Comorbidity in elderly cancer patients in relation to overall and cancer-specific mortality

Background:

Aims of this study were to describe the prevalence of comorbidity in newly diagnosed elderly cancer cases compared with the background population and to describe its influence on overall and cancer mortality.

Methods:

Population-based study of all 70+ year-olds in a Danish province diagnosed with breast, lung, colorectal, prostate, or ovarian cancer from 1 January 1996 to 31 December 2006. Comorbidity was measured according to Charlson''s comorbidity index (CCI). Prevalence of comorbidity in newly diagnosed cancer patients was compared with a control group by conditional logistic regression, and influence of comorbidity on mortality was analysed by Cox proportional hazards method.

Results:

A total of 6325 incident cancer cases were identified. Elderly lung and colorectal cancer patients had significantly more comorbidity than the background population. Severe comorbidity was associated with higher overall mortality in the lung, colorectal, and prostate cancer patients, hazard ratios 1.51 (95% CI 1.24–1.83), 1.41 (95% CI 1.14–1.73), and 2.14 (95% CI 1.65–2.77), respectively. Comorbidity did not affect cancer-specific mortality in general.

Conclusion:

Colorectal and lung cancer was associated with increased comorbidity burden in the elderly compared with the background population. Comorbidity was associated with increased overall mortality in elderly cancer patients but not consistently with cancer-specific mortality.     

What Do Prostate Cancer Patients Die Of?

Background.

A recent rise in the incidence of prostate cancer and a more favorable outcome have increased the proportions of other causes of death in affected men. Extending the survival of prostate cancer patients thus requires knowledge of all causes of death.

Methods.

Data on the population, cancers, and causes of death were gathered from the nationwide Swedish Family-Cancer Database. A Cox regression model, comparing prostate cancer patients with all other men, was applied. Hazard ratios (HR) were calculated both for the underlying cause and for dying with a specific cause listed among multiple causes of death.

Findings.

Among 686,500 observed deaths, 62,500 were prostate cancer patients. For underlying causes other than prostate cancer, the highest cause-specific HRs were found for external causes (HR, 1.24; 95% confidence interval [CI], 1.16–1.31), diseases of the pulmonary circulation (HR, 1.22; 95% CI, 1.09–1.37), and heart failure (HR, 1.18; 95% CI, 1.11–1.24). For specific multiple causes, the highest HRs were found for anemia (HR, 2.28; 95% CI, 2.14–2.42), diseases of the pulmonary circulation (HR, 1.61; 95% CI, 1.55–1.68), and urinary system disease (HR, 1.90; 95% CI, 1.84–1.96).

Interpretations.

Prostate cancer patients have a higher risk for dying from various causes other than prostate cancer, including external causes and heart failure. Mechanisms have been proposed linking these elevated risks to both cancer and treatment. More attention should be paid to comorbidities in men with prostate cancer. The present study fulfills a gap in the knowledge of death causes in prostate cancer patients.     

Trends in non-metastatic prostate cancer management in the Northern and Yorkshire region of England, 2000�C2006

Background:

Our objective was to analyse variation in non-metastatic prostate cancer management in the Northern and Yorkshire region of England.

Methods:

We included 21 334 men aged ⩾55, diagnosed between 2000 and 2006. Principal treatment received was categorised into radical prostatectomy (11%), brachytherapy (2%), external beam radiotherapy (16%), hormone therapy (42%) and no treatment (29%).

Results:

The odds ratio (OR) for receiving a radical prostatectomy was 1.53 in 2006 compared with 2000 (95% CI 1.26–1.86), whereas the OR for receiving hormone therapy was 0.57 (0.51–0.64). Age was strongly associated with treatment received; radical treatments were significantly less likely in men aged ⩾75 compared with men aged 55–64 years, whereas the odds of receiving hormone therapy or no treatment were significantly higher in the older age group. The OR for receiving radical prostatectomy, brachytherapy or external beam radiotherapy were all significantly lower in the most deprived areas when compared with the most affluent (0.64 (0.55–0.75), 0.32 (0.22–0.47) and 0.83 (0.74–0.94), respectively) whereas the OR for receiving hormone therapy was 1.56 (1.42–1.71).

Conclusions:

This study highlights the variation and inequalities that exist in the management of non-metastatic prostate cancer in the Northern and Yorkshire region of England.     

Stereotactic body radiation therapy is effective and safe in patients with early-stage non-small cell lung cancer with low performance status and severe comorbidity

Background

The purpose of this study was to assess stereotactic body radiation therapy (SBRT) results and toxicity for stage I non-small cell lung cancer patients with low performance status and severe comorbidity.

Patients and Methods

From September 2008 to April 2010, 36 patients with 38 lesions were treated with hypofractionated SBRT. All except one were medically inoperable, had low performance status and/or severe cardiovascular and/or cardiopulmonary comorbidity. The patients were immobilized in an Elekta stereotactic body frame to improve setup accuracy, and four-dimensional CT scans were used for target delineation. Fractions of 15 Gy were prescribed to cover the planning target volume, giving a total dose of 45 Gy, with 1 fraction every second day. Cone beam CT was applied at each fraction to correct for setup errors. The patients were followed with toxicity evaluation and radiographic follow-up.

Results

Median follow-up time was 13.8 months (0–21 months). The local tumor control after 12 months was 100%. Four patients developed regional relapse about 12 months after SBRT. The 1-year disease-free survival was 83%. The median tumor shrinkage at 1 year was 22 mm. Three patients experienced systemic relapse after 13 months. One patient developed grade 3 chest pain toxicity and 16 patients reported temporary grade 1 chest pain toxicity. Two patients reported temporary increased dyspnea. No patient experienced a reduction of the performance status after SBRT.

Conclusion

SBRT is an effective and safe treatment modality for elderly patients with early-stage non-small cell lung cancer, having low performance status and severe comorbidity. It is possible to achieve high local control rates with good tolerance.Key Words: Early-stage non-small cell lung cancer, Stereotactic body radiation therapy, Low performance status, Severe comorbidity     

Aspirin but not ibuprofen use is associated with reduced risk of prostate cancer: a PLCO study

Background:

Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear.

Methods:

We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55–74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified.

Results:

After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with <1 and ⩾1 pill of aspirin daily were 0.98 (95% confidence interval (CI), 0.90–1.07) and 0.92 (95% CI: 0.85–0.99), respectively, compared with never use (P for trend 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 or men who had a history of cardiovascular-related diseases or arthritis (HR (95% CI); 0.87 (0.78–0.97), 0.89 (0.80–0.99), and 0.88 (0.78–1.00), respectively). The data did not support an association between ibuprofen use and prostate cancer risk.

Conclusion:

Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer risk.     

Overdetection, overtreatment and costs in prostate-specific antigen screening for prostate cancer

Background:

Prostate cancer screening with prostate-specific antigen (PSA) has shown to reduce prostate cancer mortality in the European Randomised study of Screening for Prostate Cancer (ERSPC) trial. Overdetection and overtreatment are substantial unfavourable side effects with consequent healthcare costs. In this study the effects of introducing widespread PSA screening is evaluated.

Methods:

The MISCAN model was used to simulate prostate cancer growth and detection in a simulated cohort of 100 000 men (European standard population) over 25 years. PSA screening from age 55 to 70 or 75, with 1, 2 and 4-year-intervals is simulated. Number of diagnoses, PSA tests, biopsies, treatments, deaths and corresponding costs for 100 000 men and for United Kingdom and United States are compared.

Results:

Without screening 2378 men per 100 000 were predicted to be diagnosed with prostate cancer compared with 4956 men after screening at 4-year intervals. By introducing screening, the costs would increase with 100% to €60 695 000. Overdetection is related to 39% of total costs (€23 669 000). Screening until age 75 is relatively most expensive because of the costs of overtreatment.

Conclusion:

Introduction of PSA screening will increase total healthcare costs for prostate cancer substantially, of which the actual screening costs will be a small part.     

A four-kallikrein panel for the prediction of repeat prostate biopsy: data from the European Randomized Study of Prostate Cancer Screening in Rotterdam, Netherlands

Background:

Most men with elevated levels of prostate-specific antigen (PSA) do not have prostate cancer, leading to a large number of unnecessary biopsies. A statistical model based on a panel of four kallikreins has been shown to predict the outcome of a first prostate biopsy. In this study, we apply the model to an independent data set of men with previous negative biopsy but persistently elevated PSA.

Methods:

The study cohort consisted of 925 men with a previous negative prostate biopsy and elevated PSA (⩾3 ng ml⁻¹), with 110 prostate cancers detected (12%). A previously published statistical model was applied, with recalibration to reflect the lower positive biopsy rates on rebiopsy.

Results:

The full-kallikrein panel had higher discriminative accuracy than PSA and DRE alone, with area under the curve (AUC) improving from 0.58 (95% confidence interval (CI): 0.52, 0.64) to 0.68 (95% CI: 0.62, 0.74), P<0.001, and high-grade cancer (Gleason ⩾7) at biopsy with AUC improving from 0.76 (95% CI: 0.64, 0.89) to 0.87 (95% CI: 0.81, 0.94), P=0.003). Application of the panel to 1000 men with persistently elevated PSA after initial negative biopsy, at a 15% risk threshold would reduce the number of biopsies by 712; would miss (or delay) the diagnosis of 53 cancers, of which only 3 would be Gleason 7 and the rest Gleason 6 or less.

Conclusions:

Our data constitute an external validation of a previously published model. The four-kallikrein panel predicts the result of repeat prostate biopsy in men with elevated PSA while dramatically decreasing unnecessary biopsies.     

Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort

Background:

The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy.

Methods:

Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer.

Results:

In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10⁻⁹) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10⁻⁵), with Gleason score (P=5 × 10⁻⁴) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions.

Conclusion:

For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.     

Clinical presentation and initial management of Black men and White men with prostate cancer in the United Kingdom: the PROCESS cohort study

Background:

In the United States, Black men have a higher risk of prostate cancer and worse survival than do White men, but it is unclear whether this is because of differences in diagnosis and management. We re-examined these differences in the United Kingdom, where health care is free and unlikely to vary by socioeconomic status.

Methods:

This study is a population-based retrospective cohort study of men diagnosed with prostate cancer with data on ethnicity, prognostic factors, and clinical care. A Delphi panel considered the appropriateness of investigations and treatments received.

Results:

At diagnosis, Black men had similar clinical stage and Gleason scores but higher age-adjusted prostate-specific antigen levels (geometric mean ratio 1.41, 95% confidence interval (95% CI): 1.15–1.73). Black men underwent more investigations and were more likely to undergo radical treatment, although this was largely explained by their younger age. Even after age adjustment, Black men were more likely to undergo a bone scan (odds ratio 1.37, 95% CI: 1.05–1.80). The Delphi analysis did not suggest differential management by ethnicity.

Conclusions:

This UK-based study comparing Black men with White men found no evidence of differences in disease characteristics at the time of prostate cancer diagnosis, nor of under-investigation or under-treatment in Black men.     

A 50% higher prevalence of life-shortening chronic conditions among cancer patients with low socioeconomic status

Background:

Comorbidity and socioeconomic status (SES) may be related among cancer patients.

Method:

Population-based cancer registry study among 72 153 patients diagnosed during 1997–2006.

Results:

Low SES patients had 50% higher risk of serious comorbidity than those with high SES. Prevalence was increased for each cancer site. Low SES cancer patients had significantly higher risk of also having cardiovascular disease, chronic obstructive pulmonary diseases, diabetes mellitus, cerebrovascular disease, tuberculosis, dementia, and gastrointestinal disease. One-year survival was significantly worse in lowest vs highest SES, partly explained by comorbidity.

Conclusion:

This illustrates the enormous heterogeneity of cancer patients and stresses the need for optimal treatment of cancer patients with a variety of concomitant chronic conditions.     

Dietary cadmium exposure and prostate cancer incidence: a population-based prospective cohort study

Background:

Experimental data convincingly propose the toxic metal cadmium as a prostate carcinogen. Cadmium is widely dispersed into the environment and, consequently, food is contaminated.

Methods:

A population-based cohort of 41 089 Swedish men aged 45–79 years was followed prospectively from 1998 through 2009 to assess the association between food frequency questionnaire-based estimates of dietary cadmium exposure (at baseline, 1998) and incidence of prostate cancer (3085 cases, of which 894 were localised and 794 advanced) and through 2008 for prostate cancer mortality (326 fatal cases).

Results:

Mean dietary cadmium exposure was 19 μg per day±s.d. 3.7. Multivariable-adjusted dietary cadmium exposure was positively associated with overall prostate cancer, comparing extreme tertiles; rate ratio (RR) 1.13 (95% confidence interval (CI): 1.03–1.24). For subtypes of prostate cancer, the RR was 1.29 (95% CI: 1.08–1.53) for localised, 1.05 (95% CI: 0.87–1.25) for advanced, and 1.14 (95% CI: 0.86–1.51) for fatal cases. No statistically significant difference was observed in the multivariable-adjusted risk estimates between tumour subtypes (P_{heterogeneity}=0.27). For localised prostate cancer, RR was 1.55 (1.16–2.08) among men with a small waist circumference and RR 1.45 (1.15, 1.83) among ever smokers.

Conclusion:

Our findings provide support that dietary cadmium exposure may have a role in prostate cancer development.     

The Clinical and Economic Impacts of Skeletal‐Related Events Among Medicare Enrollees With Prostate Cancer Metastatic to Bone

Background.

Approximately 40% of men diagnosed with metastatic prostate cancer experience one or more skeletal-related events (SREs), defined as a pathological fracture, spinal cord compression, or surgery or radiotherapy to the bone. Accurate assessment of their effect on survival, health care resource utilization (HCRU), and cost may elucidate the value of interventions to prevent SREs.

Materials and Methods.

Men older than age 65 years with prostate cancer and bone metastasis diagnosed between 2004 and 2009 were identified from linked Surveillance Epidemiology and End Results–Medicare records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk for death associated with SREs were calculated by using Cox regression. HCRU and costs (in 2013 U.S. dollars) were evaluated in a propensity score-matched cohort by using Poisson regression and Kaplan-Meier sample average estimators, respectively.

Results.

Among 3,297 men with prostate cancer metastatic to bone, 40% experienced ≥1 SRE (median follow-up, 19 months). Compared with men who remained SRE-free, men with ≥1 SRE had a twofold higher risk for death (HR, 2.29; 95% CI, 2.09–2.51). Pathological fracture was associated with the highest risk for death (HR, 2.77; 95% CI, 2.38–3.23). Among men with ≥1 SRE, emergency department visits were twice as frequent (95% CI, 1.77–2.28) and hospitalizations were nearly four times as frequent (95% CI, 3.20–4.40). The attributable cost of ≥1 SRE was $21,191 (≥1 SRE: $72,454 [95% CI, $67,362–$76,958]; SRE-free: $51,263 [95% CI, $45,439–$56,100]).

Conclusion.

Among men with prostate cancer metastatic to bone, experiencing ≥1 SRE is associated with poorer survival, increased HCRU, and increased costs. These negative effects emphasize the importance of SRE prevention in this population.

Implications for Practice:

This study confirms the substantial adverse clinical and economic effects of skeletal-related events (SREs) in men with prostate cancer. Compared with men who have prostate cancer metastatic to the bones and no SREs, men with prostate cancer metastatic to the bones experiencing ≥1 SRE had a twofold increase in the risk for death, a twofold increase in the number of emergency department visits, and a fourfold increase in the number of hospitalizations; they also incurred an additional $21,000 in direct medical costs attributed to SREs. Strategies to prevent SREs are potentially of high value in this patient population.     

Impact of comorbidity on the outcome in men with advanced prostate cancer treated with docetaxel

Background

Men with metastatic castrate-resistant prostate cancer (mCRPC) may not receive docetaxel in everyday clinical practice due to comorbidities. Here we explore the impact of comorbidity on outcome in men with mCRPC treated with docetaxel in a population-based outcome study.

Methods

Men with mCRPC treated with docetaxel at the Institute of Oncology Ljubljana between 2005 and 2012 were eligible. Comorbidity was assessed by the age-adjusted Charlson comorbidity index (aa-CCI) and adult comorbidity evaluation (ACE-27) index. Hospital admissions due to the toxicity and deaths during treatment with docetaxel were used as a measure of tolerability. Association between comorbidity and overall survival (OS) was tested using the Cox proportional hazards analysis.

Results

Two hundred and eight men were treated with docetaxel. No, mild, moderate and severe comorbidity was present in 2%, 32%, 53% and 13% using aa-CCI and in 27%, 35%, 29% and 8% when assessed by ACE-27. A substantial dose reduction of docetaxel occurred more often in men with moderate or severe comorbidity as compared to those with no or mild comorbidity. At all comorbidity levels about one-third of men required hospitalization or died during treatment with docetaxel. In univariate analysis a higher level of comorbidity was not associated with worse OS (aa-CCI HR 0.99; [95% CI 0.87–1.13], p = 0.93; ACE-27: HR 0.96; [95% CI 0.79–1.17], p = 0.69).

Conclusions

Men with mCRPC, who have comorbidities may benefit from treatment with docetaxel.     

Phase II Trial of Neoadjuvant Docetaxel and CG1940/CG8711 Followed by Radical Prostatectomy in Patients With High‐Risk Clinically Localized Prostate Cancer

Background.

Prostate cancer (PC) is the most commonly diagnosed noncutaneous malignancy in American men. PC, which exhibits a slow growth rate and multiple potential target epitopes, is an ideal candidate for immunotherapy. GVAX for prostate cancer is a cellular immunotherapy, composed of PC-3 cells (CG1940) and LNCaP cells (CG8711). Each of the components is a prostate adenocarcinoma cell line that has been genetically modified to secrete granulocyte-macrophage colony-stimulating factor. Hypothesizing that GVAX for prostate cancer could be effective in a neoadjuvant setting in patients with locally advanced disease, we initiated a phase II trial of neoadjuvant docetaxel and GVAX. For the trial, the clinical effects of GVAX were assessed in patients undergoing radical prostatectomy (RP).

Methods.

Patients received docetaxel administered at a dose of 75 mg/m² every 3 weeks for 4 cycles. GVAX was administered 2–3 days after chemotherapy preoperatively for four courses of immunotherapy. The first dose of GVAX was a prime immunotherapy of 5×10⁸ cells. The subsequent boost immunotherapies consisted of 3×10⁸ cells. After RP, patients received an additional six courses of immunotherapy. Pathologic complete response, toxicity, and clinical response were assessed. The primary endpoint of the trial was a pathologic state of pT0, which is defined as no evidence of cancer in the prostate.

Results.

Six patients completed neoadjuvant docetaxel and GVAX therapy. No serious drug-related adverse events were observed. Median change in prostate-specific antigen (PSA) following neoadjuvant therapy was 1.47 ng/ml. One patient did not undergo RP due to the discovery of positive lymph nodes during exploration. Of the five patients completing RP, four had a downstaging of their Gleason score. Undetectable PSA was achieved in three patients at 2 months after RP and in two patients at 3 years after RP.

Conclusions.

Neoadjuvant docetaxel/GVAX is safe and well tolerated in patients with high-risk locally advanced PC. No evidence of increased intraoperative hemorrhage or increased length of hospital stay postoperatively was noted. These results justify further study of neoadjuvant immunotherapy.     

Comparison of Carboplatin‐ and Cisplatin‐Based Concurrent Chemoradiotherapy in Locally Advanced Cervical Cancer Patients With Morbidity Risks

Purpose.

The aim of this study was to assess the activity and toxicity of primary carboplatin-based chemoradiotherapy (CarboRT) and to compare CarboRT with cisplatin-based chemoradiotherapy (CisRT) in patients with locally advanced cervical cancer and poor general condition.

Patients and Methods.

Fifty-one locally advanced cervical cancer patients with morbidity risks were prospectively enrolled between January 2007 and April 2010. Eligible patients received weekly intravenous CarboRT with carboplatin 100 mg/m², and a comparison was made with a historical patient group that received weekly CisRT with cisplatin 40 mg/m².

Results.

Median follow-up was 36 months (range: 4–66 months) in the CarboRT group and 53 months (range: 4–121 months) in the CisRT group. Compared with the historical CisRT group, the CarboRT group showed no statistically significant differences in recurrence (hazard ratio [HR], 1.21; 95% confidence interval [CI], 0.52–2.81) and survival (HR, 1.80; 95% CI, 0.49–6.54). The mean numbers of received cycles of CarboRT and CisRT were 7.5 ± 1.4 and 6.0 ± 1.8, respectively (p < .001). The rates of grade 3–4 toxicity were similar in the two groups.

Conclusions.

CarboRT was better tolerated than CisRT without compromising tumor response and survival in patients with locally advanced cervical cancer and poor general condition.     

Men with cancer change their health behaviour: a prospective study from the Danish diet, cancer and health study

Background:

Health behaviour changes may improve the quality of life and survival among cancer survivors. We prospectively examined changes in health behaviour among and between men with prostate cancer (PC), men with cancers other than PC and cancer-free men.

Methods:

We analysed data for 20 914 men (50–65 years), 426 with cancer, and 20 488 persons who were cancer-free between baseline (1993–1997) and follow-up (2000–2002) in multiple linear regression models to determine differences in changes in body mass index (BMI) and in alcohol and tobacco consumption.

Results

Body mass index and tobacco and alcohol consumption decreased significantly (P<0.001) between baseline and follow-up among both men with cancer and cancer-free men. Men with cancers other than PC significantly decreased their BMI (β=−058; 95% confidence interval (CI): −0.77, −0.40) and tobacco consumption (β=−1.36; 95% CI: −2.22, −0.49) compared with cancer-free men and were significantly more likely to quit smoking and lose weight.

Conclusion:

Men with cancers other than PC decreased their tobacco consumption and BMI significantly more than cancer-free men. Men with cancer do change their health behaviour; clinicians should take this into account in planning follow-up care for cancer survivors.     

Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study

Background:

Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial.

Methods:

Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately.

Results:

Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38–66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer''s significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions.

Conclusion:

Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.     

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

Background:

Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.

Methods:

This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.

Results:

In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day⁻¹ on days 1–3, followed by doxorubicin (20 mg m⁻²) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day⁻¹ of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day⁻¹. Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for ⩾8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression.

Conclusion:

These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day⁻¹. The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.