Patient-Reported Symptoms of Late Toxicity in Patients With Breast Cancer Treated With Hypofractionated Radiation Therapy and the Association With Quality of Life.

PURPOSE: Our purpose was to assess the prevalence of patient-reported symptoms of local late toxicity in patients with irradiated breast cancer and determine the association between late toxicity and quality of life. METHODS: Within the prospective Utrecht cohort for Multiple BReast cancer intErvention studies and Long-term evaluation cohort, a survey on self-reported late toxicity was sent to all patients with breast cancer with ≥12 months interval since radiation therapy treated with curative intent. Patients were treated with hypofractionated radiation therapy of 40 Gy/15 fractions or 42.5 Gy/16 fractions, with or without a simultaneous integrated boost. Symptoms of late toxicity were evaluated on a 4-point Likert scale. Late toxicity was defined as moderate-severe breast or chest wall pain combined with at least 1 other mild-severe late toxicity symptom, that is, breast or arm/hand lymphedema, firmness of the breast, or impaired arm movement. Physical, role, and social functioning were measured before, during, and after the late toxicity survey using the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire-C30 and compared with a Dutch normative population. RESULTS: In the study, 1613/2248 patients (72%) were included. Of those, 16% (n = 265) reported late toxicity. The median time interval between radiation therapy and survey was 38 months (interquartile range, 21-55). Moderate/severe firmness of the breast, chest wall pain, and breast pain were reported by, respectively, 18% (n = 295), 14% (n = 225), and 10% (n = 140) of all patients. Physical, role, and social functioning were below the clinical threshold (ie, clinically relevant impairment) in 13% to 52% of patients with late toxicity and 2% to 26% of patients without late toxicity. Patients with late toxicity significantly more often received analgesics, physiotherapy, and lymphedema therapy compared with patients without late toxicity. CONCLUSIONS: This study provided insight into the prevalence of patient-reported late toxicity after hypofractionated radiation therapy and the influence of late toxicity on quality of life after breast cancer. These results may help health care professionals to inform their patients about long-term effects of breast cancer treatment including hypofractionated radiation therapy.

Factors Associated with Late Local Radiation Toxicity after Post-Operative Breast Irradiation.

Purpose: To assess determinants associated with late local radiation toxicity in patients treated for breast cancer. Methods: A systematic review was performed. All studies reporting ≥2 variables associated with late local radiation toxicity after treatment with postoperative whole breast irradiation were included. Cohort studies, randomized controlled trials, and cross-sectional studies were eligible designs. Study characteristics and definitions of determinants and outcome measures were extracted. If possible, the measure of association was extracted. Results: Twenty-one studies were included in this review. Six out of seven studies focused on the association between radiotherapy (boost) dose or irradiated breast volume and late radiation toxicity found significant results. Tumor bed boost was associated with late radiation toxicity, fibrosis, and/or edema in six out of twelve studies. Lower age was associated with late breast toxicity in one study, while in another study, higher age was significantly associated with breast fibrosis. Also, no association between age and late radiation toxicity was found in eight out of twelve studies. Similar inconsistent results were found in the association between late radiation toxicity and other patient-related factors (i.e., breast size, diabetes mellitus) and surgical and systemic treatment-related factors (i.e., complications after surgery, chemotherapy, and time between surgery and radiotherapy). Conclusion: In modern 3D radiotherapy, radiotherapy (boost) dose and volume are-like in 2D radiotherapy-associated with late local radiation toxicity, such as breast fibrosis and edema. Treatment de-escalation, for example, partial breast irradiation in selected patients might be important to decrease late local toxicity without compromising locoregional control and survival.

Synthetic CT for single-fraction neoadjuvant partial breast irradiation on an MRI-linac.

A synthetic computed tomography (sCT) is required for daily plan optimization on an MRI-linac. Yet, only limited information is available on the accuracy of dose calculations on sCT for breast radiotherapy. This work aimed to (1) evaluate dosimetric accuracy of treatment plans for single-fraction neoadjuvant partial breast irradiation (PBI) on a 1.5 T MRI-linac calculated on a) bulk-density sCT mimicking the current MRI-linac workflow and b) deep learning-generated sCT, and (2) investigate the number of bulk-density levels required. For ten breast cancer patients we created three bulk-density sCTs of increasing complexity from the planning-CT, using bulk-density for: (1) body, lungs, and GTV (sCTBD1); (2) volumes for sCTBD1plus chest wall and ipsilateral breast (sCTBD2); (3) volumes for sCTBD2plus ribs (sCTBD3); and a deep learning-generated sCT (sCTDL) from a 1.5 T MRI in supine position. Single-fraction neoadjuvant PBI treatment plans for a 1.5 T MRI-linac were optimized on each sCT and recalculated on the planning-CT. Image evaluation was performed by assessing mean absolute error (MAE) and mean error (ME) in Hounsfield Units (HU) between the sCTs and the planning-CT. Dosimetric evaluation was performed by assessing dose differences, gamma pass rates, and dose-volume histogram (DVH) differences. The following results were obtained (median across patients for sCTBD1/sCTBD2/sCTBD3/sCTDLrespectively): MAE inside the body contour was 106/104/104/75 HU and ME was 8/9/6/28 HU, mean dose difference in the PTVGTVwas 0.15/0.00/0.00/-0.07 Gy, median gamma pass rate (2%/2 mm, 10% dose threshold) was 98.9/98.9/98.7/99.4%, and differences in DVH parameters were well below 2% for all structures except for the skin in the sCTDL. Accurate dose calculations for single-fraction neoadjuvant PBI on an MRI-linac could be performed on both bulk-density and deep learning sCT, facilitating further implementation of MRI-guided radiotherapy for breast cancer. Balancing simplicity and accuracy, sCTBD2showed the optimal number of bulk-density levels for a bulk-density approach.

Assessing the effect of hyperbaric oxygen therapy in breast cancer patients with late radiation toxicity (HONEY trial): a trial protocol using a trial within a cohort design.

BACKGROUND: Breast cancer treatment with radiotherapy can induce late radiation toxicity, characterized by pain, fibrosis, edema, impaired arm mobility, and poor cosmetic outcome. Hyperbaric oxygen therapy (HBOT) has been proposed as treatment for late radiation toxicity; however, high-level evidence of effectiveness is lacking. As HBOT is standard treatment and reimbursed by insurers, performing classic randomized controlled trials is difficult. The "Hyperbaric OxygeN therapy on brEast cancer patients with late radiation toxicity" (HONEY) trial aims to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the trial within cohorts (TwiCs) design. METHODS: The HONEY trial will be conducted within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation (UMBRELLA). Within UMBRELLA, breast cancer patients referred for radiotherapy to the University Medical Centre Utrecht are eligible for inclusion. Patients consent to collection of clinical data and patient-reported outcomes and provide broad consent for randomization into future intervention studies. Patients who meet the HONEY in- and exclusion criteria (participation ≥ 12 months in UMBRELLA, moderate/severe breast or chest wall pain, completed primary breast cancer treatment except hormonal treatment, no prior treatment with HBOT, no contraindications for HBOT, no clinical signs of metastatic or recurrent disease) will be randomized to HBOT or control group on a 2:1 ratio (n = 120). Patients in the control group will not be informed about participation in the trial. Patients in the intervention arm will undergo 30-40 HBOT treatment sessions in a high pressure chamber (2.4 atmospheres absolute) where they inhale 100% oxygen through a mask. Cohort outcome measures (i.e., physical outcomes, quality of life, fatigue, and cosmetic satisfaction) of the HBOT group will be compared to the control group at 3 months follow-up. DISCUSSION: This pragmatic trial within the UMBELLA cohort was designed to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the TwiCs design. Use of the TwiCs design is expected to address issues encountered in classic randomized controlled trials, such as contamination (i.e., HBOT in the control group) and disappointment bias, and generate information about acceptability of HBOT. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04193722 . Registered on 10 December 2019.

Risk communication in a patient decision aid for radiotherapy in breast cancer: How to deal with uncertainty?

BACKGROUND AND AIM: Patient decision aids for oncological treatment options, provide information on the effect on recurrence rates and/or survival benefit, and on side-effects and/or burden of different treatment options. However, often uncertainty exists around the probability estimates for recurrence/survival and side-effects which is too relevant to be ignored. Evidence is lacking on the best way to communicate these uncertainties. The aim of this study is to develop a method to incorporate uncertainties in a patient decision aid for breast cancer patients to support their decision on radiotherapy. METHODS: Firstly, qualitative interviews were held with patients and health care professionals. Secondly, in the development phase, thinking aloud sessions were organized with four patients and 12 health care professionals, individual and group-wise. RESULTS: Consensus was reached on a pictograph illustrating the whole range of uncertainty for local recurrence risks, in combination with textual explanation that a more exact personalized risk would be given by their own physician. The pictograph consisted of 100 female icons in a 10 x 10 array. Icons with a stepwise gradient color indicated the uncertainty margin. The prevalence and severity of possible side-effects were explained using verbal labels. CONCLUSIONS: We developed a novel way of visualizing uncertainties in recurrence rates in a patient decision aid. The effect of this way of communicating risk uncertainty is currently being tested in the BRASA study (NCT03375801).

Higher reconstruction failure and less patient-reported satisfaction after post mastectomy radiotherapy with immediate implant-based breast reconstruction compared to immediate autologous breast reconstruction.

PURPOSE: To improve shared decision making, clinical- and patient-reported outcomes between immediate implant-based and autologous breast reconstruction followed by postmastectomy radiotherapy (PMRT) were compared. METHODS: All women with in situ and/or invasive breast cancer who underwent skin sparing mastectomy with immediate breast reconstruction (IBR) (autologous- or implant based, one- or two staged) followed by PMRT in the Utrecht region between 2012 and 2016 were selected from the Netherlands Cancer Registry, of which 112 (59%) agreed to participate. The primary outcome was reconstruction failure after the start of radiotherapy, and secondary outcomes were patient-reported outcomes measured with BREAST-Q. RESULTS: 109 patients underwent skin-sparing mastectomy, of which 29 (27%) underwent immediate autologous reconstruction and 80 (73%) received immediate implant-based reconstruction. After PMRT, reconstruction failure occurred in 17 patients (21%) with implant-based reconstruction, while no failure was seen in the autologous group (p = 0.04). Mean patient-reported 'Satisfaction with Breasts' (50.9 vs. 63.7, p = 0.001) and 'Sexual Well-being' (46.0 vs. 55.5, p = 0.037) were lower after implant-based reconstruction compared to autologous reconstruction. Thirteen patients with autologous flaps underwent surgical cosmetic corrections compared to ten patients in the implant group (45 vs. 13%, p = 0.001). IBR and PMRT in this study resulted in a high rate of severe capsular contraction in implant-based reconstruction (16.9%) and fibrosis in autologous reconstruction (13.8%). CONCLUSIONS: Patients treated with PMRT and one or two stage immediate implant-based reconstruction were at greater risk of developing reconstruction failure and were less satisfied when compared to one or two stage immediate autologous reconstruction. Since fairly high complication rates in both reconstruction methods after PMRT are observed, it raises the question whether immediate breast reconstruction should be considered at all when PMRT is indicated. Patients considering or potential candidates for IBR should be informed about the consequences of PMRT and especially when opting for autologous reconstruction one should possibly perform reconstruction in a secondary setting.

Patient-reported cosmetic satisfaction and the long-term association with quality of life in irradiated breast cancer patients.

PURPOSE: To evaluate patient-reported cosmetic satisfaction in women treated with radiation therapy for breast cancer and to determine the association between dissatisfaction and quality of life (QoL) and depression. METHODS: Within the prospective UMBRELLA breast cancer cohort, all patients ≥ 1 year after breast conserving treatment or mastectomy with immediate reconstruction were selected. Self-reported cosmetic satisfaction was measured on a 5-point Likert scale. QoL, social functioning, and emotional functioning were measured using EORTC QLQ-C30 and BR23 at 1, 2, and 3 years after inclusion. Mixed model analysis was performed to assess the difference in different domains of QoL between patients with good versus poor self-reported cosmetic satisfaction over time after adjustment for potential confounders. Depression scores were collected by means of the HADS-NL questionnaire. Chi-square test or Fisher's exact test was used to assess the difference in proportions of HADS score ≥ 8, indicating increased depression risk, between satisfied and dissatisfied patients. RESULTS: 808 patients were selected for analysis. Respectively one, two, and three years after surgery, 8% (63/808), 7% (45/626), and 8% (31/409) of patients were dissatisfied with their cosmetic outcome. Poor patient-reported cosmetic satisfaction was independently associated with impaired QoL, body image, and lower emotional and social functioning. Scores ≥ 8 on the HADS depression subscale were significantly more common in dissatisfied patients. CONCLUSIONS: Dissatisfaction with cosmetic outcome was low after breast cancer surgery followed by radiation therapy during 3 years follow-up. Knowing the association between dissatisfaction with cosmetic outcome and QoL and depression could help to improve the preoperative counseling of breast cancer patients.

Self-reported work ability in breast cancer survivors; a prospective cohort study in the Netherlands.

PURPOSE: To evaluate patient-reported work ability of breast cancer patients, to compare scores with the Dutch general population, and to identify determinants of reduced work ability in breast cancer patients. METHODS: In a prospective cohort study, we identified 939 patients <67 years. Employed patients filled out the Work Ability Index (WAI) questionnaire before the start of radiotherapy treatment (baseline) and at 6, 18, and 30 months. Work ability was compared with a matched Dutch cancer-free population (n=3,641). The association between (clinical) characteristics and work ability over time was assessed using mixed-effects models. RESULTS: At baseline, 68% (n=641) of the respondents were employed and 64% (n=203) were employed at 30 months. Moderate or poor work ability was reported by 71% of patients at baseline, by 24% of the patients at 30 months and by 14% of the general population. Axillary lymph node dissection, (neo)adjuvant chemotherapy and locoregional radiotherapy were associated with reduced work ability. After 30 months, 18% of employed patients reported to have reduced their working hours, made substantial modifications to their work or were unable to work. CONCLUSION: Patient-reported work ability is strongly reduced during breast cancer treatment. Thirty months after treatment the proportion of women reporting poor or moderate work ability remains higher compared to the general population. Even though the proportion of women with paid employment is rather stable over time, substantial amendments in work are needed in 18% of patients. These findings emphasize the importance of informing patients on potential changes in work ability to allow shared decision making.

The effect of chemotherapy on subjective cognitive function in younger early-stage breast cancer survivors treated with chemotherapy compared to older patients.

PURPOSE: To evaluate the impact of chemotherapy on subjective cognitive functioning according to age in a large cohort of breast cancer patients. METHODS: Within the UMBRELLA cohort, 715 patients with early-stage primary invasive breast cancer (T1-3N0-1M0) were selected. Subjective cognitive function was assessed by means of the EORTC QLQ-C30 up to 24 months and compared between patients treated with and without chemotherapy, for three different age strata (355 patients < 55 years, 240 patients aged 55-65 years, and 120 patients > 65 years). Differences between chemotherapy and non-chemotherapy patients by age at different time points were assessed by linear mixed-effect models correcting for age, tumor stage, educational level, endocrine therapy, anxiety, and depression. RESULTS: In total, 979 patients from the UMBRELLA cohort were included, of which 715 (73%) responded to baseline and at least one follow-up questionnaire. Questionnaire response rates ranged between 92 and 70%. The proportion of patients treated with chemotherapy decreased with age: 64% (n = 277) in patients < 55 years, 45% (n = 107) in patients 55-65 years, and 23% (n = 27) in patients > 65 years. Chemotherapy was associated with reduced subjective cognitive functioning. The impact of chemotherapy on subjective cognitive function was most pronounced in patients < 55 years, followed by those between 55 and 65 years. In the youngest age groups, patients treated with chemotherapy had significantly lower cognitive functioning up to 24 months. In women over 65 years, subjective cognitive functioning was comparable between patients treated with and without chemotherapy. CONCLUSION: This study confirms that chemotherapy is associated with impaired subjective self-reported cognitive functioning in breast cancer patients, and the effect persists at least up to 2 years after diagnosis. The impact of chemotherapy on self-reported cognitive functioning in the first 24 months is most pronounced in younger patients, especially those under 55 years of age.

Single dose partial breast irradiation using an MRI linear accelerator in the supine and prone treatment position.

BACKGROUND: In selected patients with early-stage and low-risk breast cancer, an MRI-linac based treatment might enable a radiosurgical, non-invasive alternative for current standard breast conserving therapy. AIM: To investigate whether single dose accelerated partial breast (APBI) to the intact tumor in both the prone and supine radiotherapy positions on the MRI-linac is dosimetrically feasible with respect to predefined coverage and organs at risk (OAR) constraints. MATERIAL & METHODS: For 20 patients with cTis or low-risk cT1N0M0 non-lobular breast carcinoma, previously treated with single dose preoperative APBI in the supine (n = 10) or prone (n = 10) position, additional intensity modulated radiotherapy plans with 7 coplanar beams in the presence of a 1.5T magnetic field were generated. A 20 Gy and 15 Gy dose was prescribed to the gross tumor and clinical target volume, respectively. The percentage of plans achieving predefined organ at risk (OAR) constraints, currently used in clinical practice, was assessed. Dosimetry differences between the prone versus supine approach and the MRI-linac versus clinically delivered plans were evaluated. RESULTS: All MRI-linac plans met the coverage and predefined OAR constraints. The prone approach appeared to be more favorable with respect to the chest wall, and ipsilateral lung dose compared to the supine position. No dosimetric differences were observed for the ipsilateral breast. No treatment position was clearly more beneficial for the skin or heart, since dosimetry varied among parameters. Overall, the MRI-linac and clinical plans were comparable, with minor absolute dosimetric differences. CONCLUSION: MRI-linac based single dose APBI to the intact tumor is a promising and a dosimetrically feasible strategy in patients with low-risk breast cancer. Preliminary OAR dosimetry favored the prone radiotherapy position.

Severe depression more common in patients with ductal carcinoma in situ than early-stage invasive breast cancer patients.

PURPOSE: Ductal carcinoma in situ (DCIS) is associated with an excellent prognosis; historical studies have shown similar levels of psychological distress in patients with DCIS and with early-stage invasive breast cancer (early-IBC). It is suggested that these results might have led to better patient education about prognosis after DCIS. This study reports the current levels of anxiety, depression, and health-related quality of life (HRQoL) in DCIS and early-IBC patients. METHODS: DCIS (n = 89) and early-IBC patients, T1-2N0, (n = 361) were selected from the UMBRELLA breast cancer cohort. Patient-reported outcomes were prospectively collected before the start of adjuvant radiotherapy (baseline) and at 3, 6, 12, 18, and 24 months thereafter. Mixed models were used to compare differences in levels of anxiety, depression, and HRQoL between DCIS and early-IBC patients. RESULTS: DCIS and early-IBC patients reported similar levels of anxiety, which were highest at baseline. Depression scores were comparable between groups, also after stratification by use of adjuvant chemotherapy. The proportion of patients reporting high-risk depression scores (i.e., Hospital Anxiety and Depression Sale score >8) was significantly higher among patients with DCIS at 6, 12 and 18 months, and this proportion increased over the first 18 months. Health-related quality of life was comparable between both groups. CONCLUSION: Severe depression scores are more common in DCIS patients, despite their excellent prognosis. These results suggest that further improvement of patient education and effective patient doctor communication about the prognostic differences between patients with DCIS and invasive breast cancer is still highly needed.

The Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA): objectives, design, and baseline results.

PURPOSE: In oncology, RCTs are often beset by slow recruitment, limited generalizability, and strong preferences for interventions by patients and physicians. The cohort multiple randomized controlled trial (cmRCT) is an innovative design with the potential to overcome those challenges. In cmRCT, a prospective cohort serves as an infrastructure for multiple RCTs. We implemented cmRCT in a clinical breast cancer setting by creating UMBRELLA-a large prospective cohort of breast cancer and DCIS patients/survivors. METHODS: For all participants, clinical data and patient-reported outcomes (PROs, i.e., quality of life, fatigue, anxiety and depression, physical activity, work ability, and cosmetic satisfaction) are being collected at regular time-intervals for a period of 10 years. These data are being used both for observational and randomized studies. For each intervention to be tested against standard care, a subcohort of eligible patients is identified within UMBRELLA. From this subcohort, a random sample of patients is offered the intervention. Their outcomes are compared to the outcomes of patients receiving standard care. RESULTS: So far, between October 2013 and July 2016, we have recruited 1308 participants. In this period, 1308/1486 (88%) patients who were invited for participation in UMBRELLA consented to cohort participation. Of these patients, 1138 (87%) gave broad consent for randomization to future interventions. Return rate for PROs at baseline were 80%, and varied from 67 to 74% during follow-up. Several observational studies-and the first randomized intervention study-are currently ongoing. CONCLUSIONS: Results from UMBRELLA show that this novel study design is feasible and acceptable to patients in a clinical breast cancer setting. We invite researchers who are interested in conducting randomized or observational studies within the UMBRELLA cohort to contact the UMBRELLA scientific advisory board.

Redefining radiotherapy for early-stage breast cancer with single dose ablative treatment: a study protocol.

BACKGROUND: A shift towards less burdening and more patient friendly treatments for breast cancer is currently ongoing. In low-risk patients with early-stage disease, accelerated partial breast irradiation (APBI) is an alternative for whole breast irradiation following breast-conserving surgery. MRI-guided single dose ablative APBI has the potential to offer a minimally burdening, non-invasive treatment that could replace current breast-conserving therapy. METHODS: The ABLATIVE study is a prospective, single arm, multicenter study evaluating preoperative, single dose, ablative radiation treatment in patients with early-stage breast cancer. Patients with core biopsy proven non-lobular invasive breast cancer, (estrogen receptor positive, Her2 negative, maximum tumor size 3.0 cm on diagnostic MRI) and a negative sentinel node biopsy are eligible. Radiotherapy (RT) planning will be performed using a contrast enhanced (CE) planning CT-scan, co-registered with a CE-MRI, both in supine RT position. A total of twenty-five consecutive patients will be treated with a single ablative RT dose of 20 Gy to the tumor and 15 Gy to the tumorbed. Follow-up MRIs are scheduled within 1 week, 2, 4 and 6 months after single-dose RT. Breast-conserving surgery is scheduled at six months following RT. Primary study endpoint is pathological complete response. Secondary study endpoints are the radiological response and toxicity. Furthermore, patients will fill out questionnaires on quality of life and functional status. Cosmetic outcome will be evaluated by the treating radiation oncologist, patient and 'Breast Cancer Conservation Treatment cosmetic results' software. Recurrence and survival rates will be assessed. The patients will be followed up to 10 years after diagnosis. If patients give additional informed consent, a biopsy and a part of the irradiated specimen will be stored at the local Biobank and used for future research on radiotherapy response associated genotyping. DISCUSSION: The ABLATIVE study evaluates MRI-guided single dose ablative RT in patients with early-stage breast cancer, aiming at a less burdening and non-invasive alternative for current breast-conserving treatment. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT02316561 . The trial was registrated prospectively on October 10th 2014.

Population based study on sentinel node biopsy before or after neoadjuvant chemotherapy in clinically node negative breast cancer patients: Identification rate and influence on axillary treatment.

The timing of the sentinel lymph node biopsy (SNB) is controversial in clinically node negative patients receiving neoadjuvant chemotherapy (NAC). We studied variation in the timing of axillary staging in breast cancer patients who received NAC and the subsequent axillary treatment in The Netherlands. Patients diagnosed with clinically node negative primary breast cancer between 1st January 2010 and 30th June 2013 who received NAC and SNB were selected from the Netherlands Cancer Registry. Data on patient and tumour characteristics, axillary staging and treatment were analysed. Two groups were defined: (1) patients with SNB before NAC (N=980) and (2) patients with SNB after NAC (N=203). Eighty-three percent of patients underwent SNB before NAC, with large regional variation (35-99%). The SN identification rate differed for SNBs conducted before and after NAC (98% versus 95%; p=0.032). A lower proportion of patients had a negative SNB when assessed before NAC compared to after (54% versus 67%; p=0.001). The proportion of patients receiving any axillary treatment was higher for those with SNB before NAC than after (45% versus 33%; p=0.006). In conclusion, variation exists in the timing of SNB in clinical practice in The Netherlands for clinically node negative breast cancer patients receiving NAC. The post-NAC SN procedure is, despite some lower SN identification rate, associated with a significantly less frequent axillary treatment and thus with less expected morbidity. The effect on recurrence rate is not yet clear. Patients in this registry will be followed prospectively for long-term outcome.

Sentinel lymph node biopsy of the internal mammary chain in breast cancer.

Routine removal of the internal mammary chain (IMC) sentinel node in breast cancer patients remains a subject of discussion. The aim of this study was to determine the impact of routinely performed IMC sentinel node biopsy on the systemic and locoregional treatments plan. All patients with biopsy proven breast cancer who underwent a sentinel node procedure between 2002 and 2011 were included in a prospective database. In cases of IMC drainage, successful exploration of the IMC (i.e., sentinel node removed) and surgical complications were registered. If the removed sentinel node contained malignant cells we determined if this altered the treatment plan when practising the current guidelines. In total, 119 of the 493 included patients showed IMC drainage on lymphoscintigraphy. Exploration of the IMC was performed in 107 (89 %) patients; in 86/107 (80 %) exploration was successful. In 14/107 patients (13 %) the IMC sentinel node was tumor positive. Macro and micro metastases were found in eight and six patients, respectively. In the group of patients who underwent surgical exploration of the IMC, systemic treatment was changed in none, radiotherapy treatment in 13/107 patients (11 %). Routine sentinel node biopsy of the IMC does not alter the systemic treatment. Radiotherapy treatment is altered in a small proportion of the patients; however, solid scientific evidence for this adjustment is lacking.

Excised and irradiated volumes in relation to the tumor size in breast-conserving therapy.

In early-stage breast cancer and DCIS patients, breast-conserving therapy is today's standard of care. The purpose of this study was to evaluate the relation between the microscopic tumor diameter (mTD), the excised specimen (ES) volume, and the irradiated postoperative complex (POC) volume, in patients treated with breast-conserving therapy. In 186 patients with pTis-2N0 breast cancer, the mTDs, ES, and POC volumes (as delineated on the radiotherapy-planning CT scan), were retrospectively determined. Linear regression analysis was performed to study the association between the mTD, and the ES and POC volumes. The explained variance (r (2)) was calculated to establish the proportion of variation in the outcome variable that could be explained by the determinant (P ≤ 0.05). Moreover, the influence of tumor characteristics, age, surgical procedures, and breast size was studied. Median mTD was 1.2 cm (range 0.1-3.6 cm), median ES volume was 60 cm(3) (range 6-230 cm(3)) and median POC volume was 15 cm(3) (range 0.5-374 cm(3)). The POC was not clearly visible on the majority of the CT scans, based on a median assigned cavity visualization score of 3 (range 1-5). The explained variance for the mTD on the ES volume was low (r(2) = 0.08, P < 0.001). A slightly stronger association was observed in palpable tumors (r(2) = 0.23, P < 0.001) and invasive lobular carcinomas (r(2) = 0.39, P = 0.01). Furthermore, weak associations were observed between POC volume and mTD (r(2) = 0.04, P = 0.01), and POC and ES volume (r(2) = 0.23, P < 0.001). A weak association was observed between breast volume and ES volume (r(2) = 0.27, P < 0.001). In conclusion, both the excised and the irradiated POC volumes did not show a clinically relevant association with the mTD in women with early-stage breast cancer treated with breast-conserving therapy. Future studies should focus on improvement of surgical localization, development of image-guided, minimally invasive operation techniques, and more accurate image-guided target volume delineation in radiotherapy.

Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients.

AIMS: To characterize determinants of the elimination of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) in patients receiving high-dose MTX therapy (HDMTX). METHODS: 24 and 48-h blood samples from 76 patients receiving HDMTX (dose range 300 mg m-2 to 12 g m-2) were analysed, and concentration-time data were subjected to population pharmacokinetic and covariate analysis using nonlinear mixed-effect modelling (NONMEM). RESULTS: Treatment-related mortality was 1.3% (one patient with renal failure). Values for MTX clearance (CLMTX) and 7-OH-MTX clearance (CL7-OH-MTX) were estimated at 8.85 and 2 L-1, respectively. Baseline creatinine clearance correlated with CLMTX and CL7-OH-MTX. Concurrent administration of benzimidazoles led to a 27% decrease in CLMTX and a 39% decrease in CL7-OH-MTX. Prior administration of nonsteroidal anti-inflammatory drugs (NSAIDs) resulted in a 16% decrease in CLMTX and a 38% decrease in CL7-OH-MTX. Plasma MTX concentrations were significantly higher in patients also receiving benzimidazoles at 24 h (2.01 micromol L-1vs. 0.66 micromol L-1, P<10(-4)) and at 48 h (0.25 micromol L-1vs. 0.12 micromol L-1, P<10(-4)). 7-OH-MTX plasma concentrations were also significantly higher in patients with concurrent benzimidazoles as compared with patients without benzimidazoles at 24 h (4.47 micromol L-1vs. 2.52 micromol L-1, P=0.0009) and at 48 h (1.11 micromol L-1vs. 0.72 micromol L-1, P=0.031). CONCLUSIONS: In patients receiving HDMTX, concurrent administration of benzimidazoles was associated with a significant decrease of CLMTX and CL7-OH-MTX, resulting in significantly higher plasma concentrations of MTX and 7-OH-MTX. The data suggest that benzimidazole treatment should be seen as a relative contraindication for HDMTX.

A population analysis of the pharmacokinetics of Cremophor EL using nonlinear mixed-effect modelling.

PURPOSE: The purpose of this study was to develop a population pharmacokinetic model for Cremophor EL used as a formulation vehicle for paclitaxel. METHODS: Plasma concentration-time data from 70 patients (85 courses) treated with paclitaxel dissolved in Cremophor EL were used. The nonlinear mixed-effect modelling (NONMEM) program was used for the population pharmacokinetic analysis. The influence of patient characteristics on the pharmacokinetics of Cremophor EL was determined. The stability of the final model was evaluated using bootstrapping. RESULTS: The data were optimally fitted to a three-compartment model with Michaelis-Menten elimination from the central compartment. The following pharmacokinetic parameters were estimated: volume of the central compartment (V1=2.59 l), volumes of two peripheral compartments (V2=1.81 l, V3=1.61 l), intercompartmental clearance between central and peripheral compartments (Q12=1.44 l/h, Q13=0.155 l/h), maximal elimination rate (Vmax=0.193 ml/h), and concentration at half Vmax (Km=0.122 ml/l). Interindividual variability of the pharmacokinetic parameters was quantified for V1 (25%), V2 (36%) and Vmax (31%). Residual variability consisted of a combined additional (0.095 ml/l) and proportional error (7%). Gender, body surface area and performance status according to the World Health Organization were significantly correlated with V1, V2 and Vmax, respectively ( P<0.0001). The median parameter estimates of 1000 bootstrap samples were in accordance with those obtained with the original data set, indicating the validity of the population model. CONCLUSIONS: The population model was able to adequately describe the pharmacokinetic parameters and influence of covariates on the pharmacokinetics of Cremophor EL. This model can be used when studying the relationship between the pharmacokinetics and toxicity of Cremophor EL, and the drug's influence on the pharmacokinetics of paclitaxel.