Quality of life after postmastectomy radiotherapy in patients with intermediate-risk breast cancer (SUPREMO): 2-year follow-up results of a randomised controlled trial.

BACKGROUND: Postmastectomy radiotherapy in patients with four or more positive axillary nodes reduces breast cancer mortality, but its role in patients with one to three involved nodes is controversial. We assessed the effects of postmastectomy radiotherapy on quality of life (QOL) in women with intermediate-risk breast cancer. METHODS: SUPREMO is an open-label, international, parallel-group, randomised, controlled trial. Women aged 18 years or older with intermediate-risk breast cancer (defined as pT1-2N1; pT3N0; or pT2N0 if also grade III or with lymphovascular invasion) who had undergone mastectomy and, if node positive, axillary surgery, were randomly assigned (1:1) to receive chest wall radiotherapy (50 Gy in 25 fractions or a radiobiologically equivalent dose of 45 Gy in 20 fractions or 40 Gy in 15 fractions) or no radiotherapy. Randomisation was done with permuted blocks of varying block length, and stratified by centre, without masking of patients or investigators. The primary endpoint is 10-year overall survival. Here, we present 2-year results of QOL (a prespecified secondary endpoint). The QOL substudy, open to all UK patients, consists of questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23, Body Image Scale, Hospital Anxiety and Depression Scale [HADS], and EQ-5D-3L) completed before randomisation, and at 1, 2, 5, and 10 years. The prespecified primary outcomes within this QOL substudy were global QOL, fatigue, physical function, chest wall symptoms, shoulder and arm symptoms, body image, and anxiety and depression. Data were analysed by intention to treat, using repeated mixed-effects methods. This trial is registered with the ISRCTN registry, number ISRCTN61145589. FINDINGS: Between Aug 4, 2006, and April 29, 2013, 1688 patients were enrolled internationally and randomly assigned to receive chest wall radiotherapy (n=853) or not (n=835). 989 (79%) of 1258 patients from 111 UK centres consented to participate in the QOL substudy (487 in the radiotherapy group and 502 in the no radiotherapy group), of whom 947 (96%) returned the baseline questionnaires and were included in the analysis (radiotherapy, n=471; no radiotherapy, n=476). At up to 2 years, chest wall symptoms were worse in the radiotherapy group than in the no radiotherapy group (mean score 14·1 [SD 15·8] in the radiotherapy group vs 11·6 [14·6] in the no radiotherapy group; effect estimate 2·17, 95% CI 0·40-3·94; p=0·016); however, there was an improvement in both groups between years 1 and 2 (visit effect -1·34, 95% CI -2·36 to -0·31; p=0·010). No differences were seen between treatment groups in arm and shoulder symptoms, body image, fatigue, overall QOL, physical function, or anxiety or depression scores. INTERPRETATION: Postmastectomy radiotherapy led to more local (chest wall) symptoms up to 2 years postrandomisation compared with no radiotherapy, but the difference between groups was small. These data will inform shared decision making while we await survival (trial primary endpoint) results. FUNDING: Medical Research Council, European Organisation for Research and Treatment of Cancer, Cancer Australia, Dutch Cancer Society, Trustees of Hong Kong and Shanghai Banking Corporation.

Inter-fraction motion and dosimetric consequences during breast intensity-modulated radiotherapy (IMRT).

BACKGROUND AND PURPOSE: Intensity-modulated radiotherapy (IMRT) can improve dose homogeneity within the breast planned target volume (PTV), but may be more susceptible to patient/organ motion than standard tangential radiotherapy (RT). We used daily cone-beam CT (CBCT) imaging to assess inter-fraction motion during breast IMRT and its subsequent impact on IMRT and standard RT dose homogeneity. MATERIALS AND METHODS: Ten breast cancer patients selected for IMRT were studied. CBCT images were acquired immediately after daily treatment. Automatic image co-registration was used to determine patient positioning variations. Daily PTV contours were used to calculate PTV variations and daily delivered IMRT and theoretically planned tangential RT dose. RESULTS: Group systematic (and random) setup errors detected by CBCT were 5.7 (3.9)mm laterally, 2.8 (3.5)mm vertically and 2.3 (3.2)mm longitudinally. Rotations >2 degrees in any axis occurred on 53/106 (50%) occasions. Daily PTV volume varied up to 23%. IMRT dose homogeneity was superior at planning and throughout the treatment compared with standard RT (1.8% vs. 15.8% PTV received >105% planned mean dose), despite increased motion sensitivity. CONCLUSIONS: CBCT revealed inadequacies of current patient positioning and verification procedures during breast RT and confirmed improved dose homogeneity using IMRT for the patients studied.

Nodular basal cell carcinoma in Gorlin's syndrome treated with systemic photodynamic therapy and interstitial optical fiber diffuser laser.

Nodular basal cell carcinomas resistant to multiple forms of treatment in two patients with nevoid basal cell carcinoma syndrome (Gorlin's syndrome) were treated with systemic porfimer sodium-based photodynamic therapy. Interstitially placed optical diffuser fibers were used to deliver light. Good response to treatment was seen on clinical evaluation and on measurement by a 20-MHz high-resolution ultrasound.

Photodynamic therapy in the management of a patient with Gorlin syndrome (naevoid basal cell carcinoma syndrome).

Gorlin syndrome (naevoid basal cell carcinoma syndrome) is a genetically linked disorder characterized by the development of multiple basal cell carcinomas (BCCs) throughout life. Cumulative surgery, cryotherapy and other conventional interventions can result in significant disfigurement by middle age. Radiotherapy is contra-indicated because the mutated gene underlying the syndrome, 'PTCH', increases sensitivity to ionising radiation, so there is significant likelihood of inducing further tumours in and around the irradiated area. Photodynamic therapy offers a non-invasive treatment option for patients with this condition, with the added advantage of causing minimal scarring.

The oligometastatic state in breast cancer: hypothesis or reality.

The term 'oligometastasis' was initially used to describe a restricted locoregional tumour load, but the term has now become synonymous with isolated distant metastases. The existence of an oligometastatic state is still not widely recognised in the management of breast cancer patients. However, there are a number of patients who do develop isolated metastases and in whom long term survival can be achieved following appropriately targeted treatment. This review article discusses the possible biological mechanisms behind the development of an oligometastatic state and the findings from different trials which describe results following radical therapy for isolated metastatic disease. Although no large scale trials in this area have yet been undertaken, there is evidence to support the existence of an oligometastatic state in patients with breast cancer and we discuss the appropriate management for this clinical scenario.

Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix.

PURPOSE: Hypoxia-inducible factor (HIF)-1alpha expression was studied retrospectively in locally advanced carcinoma of the cervix in relation to other methods for measuring/assessing tumor hypoxia and outcome after radiotherapy. EXPERIMENTAL DESIGN: HIF-1alpha expression was examined in formalin-fixed tumor biopsies using a semiquantitative scoring system and correlated with measurements of hypoxia obtained using oxygen electrodes, pimonidazole staining, and carbonic anhydrase 9. RESULTS: High HIF-1alpha expression showed a weak correlation with low pO2 (r = -0.26; P = 0.030; n = 72). Weak significant correlations were found between HIF-1alpha and pimonidazole staining (r = 0.34; P = 0.040; n = 36) and carbonic anhydrase IX (r = 0.27; P = 0.001; n = 160). There was no relationship with surviving fraction at 2 Gy. The relationship between HIF-1alpha expression and radiotherapy outcome was examined in 99 patients. HIF-1alpha expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1alpha alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1alpha expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1alpha and tumor size for survival (P = 0.046) and local control (P = 0.009). CONCLUSIONS: In this study, HIF-1alpha had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1alpha expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1alpha. Whereas angiogenesis-promoting genes might be preferentially up-regulated in small tumors, proapoptotic genes might be induced in large tumors. This hypothesis needs testing in future work.

An ultrasound analysis of the response of Gorlin syndrome-related and sporadic basal cell carcinomas to aminolaevulinic acid photodynamic therapy.

BACKGROUND: Gorlin Syndrome (naevoid basal cell carcinoma syndrome, NBCCS) predisposes the patient to the development of basal cell carcinomas (BCCs) throughout their life. The standard treatment for isolated lesions is surgical excision. However, when numerous surgical procedures are required over time, the patient can be left with multiple disfiguring scars. Photodynamic therapy (PDT) offers a non-invasive treatment option for patients with this condition, in which ionizing radiation is contraindicated. This study evaluates PDT as a treatment modality for Gorlin Syndrome and compares the treatment response of Gorlin-related basal cell carcinomas with that of the sporadic lesions. METHODS: In this un-randomized study, basal cell carcinomas in 25 Gorlin syndrome patients (with 36 lesions) and 145 sporadic patients (with 189 lesions) were treated by photodynamic therapy, using δ-5-aminolaevulinic acid (ALA) as a photosensitizer and 100Jcm(-2) of red light (630±15nm). The maximum thickness of the BCC was measured by 20MHz pulsed ultrasound prior to treatment and again 4-6 weeks and 12 months following treatment. The response of Gorlin syndrome lesions was compared to those in the overall sporadic population and then to a subpopulation matched as closely as possible for age, lesion thickness and site. RESULTS: For both populations, the average pre-treatment BCC thickness by US was 1.5mm (overall range 0.3-5.3), and the average thickness at 4-6 weeks post-treatment was 0.5mm (overall range 0-4.3). Those BCC less than 1.5mm thick prior to treatment were significantly more likely to have no US evidence of disease at 4-6 weeks than and were more likely to be controlled at 12 months. CONCLUSIONS: The average response to ALA PDT of Gorlin syndrome-related BCC closely resembles that for the sporadic population, with the same wide range of responses for a given dose. Ultrasound parameters measured at treatment and at 4-6 weeks post-treatment aid prediction of outcome and necessity for further treatment.

Prediction of radiotherapy outcome using dynamic contrast enhanced MRI of carcinoma of the cervix.

PURPOSE: To investigate whether analysis of MRI enhancement data using a pharmacokinetic model improved a previously found correlation between contrast enhancement and tumor oxygenation measured using PO2 histograph. To evaluate the prognostic value of gadolinium enhancement data for radiotherapy outcome, and to study the efficacy of combined enhancement and MRI volume data. METHODS AND MATERIALS: Fifty patients underwent dynamic gadolinium-enhanced MRI as part of their initial staging investigations before treatment. Gadolinium enhancement was analyzed using the Brix pharmacokinetic model to obtain the parameters amplitude and rate of contrast enhancement. Pretreatment tumor oxygen measurements (Eppendorf PO2 histograph) were available for 35 patients. RESULTS: Both standard and pharmacokinetic-derived enhancement data correlated with tumor oxygenation measurements, and poorly enhancing tumors had low tumor oxygen levels. However, only the pharmacokinetic-analyzed data correlated with patient outcome and patients with poorly (amplitude less than median) vs. well-enhancing tumors had significantly worse disease-specific survival (p = 0.024). For the 50 patients studied, no relationship was found between enhancement and volume data. Combining MRI volume and enhancement information highlighted large differences in outcome (p = 0.0054). At the time of analysis, only 55% of patients with large, poorly enhanced tumors were alive compared with 92% of patients with small, well-enhanced tumors. CONCLUSION: These preliminary results suggest that pharmacokinetic modeling of dynamic contrast-enhanced MRI provides data that reflect tumor oxygenation and yields useful prognostic information in patients with locally advanced carcinoma of the cervix. Combining MRI-derived enhancement and volume data delineates large differences in radiotherapy outcome.

Measurements of hypoxia using pimonidazole and polarographic oxygen-sensitive electrodes in human cervix carcinomas.

BACKGROUND AND PURPOSE: The measurement of tumour oxygenation using Eppendorf oxygen-sensitive needle electrodes can provide prognostic information but the method is limited to accessible tumours that are suitable for electrode insertion. In this paper the aim was to study the relationship between such physiological measurements of tumour hypoxia and the labelling of tumours with the hypoxia-specific marker pimonidazole. MATERIALS AND METHODS: Assessment of tumour oxygen partial pressure (pO(2)) using an Eppendorf pO(2) histograph and immunohistochemical pimonidazole labelling was carried out in 86 patients with primary cervix carcinomas. Pimonidazole was given as a single injection (0.5 g/m(2) i.v.) and 10-24 h later pO(2) measurements were made and biopsies taken. Tumour oxygenation status was evaluated as the median tumour pO(2) and the fraction of pO(2) values

GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding.

The presence of hypoxia in tumours results in the overexpression of certain genes, which are controlled via the transcription factor HIF-1. Hypoxic cells are known to be radioresistant and chemoresistant, thus, a reliable surrogate marker of hypoxia is desirable to ensure that treatment may be rationally applied. Recently, the HIF-1-regulated proteins Glut-1 and CAIX were validated as intrinsic markers of hypoxia by comparison with pO(2) measured using oxygen electrodes. We compare the expression of Glut-1 and CAIX with the binding of the bioreductive drug hypoxia marker pimonidazole. Pimonidazole was administered to 42 patients with advanced carcinoma of the cervix, 16 hr before biopsy. Sections of single or multiple biopsies were then immunostained for Glut-1 and CAIX, and the area of staining scored by eye, using a "field-by-field" semi-quantitative averaging system. Using 1 biopsy only, Glut-1 (r = 0.54, p = <0.001) correlated with the level of pimonidazole binding, and Glut-1 and CAIX expression also correlated significantly (r = 0.40, p = <0.009). Thus, our study has shown that HIF-1 regulated genes have potential for future use as predictors of the malignant changes mediated by hypoxia, and warrant further investigation as indicators of response to cancer therapy.