Impact of Oncotype DX breast Recurrence Score testing on adjuvant chemotherapy use in early breast cancer: Real world experience in Greater Manchester, UK.

BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) recommended the Oncotype DX® Breast Recurrence Score® (RS) assay as an option for informing adjuvant chemotherapy decisions in node-negative, oestrogen receptor (ER)+, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer assessed to be at intermediate risk of recurrence based on clinicopathological factors. We evaluated the impact of RS testing on adjuvant chemotherapy decision-making in routine clinical practice in a UK Cancer Network. METHODS: RS testing was performed in 201 females with newly diagnosed, ER+, HER2-negative, invasive breast cancer who underwent breast surgery with curative intent, were calculated to have a >3% overall survival benefit at 10 years from adjuvant chemotherapy based on PREDICT, and were considered for adjuvant chemotherapy. The impact of RS testing on adjuvant treatment decisions/associated cost was assessed. RESULTS: In all patients, the multi-disciplinary team recommended chemotherapy but the RS result allowed 127/201 patients (63.2%) to avoid unnecessary adjuvant chemotherapy. Amongst ER+, HER2-negative, node-negative patients (eligible for Oncotype DX testing in UK guidelines), 60.3% were spared chemotherapy. In node-positive patients, the assay reduced the use of chemotherapy by 69.2%. The use of RS testing to guide treatment in these 201 patients was associated with significant cost saving (when considering the cost of RS testing for all patients plus chemotherapy and its associated cost for 74 patients). CONCLUSIONS: Incorporating RS testing into routine clinical practice for selected node-negative and node-positive breast cancer patients significantly reduces the use of chemotherapy (p < 0.001) with its associated morbidity and costs.

Tumour bed clip localisation for targeted breast radiotherapy: compliance is proportional to trial-related research activity: tumour bed clip localisation in breast radiotherapy.

BACKGROUND: In breast cancer, with the increasing use of intensity-modulated radiotherapy (IMRT), the need for accurate tumour bed localisation is paramount. We determined current practice of clip usage in patients referred to a regional centre for radiotherapy following breast conserving surgery. We also investigated whether participation of surgical units in IMRT trials, where tumour bed clip use is emphasised, was associated with clip insertion. METHODS: A retrospective cohort study of consecutive CT planning images (n = 205), of breast cancer patients treated with radiotherapy following breast conserving surgery. Presence and number of clips; referring hospital and referring surgeon of the patient was recorded. This was correlated to previous participation of referring hospital to IMRT trials. RESULTS: Of 196 eligible patients, 126 (64%) had clips sited, of which 15 (12%) had two or fewer clips. Five referring hospitals were high recruiters (≥14 patients), and five hospitals were low/non-recruiters (≤1 patient) to IMRT trials. Of patients from low/non-recruiting centres, 29 of 43 (67%) had clips omitted, compared to 41 of 153 (27%) from high-recruiting centres (p < 0.001). Median number of clips used in centres recruiting high numbers of patients was four, compared to zero in low recruiting centres. Ten of 31 referring surgeons routinely omitted clips. CONCLUSION: Despite inclusion in national guidelines, clip insertion has not become routine in the UK in patients undergoing breast conserving surgery. However, hospitals involved in breast radiotherapy randomised controlled trials are more compliant with clip usage recommendations. Auditing of clip insertion should be considered as a quality control marker in breast surgery.

Efficacy of photodynamic therapy as a treatment for Gorlin syndrome-related basal cell carcinomas.

AIMS: The management of the multiple basal cell carcinomas (BCCs) that develop throughout life of patients with Gorlin syndrome can be challenging. Surgical excision can result in significant disfigurement from scarring and tissue defects. Radiotherapy is contraindicated because of enhanced radiation tumourigenesis in these patients. Photodynamic therapy (PDT) is a simple, repeatable out-patient procedure, which is associated with minimal skin deterioration. It is now routinely used to treat superficial sporadic BCCs, using a topically-applied photosensitiser and external light, but its role in the management of Gorlin syndrome-related BCCs has yet to be established. In particular, Gorlin syndrome is often associated thick, nodular lesions which can be resistant to treatment with topical PDT. MATERIALS AND METHODS: We report our outcome data for 33 Gorlin patients (138 lesions) treated with PDT. Lesion thicknesses were assessed using ultrasound, both prior to treatment and during follow-up, to quantify treatment response and to guide the choice of treatment methods. Topical PDT was used to treat superficial lesions (<2 mm thick) and a systemic photosensitiser +/- light delivered by interstitially-placed optical fibres was employed for thicker lesions (>2 mm). RESULTS AND CONCLUSIONS: Local control rates of 56.3% at 12 months were achieved overall. The use of a systemic photosensitiser +/- interstitial light delivery extended the remit of PDT, allowing thicker lesions (>2 mm) to be treated, resulting in local control rates of 59.3% in this group. PDT can be considered as a treatment option for patients with multiple BCCs as a result of Gorlin syndrome. The use of ultrasound to accurately assess lesion thickness helps to select the optimum treatment method. Systemic photosensitisers and interstitial optical fibres can be used to treat thicker lesions, offering a treatment option for patients with thick nodular tumours who wish to avoid surgery.

Hand function after high dose rate brachytherapy for squamous cell carcinoma of the skin of the hand.

AIMS: Current recommendations for the treatment of squamous cell carcinoma of the hand are almost unanimously in favour of ablative surgery. However, many of the patients are frail and elderly, and surgical techniques frequently involve skin grafts or amputation of digits. A non-invasive method of treatment is, therefore, often preferred. Radiotherapy using a brachytherapy technique is a well-established option. This study investigated whether patients found the treatment acceptable and assessed the outcome of treatment in terms of local control, cosmesis and hand function. MATERIALS AND METHODS: Twenty-five patients who underwent mould brachytherapy using a microselectron high dose rate radiotherapy device were available for assessment. We assessed the functional status of the hand and fingers by means of the Disability of Arm, Shoulder and Hand and Michigan Hand Outcomes questionnaires. We examined the hand to assess the severity of post-radiation stigmata. We enquired as to patient acceptability of treatment and outcome. RESULTS: Of 25 patients who agreed to participate, the fingers were affected in 15 and the dorsum of the hand in 10. The mean age at the time of radiotherapy was 69 years (range 50-87). There were no significant differences in parameters, such as range of motion of fingers and wrist, hand/finger grip strength, between the treated and opposite sides. Sensation, including two-point discrimination, was not significantly different from the untreated hand. Seventeen patients had minor skin changes. No patient found the treatment painful or unacceptable. Twenty patients were very satisfied and five patients were moderately satisfied with the cosmetic result. CONCLUSIONS: We conclude that high dose rate brachytherapy is a safe and simple alternative to surgical treatment for squamous cell carcinoma of the hand, as it is not only successful in eradicating tumour, but also preserves hand function.

A prospective observational study of chemotherapy-related nausea and vomiting in routine practice in a UK cancer centre.

OBJECTIVE: The aim of the study was to assess levels of chemotherapy-induced nausea and vomiting (CINV) in routine practice. MATERIALS AND METHODS: The study was an observational prospective evaluation using patient self-reports. One hundred and two patients with cancer in a single cancer centre in UK receiving their first chemotherapy treatment participated in the study and were followed up over four cycles, providing a total of 272 assessments of nausea and vomiting. Data was collected with the use of the MASCC Antiemesis Tool (MAT), which is an eight-item short clinical scale assessing acute and delayed nausea and vomiting after chemotherapy. RESULTS: Results indicated that acute vomiting was experienced by 15.7% of the patients in cycle 1 and delayed vomiting by 14.7%, while acute nausea was present in 37.3% of the patients and delayed nausea in 47.1%, increasing over the subsequent cycles. Moderately emetogenic and highly emetogenic chemotherapy had the highest incidence of CINV, whereas patients receiving highly emetogenic chemotherapy showed significant levels of delayed nausea. Acute symptoms were more easily controlled than delayed symptoms. DISCUSSION: The data suggest that, while vomiting is well controlled, nausea remains a significant problem in practice, and optimal management of CINV is yet to be achieved. Understanding more clearly the biological basis of nausea will assist in managing this complex symptom more effectively in practice.

No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix.

The expression of hypoxia-regulated genes promotes an aggressive tumour phenotype and is associated with an adverse cancer treatment outcome. Thymidine phosphorylase (TP) levels increase under hypoxia, but the protein has not been studied in association with hypoxia in human tumours. An investigation was made, therefore, of the relationship of tumour TP with hypoxia, the expression of other hypoxia-associated markers and clinical outcome. This retrospective study was carried out in patients with locally advanced cervical carcinoma who underwent radiotherapy. Protein expression was evaluated with immunohistochemistry. Hypoxia was measured using microelectrodes and the level of pimonidazole binding. There was no relationship of TP expression with tumour pO(2) (r=-0.091, P=0.59, n=87) or pimonidazole binding (r=0.13, P=0.45, n=38). There was no relationship between TP and HIF-1alpha, but there was a weak borderline significant relationship with HIF-2alpha expression. There were weak but significant correlations of TP with the expression of VEGF, CA IX and Glut-1. In 119 patients, the presence of TP expression predicted for disease-specific (P=0.032) and metastasis-free (P=0.050) survival. The results suggest that TP is not a surrogate marker of hypoxia, but is linked to the expression of hypoxia-associated genes and has weak prognostic power.

Systemic photodynamic therapy with Photofrin for naevoid basal cell carcinoma syndrome-A pilot study.

BACKGROUND: Treatment of basal cell carcinomas in naevoid basal cell carcinoma syndrome (NBCCS) poses several challenges. The sheer numbers of such lesions in these patients makes traditional therapeutic modalities like surgery, impractical. Topical photodynamic therapy (PDT) with δ-5-amino levulinic acid has increasingly been recognised as and safe and effective choice in the treatment of BCC. The probability of local control of BCC treated by PDT depends strongly on lesion thickness, thick nodular lesions being less responsive. Response to treatment is monitored by the reduction in the lesional size, but histopathological confirmation of regression is often required. METHOD: We used systemic photodynamic therapy with Porfimer Sodium (Photofrin(®), Axcan Pharma Inc., Quebec, Canada), a systemic photosensitizer for treating multiple BCC in seven patients with NBCCS. Treatment response was monitored using a high resolution 20MHz ultrasound. RESULTS: There was a substantial reduction in the number of superficial basal cell carcinomas with complete US regression after one treatment. A 74.2% reduction was seen in the size of thick lesions treated with external light. Thick nodular lesions in two patients treated with interstitial optical diffuser fibres in addition to external light showed 87.6% reduction in size as measured by high resolution ultrasound. CONCLUSIONS: Our preliminary results indicate that systemic photodynamic therapy using Photofrin and external light either alone or with interstitial optical diffuser fibres; may be effective in treatment of multiple, thick and nodular BCC lesions in Naevoid basal cell carcinoma syndrome. Further studies are needed to confirm our observations. We found high resolution ultrasound an effective alternative to histopathological analysis in monitoring the response to treatment.

Extramammary Paget's disease treated with topical and systemic photodynamic therapy.

Surgical excision and radiotherapy for extramammary Paget's disease (EMPD) at specific sites such as the groin and genitalia is often inappropriate. An 80-year-old man with histologically proven EMPD of the left groin and scrotum was referred for PDT. The lesion and normal skin thickness were measured by a 20MHz, two-dimensional 'B' ultrasound scanner (US). δ-5-Aminolaevulinic acid (ALA), was applied followed 6h later by irradiation using a filtered xenon-arc lamp. Clinical improvement was apparent four weeks after first PDT session with a reduction in ulceration and lesion size and moderate thickness reduction on US. Superficial ulceration recurred 9 months after the fifth treatment. This recurrence was treated with intravenously administered porfimer sodium. This, followed by one topical PDT treatment resulted in significant clinical and US cure and the patient remains disease free at 1-year follow-up.

Adjuvant radiotherapy after conservative surgery for breast cancer: is it always necessary?

Breast irradiation is used to reduce the risk of within-breast recurrence following conservative surgery. This review examines factors--particularly patient age--that may be used to select patients at low risk of local failure where radiotherapy may not be necessary.

Adjuvant radiotherapy in breast cancer. Are there factors that allow selection of patients who do not require adjuvant radiotherapy following breast-conserving surgery for breast cancer?

Postoperative adjuvant radiotherapy is used to reduce local recurrences following breast-conserving surgery for early breast cancer. This review examines factors that may be used to select patients at low risk of local failure following breast-conserving surgery alone.

Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix.

There is increasing evidence that hypoxia-regulated gene expression influences tumor aggressiveness, contributing to the poorer outcome of patients with hypoxic tumors. The role of the transcriptional complex hypoxia-inducible factor-1 as an important mediator of hypoxia-regulated gene expression is one of the best documented pathways. Recently, it has emerged that certain tumor-associated carbonic anhydrases (CAs) can be added to the list of known hypoxia-inducible factor-responsive genes. Here we show that the immunohistochemical expression of the tumor-associated CA IX is correlated with the level of hypoxia in human cervical tumors. We performed a prospective study in 68 patients where needle electrodes were used to make direct measurements of tumor oxygenation levels. CA IX expression was evaluated immunohistochemically in pretreatment tumor biopsies. There was a significant positive correlation between the level of tumor hypoxia (HP5) and the extent of CA IX expression. A retrospective study of 130 squamous cell cervical carcinomas demonstrated that a semiquantitative immunohistochemical analysis of CA IX expression in tumor biopsies is a significant and independent prognostic indicator of overall survival and metastasis-free survival after radiation therapy. These studies provide clinical evidence that CA IX expression is up-regulated in hypoxic human cervical tumors and is associated with a poor prognosis. CA IX may act as an intrinsic marker of tumor hypoxia and poor outcome after radiation therapy. The level of CA IX expression may be used to aid in the selection of patients who would benefit most from hypoxia-modification therapies or bio-reductive drugs.

Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix.

Hypoxic tumors are known to be more malignant, to be more likely to metastasize, and to have a poor prognosis. They are also radio- and chemoresistant. For this reason, it is desirable that a clinically useful marker of hypoxia is found, so that treatment with radiotherapy and bioreductive chemotherapy can be rationally applied to individual patients. Glut-1 is a facilitative glucose transporter that is ubiquitously expressed in normal tissue and expressed at higher levels in a number of tumors. Its potential as an intrinsic hypoxia marker arises from its dual control in hypoxic conditions by reduced oxidative phosphorylation and the hypoxia-inducible factor (HIF-1) oxygen-sensing pathway. Eppendorf histography, by virtue of its proven predictive qualities, is a suitable gold standard used in our laboratory to validate new hypoxia markers. Using this technique, pretreatment pO(2) measurements were performed on 54 patients with locally advanced cervical carcinoma. Then, immunohistochemical staining was used to detect Glut-1 protein in individual tumor biopsy sections. Both measurements were made before initiation of treatment. By using a low-tech scoring system, pO(2) was found to correlate weakly with Glut-1 score (r = 0.28; P = 0.04). To extrapolate this correlation to the known adverse effects of tumor hypoxia on outcome, we examined the prognostic significance of Glut-1 staining in a retrospective series of 121 patients. An absence of Glut-1 significantly increased the likelihood of metastasis-free survival (P = 0.022) but did not significantly effect disease-free or recurrence-free survival. These findings suggest that Glut-1 be an intrinsic marker of hypoxia that can easily be applied in a clinical setting.

Tumor vascularity: a histological measure of angiogenesis and hypoxia.

In this study we sought to clarify the relationship between tumor vascularity, hypoxia, and angiogenesis in human cervix tumors. Two hypotheses were established: first, that measurement of tumor vascularity can provide a histological assessment of both hypoxia and angiogenesis; and second, that expression of angiogenesis-related proteins will provide a surrogate measure of tumor hypoxia. To test the first hypothesis, we studied the prognostic significance of tumor vascularity measured as both intercapillary distance (ICD; thought to reflect tumor oxygenation) and microvessel density (MVD; the hotspot method that provides a histological assessment of tumor angiogenesis). The relationship was also examined of tumor hypoxia, measured using an Eppendorf needle electrode [percentage of values less than 5 mm Hg (HP5)], with ICD and MVD. To test the second hypothesis we examined the relationship between HP5 and the expression of angiogenesis-associated proteins [vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF)]. All of the biological measurements were made on pretreatment tumors. Analysis of data was carried out using log-rank statistics, Cox multivariate analysis, and Spearman's rank correlation. Both ICD and MVD were significant independent prognostic factors for local control. Patients with poorly vascularized tumors (long ICD) had poor local control (P = 0.042). However, patients with poorly vascularized tumors, measured as low MVD, had good local control (P = 0.036). For 107 patients in whom both of the measurements were obtained on the same tumor sections, ICD and MVD provided independent prognostic information in multivariate analysis. There was a significant correlation between tumor hypoxia and ICD (P < 0.005) but not MVD (P = 0.41). There was no relationship between hypoxia and the expression of angiogenic factors (VEGF, PD-ECGF). These analyses show that measurement of tumor vascularity can provide different biological information that is dependent on the method used. It is, therefore, important that studies measuring vascularity should include an appropriate definition. There is no relationship between hypoxia and angiogenesis in advanced carcinoma of the cervix and examining the levels of angiogenic proteins may not have a role in assessing hypoxia in cervix cancer.

Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma.

PURPOSE: This study was designed to compare tumor hypoxia assessed by invasive O2 sensitive electrodes and pimonidazole labeling in primary human cervix carcinomas. METHODS AND MATERIALS: Twenty-eight patients with primary cervix carcinomas (FIGO Stage Ib-IVa) were investigated. Both invasive pO2 measurements and pimonidazole labeling were obtained in all patients. Before treatment, patients were given pimonidazole as a single injection (0.5 g/m2 i.v.). Ten to 24 h later, oxygenation measurements were done by Eppendorf histography, and after this procedure biopsies were taken for pimonidazole-binding analysis. Tumor oxygen partial pressure (pO2) was evaluated as the median tumor pO2 and the fraction of pO2 values < or = 10 mmHg (HF10). Biopsies were formalin fixed and paraffin embedded, and hypoxia was detected by immunohistochemistry using monoclonal antibodies directed against reductively activated pimonidazole. Pimonidazole binding was evaluated by a semiquantitative scoring system. RESULTS: Both Eppendorf measurements and pimonidazole binding showed large intra-and intertumor variability. A comparison between pimonidazole binding expressed as the fraction of fields at the highest score and HF10 showed a trend for the most well-oxygenated tumors having a low fraction of fields; however, the correlation did not reach statistical significance (p = 0.43, r = 0.165; Spearman's rank correlation test). CONCLUSION: Hypoxia measured in human uterine cervix carcinomas is heterogeneously expressed both within and between tumors when assessed by either invasive pO2 measurements or pimonidazole binding. Despite a trend that tumors with high pO2 values expressed less pimonidazole binding, no correlation was seen between the two assays in this preliminary report.

Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix.

BACKGROUND AND PURPOSE: The Eppendorf pO(2) histograph is the 'gold standard' method for measuring tumour oxygenation. The method is not suitable for widespread application because its use is limited to accessible tumours. A non-invasive imaging technique would be an attractive alternative. Therefore, the relationships between tumour oxygenation and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters were investigated. MATERIALS AND METHODS: The study comprised 30 patients with carcinoma of the cervix. Tumour oxygenation was measured pre-treatment as median pO(2) and the proportion of values less than 5 mmHg (HP5) using a pO(2) histograph. Repeat measurements were obtained for nine patients following 40-45 Gy external beam radiotherapy giving a total of 39 measurements. Dynamic contrast-enhanced MRI using gadolinium was performed prior to obtaining the oxygenation data. Time/signal intensity curves were generated to obtain two standard parameters: maximum enhancement over baseline (SI-I) and the rate of enhancement (SI-I/s). RESULTS: Using the 39 measurements, there was a significant correlation between SI-I and both median pO(2) (r=0.59; P<0.001) and HP5 (r=-0. 49; P=0.002). There was a weak, borderline significant correlation between SI-I/s and both median pO(2) (r=0.29; P=0.071) and HP5 (r=-0. 34; P=0.037). There was a significant relationship between tumour size and SI-I (r=0.54; P<0.001), but not SI-I/s. In 29 tumours, where data were available, there was no relationship between histological assessment of tumour angiogenesis (intra-tumour microvessel density; IMD) and either MRI parameter. CONCLUSIONS: Tumour oxygenation levels measured using a pO(2) histograph correlate with dynamic contrast-enhanced MRI parameters. Therefore, non-invasive dynamic MRI may be a method for measuring hypoxia in human tumours.

Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix.

The aim of the study was to evaluate VEGF expression in tumour biopsies as a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. A retrospective study was carried out on 100 patients. Pre-treatment tumour VEGF expression was examined immunohistochemically in formalin-fixed, paraffin-embedded biopsies using a widely available commercial antibody. A semi-quantitative analysis was made using a scoring system of 0, 1, 2, and 3, for increasing intensity of staining. High VEGF expression was associated with a poor prognosis. A univariate log rank analysis found a significant relationship with overall survival (P = 0.0008) and metastasis-free survival (P = 0.0062), but not local control (P = 0.23). There was no correlation between VEGF expression and disease stage, tumour differentiation, patient age, or tumour radiosensitivity (SF2). In a Cox multivariate analysis of survival VEGF expression was the most significant independent prognostic factor (P = 0.001). After allowing for VEGF only SF2 was a significant prognostic factor (P = 0.003). In conclusion, immunohistochemical analysis of VEGF expression is a highly significant and independent prognostic indicator of overall and metastasis-free survival for patients treated with radiotherapy for advanced carcinoma of the cervix. It is also a rapid and easy method that could be used in the clinical setting, to identify patients at high risk of failure with conventional radiotherapy who may benefit from novel approaches or chemoradiotherapy.