Kjersti Bruheim

LATE SIDE EFFECTS AND QUALITY OF LIFE AFTER RADIOTHERAPY FOR RECTAL CANCER

PURPOSE There is little knowledge on long-term morbidity after radiotherapy (50 Gy) and total mesorectal excision for rectal cancer. Therefore, late effects on bowel, anorectal, and urinary function, and health-related quality of life (QoL), were studied in a national cohort (n = 535). METHODS AND MATERIALS All Norwegian patients who received pre- or postoperative (chemo-)radiotherapy for rectal cancer from 1993 to 2003 were identified. Patients treated with surgery alone served as controls. Patients were without recurrence or metastases. Bowel and urinary function was scored with the LENT SOMA scale and the St. Marks Score for fecal incontinence and QoL with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). RESULTS Median time since surgery was 4.8 years. Radiation-treated (RT+) patients (n = 199) had increased bowel frequency compared with non-radiation-treated (RT-) patients (n = 336); 19% vs. 6% had more than eight daily bowel movements (p < 0.001). In patients without stoma, a higher proportion of RT+ (n = 69) compared with RT- patients (n = 240), were incontinent for liquid stools (49% vs. 15%, p < 0.001), needed a sanitary pad (52% vs. 13%, p < 0.001), and lacked the ability to defer defecation (44% vs. 16%, p < 0.001). Daily urinary incontinence occurred more frequently after radiotherapy (9% vs. 2%, p = 0.001). Radiation-treated patients had worse social function than RT- patients, and patients with fecal or urinary incontinence had impaired scores for global quality of life and social function (p < 0.001). CONCLUSIONS Radiotherapy for rectal cancer is associated with considerable long-term effects on anorectal function, especially in terms of bowel frequency and fecal incontinence. RT+ patients have worse social function, and fecal incontinence has a negative impact on QoL.

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.

Late Patient-Reported Toxicity After Preoperative Radiotherapy or Chemoradiotherapy in Nonresectable Rectal Cancer: Results From a Randomized Phase III Study

PURPOSE Preoperative chemoradiotherapy (CRT) is superior to radiotherapy (RT) in locally advanced rectal cancer, but the survival gain is limited. Late toxicity is, therefore, important. The aim was to compare late bowel, urinary, and sexual functions after CRT or RT. METHODS AND MATERIALS Patients (N = 207) with nonresectable rectal cancer were randomized to preoperative CRT or RT (2 Gy × 25 ± 5-fluorouracil/leucovorin). Extended surgery was often required. Self-reported late toxicity was scored according to the LENT SOMA criteria in a structured telephone interview and with questionnaires European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), International Index of Erectile Function (IIEF), and sexual function-vaginal changes questionnaire (SVQ). RESULTS Of the 105 patients alive in Norway and Sweden after 4 to 12 years of follow-up, 78 (74%) responded. More patients in the CRT group had received a stoma (73% vs. 52%, p = 0.09). Most patients without a stoma (7 of 12 in CRT group and 9 of 16 in RT group) had incontinence for liquid stools or gas. No stoma and good anal function were seen in 5 patients (11%) in the CRT group and in 11 (30%) in the RT group (p = 0.046). Of 44 patients in the CRT group, 12 (28%) had had bowel obstruction compared with 5 of 33 (15%) in the RT group (p = 0.27). One-quarter of the patients reported urinary incontinence. The majority of men had severe erectile dysfunction. Few women reported sexual activity during the previous month. However, the majority did not have concerns about their sex life. CONCLUSIONS Fecal incontinence and erectile dysfunction are frequent after combined treatment for locally advanced rectal cancer. There was a clear tendency for the problems to be more common after CRT than after RT.

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.

Radiotherapy for Rectal Cancer Is Associated With Reduced Serum Testosterone and Increased FSH and LH

PURPOSE It is known that scattered radiation to the testes during pelvic radiotherapy can affect fertility, but there is little knowledge on its effects on male sex hormones. The aim of this study was to determine whether radiotherapy for rectal cancer affects testosterone production. METHODS AND MATERIALS All male patients who had received adjuvant radiotherapy for rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Patients treated with surgery alone were randomly selected from the same registry as control subjects. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone binding globulin (SHBG) were analyzed, and free testosterone was calculated (N = 290). Information about the radiotherapy treatment was collected from the patient hospital charts. RESULTS Serum FSH was 3 times higher in the radiotherapy group than in the control group (median, 18.8 vs. 6.3 IU/L, p <0.001), and serum LH was 1.7 times higher (median, 7.5 vs. 4.5 IU/l, p <0.001). In the radiotherapy group, 27% of patients had testosterone levels below the reference range (8-35 nmol/L), compared with 10% of the nonirradiated patients (p <0.001). Irradiated patients had lower serum testosterone (mean, 11.1 vs. 13.4 nmol/L, p <0.001) and lower calculated free testosterone (mean, 214 vs. 235 pmol/L, p <0.05) than control subjects. Total testosterone, calculated free testosterone, and gonadotropins were related to the distance from the bony pelvic structures to the caudal field edge. CONCLUSIONS Increased serum levels of gonadotropins and subnormal serum levels of testosterone indicate that curative radiotherapy for rectal cancer can result in permanent testicular dysfunction.

The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies

Graphical abstract

Dose painting by numbers in a standard treatment planning system using inverted dose prescription maps

ABSTRACT Background. Dose painting by numbers (DPBN) is a method to deliver an inhomogeneous tumor dose voxel-by-voxel with a prescription based on biological medical images. However, planning of DPBN is not supported by commercial treatment planning systems (TPS) today. Here, a straightforward method for DPBN with a standard TPS is presented. Material and methods. DPBN tumor dose prescription maps were generated from 18F-FDG-PET images applying a linear relationship between image voxel value and dose. An inverted DPBN prescription map was created and imported into a standard TPS where it was defined as a mock pre-treated dose. Using inverse optimization for the summed dose, a planned DPBN dose distribution was created. The procedure was tested in standard TPS for three different tumor cases; cervix, lung and head and neck. The treatment plans were compared to the prescribed DPBN dose distribution by three-dimensional (3D) gamma analysis and quality factors (QFs). Delivery of the DPBN plans was assessed with portal dosimetry (PD). Results. Maximum tumor doses of 149%, 140% and 151% relative to the minimum tumor dose were prescribed for the cervix, lung and head and neck case, respectively. DPBN distributions were well achieved within the tumor whilst normal tissue doses were within constraints. Generally, high gamma pass rates (> 89% at 2%/2 mm) and low QFs (< 2.6%) were found. PD showed that all DPBN plans could be successfully delivered. Conclusions. The presented methodology enables the use of currently available TPSs for DPBN planning and delivery and may therefore pave the way for clinical implementation.

Spatial dosimetric sensitivity of contouring uncertainties in gynecological 3D-based brachytherapy

BACKGROUND AND PURPOSE This study aims to analyze subsections of the target volume that are sensitive to delineation uncertainties with respect to underdosage (spatial dosimetric uncertainty) in MRI-based brachytherapy of cervical cancer. MATERIAL AND METHODS A methodology was developed to simulate delineation uncertainties by shifting an angular segment of the contour perpendicular to the original HR-CTV. For shifts of 3, 6 and 9mm resulting D90 and D98 were calculated for the modified contour. The sensitivity of the dose plan to the locally introduced error was estimated by linear regression of D90 or D98 against the magnitude of the shift. The methodology was employed on 20 patients treated with tandem ring brachytherapy. RESULTS Topographic maps resulting from the dosimetric sensitivity analysis showed both large spatial variations and substantial inter-patient variations. For all plans included the spatial sensitivity in D90 ranged from 0.0 to -1.6%/mm, correspondingly sensitivity in D98 ranged from 0 to -4.6%/mm. A significantly increased dosimetric sensitivity was found in anterior direction and the cranial part of the tumor (p<0.05). CONCLUSIONS The developed methodology identifies specific tumor regions and patients with increased risk of underdosage from delineation uncertainties in brachytherapy of cervical cancer.

Fatigue, insomnia and hot flashes after definitive radiochemotherapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: An analysis from the EMBRACE study

OBJECTIVE To evaluate the pattern of manifestation of fatigue, insomnia and hot flashes within the prospective, observational, multi-center EMBRACE study. METHODS Morbidity was prospectively assessed according to CTCAE v.3 and patient-reported outcome with EORTC QLQ-C30/CX24 at baseline and regular follow-up. Analyses of crude incidence, prevalence rates and actuarial estimates were performed. RESULTS A total of 1176 patients were analyzed with a median follow-up of 27 months. At baseline, CTCAE G1/G2 prevalence rates for fatigue were 29%/6.2%, for insomnia 18%/3.1% and for hot flashes 7.9%/1.6% with respective 3-year prevalence rates of 29%/6.8%, 17%/4.4% and 19%/5.9%. Similar patterns of manifestation were seen in patient-reported EORTC outcomes. The 3-year actuarial estimates for G ≥ 3 CTCAE fatigue, insomnia and hot flashes were 5.5%, 4.7% and 1.9%. Younger age was associated with significantly higher risk for fatigue, insomnia and hot flashes. CONCLUSION Fatigue, insomnia and hot flashes occurred mainly in the mild to moderate range. Fatigue and insomnia were already present before treatment and showed minor fluctuations or recovery during follow-up, whereas hot flashes showed a considerable increase after treatment. More research is needed to evaluate contributing risk factors in order to define intervention strategies.

Physician assessed and patient reported lower limb edema after definitive radio(chemo)therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: A report from the EMBRACE study

BACKGROUND/PURPOSE To evaluate the pattern of manifestation and risk factors for lower limb edema (LLE) within the prospective, observational, multi-center EMBRACE study on radiochemotherapy and MRI-guided brachytherapy in locally advanced cervical cancer (LACC). MATERIAL/METHODS LLE was prospectively assessed according to the physician-reported CTCAE v.3 and patient-reported EORTC QLQ-CX24 questionnaire at baseline and regular follow-up. RESULTS In total, 1176 patients were evaluated with a median follow-up of 27 months. Actuarial analyses revealed 3/5-year estimates of 27%/31% of CTCAE G ≥ 1, 6.1%/6.6% of G ≥ 2 and 0.5%/0.5% for G ≥ 3. Prevalence rates for G ≥ 1 LLE at 3 months, 1, 3 and 5 years after end of treatment were 7%, 12%, 12%, 15% for physician-assessed and 25%, 30%, 30%, 34% for any patient-reported symptoms and showed a steady increase over time. Invasive lymph node staging and obesity at diagnosis are independent significant risk factors for G ≥ 1 LLE, whereas nodal boost has no impact. Extended radiation fields including para-aortic and/or inguinal nodes show a tendency to increase the risk. CONCLUSION Severe LLE after definitive radiochemotherapy in LACC is rare. However, the risk for mild LLE is considerable, and related to patient-, diagnostic- and treatment characteristics. Less invasive diagnostic surgical procedures or non-invasive assessment, less invasive radiotherapy management and active rehabilitation are important pathways for future developments.