Improved relapse-free survival after autologous stem cell transplantation does not translate into better quality of life in chronic lymphocytic leukemia: lessons from the randomized European Society for Blood and Marrow Transplantation-Intergroup study.

In chronic lymphocytic leukemia (CLL) medical progress is driven by clinical studies with relapse-free survival (RFS) as the primary endpoint. The randomized EBMT-Intergroup trial compared high-dose therapy and autologous stem cell transplantation (ASCT) to observation and demonstrated a substantial improvement of RFS without showing improved overall survival for the transplant arm. Here we report quality of life (QoL) information of the first 3 years following randomization from that study. The main objective was to assess the impact of treatment on QoL over time. Two secondary analyses were performed to further investigate the impact of ASCT and relapse on QoL. In the primary analysis, we demonstrate an adverse impact of ASCT on QoL which was largest at 4 months and continued throughout the first year after randomization. Further, we demonstrated a sustained adverse impact of relapse on QoL which worsened over time. Despite better disease control by ASCT the side effects thus turned the net effect towards inferior QoL in the first year and comparable QoL in the following 2 years after randomization. This study emphasizes the importance of information concerning QoL impacts when patients are counseled about treatments aimed at improving RFS in the absence of a survival benefit.

Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial.

BACKGROUND: Standard curative schedules of radiotherapy to the breast deliver 25 fractions of 2.0 Gy over 5 weeks. In a randomised trial, we tested whether fewer, larger fractions were at least as safe and as effective as standard regimens. In this analysis, we assessed the long-term results of tumour control in the same population. METHODS: In 1986-98, we randomly assigned 1410 women with invasive breast cancer (tumour stage 1-3 with a maximum of one positive node and no metastasis) who had had local tumour excision of early stage breast cancer to receive 50 Gy radiotherapy given in 25 fractions, 39 Gy given in 13 fractions, or 42.9 Gy given in 13 fractions, all given over 5 weeks. The primary endpoint was late change in breast appearance, which has been reported elsewhere. Here, we report ipsilateral tumour relapse, one of the secondary endpoints. Relapse was defined as any appearance of cancer in the irradiated breast. Analysis was by intention to treat. FINDINGS: After a median follow-up of 9.7 years (IQR 7.8-11.8) for the 838 (95%) patients who survived, the risk of ipsilateral tumour relapse after 10 years was 12.1% (95% CI 8.8-15.5) in the 50 Gy group, 14.8% (11.2-18.3) in the 39 Gy group, and 9.6% (6.7-12.6) in the 42.9 Gy group (difference between 39 Gy and 42.9 Gy groups, chi2 test, p=0.027). The sensitivity of breast cancer to dose per fraction was estimated to be 4.0 Gy (95% CI 1.0-7.8), similar to that estimated for the late adverse effects in healthy tissue from breast radiotherapy. INTERPRETATION: Breast cancer tissue is probably just as sensitive to fraction size as dose-limiting healthy tissues. If this finding is confirmed, radiotherapy schedules can be greatly simplified by the delivery of fewer, larger fractions without compromising effectiveness or safety, and possibly improving both.

Influence of psychological response on breast cancer survival: 10-year follow-up of a population-based cohort.

The possibility that psychological response within a few weeks of a breast cancer diagnosis can influence the outcome of the disease is a contentious issue. Psychological response, including helplessness/hopelessness, fighting spirit and depression was assessed in early-stage breast cancer patients between 1 and 3 months post-diagnosis, in order to ascertain effect on cancer prognosis. Patients were followed up for a period of 10 years in order to clarify the effect of psychological response on disease outcome. After 10 years, there is a continuing effect of helplessness/hopelessness on disease-free survival (adjusted hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.11-2.11) but not of depression (adjusted HR for overall survival for 'cases' 2.43, 95% CI 0.97-6.10). Longer follow-up also indicates that a high fighting spirit confers no survival advantage. The results showed that, in patients who were disease-free at 5 years, their baseline helpless/hopeless response still exerted a significant effect on disease-free survival beyond 5 (and up to 10) years. The effect is therefore maintained for up to 10 years of follow-up. Clinicians may wish to screen for helplessness around the time of diagnosis in order to target psychological care resources. Further large studies, with similarly prolonged follow-up, are needed to replicate this effect and clarify its mechanism of action.

Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial.

BACKGROUND AND PURPOSE: Unlike squamous carcinomas, breast adenocarcinoma may be as sensitive to fraction size as late dose-limiting normal tissues. If so, fewer larger fractions would be as safe and effective as regimens based on 2.0 Gy fractions. The first step is to test the effects of radiotherapy fractions >2.0 Gy on late normal tissue responses in the breast after tumour excision and radiotherapy for early breast cancer. PATIENTS AND METHODS: One thousand four-hundred and ten women with T1-3 N0-1 M0 invasive breast cancer were randomised between 1986-98 into one of three radiotherapy regimens after local tumour excision of early stage breast cancer; 50 Gy in 25 fractions (F) vs two dose levels of a test schedule giving 39 or 42.9 Gy in 13 F over 5 weeks. Fraction sizes were 2.0, 3.0 and 3.3 Gy, respectively. The primary endpoint was late change in breast appearance compared to post-surgical appearance scored from annual photographs blinded to treatment allocation. Secondary endpoints included palpable breast induration (fibrosis) and ipsilateral tumour recurrence. RESULTS: After a minimum 5-year follow up, the risk of scoring any change in breast appearance after 50 Gy/25 F, 39 Gy/13 F and 42.9 Gy/13 F was 39.6, 30.3 and 45.7%, from which an alpha/beta value of 3.6 Gy (95% CI 1.8-5.4) is estimated. The alpha/beta value for palpable breast induration was 3.1 Gy (95% CI 1.8-4.4). CONCLUSIONS: An alpha/beta value of around 3 Gy for late normal tissue changes in the breast is derived from the estimated equivalence of 41.6 Gy in 13 fractions and 50 Gy in 25 fractions over 5 weeks, in line with trial predictions.

TGFB1 polymorphisms are associated with risk of late normal tissue complications in the breast after radiotherapy for early breast cancer.

Recent studies suggest that normal tissue radiosensitivity is influenced by single nucleotide polymorphisms (SNPs) in certain genes. In order to seek a confirmation of these findings, this study investigated SNPs in genes TGFB1 (position -509, codon 10 and codon 25), SOD2 (codon 16), XRCC1 (codon 399), XRCC3 (codon 241), APEX (codon 148) and ATM (codon 1853) in 26 breast cancer patients with marked changes in breast appearance after radiotherapy and 26 matched controls. Statistically significant associations were found between the TGFB1 codon 10 Pro allele (P=0.005) as well as the TGFB1 position -509 T allele (P=0.018) and increased risk of altered breast appearance. No significant associations were found for the remaining SNPs.

Treatment of CML using IFN-alpha: impact on quality of life.

Treatment of chronic myeloid leukaemia (CML) with IFN-alpha (IFN) is known to confer significant survival benefit, but the drug's impact on quality of life (QoL) in CML is unclear. We describe a cross-sectional comparison of QoL in patients randomised to long-term treatment with IFN versus no IFN within the UK MRC CML 3 trial, assessing the long-term consequences and psychosocial side effects of IFN therapy. Patients completed the EORTC QoL QLQ-C30, an in-house leukaemia/IFN questionnaire, a brief assessment of sexual functioning and demographic details. In total, 163 eligible patients completed questionnaires (85% response). Patients receiving IFN reported significantly worse QoL for emotional, cognitive and social functioning, pain and dyspnoea (P<0.01), and marginally worse fatigue, nausea and vomiting (P<0.05). As expected from other IFN use, those on IFN experienced more flu-like and febrile symptoms and skin problems than those not on IFN. In all, 35% of patients stopped IFN before questionnaire completion. This made no material difference to the results, except that those continuing on IFN had slightly better self-assessed Global health/QoL than those who had stopped (P<0.03). IFN treatment adversely affected sexual health after allowing for age and gender. In conclusion, IFN treatment has a significant adverse impact on QoL. Patient awareness of the survival benefits and these QoL effects should enable better-informed decision-making. The impact on QoL of IFN dose, and of imatinib therapy versus IFN in early CP CML, are being investigated. QoL will need evaluating in future studies of combination treatment (IFN+imatinib).