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Background: Image-driven dose escalation to tumor subvolumes has been proposed to improve treatment outcome in head and neck cancer (HNC). We used 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) acquired at baseline and into treatment (interim) to identify biologic target volumes (BTVs). We assessed the feasibility of interim dose escalation to the BTV with proton therapy by simulating the effects to organs at risk (OARs)., Methods: We used the semiautomated just-enough-interaction (JEI) method to identify BTVs in 18 F-FDG-PET images from nine HNC patients. Between baseline and interim FDG-PET, patients received photon radiotherapy. BTV was identified assuming that high standardized uptake value (SUV) at interim reflected tumor radioresistance. Using Eclipse (Varian Medical Systems), we simulated a 10% (6.8 Gy(RBE 1.1 )) and 20% (13.6 Gy(RBE 1.1 )) dose escalation to the BTV with protons and compared results with proton plans without dose escalation., Results: At interim 18 F-FDG-PET, radiotherapy resulted in reduced SUV compared to baseline. However, spatial overlap between high-SUV regions at baseline and interim allowed for BTV identification. Proton therapy planning demonstrated that dose escalation to the BTV was feasible, and except for some 20% dose escalation plans, OAR doses did not significantly increase., Conclusion: Our in silico analysis demonstrated the potential for interim 18 F-FDG-PET response-adaptive dose escalation to the BTV with proton therapy. This approach may give more efficient treatment to HNC with radioresistant tumor subvolumes without increasing normal tissue toxicity. Studies in larger cohorts are required to determine the full potential for interim 18 F-FDG-PET-guided dose escalation of proton therapy in HNC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: This study aimed to develop fully automated script-based radiotherapy treatment plans for cervical cancer patients, and evaluate them against clinically accepted plans, as validation before clinical implementation., Material and Methods: In this retrospective planning study, treatment plans for 25 locally advanced cervical cancer (LACC) patients with up to three dose levels were included. Fully automated plans were created using an in-house developed Python script in RayStation, and compared to clinically accepted manually made plans. Quantitatively, relevant dose statistics were compared, and average dose volume histograms (DVHs) were analyzed. Qualitatively, a blinded plan comparison was conducted between the clinical and automatic plans. The accuracy of treatment plan delivery was verified with the Delta4 Phantom+., Results: The quantitative evaluation showed that target coverage was acceptable for all the automatic and clinical plans. The automatic plans were significantly more conformal than the clinical plans; median of 1.03 vs. 1.12. Mean doses to almost all organs at risk (OARs) were reduced in the automatic plans, with a median reduction of between 0.6 Gy and 1.9 Gy. In the blinded plan comparison, the automatic plans were the preferred plans or of equal quality as the clinical plans in 99% of the cases. In addition, plan delivery was excellent, with a mean gamma passing rate of 99.8%. Complete script-based plans were generated in 30-45 min; about four to ten times faster than manually made plans., Conclusion: The automatic plans had acceptable target coverage, lower doses to almost all OARs, more conformal dose distributions, and were predominantly preferred by the clinicians. Based on these results, our institution has implemented the script for clinical use.

Aim: To train and validate a comprehensive deep-learning (DL) segmentation model for loco-regional breast cancer with the aim of clinical implementation., Methods: DL segmentation models for 7 clinical target volumes (CTVs) and 11 organs at risk (OARs) were trained on 170 left-sided breast cancer cases from two radiotherapy centres in Norway. Another 30 patient cases were used for validation, which included the evaluation of Dice similarity coefficient and Hausdorff distance, qualitative scoring according to clinical usability, and relevant dosimetric parameters. The manual inter-observer variation (IOV) was also evaluated and served as a benchmark. Delineation of the target volumes followed the ESTRO guidelines., Results: Based on the geometric similarity metrics, the model performed significantly better than IOV for most structures. Qualitatively, no or only minor corrections were required for 14% and 71% of the CTVs and 72% and 26% of the OARs, respectively. Major corrections were required for 15% of the CTVs and 2% of the OARs. The most frequent corrections occurred in the cranial and caudal parts of the structures. The dose coverage, based on D98 > 95%, was fulfilled for 100% and 89% of the breast and lymph node CTVs, respectively. No differences in OAR dose parameters were considered clinically relevant. The model was implemented in a commercial treatment planning system, which generates the structures in 1.5 min., Conclusion: Convincing results from the validation led to the decision of clinical implementation. The clinical use will be monitored regarding applicability, standardization and efficiency., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Children with brain tumors undergoing radiotherapy are at particular risk of radiation-induced morbidity and are therefore routinely considered for proton therapy (PT) to reduce the dose to healthy tissues. The aim of this study was to apply pediatric constraints and normal tissue complication probability (NTCP) models when evaluating the differences between PT and contemporary photon-based radiotherapy, volumetric modulated arc therapy (VMAT). Methods: Forty patients (aged 1-17 years) referred from Norwegian institutions to cranial PT abroad during 2014-2016 were selected for VMAT re-planning using the original CT sets and target volumes. The VMAT and delivered PT plans were compared by dose/volume metrics and NTCP models related to growth hormone deficiency, auditory toxicity, visual impairment, xerostomia, neurocognitive outcome and secondary brain and parotid gland cancers. Results: The supratentorial brain, temporal lobes, hippocampi, hypothalamus, pituitary glands, cochleas, salivary glands, optic nerves and chiasm received lower mean doses from PT. Reductions in population median NTCP were significant for auditory toxicity (VMAT: 3.8%; PT: 0.3%), neurocognitive outcome (VMAT: 3.0 IQ points decline at 5 years post RT; PT: 2.5 IQ points), xerostomia (VMAT: 2.0%; PT: 0.6%), excess absolute risk of secondary cancer of the brain (VMAT: 9.2%; PT: 6.7%) and salivary glands (VMAT: 2.8%; PT:0.5%). Across all patients, 23/38 PT plans had better or comparable estimated risks for all endpoints (within ±10% of the risk relative to VMAT), whereas for 1/38 patients all estimates were better or comparable with VMAT. Conclusions: PT reduced the volumes of normal tissues exposed to radiation, particularly low-to-intermediate dose levels, and this was reflected in lower NTCP. Of the included endpoints, substantial reductions in population medians were seen from the delivered PT plans for auditory complications, xerostomia, and risk of secondary cancers of the brain and salivary glands.

Adult height and body weight are positively associated with breast cancer risk after menopause, but few studies have investigated these factors according to molecular breast cancer subtype. A total of 18,562 postmenopausal Norwegian women who were born between 1886 and 1928 were followed up for breast cancer incidence from the time (between 1963 and 1975) height and weight were measured until 2008. Immunohistochemical and in situ hybridization techniques were used to subtype 734 incident breast cancer cases into Luminal A, Luminal B [human epidermal growth factor receptor 2 (HER2-)], Luminal B (HER2+), HER2 subtype, basal-like phenotype (BP) and five-negative phenotype (5NP). We used Cox regression analysis to assess adult height and body mass index (BMI) in relation to risk of these subtypes. We found a positive association of height with risk of Luminal A breast cancer (ptrend , 0.004), but there was no clear association of height with any other subtype. BMI was positively associated with risk of all luminal breast cancer subtypes, including Luminal A (ptrend , 0.002), Luminal B (HER2-) (ptrend , 0.02), Luminal B (HER2+) (ptrend , 0.06), and also for the HER2 subtype (ptrend , 0.04), but BMI was not associated with risk of the BP or 5NP subtypes. Nonetheless, statistical tests for heterogeneity did not provide evidence that associations of height and BMI differed across breast cancer subtypes. This study of breast cancer risk among postmenopausal women suggests that height is positively associated with risk of Luminal A breast cancer. BMI is positively associated with risk of all luminal subtypes and for the HER2 subtype., (© 2014 UICC.)

Background: Adult weight gain is associated with increased risk of postmenopausal breast cancer. Most previous studies are limited by using recalled or self-reported data, and it is not known if age-specific weight changes are important for breast cancer risk., Methods: In a Norwegian cohort of 28,153 women (and 900 incident breast cancers) with longitudinal anthropometric measurements over up to 30 years, we studied both overall and age-related weight changes in adulthood and risk of postmenopausal breast cancer., Results: Overall, weight gain in adulthood was associated with increased breast cancer risk (hazard ratio (HR) per kg per year 1.31, 95% confidence interval (CI) 1.11-1.54). Weight gain before (HR per kg per year 1.38, 95% CI 1.09-1.75) or around menopause (1.69, 95% CI 1.32-2.16) was associated with increased risk, but there was no clear risk increase associated with later weight gain (HR per kg per year 0.92, 95% CI 0.73-1.18)., Conclusion: Weight gain in adulthood was associated with increased risk of breast cancer. Our results suggest that weight gain before and around menopausal age may be particularly important for breast cancer risk among postmenopausal women.

Reproductive factors that have a well-documented effect on breast cancer risk may also influence the prognosis of the disease, but previous studies on breast cancer survival have yielded conflicting results. We combined information from two population-based registries and obtained information on 16,970 parous women with invasive breast cancer. Cox regression analysis was used to assess breast cancer survival in relation to age at diagnosis, age at first birth, time since last birth and parity. We stratified the analyses by age at diagnosis (<50 and ≥ 50 years) as an approximation for menopausal age. In women diagnosed before 50 years of age, breast cancer survival was reduced with younger age at diagnosis (p for trend <0.001), whereas in women diagnosed at 50 years or later, survival was reduced with older age at diagnosis (p for trend 0.011). For breast cancer diagnosed before 50 years, survival was poorer in women with four or more births compared to women with one or two births (hazard ratio 1.3, 95% confidence interval 1.1-1.6). A short time since last birth was associated with reduced survival (p for trend 0.05), but adjustment for stage and grade attenuated the association. Among women diagnosed at 50 years or later, we found no association with survival for any of the reproductive factors. In summary, reproductive factors were associated with survival from breast cancer diagnosed before but not after age 50 years. Young women had a particularly poor prognosis throughout the study period., (Copyright © 2012 UICC.)

Background: Pregnancy has a short-term risk-increasing effect on breast cancer that may be attributed to growth-promoting effects of pregnancy hormones on prevalent but undetected tumors. Results of two previous studies suggested that placental weight may be positively associated with breast cancer risk., Methods: In a cohort of 338,051 women followed from 1999 to 2008, on the basis of data linkage between the Medical Birth Registry of Norway and the Cancer Registry of Norway, we assessed whether placental weight in a woman's most recent pregnancy was related to breast cancer risk during the first years following pregnancy., Results: During follow-up (median, 6.0 years; interquartile range, 3.0-8.3 years), 648 women were diagnosed with breast cancer at a mean age of 38.4 years (standard deviation, 5.3 years). Placental weight in the most recent pregnancy was not associated with breast cancer risk: the hazard ratio per 100-gram increase in placental weight was 1.03 [95% confidence interval, 0.96-1.10]. There was a similar lack of association related to mean placental weight across pregnancies and to placental weight associated with the first birth., Conclusion: We could not confirm previous reports that women who develop large placentas are at increased risk of breast cancer., Impact: The epidemiologic support for an association of placental weight with breast cancer risk remains inconclusive. More research is needed to identify factors that influence breast cancer risk in young women., (©2012 AACR)

Background: Hypertensive diseases in pregnancy may be associated with a reduced risk of breast cancer. Most previous studies are small and have shown conflicting results., Methods: In a cohort of 919 712 women who gave their first birth between 1967 and 2008, with linkage of information from two national registries, we assessed whether women with pregnancy hypertensive diseases are at reduced breast cancer risk. We used Cox regression to estimate hazard ratios (HRs) with 95% confidence intervals (CI)., Results: Compared with women with a normotensive first pregnancy, women with hypertension or preeclampsia in their first pregnancy had a reduced breast cancer risk (HR 0.83, 95% CI 0.77, 0.90). A reduced risk was consistently observed for hypertensive disease in any pregnancy, for recurrent hypertensive disease in pregnancy, and before and after 50 years of age at breast cancer diagnosis. The association was strongest for women with hypertension in pregnancy, who delivered at term/post-term (HR 0.81, 95% CI 0.75, 0.88) or had a child of average birth weight (HR 0.77, 95% CI 0.69, 0.85)., Conclusion: Women with pregnancy hypertensive diseases are at reduced breast cancer risk. Whether this association can be attributed to pregnancy-specific events or to underlying biological traits remains unclear.

Reproductive factors that influence breast cancer risk may also have an impact on survival, once the disease is diagnosed. In this study, 2,640 women were diagnosed with invasive breast cancer during follow-up after a breast cancer screening that took place in 1956-1959. Survival was assessed in relation to age at menarche, age at first birth, parity, history of breastfeeding, age at menopause, and the effect of BMI was assessed in a subset of patients. It is a special feature that the patients of this study have not been subjected to organized mammography screening and their use of exogenous hormones has been negligible. By the end of follow-up (2008), 2,301 (87%) of the patients had died and 1,022 (44%) of the deaths were caused by breast cancer. Breast cancer survival was not associated with age at menarche, parity or time since last birth, but survival was consistently poorer with increasing age at first birth (P for trend 0.03): comparing a first birth after 35 years with 25-29 years, the hazard ratio was 1.32 (95% CI 1.02-1.72). There was no evidence for a dose-related effect of breastfeeding, but BMI measured many years prior to diagnosis was inversely associated with survival (P for trend <0.01). The main finding was that reproductive factors, including breastfeeding, appear to have little influence on the survival of breast cancer patients. Age at first birth may be an exception to this, since we found a gradually poorer survival with increasing age at first birth. We also found that overweight and obesity, as measured many years prior to diagnosis, were associated with poorer survival.

Background: Pregnancy may reduce breast cancer risk through induction of persistent changes of the mammary gland that make the breast less susceptible to carcinogenic factors. It is not known to what extent the effects of parity are independent of other breast cancer risk factors., Methods: In a Norwegian cohort of 58 191 women (2890 breast cancers), we assessed whether the effects of parity on postmenopausal breast cancer risk may be modified by menstrual and anthropometric factors. We calculated attributable proportions due to interaction as a measure of synergism., Results: Parity, height, body mass index (BMI), age at menarche and menopause were all associated with breast cancer risk in the expected directions. For BMI, follow-up was stratified into two age groups because of non-proportional hazards. We found that nulliparity and overweight may amplify each other's effect on breast cancer risk among women after 70 years of age (attributable proportion 0.21, 95% confidence interval 0.04-0.39). There was some indication that parity and age at menopause may antagonise each other's effect. Effects of parity were largely unaffected by age at menarche and height., Conclusion: Nulliparity and overweight may have a synergistic effect on breast cancer risk in elderly women. If confirmed by others, the findings may help disentangle the interplay of different causes of breast cancer.