The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial.

BACKGROUND: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes. METHODS: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. INTERPRETATION: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial. FUNDING: AstraZeneca and Cancer Research UK.

Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST).

PURPOSE: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI (v CT) or three scans (v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

Clinical Outcomes of a Randomized Trial of Adaptive Plan-of-the-Day Treatment in Patients Receiving Ultra-hypofractionated Weekly Radiation Therapy for Bladder Cancer.

PURPOSE: Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy. METHODS: HYBRID is a Phase II randomized trial that was conducted at 14 UK hospitals. Patients with T2-T4aN0M0 muscle-invasive bladder cancer unsuitable for radical therapy received 36 Gy in 6 weekly fractions, randomized (1:1) to standard planning (SP) or adaptive planning (AP) using a minimization algorithm. For AP, a pretreatment cone beam computed tomography (CT) was used to select the POD from 3 plans (small, medium, and large). Follow-up included standard cystoscopic, radiologic, and clinical assessments. The primary endpoint was nongenitourinary Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (≥G3) toxicity within 3 months of radiation therapy. A noncomparative single stage design aimed to exclude ≥30% toxicity rate in each planning group in patients who received ≥1 fraction of radiation therapy. Local control at 3-months (both groups combined) was a key secondary endpoint. RESULTS: Between April 15, 2014, and August 10, 2016, 65 patients were enrolled (SP, n = 32; AP, n = 33). The median follow-up time was 38.8 months (interquartile range [IQR], 36.8-51.3). The median age was 85 years (IQR, 81-89); 68% of participants (44 of 65) were male; and 98% of participants had grade 3 urothelial cancer. In 63 evaluable participants, CTCAE ≥G3 nongenitourinary toxicity rates were 6% (2 of 33; 95% confidence interval [CI], 0.7%-20.2%) for the AP group and 13% (4 of 30; 95% CI, 3.8%-30.7%) for the SP group. Disease was present in 9/48 participants assessed at 3 months, giving a local control rate of 81.3% (95% CI, 67.4%-91.1%). CONCLUSIONS: POD adaptive radiation therapy was successfully implemented across multiple centers. Weekly ultrahypofractionated 36 Gy/6 fraction radiation therapy is safe and provides good local control rates in this older patient population.

Cancer Treatment and Research During the COVID-19 Pandemic: Experience of the First 6 Months.

The coronavirus disease-2019 (COVID-19) pandemic has had a significant impact on patients with underlying malignancy. In this article, we summarize emerging data related to patients with cancer and COVID-19. Among patients with COVID-19, a higher proportion have an underlying diagnosis of cancer than seen in the general population. Also, patients with malignancy are likely to be more vulnerable than the general population to contracting COVID-19. Mortality is significantly higher in patients with both cancer and COVID-19 compared with the overall COVID-19-positive population. The early months of the pandemic saw a decrease in cancer screening and diagnosis, as well as postponement of standard treatments, which could lead to excess deaths from cancer in the future.

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.

BACKGROUND: Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6-11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0-13·2) in the capivasertib group versus 4·8 months (3·1-7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39-0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3-4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related. INTERPRETATION: Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials. FUNDING: AstraZeneca and Cancer Research UK.

Toxicity and Patient-Reported Outcomes of a Phase 2 Randomized Trial of Prostate and Pelvic Lymph Node Versus Prostate only Radiotherapy in Advanced Localised Prostate Cancer (PIVOTAL).

PURPOSE: To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers. METHODS AND MATERIALS: In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity. RESULTS: One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group. CONCLUSIONS: PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.

Assessment of chemotherapy-induced peripheral neuropathy using the LDIFLARE technique: a novel technique to detect neural small fiber dysfunction.

INTRODUCTION: The diagnosis and quantification of chemotherapy-induced peripheral neuropathy (CIPN) remains a challenge. Conventional methods including quantitative sensory testing (QST), nerve conduction tests, and biopsy are unable to detect subclinical changes, and do not consistently correlate with severity of patients' symptoms and functional impairment. This study aims to determine the utility of the LDI (laser Doppler imager) FLARE technique in the diagnosis of CIPN and whether it correlates with symptom severity. MATERIALS AND METHODS: We assessed 24 patients with established CIPN [12 due to platinum analogs (PA) and 12 to Taxanes (TX)] and 24 matched healthy controls (HC). All underwent neurophysiological examination including vibration perception threshold (VPT), sural nerve amplitude (SNAP) and conduction velocity (SNCV), LDIFLARE, and fasting biochemistry. The QLQ-CIPN20 questionnaire was used to assess symptom severity. RESULTS: HC, combined chemotherapy (CG), PA , and TX groups were matched for age, sex, BMI, and blood pressure. The LDIFLARE was significantly reduced in CG compared to HC (P =< 0.0001), whereas SNAP (P = 0.058) and SNCV (P = 0.054) were not. The LDIFLARE correlated with the QLQ-CIPN20 symptom scores in all three categories namely, CG (P =< 0.0001), PA (P = 0.001) and TX (P = 0.027) whilst, VPT, SNAP, and SNCV did not. CONCLUSION: Our findings suggest that the LDIFLARE technique is more helpful in confirming the diagnosis of CIPN in patients with distal sensory symptoms than current commonly used methods. Moreover, this novel test fulfils the unmet need for a diagnostic test that relates to the severity of symptoms. This may be useful in quantifying early changes in small fibre function indicating early CIPN.

A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer.

BACKGROUND: Prednisolone is widely used as secondary hormonal treatment for castration-resistant prostate cancer (CRPC). We hypothesised that dexamethasone, another corticosteroid, is more active. OBJECTIVE: To compare the activity of prednisolone and dexamethasone in CRPC. DESIGN, SETTING, AND PARTICIPANTS: This single-centre, randomised, phase 2 trial was performed in 82 men with chemotherapy-naïve CRPC enrolled from 2006 to 2010. INTERVENTION: Prednisolone 5mg twice daily versus dexamethasone 0.5mg once daily versus intermittent dexamethasone 8mg twice daily on days 1-3 every 3 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main end point was prostate-specific antigen (PSA) response rate. Secondary end points included time to PSA progression, radiologic response rate using Response Evaluation Criteria In Solid Tumors (RECIST), and safety. RESULTS AND LIMITATIONS: The intermittent dexamethasone arm was dropped after no response was seen in seven patients. By intention to treat, confirmed PSA response was seen in 41% versus 22% for daily dexamethasone versus prednisolone, respectively (p=0.08). In evaluable patients, the PSA response rates were 47% versus 24% for dexamethasone and prednisolone, respectively (p=0.05). Median time to PSA progression was 9.7 mo on dexamethasone versus 5.1 mo on prednisolone (hazard ratio: 1.6; 95% confidence interval, 0.9-2.8). In 43 patients with measurable disease, the response rate by RECIST was 15% and 6% for dexamethasone and prednisolone, respectively (p=0.6). Of 23 patients who crossed over at PSA progression on prednisolone, 7 of the 19 evaluable (37%) had a confirmed PSA response to dexamethasone. Clinically significant toxicities were rare. CONCLUSIONS: Dexamethasone may be more active than prednisolone in CRPC. In the absence of more definitive trials, dexamethasone should be used in preference to prednisolone. PATIENT SUMMARY: We compared two different steroids used for treating men with advanced prostate cancer. Our results suggest that dexamethasone may be more effective than prednisolone and that both are well tolerated. CLINICAL TRIAL REGISTRY: EUDRAC 2005-006018-16.

Lobular neoplasia of the breast.

Lobular neoplasia is increasingly being detected, probably due to the widespread screening for breast malignancies. The understanding of lobular neoplasia is undergoing a paradigm shift, from being considered a predictor of recurrence to being considered a pre-invasive lesion, based on molecular studies suggesting a clonal link with invasive lobular cancer. The management of patients diagnosed to have lobular neoplasia is in evolution, with the increasing need for risk stratification and hence the necessity to identify this entity separately as either lobular carcinoma in-situ and atypical lobular hyperplasia. The indications for wide local excision for patients diagnosed to have lobular neoplasia on biopsy are being defined. The evidence for preventive strategies like hormonal treatment with Tamoxifen or aromatase inhibitors for high risk patients is increasing, with the results from prospective interventional trials. The role of screening magnetic resonance imaging for surveillance of high risk patients with lobular neoplasia is under evaluation.

Development of the European Organisation for Research and Treatment of Cancer quality of life questionnaire module for older people with cancer: The EORTC QLQ-ELD15.

BACKGROUND AND AIM: There is a lack of instruments that focus on the specific health-related quality of life (HRQOL) issues that affect older people with cancer. The aim of this study was to develop a HRQOL questionnaire module to supplement the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire, the EORTC QLQ-C30 for older (>70years) patients with cancer. METHODS: Phases 1-3 were conducted in seven countries following modified EORTC Quality of Life Group guidelines for module development. Phase 1: potentially relevant issues were identified by a systematic literature review, a questionnaire survey of 17 multi-disciplinary health professionals and two rounds of qualitative interviews. The first round included 9 patients aged >70. The second round was a comparative series of interviews with 49 patients >70years with a range of cancer diagnoses and 40 patients aged 50-69years matched for gender and disease site. In Phase 2 the issues were formulated into a long provisional item list. This was administered in Phase 3 together with the QLQ-C30 to two further groups of cancer patients aged >70 (n=97) or 50-69years (n=85) to determine the importance, relevance and acceptability of each item. Redundant and duplicate items were removed; issues specific to the older group were selected for the final questionnaire. RESULTS: In Phase 1, 75 issues were identified. These were reduced in Phase 2 to create a 45 item provisional list. Phase 3 testing of the provisional list led to the selection of 15 items with good range of response, high scores of importance and relevance in the older patients. This resulted in the EORTC QLQ-ELD15, containing five conceptually coherent scales (functional independence, relationships with family and friends, worries about the future, autonomy and burden of illness). CONCLUSION: The EORTC QLQ-ELD15 in combination with the EORTC QLQ-C30 is ready for large-scale validation studies, and will assess HRQOL issues of most relevance and concern for older people with cancer across a wide range of cancer sites and treatment stages.

Late solitary testicular metastasis from rectal cancer.

Isolated testicular metastasis from rectal cancer is rare. We describe the case of a patient who presented with a locally advanced rectal malignancy and underwent multimodality treatment with low anterior resection, postoperative radiotherapy and adjuvant chemotherapy. He developed a painless testicular nodule while on follow-up, five years after the diagnosis of primary rectal cancer. Histopathology and immunohistochemistry of orchidectomy specimen were compatible with a metastatic adenocarcinoma of rectal origin. We hypothesize that this phenomenon of isolated relapse in a sanctuary site could be due to the altered biology and pattern of metastasis as a result of effective adjuvant systemic chemotherapy. Treatment of late isolated relapse in the testis needs to be ascertained.

Serum micronutrient and antioxidant levels at baseline and the natural history of men with localised prostate cancer on active surveillance.

The aim of this study was to determine whether serum concentrations of micronutrients, antioxidants and vitamins predict rate of disease progression in untreated, localised prostate cancer. Patients with localised prostatic adenocarcinoma on a prospective study of active surveillance underwent monitoring with serial PSA levels and repeat prostate biopsies. Disease progression was defined as either adverse histology on repeat biopsy (primary Gleason grade >or=4 or >50% positive cores of total) or radical treatment for PSA velocity >1 ng ml(-1) year(-1). Time to disease progression was analysed with respect to baseline levels of alpha-tocopherol, gamma-tocopherol, alpha-carotene and beta-carotene, lycopene, retinol and selenium. One hundred four patients were evaluable, with a median follow-up of 2.5 years. Thirty-eight patients experienced disease progression, 13 biochemical and 25 histologic progression. Median time to disease progression was 2.62 years. No significant association was seen between time to disease progression and baseline serum levels of alpha-tocopherol (p = 0.86), gamma-tocopherol (p = 0.84), alpha-carotenoid (p = 0.66), beta-carotene (p = 0.65), lycopene (p = 0.0.15), retinol (p = 0.76) or selenium (p = 0.76). No significant association was seen between serum levels of the micronutrients, antioxidants or vitamins and either adverse histology on repeat biopsy or PSA velocity. Our data do not support the hypothesis that high serum concentrations of micronutrients, antioxidants and vitamins prevent disease progression in men with localised prostate cancer.

Triple-negative/basal-like breast cancer: clinical, pathologic and molecular features.

Review of the spectrum of breast cancer tumor subtypes, which include basal-like, triple-negative and BRCA1-positive tumors, suggest that they have overlapping clinical, pathologic and molecular features, which are different from endocrine responsive breast cancers. Although response to chemotherapy is high in the neoadjuvant setting, the overall prognosis of this subset of tumors remains poor. Gene-profiling studies of this heterogeneous subset have lead to a better understanding of the molecular pathology of these aggressive tumors and the identification of possible therapeutic targets. Ongoing clinical studies of newer targeted agents, along with optimal chemotherapy, portend an improved clinical outcome for patients with aggressive basal-like/triple-negative breast cancer in the future.

Is electroglottography-based videostroboscopic assessment of post-laryngectomy prosthetic speech useful?

OBJECTIVES: To use an electroglottography (EGG)-based videostroboscopy tool to assess the anatomical and morphologic characteristics of the pharyngoesophageal (PE) segment in tracheoesophageal (TO) speakers. STUDY DESIGN: Cross-sectional cohort study. SUBJECTS: Fifty-two post-laryngectomy patients with no recurrence and using prosthetic (Blom-Singer) speech. INTERVENTION: An electroglottography (EGG)-based videostroboscopy tool EGG-based rigid videostroboscopy as well as perceptual evaluation. OUTCOME MEASURES: Stroboscopic protocol included nine subjective/visual parameters to evaluate the neoglottis and study correlation of the G (GRBAS scale) and the overall voice quality (OVQ) with the treatment variables. RESULTS: Of the 52 laryngectomees, videostroboscopic recordings were possible in 46 patients (36 males and 10 females) with a mean age of 63.4 +/-10.5 (SD) an electroglottography (EGG)-based videostroboscopy tool years. All used the Blom-Singer valve and the median time since Total Laryngectomy was 2 years. The neoglottis was assessable in 26 patients. We were able to strobe only 9 patients. There was excellent correlation between G and OVQ (Spearman rho > 0.9). Statistically significant correlation was found between G1 and saliva (P = 0.03) and between good OVQ and saliva (P = 0.02); similarly, there was significant correlation between G1 and LVV (P = 0.05) and between good OVQ and LVV (P = 0.03). CONCLUSIONS: This study is the first to examine the use of an EGG-based stroboscopy instrument to evaluate TO speech. Our observations suggest that from the standpoint of functional voice, saliva and the LVV had statistically significant effect in determining voice quality.

Results of combined modality treatment for nasopharyngeal cancer.

CONTEXT: Radiotherapy is the cornerstone of treatment in nasopharyngeal cancer (NPC); the addition of chemotherapy has shown improved results. AIMS: To compare the results of concurrent chemoradiation with that of radiotherapy alone in NPC. MATERIALS AND METHODS: One hundred and ninety consecutive NPC patients, without distant metastasis, who reported to the institute from January 1992 to December 2001, received external-beam radiation to 66 Gy in 33 fractions. Seventy-five of these patients received concurrent chemotherapy with cisplatin and 5-fluorouracil (5-FU) for four cycles. We compared the results of treatment in these two groups. RESULTS: The 5-year disease-free survival rates were 40% and 60%, respectively, for patients who had radiotherapy alone and those who had chemoradiation (P = 0.002), while the median survival was 45 months and 60 months, respectively (P = 0.0028). CONCLUSION: A significant improvement in local control and survival was observed by the addition of concurrent chemotherapy with cisplatin and 5-FU to radical radiation in this nonrandomized study on patients with NPC.

Primary Adult Renal Ewing's Sarcoma: A Rare Entity.

Background. Ewing's sarcoma of extraskeletal origin is uncommon and that is of primary renal origin in adults are rare. There is no consensus on the optimal management of Ewing's tumors of renal origin. Methods. A retrospective review of the clinical features, treatment, and outcome of adult patients with primary renal extra-skeletal Ewing's sarcoma who were treated at the Royal Marsden hospital from January 1993-December 2007 is reported. Results. Seven adult patients with primary renal Ewing's sarcoma were identified. All four patients with nonmetastatic disease had radical nephrectomy and received adjuvant chemotherapy +/- radiotherapy. Two developed metastatic disease while on adjuvant chemotherapy, and one patient relapsed after 55 months. The three patients with metastatic disease at presentation did not have nephrectomy and were treated with chemotherapy. All three patients had disease progression with a dismal outcome. Only one patient in the whole group is alive and disease free. The median overall survival was 62.8 months, and the median disease-free survival in patients with nonmetastatic disease after combined modality treatment was 30.3 months. Conclusion. Primary adult renal Ewing's sarcoma is an aggressive tumor with a propensity for early metastasis. Radical nephrectomy with adjuvant combination chemotherapy produced the best results but the outlook remained poor with only one patient experiencing long disease-free survival.

Electroglottographic and perceptual evaluation of tracheoesophageal speech.

To optimize tracheoesophageal (TO) speech after total laryngectomy, it is vital to have a robust tool of assessment to help investigate deficiencies, document changes, and facilitate therapy. We sought to evaluate and validate electroglottography (EGG) as an important tool in the multidimensional assessment of TO speech. This study is a cross-sectional study of the largest cohort of TO speakers treated by a single surgeon. A second group of normal laryngeal speakers served as a control group. EGG analysis of both groups using connected speech and sustained vowels was performed. Two trained expert raters undertook perceptual evaluation using two accepted scales. EGG measures were then analyzed for correlation with treatment variables. A separate correlation analysis was performed to identify EGG measures that may be associated with perceptual dimensions. Our data from EGG analysis are similar to data obtained from conventional acoustic signal analysis of TO speakers. Sustained vowel and connected speech parameters were poorer in TO speakers than in normal laryngeal speakers. In perceptual evaluation, only grade (G) of the GRBAS scale and Overall Voice Quality appeared reproducible and reliable. T stage, pharyngeal reconstruction and method of closure, cricopharyngeal myotomy, and postoperative complications appear to be correlated with the EGG measures. Five voice measures-jitter, shimmer, average frequency, normalized noise energy, and irregularity-correlated well with the key dimensions of perceptual assessment. EGG is an important assessment tool of TO speech, and can now be reliably used in a clinical setting.