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Article of the Week: Oncological outcomes and toxicity for LDR prostate brachytherapy

January 3, 2018/by admin Z.9

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Long-term oncological outcomes and toxicity in 597 men aged ≤60 years at time of low-dose-rate brachytherapy for localised prostate cancer

Stephen E. M. Langley, Ricardo Soares, Jennifer Uribe, Santiago Uribe-Lewis, Julian Money-Kyrle, Carla Perna, Sara Khaksar and Robert Laing

St Luke’s Cancer Centre, Guildford, Surrey, UK

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Objectives

To report oncological and functional outcomes of men treated with low-dose-rate (LDR) prostate brachytherapy aged ≤60 years at time of treatment.

Patients and Methods

Of 3262 patients treated with LDR brachytherapy at our centre up to June 2016, we retrospectively identified 597 patients aged ≤60 years at treatment with ≥3-years post-implantation follow-up and four prostate-specific antigen (PSA) measurements, of which one was at baseline. Overall survival (OS), prostate cancer-specific survival (PCSS) and relapse free survival (RFS) were analysed together with prospectively collected physician-reported adverse events and patient-reported symptom scores.

Results

The median (range) age was 57 (44-60) years, follow-up was 8.9 (1.5-17.2) years, and PSA follow-up 5.9 (0.8-15) years. Low-, intermediate- and high-risk disease represented 53%, 37% and 10% of the patients, respectively. At 10 years after implantation OS and PCSS were 98% and 99% for low-risk, 99% and 100% for intermediate-risk, and 93% and 95% for high-risk disease, respectively. At 10 years after implantation RFS, using the PSA level nadir plus 2 ng/mL definition, was 95%, 90% and 87% for low-, intermediate-, and high-risk disease, respectively. Urinary stricture was the most common genitourinary adverse event occurring in 19 patients (3.2%). At 5 years after implantation erectile function was preserved in 75% of the patients who were potent before treatment.

Conclusion

LDR brachytherapy is an effective treatment with long-term control of prostate cancer in men aged ≤60 years at time of treatment. It was associated with low rates of treatment-related toxicity and can be considered a first-line treatment for prostate cancer in this patient group.

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Editorial: LDR prostate brachytherapy in younger men

January 3, 2018/by admin Z.9

Langley et al.¹ report on the oncological and functional outcomes of men treated with low dose rate (LDR) prostate brachytherapy in men 60 years old or younger. 597 patients with a median (range) age of 57 (44-60) years had a median follow-up of 8.9 (1.5-17.2) years. The 10- year post-implant relapse free survival using the Phoenix definition for biochemical failure (nadir plus 2 ng/ml) was 95%, 90% and 87% for low, intermediate and high-risk disease, respectively. Potency was preserved in 75% of men potent before treatment. The authors concluded that LDR brachytherapy is an efficacious treatment with excellent long-term control of prostate cancer in men ≤60 years at time of treatment. While the results from this investigation are encouraging, enthusiasm should be tempered given the short follow up, long natural history of prostate cancer and the long-life expectancy for these younger patients.

Although the overall median follow-up was 8.9 years, the calculation of PSA-free failure was derived from a median follow-up of 5.9 years. As this investigation did not identify men who may also be at risk of failure because of a rising PSA and who have not yet reached the Phoenix threshold, I anticipate longer-follow up will further reduce their favorable results. Of the 597 men, 6 (1%) died from prostate cancer. The low incidence of prostate cancer mortality, while impressive, also reflects the short follow-up. Our group has previously reported that PCSM substantially increases between the 10th and 15th year post treatment. The experience of these physicians in prostate brachytherapy is demonstrated in their favorable dosimetry outcomes-the median D90 was 106.4% of the prescription (145 Gy). These results (median D90 154.3 Gy), which were determined and computed on the day of the implant would be 10-15% higher had the CT scans been done on day 30 as most centers do. We and others have reported that patients receiving higher dose implants have improved biochemical and cancer-specific outcomes. While these data help explain their favorable oncological outcomes, they should also serve as a guide to other brachytherapy programs where implant quality should be a primary objective. Erectile function was preserved in 75% of men. These data are consistent with other reports of younger men who were treated for prostate cancer with surgery or radiation. Because this was not a randomized study, it is not possible to make direct comparisons between surgery and brachytherapy. The selection of an IIEF score of > 11 as potent might be challenged as the 12-16 group is considered to have mild to moderate ED. Nonetheless, these data are still encouraging for younger men who are considering treatment for localized prostate cancer where sexual function preservation is important.

Nelson Stone

Mount Sinai Medical Center – Urology 350 E 72nd Street, New York, New York 10021 United States

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Reference

Langley SM, Soares R, Uribe J, et al. Long-term oncological outcomes and toxicity in 597 men ≤60 years of age at time of low dose rate brachytherapy for localised prostate cancer. BJU Int 2017

Article of the Week: Risk Factors and Timing of VTE after RC

November 16, 2016/by admin Z.9

If you only have time to read one article this week, it should be this one.

Risk factors and timing of venous thromboembolism after radical cystectomy in routine clinical practice: a population-based study

R. Christopher Doiron*, Christopher M. Booth†,‡,§, Xuejiao Wei§ and D. Robert Siemens*,†,§

*Department of Urology, Queen’s University, Kingston, ON, Canada, †Department of Oncology, Queen’s University, ‡Department of Public Health Sciences, Queen’s University, and §Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Kingston, ON, Canada

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Objective

To describe the risk factors and timing of perioperative venous thromboembolism (VTE) and its association with survival for patients undergoing radical cystectomy (RC) in routine clinical practice.

Patients and Methods

The population-based Ontario Cancer Registry was linked to electronic records of treatment to identify all patients who underwent RC between 1994 and 2008; VTE events were identified from hospital diagnostic codes. Multivariate logistic regression analysis was used to determine the factors associated with perioperative VTE. A Cox proportional hazards regression model explored the associations between VTE and survival.

Results

Of the 3 879 patients included in the study, 3.6% (141 patients) were diagnosed with VTE at ≤1 month of their surgical admission date. This increased to 4.7% (181) at ≤2 months and 5.4% (211) at ≤3 months. In all, 55% of VTE events presented after hospital discharge. In multivariate analysis, factors associated with VTE included higher surgeon volume (P = 0.004) and increased length of hospital stay (LOS; P< 0.001). Lymph node yield and adjuvant chemotherapy were not associated with VTE. VTE was associated with an inferior cancer-specific survival [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.13–1.62] and overall survival (HR 1.27, 95% CI 1.08–1.49).

Conclusions

Over half of VTE events in RC patients occur after hospital discharge, with a substantial incidence up to 3 months after surgery. Limited actionable risk factors for VTE were identified other than LOS. In this population-based cohort, VTE was associated with inferior long-term survival.

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Editorial: RC & VTE – Are We Doing Enough?

November 16, 2016/by Nawar Hanna

Using a large comprehensive population-based cohort from Canada, Doiron et al. [1] present an in-depth analysis of risk factors and timing of venous thromboembolism (VTE) after radical cystectomy (RC) for bladder cancer. This report reiterates what is already known, which is that VTE after RC occurs at a non-negligible rate (5.4%) and most VTEs occur after hospital discharge (55%). VTE is an established complication in patients undergoing major oncological surgery, with some guidelines recommending 4 weeks of VTE prophylaxis after major pelvic surgery. This significant incidence of VTE after discharge highlights the potential impact of extended VTE prophylaxis for up to 28 days. Level I evidence for such practice was published more than a decade ago [2]. Yet, the uptake of these data remains low, at least in urological oncology. A recent survey-based study of pelvic cancer centres from the UK showed that only two-thirds of centres use post-discharge prophylaxis [3]. Using highly granular data, Doiron et al. [1] provide a detailed timeline of VTE occurrence after RC. They found that among patients who were diagnosed with VTE after discharge, >60% of these events occurred at ≤4 weeks of discharge. Unfortunately, there were no data on whether VTE prophylaxis was used in the study population.

The authors identified greater surgeon volume and increased length of hospital stay as risk factors for postoperative VTE, while accounting for important disease-related covariates. As mentioned by the authors, surgeon volume is most likely a surrogate for another unmeasured confounder. Higher volume surgeons, who often practice in large/academic institutions, may have increased case complexity with patients at higher risk for VTE. Additionally, such institutions may be more prone to perform diagnostic testing in high-risk patients and identify VTEs that would have otherwise gone unnoticed. A report from France found that the rate of VTE after RC was 24% in a cohort of patients who all underwent complete lower limb ultrasound, yet the vast majority (92%) were asymptomatic [4]. In other words, if you are looking for a VTE, you are more likely to find one. However, the clinical relevance of these VTEs remains unclear.

As shown from prior studies, length of stay was also found to be a risk factor for VTEs. Why does an increase in length of stay lead to a higher rate of VTE? One explanation is that patients who stay in the hospital longer are more likely to be immobilised for longer. This may explain why patients undergoing RC have higher rates of VTE than those undergoing other urological oncology procedures. However, immobilisation is a difficult variable to define or to measure. If longer immobilisation leads to increased VTE incidence, recently implemented enhanced recovery after surgery (ERAS) protocols that lead to earlier mobilisation would be expected to be associated with fewer VTEs. It is important to mention that other previously associated factors with VTE, including operative time and body mass index, which may be related to immobilisation time are not recorded in this study.

The use of neoadjuvant chemotherapy (NACT) for muscle-invasive bladder cancer has been shown to improve overall survival and is being increasingly used in RC patients. This study examined NACT as a risk factor but did not find an association. Notably, they were limited by the few patients who had received NACT. The use of chemotherapy in patients with cancer is a well-recognised risk factor for VTE [5]. It will be important in the future to continue to examine the incidence of VTE in NACT patients as this population grows.

Taken together, patients undergoing major cancer surgery have a significant risk of postoperative VTE, with evidence showing that rates of VTE are increasing over time [6]. Although guidelines for VTE prophylaxis are not uniform, this study’s findings [1] that most VTEs occur after discharge is a reason for urological surgeons to strongly consider extended VTE prophylaxis in this high-risk population.

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Nawar Hanna and Jacqueline M. Speed

Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

References

1 Doiron RC, Booth CM, Wei X, Siemens DR. Risk factors and timing of venous thromboembolism after radical cystectomy in routine clinical practice: a population-based study. BJU Int 2016; 118: 714–22

2 Bergqvist D, Agnelli G, Cohen AT et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346: 975–80

3 Pridgeon S, Allchorne P, Turner B, Peters J, Green J. Venous thromboembolism (VTE) prophylaxis and urological pelvic cancer surgery: a UK national audit. BJU Int 2015; 115: 223–9

4 Clement C, Rossi P, Aissi K et al. Incidence, risk proﬁle and morphological pattern of lower extremity venous thromboembolism after urological cancer surgery. J Urol 2011; 186: 2293–7

5 Blom JW, Vanderschoot JPM, Oostindier MJ, Osanto S, van der Meer FJM, Rosendaal FR. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost 2006; 4: 529–35

6 Trinh VQ, Karakiewicz PI, Sammon J et al. Venous thromboembolism after major cancer surgery: temporal trends and patterns of care. JAMA Surg 2014; 149: 43–9

Staring Into The Abyss

July 22, 2014/by James Duthie

I was surprised at the referral in the first place, but baffled after seeing the patient in the flesh. It was someone else’s clinic, and the note read that this 94 year-old man on androgen deprivation for asymptomatic low volume metastatic prostate cancer for many years had a climbing PSA. About 8. Please discuss combined androgen blockade with him. I began the talk about how combined blockade has a pretty weak benefit at the best of times, and that in a 94 year-old it almost certainly would not make him live any longer. He was asymptomatic, so he would not feel any better, and he may have a worsening of his side effects. I wrapped it up by telling him he was old enough to make his own decisions about his treatment, and if he didn’t want another pill to take, he could certainly say no. He said yes. I clarified the points about limited or no benefit, and possible exacerbation of side effects. He said if it would give him a few more years, he’d take it. I told him it wouldn’t. He wanted it anyway. I could not promise the treatment would not make him live any longer, and that was good enough for him. At the end of the consultation he was well counseled, and had made his decision. You might think of an 80 year-old you have seen who seemed more like a 60-year old, and think I was being unfair to the man, but I can confirm he was a 94 year-old who seemed very much to be 94.

I tend to assume that when people get to a certain age, they have come to terms with a few things, including death. This is not always the case, and I think running from death is becoming more popular. While research confirms that doctors have few illusions about treatment leading up to their own demise, and plan to refuse much of it, laypeople are hungry for all the invasive treatment they can get. As doctors, we don’t always help with this. We have pills and procedures that make statistically significant improvements in cancer specific survival, and what cancer sufferer would say no to that? We spend a lot more time studying how to hold failing anatomy together than we do learning to let entropy take its course. We have treatments that hint at immortality, nobody needs to die of Condition X anymore, now that we have Drug Y. What if this patient in front of us is the one in a hundred that has a durable remission? What if we kill them through inaction? What about the guilt-ridden estranged son who wants “Everything Done”?

Popular media have kept up a sustained and determined campaign for cardiovascular resuscitation in particular. Having an intelligent, sensitive, pragmatic talk to a family about not resuscitating the palliative patient due to the invasive, undignified nature of resuscitation for a virtually negligible chance of durable success is not as convincing as James Bond being defibrillated in his Aston Martin.

What is the definition of “good survivor” if not continuing to drink, gamble, and assassinate day zero post-resuscitation? Sadly, days or weeks of vegetative decline is much more common.

So what of the 94 year-old, who has already outlasted his cohort’s life expectancy by over 20 years? Who lived through two world wars, the rise and fall of the Soviet Communist state, the invention of Rock ‘n’ Roll, space flight, and electric foot spas? Objectively, he made an informed decision about his health care, prioritizing his values and concluding that the chance of increased quantity, however tiny, trumped quality. I can’t help think that in reality he kidded himself that he was beating death once again. He had evaded those cruel icy fingers, and secretly maybe thought he could live to a hundred and fifty. If he was my Grandpa, maybe I could have talked to him about embracing the end as a part of the natural cycle; not fearing, but accepting. But then, I was just his doctor.

Jim Duthie is a Urological Surgeon/Robotic Surgeon. Interested in Human Factors Engineering, training & error, and making people better through electronic means. Tauranga, New Zealand. @Jamesduthie1

Article of the week: Pilot study of EGFR-targeted therapies in men with penile SCC shows promising initial results

June 18, 2014/by admin Z.9

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Pagliaro discussing his paper.

If you only have time to read one article this week, it should be this one.

Epidermal growth factor receptor-targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis

Bradley C. Carthon*^§, Chaan S. Ng^†, Curtis A. Pettaway^‡ and Lance C. Pagliaro*

Departments of *Genitourinary Medical Oncology, ^†Radiology, and ^‡Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA^§Current address: Winship Cancer Institute, Emory University,Atlanta, Georgia, USA

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OBJECTIVE

• To evaluate the safety and efficacy of epidermal growth factor receptor (EGFR)-targeted therapy in patients with advanced penile or scrotal cancer.

PATIENTS AND METHODS

• We retrospectively reviewed the charts of patients with penile or scrotal squamous cell carcinoma who had visited our tertiary cancer centre between 2002 and 2009, including their subsequent treatment and follow-up.

• We collected details of EGFR-targeted therapy and clinical outcomes. Treatment-associated time-to-disease-progression (TTP), overall survival (OS), responses to therapy and toxicity were evaluate

RESULTS

• A total of 24 patients had received EGFR-targeted therapies, including cetuximab, erlotinib and gefitinib. The most common treatment given (to 67% of patients) was cetuximab combined with one or more cytotoxic drugs.

• The most common adverse effect was skin rash (71%). The median (range) TTP and OS were 11.3 (1–40) and 29.6 (2–205) weeks, respectively. The OS time for patients with visceral or bone metastases was significantly shorter than it was for those without (24.7 vs 49.9 weeks, P = 0.013).

• Among 17 patients treated with cetuximab alone or in combination with cisplatin, there were four partial responses (23.5%) including two patients with apparently chemotherapy-resistant tumours.

CONCLUSIONS

• Our results suggest that cetuximab has antitumour activity in metastatic penile cancer, and may enhance the effect of cisplatin-based chemotherapy.

• Prospective studies of EGFR-targeted therapies in men with these tumours are warranted

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Editorial: Squamous cell carcinoma of the penis: therapeutic targeting of the EGFR

June 18, 2014/by Suks Minhas

Squamous cell carcinoma of the penis is a rare genitourinary malignancy. There are wide variations in its incidence, ranging from 0.1 to 0.9/100 000 men in Europe, where it accounts for 1% of male malignancies, to as high as 4.4 and 4.2/100 000 men in Uganda and Paraguay, where it accounts for up to 10% of male malignancies.

The management of patients with advanced squamous cell carcinoma of the penis, including those patients with node-positive disease and metastatic disease, remains challenging. The beneficial effects of chemotherapy and radiotherapy are not established, partly because of the small numbers of patients within studies, but also because of the multiple regimens used for treatment, combined with relatively low response rates and high toxicities.

The presence and extent of lymph node metastasis is the single most common factor predictive of survival in men with penile carcinoma, with 5-year survival rates of 88% in men with minimal or no metastases (one to two nodes), compared with ∼25% in those men with two or more inguinal nodes involved. In men with extra nodal spread of the cancer and pelvic metastases, 5-year survival rates fall as low as 5–10%.

The most important aetiological factors for the development of squamous cell cancer of the penis appear to be the presence of a foreskin, immunosuppression and smoking. In addition to this, human papillomavirus (HPV) has been shown to have a central role in tumorogenesis [1]. HPV DNA can be identified in up to 80% of tumour specimens. The commonest subtypes expressed are the 16/18 subtypes (high risk) and the 6/11 subtypes (low risk). The virus exerts its tumorogenic effect via expression of viral oncogenes E6 and E7, which inhibit the activity of tumour suppressor genes p53 and RB. Whilst a number of potential biomarkers have been identified as prognostic indices of survival, translational research to date is limited [2].

A recent study from the UK has reported that survival rates in men with node-positive penile carcinoma have not improved significantly in the last 20 years [3]. In view of the poor response rates from chemotherapeutic agents, combined with their high toxicity and the poor survival rates in men with node-positive disease, it is imperative that more novel treatment methods, including targeted therapies, are developed to treat this devastating tumour.

A potential biological target in all squamous cell cancers, including the penis, is the epidermal growth factor family of receptors. A number of trials have been conducted to evaluate the safety profile and activity of a combination of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, including cetuximab, with schedules of platinum-based chemotherapy in a number of tumour sites. These combinations have shown good tolerability. The addition of cetuximab to platinum-based chemotherapy prolongs survival in patients with recurrent or metastatic squamous cell tumours of the head and neck.

Penile squamous cell tumours and their metastases also highly express EGFRs with ∼90 to 100% of tumours expressing the EGFR. The EGFR is a cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands. The EGFR is a member of the ErbB family of receptors, which consist of a sub-family of four closely related tyrosine kinases (EGFR [ErbB-1], HER2/c-neu [ErbB-2], Her 3 [ErbB-3] and Her 4 [ErbB-4]). EGFR can be activated by binding its specific ligands, including EGF and TGF-α. Dimerization of the EGFR stimulates tyrosine kinase activity and autophosphorylation of a number of tyrosine residues in the C-terminal domain of the EGF receptor, which downstream initiates a number of signal transduction cascades, ultimately resulting in cell migration and proliferation.

Cetuximab and panitumumab are monoclonal antibody inhibitors of the EGFR, which block the extracellular ligand-binding domains on the EGFR receptor. Furthermore, cetuximab induces the internalization of EGFR leading to downregulation of the EGFR. It also targets cytotoxic immune effector cells towards EGFR-expressing tumour cells (antibody-dependent cell-mediated cytotoxicity). Drugs, such as gefitinib are EGFR tyrosine kinase inhibitors, which bind and inhibit the EGFR tyrosine kinase by binding to the ATP-binding site of the enzyme. In lung tumours, patients who are EGFR-positive have shown relatively high response rates to tyrosine kinase inhibitors, although many patients develop resistance.

Two studies have analysed the expression of the EGFR receptor status in penile cancer [4, 5]. In both studies, the EGFR receptor was overexpressed in tumour tissue. In one study [4], 40 out of 44, i.e. 91% of patients, showed a positive EGFR expression in the primary tumour as well as in metastases. Importantly, a correlation between EGFR receptor expression and survival was not demonstrated.

In the present study by Carthon et al. [6], the authors evaluate the safety and efficacy of EGFR-targeted therapy using both cetuximab and tyrosine kinase inhibitors, including gefitinib. This pilot study evaluated 24 patients receiving EGFR-targeted therapies. Among 17 patients treated with cetuximab alone, or in combination with cisplatin, there were four partial responses. Whilst the presence of visceral metastases at the start of EGFR-based therapy was associated with poor time to progression and overall survival, several patients in that study were shown to have regression of predominantly inguinal and pelvic tumours. Interestingly, there were no objective responses to the small molecule inhibitors gefitinib or erlotinib. This pilot study would suggest that further prospective studies of EGFR-targeted therapies in men with squamous cell carcinoma of the penis are warranted and these initial results are promising; however, the number of regimens and agents used in the study is varied. This variation and the small number of patients and the retrospective nature of the study represent study limitations. Nevertheless, the concept of targeted therapies for squamous cell carcinoma of the penis should certainly be evaluated further, as it is clear that surgery alone is insufficient to improve survival in patients with N+ or M1 disease.

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Suks Minhas
Department of Urology, University College Hospital, London, UK

Minhas S, Manseck A, Watya S, Hegarty PK. Penile cancer. Prevention and premalignant conditions. Urology 2010; 76 (2 Suppl. 1): S24–35
Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol 2007; 8: 420–429
Kayes O, Freeman A, Lau D et al. Longitudinal analysis of outcomes for men with node positive penile cancer – are we improving? BJU Int 2013; 111 (S3): P19
Börgermann C, Schmitz KJ, Sommer S, Rübben H, Krege S. Characterization of the EGF receptor status in penile cancer: retrospective analysis of the course of the disease in 45 patients. Urologe A 2009; 48: 1483–1489
Lavens N, Gupta R, Wood LA. EGFR overexpression in squamous cell carcinoma of the penis. Curr Oncol 2010; 17: 4–6
Carthon B, Ng C, Pettaway C, Pagliaro L. Epidermal growth factor receptor–targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis. BJU Int 2014; 113: 871–877

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Video: EGFR-targeted therapy in metastatic penile SCC

June 18, 2014/by admin Z.9