Diane Severin

Novel DNA sequence variants in the hHR21 DNA repair gene in radiosensitive cancer patients

PURPOSE Radiation therapy is an important treatment modality for oncology patients. DNA sequence variants have so far been identified in only a few genes in radiosensitive cancer patients. Patients known to be clinically radiosensitive were tested for mutation of a gene involved in DNA double-strand break repair and sister chromatid cohesion--hHR21. METHODS AND MATERIALS Clinically radiation-sensitive patients were accrued to the study after giving informed consent. Blood samples were obtained and lymphoblastoid cell lines established. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to amplify the hHR21 gene, and the DNA product was sequenced to identify any genetic abnormalities. Northern blot analysis, cell survival, and growth assays were performed on control cells and cells with hHR21 variants, and a restriction digest assay was developed to screen for carriers of a detected gene variant. RESULTS The DNA sequence of the hHR21 gene was determined in 19 radiation-sensitive cancer patients. In 6 of the 19 patients, a thymidine (T) to cytosine (C) transition was detected at position 1440 of the hHR21 open reading frame (T1440C). This variant did not alter the amino acid sequence and was likely to be a polymorphism. One patient with a particularly severe radiation reaction had a second sequence variant immediately adjacent to the first. This was a guanine (G) to adenine (A) transition (G1441A), resulting in a change of the amino acid sequence (glycine --> arginine) in a portion of the protein conserved in evolution. This suggests that this DNA alteration may be biologically significant. Restriction digest with the HpaII enzyme confirmed the presence of both sequence variants on the same allele. CONCLUSIONS We describe the first two DNA sequence variants ever found in the hHR21 gene, in patients with clinical radiation hypersensitivity. Although no direct evidence for the involvement of hHR21 alterations in the radiosensitivity of the cancer patients examined has been demonstrated, the possibility exists that homozygous mutations or other mutations of this gene could contribute to radiosensitivity. A simple test is described that could be applied to screening for these variants in relevant populations.

Breast radiotherapy with inclusion of internal mammary nodes: a comparison of techniques with three-dimensional planning.

PURPOSE To compare the partially wide tangent (PWT) technique of breast and internal mammary chain irradiation with photon/electron (P/E) and standard tangent (ST) techniques in terms of dose homogeneity within breast and the dose to critical structures such as the heart and lung. METHODS AND MATERIALS Sixteen left breast cancer patients underwent CT simulation. The breasts, lungs, heart, and internal mammary chain were contoured and treatment plans generated on a three-dimensional planning system (Helax-TMS). RESULTS The mean dose to the left breast volume with the ST, P/E, and PWT techniques was 94.7%, 98.4%, and 96.5%, respectively (p = 0.029). The left lung received the lowest mean dose with the ST technique (13.9%) compared with PWT (22.8%) and P/E (24.3%). The internal mammary chain volume was most consistently treated with the PWT (mean dose 99%) vs. P/E (86%) and ST (38.4%) techniques. The heart received the least dose with ST (mean dose 6.7%) vs. PWT (10.3%) and P/E (19%). The PWT treated the greatest amount of contralateral breast (mean dose 5.8%) vs. ST (3.2%) vs. P/E (2.8%). CONCLUSION The PWT technique treats the internal mammary chain with acceptable toxicity to major organs, especially the heart, and with reasonable dose homogeneity in patients with mastectomy or intact breasts.

A treatment planning study comparing helical tomotherapy with intensity-modulated radiotherapy for the treatment of anal cancer

PURPOSE A planning study to compare helical tomotherapy (HT) and intensity-modulated radiotherapy (IMRT) for the treatment of anal canal cancer. MATERIALS AND METHODS Sixteen (8 males and 8 females) patients with anal cancer previously treated radically were identified. HT and IMRT plans were generated and dosimetric comparisons of the plans were performed. The planning goals were to deliver 54Gy to the tumor (PTV(54Gy)) and 48Gy to the nodes at risk (PTV(Node)) in 30 fractions. RESULTS PTVs: HT plans were more homogeneous for both men and women. Male patients: HT vs. IMRT: D(max): 55.87+/-0.58 vs. 59.17+/-3.24 (p=0.036); D(min): 52.91+/-0.36 vs. 44.09+/-6.84 (p=0.012); female patients: HT vs. IMRT: D(max): 56.14+/-0.71 vs. 59.47+/-0.81 (p=0.012); D(min): 52.36+/-0.87 vs. 50.97+/-1.42 (p=0.028). OARs: In general, HT plans delivered a lower dose to the peritoneal cavity, external genitalia and the bladder and IMRT plans resulted in greater sparing of the pelvic bones (iliac crest/femur) for both men and women. Iliac crest/femur: the difference was significant only for the mean V10Gy of iliac crest in women (p< or =0.012). External genitalia: HT plans achieved better sparing in women compared to men (p< or =0.046). For men, the mean doses were 18.96+/-3.17 and 15.72+/-3.21 for the HT and IMRT plan, respectively (p< or =0.017). Skin: both techniques achieved comparable sparing of the non-target skin (p=NS). CONCLUSIONS HT and IMRT techniques achieved comparable target dose coverage and organ sparing, whereas HT plans were more homogeneous for both men and women.

First report on the patient database for the identification of the genetic pathways involved in patients over-reacting to radiotherapy: GENEPI-II

BACKGROUND Identifying the most radiosensitive patient group would have huge clinical implications. METHODS A tissue bank containing skin fibroblasts, whole blood, lymphocytes, plasma and lymphoblastoid cell lines from clinically radiation hypersensitive patients was established from patients in Europe and Canada. Over-reacting individuals had CTCAE3.0 severe acute side effects grade 2 or more occurring at very low radiation doses where these side effects are unexpected or grade 3-4 lasting more than 4 weeks after the end of radiotherapy and/or requiring surgical intervention at any time or severe late side effects grade 3-4. RESULTS Eleven patients have been identified with a mean age of 61.6±8.5 years (range 49-74). Two patients were male, 9 female. One patient had non-small cell lung cancer, 6 breast cancer, 2 head and neck cancer, one lymphoma and one meningioma. The mean follow-up time after radiotherapy was 1658±1048 days (range 84-3752). CONCLUSIONS The establishment of an international tissue bank of the rare group of patients with extreme hypersensitivity to radiotherapy was proven to be feasible and should enable in-depth molecular studies.

Three-Arm Randomized Phase III Trial: Quality Aloe and Placebo Cream Versus Powder as Skin Treatment During Breast Cancer Radiation Therapy

BACKGROUND The efficacy of aloe extract in reducing radiation-induced skin injury is controversial. The purpose of the present 3-arm randomized trial was to test the efficacy of quality-tested aloe extract in reducing the severity of radiation-induced skin injury and, secondarily, to examine the effect of a moist cream versus a dry powder skin care regimen. MATERIALS AND METHODS A total of 248 patients with breast cancer were randomized to powder, aloe cream, or placebo cream. Acute skin toxicity was scored weekly and after treatment at weeks 1, 2, and 4 using a modified 10-point Catterall scale. The patients scored their symptom severity using a 6-point Likert scale and kept an acute phase diary. RESULTS The aloe formulation did not reduce acute skin toxicity or symptom severity. Patients with a greater body mass index were more likely to develop acute skin toxicity. A similar pattern of increased skin reaction toxicity occurred with both study creams compared with the dry powder regimen. CONCLUSION No evidence was found to support prophylactic application of quality aloe extract or cream to improve the symptoms or reduce the skin reaction severity. Our results support a dry skin care regimen of powder during radiation therapy.

Prospective phase II study of tomotherapy based chemoradiation treatment for locally advanced anal cancer

BACKGROUND AND PURPOSE To evaluate toxicity, local control, and survival of anal cancer patients treated with helical tomotherapy (HT) and concurrent 5-fluorouracil and mitomycin-C (5FU/MMC). MATERIALS AND METHODS Fifty-seven patients were treated with HT and concurrent 5FU/MMC. The planning objectives were to deliver 54 Gy to the tumor (PTV54) and 45 Gy to the nodes at risk (PTV45) in 30 fractions. Patients were reviewed for toxicity weekly during HT, every 6 weeks for 3 months, and then every 3-4 months for 5 years. RESULTS The median follow-up was 40 months. The median age was 58 years (range: 37-83). Stage distribution: stage II-48%, IIIA-18%, IIIB-34%. The majority of patients developed ⩽ grade 2 acute toxicity scores. The most common ⩾ grade 3 acute toxicity was neutropenia (40%). Common late toxicities were grade 2 anal incontinence (16%) and telangiectasia (12%). The 3 year colostomy-free survival rate was 77% (95% CI: 61-87%), 3 year disease-free survival rate was 80% (CI: 66-89%), and 3 year overall survival was 91% (CI: 77-96%). CONCLUSIONS Incorporation of HT with concurrent 5FU/MMC had low treatment-related acute and late morbidity with few treatment breaks. However, the expected dosimetric benefit for hematological toxicity was not experienced clinically.

Patient reported quality of life after helical IMRT based concurrent chemoradiation of locally advanced anal cancer

BACKGROUND AND PURPOSE Concurrent chemoradiation (CCRT) is the standard treatment for locally advanced anal canal carcinoma, although treatment-related side effects can affect patient quality of life (QOL). The purpose was to prospectively evaluate the effects of Tomotherapy (HT) based CCRT on patient reported QOL in locally advanced anal cancer. PATIENTS AND METHODS Fifty-four patients treated with HT and concurrent 5-fluorouracil/mitomycin-C underwent QOL evaluation at baseline, after treatment, and during follow-up with EORTC core (QLQ-C30) and colorectal (QLQ-CR29) questionnaires. The QOL scores at baseline and post-treatment were compared. RESULTS All C30 functional symptoms, except emotional and cognitive functioning, were impaired end-of-treatment and recovered by 3months follow-up. The majority of symptom scores were worse end-of-treatment but recovered by 3months except for fecal incontinence (FI), diarrhea, urinary incontinence (UI), and dyspareunia which persisted. FI returned to baseline at 12months while diarrhea, UI, and dyspareunia persisted. CONCLUSIONS Most impaired functions and symptoms following HT based CCRT were temporary and improved by 3months post-therapy. Late complications affecting QOL were FI, sexual function, UI, and diarrhea. Our observations support routine use of IMRT and emphasize the significance of precise evaluation of sexual, urinary, and anorectal functions before starting CCRT and routine incorporation of QOL evaluations.

A Phase I Study Examining the Feasibility and Safety of an Aerobic Exercise Intervention in Patients With Rectal Cancer During and After Neoadjuvant Chemoradiotherapy

PURPOSE/OBJECTIVES To assess the feasibility and safety of an aerobic exercise intervention in patients with rectal cancer during and after neoadjuvant chemoradiotherapy (NACRT).
. DESIGN A prospective, single-group design with assessments at pre-NACRT, post-NACRT, and presurgery.
. SETTING The Cross Cancer Institute and University of Alberta in Edmonton, Canada.
. SAMPLE 18 patients with rectal cancer scheduled to receive long-course NACRT followed by definitive surgery. 
. METHODS Participants received a supervised moderate-intensity aerobic exercise program three days per week during six weeks of NACRT followed by an unsupervised aerobic exercise program for 150 minutes or more per week for 6-8 weeks prior to surgery.
. MAIN RESEARCH VARIABLES Eligibility rate, recruitment rate, follow-up rate, exercise adherence, serious adverse events, health-related fitness outcomes, and patient-reported outcomes.
. FINDINGS Follow-up rates post-NACRT were 83% for health-related fitness outcomes and 94% for patient-reported outcomes. Patients attended a median of 83% of their supervised exercise sessions and completed a mean of 222 minutes per week (SD = 155) of their unsupervised exercise. No serious adverse events were observed or reported. Most health-related fitness outcomes and patient-reported outcomes declined during NACRT and recovered after NACRT. 
. CONCLUSIONS Aerobic exercise is feasible and safe for patients with rectal cancer during and after NACRT.
. IMPLICATIONS FOR NURSING Patients with rectal cancer are able to engage in moderate-intensity aerobic exercise during NACRT.

Beyond the pilot: Navigating through 8 years of palliative radiotherapy integrated symptom management (PRISM).

156 Background: Patients with incurable cancer often have problematic symptoms and functional impairment despite active cancer care. Opportunities to assess and address these unmet needs exist at every care point. METHODS In 2007, we piloted a holistic model of care in an outpatient Palliative Radiation Oncology clinic. Twin goals (timely access to radiotherapy (RT) and multidisciplinary (MDT) symptom assessment/management) were met: a one-stop-shop to see a radiation oncologist (RO), nurse (RN), radiation therapist (MRT(T)) and pharmacist, with Social Work, Nutrition and Rehabilitation as needed. The model has since evolved, adapting to shifting system-level barriers, with continued attention to patient-reported outcomes. We discuss our teams 8-year effort to integrate symptom management and palliative RT in a tertiary cancer center. RESULTS Despite challenges (patient-, provider-, facility-, service- or logistics-related), our target RT population grew from initially only those with bone metastases (served by 1 RO once weekly), to include brain or chest disease (seeing any local RO, any day). Priorities were complex, even at odds, to cater to broadly defined stakeholders: access to RT, systematic basic supportive care (BSC), operational efficiency, care transitions. From strong interdisciplinary focus and task-shifting emerged a critical patient navigation piece. Informal, then formal quality improvement work recast key functions by person/time/place, recently streamlining (e.g. intake/triage/referral pathways) and upgrading (e.g. shared RN/MRT(T) navigator role). Interfaces are layered, broad now between BSC (e.g. horizontal pre-/post-visit telephone symptom screening and goal-setting) and RT processes (e.g. more consistently vertical, less disruptive to technical workflows), enabling scale-up and alignment by design with quality dimensions. Operational and patient outcome metrics remain under periodic review. CONCLUSIONS Integrating MDT BSC with outpatient palliative RT is feasible and scalable, when incrementally tailored to context. Further work, to formally assess patient satisfaction and downstream care needs, will inform PRISM as our local standard.

Predictors of adherence to aerobic exercise in rectal cancer patients during and after neoadjuvant chemoradiotherapy

Abstract This pilot study explored predictors of adherence to exercise during and after neoadjuvant chemoradiotherapy (NACRT) in rectal cancer patients. Eighteen rectal cancer patients were prescribed three supervised aerobic exercise sessions/week during NACRT followed by ≥150 min/week of unsupervised aerobic exercise after NACRT. Although not statistically significant, adherence to supervised exercise during NACRT was meaningfully better for patients who were women (d = .82; P = .12), younger (d = −.62; P = .30), married (d = .62; P = .42), with better mental health (r = .32; P = .21), fewer diarrhea symptoms (r = .48; P = .052), and higher anticipated enjoyment (r = .31; P = .23), support (r = .32; P = .22), and motivation (r = .31; P = .23). After NACRT, adherence was significantly better for patients who reported worse mental health (r = −.56; P = .046) and meaningfully better for patients who were women (d = .54; P = .38), better educated (d = .77; P = .22), had no comorbidities (d = −.63; P = .17), and exercised at baseline (d = 1.05; P = .12). Demographics, tumor side effects, and motivational variables may predict adherence to exercise during and after NACRT.