of epidermal growth factor receptor (EGFR) expression in pretreatment tumor biopsy specimens of patients with anal cancer treated with concurrent 5-fluorouracil and mitomycin C-based chemoradiation therapy (CRT). METHODS AND MATERIALS: Immunohistochemical staining for EGFR was performed in pretreatment biopsy specimens of 103 patients with anal carcinoma. EGFR expression was correlated with clinical and histopathologic characteristics and with clinical endpoints, including local failure-free survival (LFFS), colostomy-free survival (CFS), distant metastases-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: EGFR staining intensity was absent in 3%, weak in 23%, intermediate in 36% and intense in 38% of the patients. In univariate analysis, the level of EGFR staining was significantly correlated with CSS (absent/weak vs intermediate/intense expression: 5-year CSS, 70% vs 86%, P=.03). As a trend, this was also observed for DMFS (70% vs 86%, P=.06) and LFFS (70% vs 87%, P=.16). In multivariate analysis, N stage, tumor differentiation, and patients' sex were independent prognostic factors for CSS, whereas EGFR expression only reached borderline significance (hazard ratio 2.75; P=.08). CONCLUSION: Our results suggest that elevated levels of pretreatment EGFR expression could be correlated with favorable clinical outcome in anal cancer patients treated with CRT. Further studies are warranted to elucidate how EGFR is involved in the response to CRT.

High survivin expression as a risk factor in patients with anal carcinoma treated with concurrent chemoradiotherapy.

PURPOSE: To investigate the prognostic value of survivin expression in pretreatment specimens from patients with anal cancer treated with concurrent 5-FU and mitomycin C-based chemoradiation (CRT). MATERIAL AND METHODS: Immunohistochemical staining for survivin was performed in pretreatment biopsies of 62 patients with anal carcinoma. Survivin expression was correlated with clinical and histopathological characteristics as well as local failure free- (LFFS), distant metastases free- (DMFS), cancer specific- (CSS), and overall survival (OS). RESULTS: Survivin staining intensity was weak in 10%, intermediate in 48% and intense in 42% of the patients. No association between survivin expression and clinicopathologic factors (tumor stage, age and HIV status) could be shown. In univariate analysis, the level of survivin staining was significantly correlated with DMFS (low survivin vs. high survivin: 94% vs. 74%, p = 0.04). T-stage, N-stage and the tumor grading were significantly associated with OS and CSS and with DMFS and LFFS, respectively. In multivariate analysis, survivin was confirmed as independent prognostic parameter for DMFS (RR, 0.04; p = 0.02) and for OS (RR, 0.27; p = 0.04). CONCLUSION: Our results demonstrated that the level of pretreatment survivin is correlated with the clinical outcome in patients with anal carcinoma treated with concurrent CRT. Further studies are warranted to elucidate the complex role of survivin for the oncologic treatment and to exploit the protein as a therapeutic target in combined modality treatment of anal cancer.

Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy?

PURPOSE: To report treatment compliance, toxicity and clinical outcome of chemoradiotherapy (CRT) for anal carcinoma in HIV-negative vs. HIV-positive patients treated with highly active antiretroviral therapy. MATERIAL AND METHODS: Between 1997 and 2008, 25 HIV-positive and 45 HIV-negative patients received CRT (50.4 Gy at 1.8 Gy/fraction plus 5.4-10.8 Gy boost; 5-fluorouracil, 1000 mg/m(2), Days 1-4 and 29-32, mitomycin C, 10 mg/m(2), Days 1 and 29). Median follow-up was 51 (range, 3-235) months. RESULTS: HIV-positive patients were significantly younger (mean age, 47 vs. 57 years, p<0.001) and predominantly male (92% vs. 29%, p<0.001). CRT could be completed in all patients with a reduction of chemotherapy and/or RT-interruption in 28% and 8%, respectively, in HIV-positive patients, and in 9% and 11%, respectively, in HIV-negative patients. Acute Grade 3/4-toxicity occurred in 44% vs. 49% (p=0.79). Initial complete response (84% vs. 93%, p=0.41), 5-year rates of local control (65% vs. 78%, p=0.44), cancer-specific (78% vs. 90%, p=0.17) and overall survival (71% vs. 77%, p=0.76) were not significantly different. CONCLUSION: HIV-positive patients with anal cancer can be treated with standard CRT, with the same tolerability and toxicity as HIV-negative patients. Long-term local control and survival rates are not significantly different between these groups.

Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for invasive anal carcinoma in human immunodeficiency virus-positive patients receiving highly active antiretroviral therapy.

PURPOSE: To report the clinical outcomes of chemoradiotherapy (CRT) for anal carcinoma in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy. PATIENTS AND METHODS: Between 1997 and 2008, 21 HIV-positive patients who were receiving highly active antiretroviral therapy were treated with CRT (50.4 Gy at 1.8 Gy/fraction plus a 5.4-10.8-Gy external boost; 5-fluorouracil, 1,000 mg/m(2), Days 1-4 and 29-32; and mitomycin C, 10 mg/m(2), Days 1 and 29). A retrospective analysis was performed with respect to the tumor response, local control, cancer-specific and overall survival, and toxicity. The immunologic parameters, including pre- and post-treatment CD4 count, viral load, and acquired immunodeficiency syndrome-specific morbidity was recorded during follow-up (median, 53 months; range, 10-99). RESULTS: CRT could be completed in all 21 patients with a reduction in the chemotherapy dose and/or interruption of radiotherapy in 5 and 5 cases, respectively. Acute Grade 3 toxicity occurred in 8 (38%) of the 21 patients. A complete response was achieved in 17 patients (81%), and tumor persistence or early progression was noted in 4 (19%). Six patients (29%) died, 5 of cancer progression and 1 of treatment-related toxicity. The 5-year local control, cancer-specific, and overall survival rate was 59%, 75%, and 67%, respectively. The median CD4 count significantly decreased from 347.5 cells/microL before CRT to 125 cells/microL 3-7 weeks after CRT completion (p <.001). In 6 (32%) of 19 patients, an increase of the HIV viral load was noted. Both parameters returned to the pretreatment values with additional follow-up. CONCLUSION: Our data have confirmed that in the highly active antiretroviral therapy era, HIV-related anal cancer can be treated with standard CRT without dose reductions. Close surveillance of the immunologic parameters is necessary.

Selenium levels during the course of radiotherapy. No influence of irradiation on blood selenium concentration.

PURPOSE: To evaluate the influence of tumor characteristics and irradiation on blood selenium concentrations and their course during radiotherapy. MATERIAL AND METHODS: Selenium Levels were determined at various times during radiotherapy (I: beginning, II: mid, III: end, IV: 6 weeks after) by atomic absorption spectrometry in whole blood. The values were correlated with patient-, tumor- and irradiation-related parameters. RESULTS: A total of 690 samples were analyzed in 224 patients. The mean selenium value was 75.64 microg/l at the beginning of radiotherapy. 170 patients (77%) had reduced selenium Levels < 89 microg/l. Twelve patients (5.4%), mostly with head-and-neck cancer, had critically low values which need to be controlled and monitored. Three patients (1.3%) with breast cancer had critically increased values. Female patients showed higher seLenium concentrations than male patients (p = 0.0404). Patients diagnosed for head-and-neck cancer had significantly lower seLenium values than breast cancer patients (p = 0.016). Previous treatment by surgery and/or chemotherapy was correlated with lower selenium concentrations compared with irradiation as primary treatment (p = 0.039). According to analysis of variance, there was no significant change of the selenium concentration during the course of radiotherapy (p > 0.05). CONCLUSION: A preexisting selenium deficiency could be diagnosed in the broad majority of cancer patients undergoing radiotherapy. In contrast to the widely held opinion, it was not further aggravated by standard radiotherapy protocols.

Results of postoperative (90)Sr radiotherapy of keloids in view of patients' subjective assessment.

BACKGROUND AND PURPOSE: As treatment of keloids is mainly a cosmetic indication, the authors investigated, beyond the recurrence rate, the patients' satisfaction with the result and its correlation with objective medical findings. PATIENTS AND METHODS: 83 keloids of 66 patients had been irradiated after excision by a uniform protocol with 4 x 5 Gy (strontium- 90 [(90)Sr] surface applicator). A questionnaire was developed and sent out in which, above all, the satisfaction with the therapeutic and cosmetic outcome was obtained. These results were correlated with objective parameters and medical findings which were ascertained during an extra follow-up examination. RESULTS: Among 18 of the 41 patients (44%), who had answered the questionnaire, 19 of the 53 keloids treated (36%) had relapsed. 61% of the patients were extremely or mainly satisfied with the therapeutic outcome, 51% extremely or mainly satisfied with the cosmetic outcome. The relief from former keloid-caused symptoms (therapeutic outcome: p = 0.0005; cosmetic outcome: p = 0.0011), the ear as keloid localization (p = 0.0008 and p = 0.0197), and male gender (therapeutic outcome: p = 0.0423) were significantly associated with higher satisfaction. The recurrence rate as well as the extent of radiation side effects had no significant influence on patients' assessment. CONCLUSION: Cosmetic aspects like the dermal side effects and the patients' satisfaction should be taken into account when evaluating the results of radiotherapy in keloids.