Summary Background Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the ...optimum palliative treatment in patients aged 60 years and older with glioblastoma. Methods Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m2 on days 1–5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. Findings 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months 95% CI 7·1–9·5; n=93 vs 6·0 months 95% CI 5·1–6·8; n=100, hazard ratio HR 0·70; 95% CI 0·52–0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months 6·5–8·6; n=98, HR 0·85 0·64–1·12, p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months 7·3–9·4; n=119 vs 7·4 months 6·4–8·4; n=123; HR 0·82, 95% CI 0·63–1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 0·21–0·56, p<0·0001; HR for hypofractionated vs standard radiotherapy 0·59 95% CI 0·37–0·93, p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months 95% CI 8·0–11·4 vs 6·8 months 5·9–7·7; HR 0·56 95% CI 0·34–0·93, p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 95% CI 0·69–1·38; p=0·81). As expected, the most common grade 3–4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3–5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. Interpretation Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide. Funding Merck, Lion's Cancer Research Foundation, University of Umeå, and the Swedish Cancer Society.
Hypofractionated radiotherapy for prostate cancer has gained increased attention due to its proposed high radiation-fraction sensitivity. Recent reports from studies comparing moderately ...hypofractionated and conventionally fractionated radiotherapy support the clinical use of moderate hypofractionation. To date, there are no published randomised studies on ultra-hypofractionated radiotherapy. Here, we report the outcomes of the Scandinavian HYPO-RT-PC phase 3 trial with the aim to show non-inferiority of ultra-hypofractionation compared with conventional fractionation.
In this open-label, randomised, phase 3 non-inferiority trial done in 12 centres in Sweden and Denmark, we recruited men up to 75 years of age with intermediate-to-high-risk prostate cancer and a WHO performance status between 0 and 2. Patients were randomly assigned to ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) or conventional fractionated radiotherapy (78·0 Gy in 39 fractions, 5 days per week for 8 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure, analysed in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio (HR) limit of 1·338. Physician-recorded toxicity was measured according to the Radiation Therapy Oncology Group (RTOG) morbidity scale and patient-reported outcome measurements with the Prostate Cancer Symptom Scale (PCSS) questionnaire. This trial is registered with the ISRCTN registry, number ISRCTN45905321.
Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionation (n=602) or ultra-hypofractionation (n=598), of whom 1180 (591 conventional fractionation and 589 ultra-hypofractionation) constituted the per-protocol population. 1054 (89%) participants were intermediate risk and 126 (11%) were high risk. Median follow-up time was 5·0 years (IQR 3·1–7·0). The estimated failure-free survival at 5 years was 84% (95% CI 80–87) in both treatment groups, with an adjusted HR of 1·002 (95% CI 0·758–1·325; log-rank p=0·99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 28% of 569 patients vs 132 23% of 578 patients; p=0·057). There were no significant differences in grade 2 or worse urinary or bowel late toxicity between the two treatment groups at any point after radiotherapy, except for an increase in urinary toxicity in the ultra-hypofractionation group compared to the conventional fractionation group at 1-year follow-up (32 6% of 528 patients vs 13 2% of 529 patients; (p=0·0037). We observed no differences between groups in frequencies at 5 years of RTOG grade 2 or worse urinary toxicity (11 5% of 243 patients for the ultra-hypofractionation group vs 12 5% of 249 for the conventional fractionation group; p=1·00) and bowel toxicity (three 1% of 244 patients vs nine 4% of 249 patients; p=0·14). Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with the physician-evaluated toxicity.
Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival. Early side-effects are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups. The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer.
The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.
No reliable, non-invasive biomarker of metastatic breast cancer (mBC) exists: circulating CA15-3 (cCA15-3) is the marker mostly used to monitor mBC. Circulating collagen IV (cCOLIV) has been ...evaluated in other metastatic cancers and has been found to be a promising biomarker. The overarching aim of this study was to evaluate cCOLIV as a potential biomarker in patients with mBC. The first aim was to determine the levels of cCOL IV and cCA15-3 in patients with healthy controls, primary breast cancer (pBC) and mBC. The second aim was to compare levels of cCOLIV and cCA15-3 in patients with different metastatic sites of BC. The third aim was to investigate the prognostic value of cCOLIV and cCA15-3 for mBC patients. The fourth aim was to analyse whether a combination of the two biomarkers was more accurate in detecting mBC than a single marker. Lastly, we investigated the tissue expression levels of COLIV in BC bone metastases (BM) and liver metastases (LM). Plasma levels of cCOLIV and cCA15-3 from healthy controls and patients with pBC and mBC were measured. COLIV expression in tissue from patients with LM and BM was analysed using immunohistochemistry. Clinical and survival data were collected from medical charts. The levels of cCOLIV and cCA15-3 were significantly elevated in mBC patients compared with healthy controls and pBC patients. No differences in cCOLIV and cCA15-3 levels were found based on the metastatic site. High levels of cCOLIV, but not cCA15-3, correlated with poorer survival. cCOLIV alone and the combination of cCA15-3 and cCOLIV were superior to cCA15-3 at detecting mBC. COL IV was highly expressed in the tissue of LM and BM. Our study suggests that cCOLIV is a potential marker to monitor patients with BC.
Abstract Background If patient age affects the quality of end-of-life care in cancer is unknown. Using data from a population-based register of palliative care in Sweden, we addressed this question. ...Methods This nation-wide study focused on the last week of life of adults dying from cancer in 2011–2012, based on data reported to a national quality register for end-of-life care ( N = 26,976). We specifically investigated if age-dependent differences were present with respect to thirteen indicators of palliative care quality. Patients were categorised in one out of five pre-defined age groups. Odds ratios (OR) with 95% confidence intervals (CIs), adjusted for type of end-of-life care unit, were calculated using logistic regression, with the oldest group as reference. Findings Age-dependent differences in implementation rate were detected for ten out of thirteen end-of-life care quality indicators, most of which were progressively less well met with each increment in age group. Compared to elderly cancer patients, young patients were more often informed about imminent death, (OR, 3.9; 95% CI 2.5–5.9, p < 0.001), were more often systematically assessed for the presence and severity of pain (OR, 1.6; 95% CI 1.2–2.1, p < 0.001) or other symptoms (OR, 1.4; 95% CI 1.0–1.9, p = 0.044), were more likely to be assessed by palliative care consultation services (OR, 4.3; 95% CI 3.3–5.7, p < 0.001) and to have injections prescribed as needed against pain (OR, 3.4; 95% CI 1.3–9.4, p = 0.016), anxiety (OR, 3.8; 95% CI 2.0–7.1, p < 0.001) or nausea (OR, 3.6; 95% CI 2.3–5.7, p < 0.001). The families of young patients were more likely to be informed about imminent death (OR, 2.6; 95% CI 1.5–4.3, p = 0.001) and to be offered bereavement support (OR, 4.6; 95% CI 2.7–7.8, p < 0.001). Interpretation Old age is a risk indicator for poor end-of-life care quality among cancer patients in Sweden. Funding The executive committee of the National Quality Registries in Sweden.
The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was non-inferior to ...conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial.
HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c–T3a with one or two of the following risk factors: stage T3a; Gleason score ≥7; and prostate-specific antigen 10–20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0–2. Participants were randomly assigned (1:1) to conventional fractionation (78·0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the per-protocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321.
Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25–72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency p<0·0001, rush to toilet p=0·0013, flatulence p=0·0013, bowel cramp p<0·0001, mucus p=0·0014, blood in stool p<0·0001, and limitation in daily activity p=0·0014). There were no statistically significant differences in the proportions of patients with clinically relevant acute urinary symptoms or problems (total 14 items) and sexual functioning between the two treatment groups at end of radiotherapy. Thereafter, there were no clinically relevant differences in urinary, bowel, or sexual functioning between the groups. At the 6-year follow-up there was no difference in the incidence of clinically relevant deterioration between the groups for overall urinary bother (43 33% of 132 for conventional fractionation vs 33 28% of 120 for ultra-hypofractionation; mean difference 5·1% 95% CI –4·4 to 14·6; p=0·38), overall bowel bother (43 33% of 129 vs 34 28% of 123; 5·7% –3·8 to 15·2; p=0·33), overall sexual bother (75 60% of 126 vs 59 50% of 117; 9·1% –1·4 to 19·6; p=0·15), or global health/QOL (56 42% of 134 vs 46 37% of 125; 5·0% –5·0 to 15·0; p=0·41).
Although acute toxicity was higher for ultra-hypofractionation than conventional fractionation, this long-term patient-reported QOL analysis shows that ultra-hypofractionation was as well tolerated as conventional fractionation up to 6 years after completion of treatment. These findings support the use of ultra-hypofractionation radiotherapy for intermediate-to-high-risk prostate cancer.
The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.
Sex disparities in glioblastoma (GBM) have received increasing attention. Sex-related differences for several molecular markers have been reported, which could impact on clinical factors and ...outcomes. We therefore analyzed data on all patients with GBM reported to the Swedish National Quality Registry for Primary Brain Tumors, according to sex, with a focus on prognostic factors and survival. All glioma patients registered during 20 years, from 1 January 1999 until 31 December 2018, with SNOMED codes 94403, 94413, and 94423, were analyzed. Chi
-test, log-rank test, and Kaplan-Meier analyses were performed. We identified 5243 patients, of which 2083 were females and 3160 males, resulting in a ratio of 1:1.5. We found sex related differences, with women having diagnostic surgery at a significantly higher age (
= 0.001). Women were also reported to have a worse preoperative performance status (PPS) (<0.001). There was no gender difference for the type of surgery performed. For women with radical surgery, overall survival was slightly better than for men (
= 0.045). The time period did not influence survival, neither for 1999-2005 nor 2006-2018, after temozolomide treatment was introduced (
= 0.35 and 0.10, respectively). In the multivariate analysis including sex, age, surgery, and PPS, a survival advantage was noted for women, but this was not clinically relevant (HR = 0.92,
= 0.006). For patients with GBM; sex-related differences in clinical factors could be identified in a population-based cohort. In this dataset, for survival, the only advantage noted was for women who had undergone radical surgery, although this was clinically almost negligible.
To determine the predictive value of vascular endothelial growth factor (VEGF) for relapse-free survival (RFS) and overall survival (OS) in primary node-positive breast cancer (NPBC) after adjuvant ...endocrine treatment or adjuvant chemotherapy.
VEGF was quantitatively measured in tumor cytosols from 362 consecutive patients with primary NPBC using an enzyme immunoassay for human VEGF(165). Adjuvant treatment was given to all patients, either as endocrine therapy (n = 250) or chemotherapy (n = 112). The median follow-up time was 56 months.
Univariate analysis showed VEGF to be a significant predictor of RFS (P =.0289) and OS (P =.0004) in the total patient population and in patients who received adjuvant endocrine treatment (RFS, P =.0238; OS, P =.0121). In the group of patients who received adjuvant chemotherapy, no significant difference was seen in RFS, but a difference was seen in OS (P =.0235). Patients with bone recurrences tended to have lower VEGF expression (median, 2.17 pg/microg DNA) than patients with visceral metastasis (4.41 pg/microg), brain metastasis (8.29 pg/microg), or soft tissue recurrences (3.16 pg/microg). Multivariate analysis showed nodal status (P =.0004), estrogen receptor (ER) status (P <.0001), and tumor size (P =.0085) to be independent predictors of RFS. VEGF was found to be an independent predictor of OS (P =.0170; relative risk RR = 1.82), as were ER (P <.0001; RR = 5.19) and nodal status (P =.0002; RR = 2.58). For patients receiving adjuvant endocrine treatment, multivariate analysis showed VEGF content to be an independent predictor of OS (P =.0420; RR = 1.90) but not of RFS.
The results suggest that VEGF(165) content in tumor cytosols is a predictor of RFS and OS in primary NPBC. VEGF content might also predict outcome after adjuvant endocrine treatment, but further studies in a prospective setting with homologous treatments are required.
Aims
We assessed the association between insulin resistance and blood glucose concentrations at type 2 diabetes diagnosis and future development of diabetes‐related complications and mortality.
...Materials and Methods
This retrospective cohort study included 864 individuals with type 2 diabetes (median age 60 years) whose fasting C‐peptide and HbA1c were measured at diabetes diagnosis. The median follow‐up time until death or study end was 16.4 years (interquartile range 13.3−19.6). The association between C‐peptide and mortality/complications was estimated by Cox regression adjusted for sex, age at diabetes diagnosis, smoking, hypertension, BMI, total cholesterol, and HbA1c. C‐peptide and HbA1c were converted to Z scores before the Cox regression analysis.
Results
An increase by one standard deviation in fasting C‐peptide at diabetes diagnosis was associated with all‐cause (hazard ratio HR 1.33; 95% confidence intervals CI 1.12–1.58; p = 0.001) and cancer mortality (HR 1.51; 95% CI 1.13–2.01; p = 0.005) in the fully adjusted model. An increase by one standard deviation in HbA1c at diabetes diagnosis was associated with all‐cause mortality (HR 1.24; 95% CI 1.07–1.44; p = 0.005), major cardiovascular events (HR 1.20; 95% CI 1.04–1.39; p = 0.015), stroke (HR 1.36; 95% CI 1.09–1.70; p = 0.006), and retinopathy (HR 1.54; 95% CI 1.34–1.76; p < 0.0001) in the fully adjusted model.
Conclusions
Fasting C‐peptide at type 2 diabetes diagnosis is an independent risk factor for total and cancer‐related mortality. Thus, treatment of type 2 diabetes should focus not only on normalising blood glucose levels but also on mitigating insulin resistance.
Cryoprevention (CP) using ice (IC) is an effective strategy to prevent chemotherapy-induced oral mucositis (OM). However, the use of IC may cause adverse reactions and requires water of safe quality ...to minimize risk of serious infections. This randomized, blinded, parallel group, phase 3 trial was conducted in five Scandinavian centers. Eligible patients were diagnosed with multiple myeloma or lymphoma, scheduled to receive conditioning with high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (ASCT). Patients were assigned to cooling with IC or a novel intraoral cooling device (ICD). The primary outcome was the highest OM score during the study period, expressed as peak value on the Oral Mucositis Assessment Scale (OMAS-total). When the entire study population (n = 172) was analyzed for peak OMAS-total, the two cooling methods were equally effective. However, when the lymphoma group was analyzed separately, the ICD significantly reduced the peak OMAS-total score to a greater extent compared to IC (x̄ ± SD; 1.77 ± 1.59 vs. 3.08 ± 1.50; p = 0.047). Combined with existing evidence, the results of the present trial confirm that CP is an effective method to prevent OM. ClinicalTrials.gov. NCT03203733.
Abstract Background Glioblastoma is the most common malignant brain tumor in adults. Non-invasive clinical parameters could play a crucial role in treatment planning and serve as predictors of ...patient survival. Our register-based real-life study aimed to investigate the prognostic value of presenting symptoms. Methods Data on presenting symptoms and survival, as well as known prognostic factors, were retrieved for all glioblastoma patients in Sweden registered in the Swedish Brain Tumor Registry between 2018 and 2021. The prognostic impact of different presenting symptoms was calculated using the Cox proportional hazard model. Results Data from 1458 adults with pathologically verified IDH wild-type glioblastoma were analyzed. Median survival time was 345 days. The 2-year survival rate was 21.5%. Registered presenting symptoms were focal neurological deficits, cognitive dysfunction, headache, epilepsy, signs of raised intracranial pressure, and cranial nerve symptoms, with some patients having multiple symptoms. Patients with initial cognitive dysfunction had significantly shorter survival than patients without; 265 days (245–285) vs. 409 days (365–453; P < .001). The reduced survival remained after Cox regression adjusting for known prognostic factors. Patients presenting with seizures and patients with headaches had significantly longer overall survival compared to patients without these symptoms, but the difference was not retained in multivariate analysis. Patients with cognitive deficits were less likely to have radical surgery and to receive extensive anti-neoplastic nonsurgical treatment. Conclusions This extensive real-life study reveals that initial cognitive impairment acts as an independent negative predictive factor for treatment decisions and adversely affects survival outcomes in glioblastoma patients.
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