Lise Balteskard

First Clinical Experience with α-Emitting Radium-223 in the Treatment of Skeletal Metastases

Purpose: The main goals were to study the safety and tolerability of the α-emitter radium-223 (223Ra) in breast and prostate cancer patients with skeletal metastases. In addition, pain palliation was evaluated. Experimental Design: Fifteen prostate and 10 breast cancer patients enrolled in a phase I trial received a single i.v. injection of 223Ra. Five patients were included at each of the dosages: 46, 93, 163, 213, or 250 kBq/kg and followed for 8 weeks. Palliative response was evaluated according to the pain scale of the European Organization for Research and Treatment of Cancer QLQ C30 questionnaire at baseline and at 1, 4, and 8 weeks after injection. Results: Weekly blood sampling during follow-up revealed mild and reversible myelosuppression with nadir 2 to 4 weeks after the injection. Importantly, for thrombocytes only grade 1 toxicity was reported. Grade 3 neutropenia and leucopenia occurred in two and three patients, respectively. Mild, transient diarrhea was observed in 10 of the 25 patients. Nausea and vomiting was more frequently observed in the highest dosage group. Serum alkaline phosphatase decreased with nadir averages of 29.5% in females and 52.1% in males. Pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4, and 8 weeks, respectively. 223Ra cleared rapidly from blood and was below 1% of initial level at 24 hours. Gamma camera images indicated, in accordance with pretreatment 99mTc-MDP scans, accumulation of 223Ra in skeletal lesions. Elimination was mainly intestinal. Median survival exceeded 20 months. Conclusions:223Ra was well tolerated at therapeutically relevant dosages. Phase II studies have therefore been initiated.

Sexual Function in Males After Radiotherapy for Rectal Cancer

PURPOSE Knowledge of sexual problems after pre- or postoperative radiotherapy (RT) with 50 Gy for rectal cancer is limited. In this study, we aimed to compare self-rated sexual functioning in irradiated (RT+) and nonirradiated (RT-) male patients at least 2 years after surgery for rectal cancer. METHODS AND MATERIALS Patients diagnosed with rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Male patients without recurrence at the time of the study. The International Index of Erectile Function, a self-rated instrument, was used to assess sexual functioning, and serum levels of serum testosterone were measured. RESULTS Questionnaires were returned from 241 patients a median of 4.5 years after surgery. The median age was 67 years at survey. RT+ patients (n = 108) had significantly poorer scores for erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction with sex life compared with RT- patients (n = 133). In multiple age-adjusted analysis, the odds ratio for moderate-severe erectile dysfunction in RT+ patients was 7.3 compared with RT- patients (p <0.001). Furthermore, erectile dysfunction of this degree was associated with low serum testosterone (p = 0.01). CONCLUSION RT for rectal cancer is associated with significant long-term effects on sexual function in males.

Sexual function in females after radiotherapy for rectal cancer

Abstract Background. Knowledge about female sexual problems after pre- or postoperative (chemo-)radiotherapy and radical resection of rectal cancer is limited. The aim of this study was to compare self-rated sexual functioning in women treated with or without radiotherapy (RT+ vs. RT−), at least two years after surgery for rectal cancer. Methods and materials. Female patients diagnosed from 1993 to 2003 were identified from a national database, the Norwegian Rectal Cancer Registry. Eligible patients were without recurrence or metastases at the time of the study. The Sexual function and Vaginal Changes Questionnaire (SVQ) was used to measure sexual functioning. Results. Questionnaires were returned from 172 of 332 invited and eligible women (52%). The mean age was 65 years (range 42–79) and the time since surgery for rectal cancer was 4.5 years (range 2.6–12.4). Sexual interest was not significantly impaired in RT+ (n=62) compared to RT− (n=110) women. RT+ women reported more vaginal problems in terms of vaginal dryness (50% vs. 24%), dyspareunia (35% vs. 11%) and reduced vaginal dimension (35% vs. 6%) compared with RT− patients; however, they did not have significantly more worries about their sex life. Conclusion. An increased risk of dyspareunia and vaginal dryness was observed in women following surgery combined with (chemo-)radiotherapy compared with women treated with surgery alone. Further research is required to determine the effect of adjuvant therapy on female sexual function.

Impaired health-related quality of life after chemoradiotherapy for anal cancer: Late effects in a national cohort of 128 survivors

Abstract Background. Chemoradiotherapy is an effective treatment for anal cancer, yet from follow-up many survivors seem to suffer from late effects. Data of long-term health-related quality of life (HRQOL) in anal cancer survivors are limited, and there is a growing interest in cancer survivorship. Material and methods. A national cohort of all anal cancer survivors treated with curative chemoradiotherapy in 2000–2007 was invited to a cross-sectional study. Of 199 eligible survivors, 128 (64%) returned the questionnaires, the median time since diagnosis was 66 months. The median age was 61 years and 79% were women. HRQOL was evaluated with EORTC questionnaires QLQ-C30 and QLQ-CR29, and neurotoxicity with the Scale of Chemotherapy-Induced Neurotoxicity. An age- and sex-matched reference group of volunteers (n = 269) not treated for pelvic cancer answered the same questionnaires. Results from QLQ-C30 of the reference group were compared to Norwegian and Dutch normative data. Results. The mean scores of anal cancer survivors were poorer compared to volunteers and normative data. Anal cancer survivors reported significant impairment of function, especially social and role function, compared to the volunteers (difference ≥ 20 points, p < 0.001). Survivors had markedly increased scores for fatigue, dyspnoea, insomnia and diarrhoea (difference ≥ 15 points, p < 0.001). The global quality of life was significantly reduced (difference 15 points, p < 0.001). Anal cancer survivors had increased stool frequency, more buttock pain, flatulence, faecal incontinence, impotence (males), dyspareunia and reduced sexual interest (females) (difference ≥ 15 points, p < 0.001). There was increased frequency of tinnitus in survivors treated with cisplatin-based chemotherapy (p = 0.004). Conclusions. Survivors after chemoradiotherapy for anal cancer have significant long-term impairment of HRQOL. Reduced social, role and sexual function, and increased diarrhoea, incontinence for gas and stools, and buttock pain were commonly reported. Increased awareness of this may lead to better management of late effects and better care for cancer survivors.

Information and communication technology (ICT) in oncology. Patients' and relatives' experiences and suggestions

Cancer patients and relatives worldwide are turning more and more to the internet to obtain health information. The goal of this survey was to clarify their experiences and suggestions on the implementation of information and communication technology (ICT) in oncology. A total of 127 patients and 60 relatives visiting the outpatient clinic at the Department of Oncology, University of North Norway (UNN), the regional office of the Norwegian Cancer Union (NCU) and the Montebello Centre were included in a questionnaire-based study. Participants were recruited during the period September 2001 to February 2002. There were 92 women and 95 men. We revealed that hospital doctors, followed by nurses and friends, were the most important informants. Two-thirds of patients and relatives had access to the internet, but fewer than one-third had searched the internet for medical information and only one-fifth had discussed information accessed with their doctor. Only one-tenth had visited a hospital website. Internet access was correlated with young age. Almost two-thirds suggested that e-mail and/or WAP (wireless application protocol) communication should be included in hospital–patient communication. Concerning hospital websites, waiting time, treatment offer and addresses were considered the top three topics of interest. In conclusion, the majority of cancer patients and relatives have access to the internet. They recommend ICT employed in patient–hospital communication and suggest waiting time, treatment offers and addresses the three most important topics on hospital websites.

A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer

BACKGROUND To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. PATIENTS AND METHODS Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). RESULTS Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. CONCLUSIONS Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

Colorectal Cancer Metastatic to the Brain: Time Trends in Presentation and Outcome

Objective: It was the aim of this study to compare differences in disease pattern, patient characteristics and survival in patient cohorts treated during different decades. Methods: We conducted a retrospective analysis of all patients with brain metastases from colorectal cancer treated between 1983 and June 2008 in Northern Norway. The patients were assigned to 3 different groups, based on the decade of treatment. Results: The time interval between first cancer diagnosis and brain metastases has significantly increased over time. The use of chemotherapy before development of brain metastases has also increased. Only few patients did not harbour extracranial metastases. Chemotherapy after diagnosis of brain metastases has been used exclusively in the present decade, but in only 3 patients. Combined surgical resection or radiosurgery plus whole-brain radiotherapy has increasingly been utilized, but whole-brain radiotherapy alone remained the cornerstone. Neither survival from first cancer diagnosis nor from brain metastasis treatment has improved significantly; however, with up to 17 patients, the groups were small. Three factors were significantly associated with better survival: good performance status, limited number of brain metastases (1 vs. 2–3 vs. 4 or more) and absence of extracranial metastases. The prognostic impact of the recursive partitioning analysis classes was confirmed, while the new graded prognostic assessment index performed less well. Conclusions: Median survival was maximum 6 months in all decades, despite the increasing use of more aggressive treatment. As most patients harbour extracranial metastases that threaten their lives, systemic treatment might theoretically play a role in the management of these patients, but more data need to be collected to confirm the clinical impact of this approach.

MicroRNA-15b is induced with E2F-controlled genes in HPV-related cancer.

Background:MicroRNAs (miRNAs) are important regulators of cellular processes and are found to be deregulated in many cancers. We here analysed the miRNA expression in anal carcinomas. In a previous study, we found that our anal carcinoma tumours were divided into two groups based on the expression of E2F-regulated genes. Therefore, we searched for miRNAs that could reproduce this grouping.Methods:A global screen of the miRNA population was performed using real-time quantitative PCR (RT–qPCR) array methods and differentially expressed miRNAs were identified. Real-time–qPCR was used to verify the expression levels of selected miRNAs and genes in a larger collection of biopsies. A siRNA-mediated knockdown of human papilloma virus (HPV)16 E7 in a cervical cell line was performed to assess the effect of E7 on miR-15b.Results:The grouping of tumours into two groups based on the expression of E2F-controlled genes was confirmed in a larger collection of anal carcinoma tumours. The expression of miR-15b was shown to be highly correlated with that of five selected E2F-induced genes (CCNA2, CCNB1, CCNB2, MSH6 and MCM7). A knockdown of HPV16 E7 resulted in decreased levels of miR-15b in Ca Ski cells.Conclusion:MiR-15b expression correlates with E2F-regulated genes in anal carcinoma and appears to be part of the E2F-regulatory network.

Faecal incontinence after chemoradiotherapy in anal cancer survivors: Long-term results of a national cohort

PURPOSE To examine the prevalence and severity of faecal incontinence amongst anal cancer survivors after chemoradiotherapy. MATERIAL AND METHODS Anal cancer survivors from a complete, unselected, national cohort, minimum 2-years follow-up, were invited to a cross-sectional study. The St. Marks incontinence score was used to evaluate occurrence and degree of faecal incontinence the last four weeks. The results were compared to age- and sex-matched volunteers from the general population. RESULTS Of 199 invited survivors and 1211 volunteers, 66% and 21%, respectively, signed informed consent. The survivors had significantly higher St. Marks score than the volunteers (mean 9.7 vs. 1.1, p<0.001). Incontinence of stool of any degree was reported by 43% vs. 5% (OR 4.0, CI 2.73-6.01), and urgency was reported by 64% vs. 6% (OR 6.6, CI 4.38-9.90) of the survivors and volunteers, respectively. Only 29% of those with leakage of liquid stool used constipating drugs. Survivors of locally advanced tumours had a higher incontinence score (p<0.01). CONCLUSIONS Moderate to severe faecal incontinence is common amongst anal cancer survivors. Post-treatment follow-up should include the evaluation of continence, and incontinent survivors should be offered better symptom management and multidisciplinary approach if simple measures are insufficient.

Gene expression reveals two distinct groups of anal carcinomas with clinical implications

Human papillomavirus (HPV) is a major aetiological agent in anal carcinomas. We here present a study of global gene expression using microarray hybridisation in a collection of anal carcinoma biopsies. Quantitative PCR was used to verify expression of selected genes. All biopsies contained integrated DNA of human papillomavirus subtype 16 (HPV16) and expressed HPV16 E7 mRNA. No other subspecies of HPV were detected in these 13 biopsies as assessed by PCR amplification and DNA sequencing. Unsupervised cluster analysis, based on global mRNA expression, divided the tumour biopsies into two distinct groups. Cluster analysis based on a number of high-risk HPV and/or E2F-regulated genes reproduced this biopsy grouping, suggesting that integrated HPV16 substantially influenced global gene expression in approximately half the biopsies studied. The levels of HPV16 E7 mRNA were significantly different between the two groups, but with considerable overlap. Thus, influence on global gene expression could not be absolutely ascribed to the expression level of HPV16. To investigate whether this distinction in gene expression had prognostic impact, we studied protein expression in an independent cohort of 55 anal carcinomas not included in the microarray study of two differentially expressed candidate genes, minichromosome maintenance complex component 7 (MCM7) and cyclin-dependent kinase inhibitor 2A (CDKN2A or p16). HPV status was assessed by in situ hybridisation. There was a significant association between in situ staining for HPV E7 mRNA and immunostaining for CDKN2A (p16) and MCM7 protein. CDKN2A (p16) mRNA was found significantly differentially expressed between the two tumour groups. However, cluster analysis on genes directly regulated by CDKN2A (p16) could not reproduce this split of biopsies into two groups, suggesting that the transcriptional regulatory activity of CDKN2A in these biopsies is inhibited. Furthermore, protein expression of CDKN2A (p16) could not be associated with survival. MCM7 is directly regulated by E2F and induced by HPV, and its mRNA was found differentially expressed between the two tumour groups. High level of MCM7 protein was found to be associated with both improved relapse-free survival (RFS, P=0.02) and cancer-specific survival (CSS, P=0.03) in anal cancer patients treated with radiation with or without additional chemotherapy.