Alice Goodman

Treatment initiation for hormone-sensitive metastatic prostate cancer should include the addition of docetaxel to androgen deprivation therapy (ADT) as standard of care. This recommendation is based on a meta-analysis

of three large, relatively recent, randomized trials showing that docetaxel improves survival and failure-free survival (FFS) in metastatic hormone-sensitive prostate cancer. These findings move docetaxel up to the hormone-sensitive setting from its previous role as upfront treatment in the castrate-resistant setting.

In men with metastatic hormone-sensitive prostate cancer, docetaxel added to ADT improved 4-year survival by an absolute value of 9% and reduced FFS by an absolute value of 16%.

According to the findings in men with nonmetastatic hormone-sensitive prostate cancer, docetaxel improves FFS, but more evidence is needed to show a survival benefit in this setting.  Vale and co-authors plan to do an individual-participant analysis of men enrolled in the trials included in the meta-analysis to find more reliable evidence about the effect of docetaxel on survival and prostate cancer-specific survival in the nonmetastatic setting. The addition of docetaxel to ADT is not recommended in nonmetastatic high-risk hormone-sensitive prostate cancer at this time.&nbsp;

The meta-analysis also evaluated the addition of zoledronic acid to ADT and found little or no benefit for this bisphosphonate in high-risk localized or metastatic hormone-sensitive disease.

"This meta-analysis provides substantial and reliable evidence that adding docetaxel to standard of care improves the survival of men with metastatic hormone-sensitive prostate cancer. The addition of docetaxel to androgen deprivation therapy is the new standard of care, and this combination should be offered to men who are fit to receive chemotherapy," wrote lead author Claire L. Vale, MD, MRC Clinical Trials Unit at UCL, London, UK, and co-authors. "We found no evidence that zoledronic acid improves survival."

Survival data for docetaxel were based on results from the CHAARTED, GETUG-15, and STAMPEDE trials in a total of 2292 (93%) of 3206 men with metastatic disease initiating treatment for the first time. At the time of the publication of results, 1271 deaths had occurred.  The authors assumed a 4-year survival of 40% with standard of care; the hazard ratio (HR) of 0.77 (95% CI, 0.68-0.87) for the meta-analysis showed a significant benefit in survival with the addition of docetaxel to standard of care (

<.0001). There was no evidence of variation among trial results.

FFS was defined similarly in all three trials. FFS results were based on the same group of 2292 men as in the survival analysis; 2204 events signaling failure were recorded. Assuming a baseline 4-year FFS of 20% with standard therapy, the FFS HR was 0.64 (95% CI, 0.58-0.70;

<.0001), an improvement from 80% to 64%, which represents an absolute benefit of 16% for the addition of docetaxel.

Across the three trials, docetaxel was associated with an increase in grade 3 to 4 toxicities, most notably neutropenia. Overall, 16 deaths were deemed treatment related in patients treated with docetaxel.

The authors state that despite these risks, docetaxel should be considered the new standard of care and offered to "men with metastatic disease starting on long-term androgen deprivation therapy for the first time who are fit enough to receive chemotherapy and willing to accept these risks. Future trials in this setting should also consider this as an appropriate control group."

Vale CI, Burdett S, Rydzewska LHM, et al.

. 2015; pii: S1470-2045(15)00489-1. doi: 10.1016/S1470-2045(15)00489-1.

Articles

Treatment initiation for hormone-sensitive metastatic prostate cancer should include the addition of docetaxel to androgen deprivation therapy (ADT) as standard of care.

Metastatic Hormone-Sensitive Prostate Cancer Should Include Docetaxel Alongside ADT

suggests that the presence of persistent genetic mutations, 30 days after induction chemotherapy, predicted relapse and survival in patients with acute myeloid leukemia (AML), as well as intermediate-risk patients. Patients with persistent mutations following induction chemotherapy were about 3 times more likely to relapse and die, compared with those whose mutations cleared after induction chemotherapy.

Genetic profiling at the time of AML presentation did not add prognostic information above and beyond currently used stratification factors.

Although this was a small, retrospective, single-institution study, the findings provide a foundation for future research on the optimal use of genomics, in order to evaluate risk of relapse in the majority of patients with AML.  If results are replicated in larger prospective studies, whole-genome sequencing to identify persistent mutations following induction chemotherapy could be used to select patients who should receive allogeneic transplantation and optimize their chances of survival.

"Most patients diagnosed with AML fall into a gray area, when it comes to being able to predict their risk of relapse. About 80% of patients with AML go into remission with chemotherapy, but most will eventually relapse. Unfortunately, we still don't have a definitive test that tells us early on which patients will relapse," stated senior author Timothy J. Ley, MD, the Lewis T. and Rosalind B. Apple Professor of Oncology at Washington University School of Medicine, St. Louis.

"Such information is important to know because high-risk patients need aggressive, potentially curative therapy with a stem-cell transplant when they are in remission, early in the course of disease. However, we don't want to transplant patients who are unlikely to relapse following conventional chemotherapy, because the transplant procedure is expensive and carries a significant risk of severe side effects and even death," he continued, in a press release from his institution.

"With deep-exome sequencing, we could identify mutations that could be tracked in the day 30 bone marrow samples that were in remission. If even one mutation was detectable in these samples, it was associated with a 3-fold increase in the risk of relapse. If all mutations were cleared below a threshold of 5% of cells, patients had better outcomes. The patterns of mutation clearance were informative as well: mutations involved in AML initiation often failed to be cleared, while mutations that usually contribute to subclone generation and outgrowth were usually absent on day 30. So, persistence of the founding clone after induction therapy seems to predict a high risk of relapse. This is the information that is missing when you try to assess risk only at presentation. You just cannot make this prediction based on the initial mutations alone," said Ley in an interview with

The researchers analyzed bone marrow samples obtained at diagnosis from 71 patients with AML, in order to determine if specific leukemia-related mutations found in each patient were associated with relapse following induction chemotherapy. However, comprehensive genomic sequencing of these 71 patients did not add prognostic value above and beyond standard approaches such as cytogenetics, age, or identification of coding mutations in genes that are recurrently mutated in AML.

The next step in the study was to conduct genome sequencing on bone marrow samples obtained from 50 patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when they were in apparent remission. Of these samples, 24 patients (48%) were found to have persistent mutations in bone marrow cells, despite the fact that they were considered to be in remission by standard criteria.

The presence of persistent mutations was significantly associated with relapse, as measured by event-free survival (EFS) and overall survival (OS).

EFS was a median of 6 months in those with persistent mutations versus 17.9 months in those with cleared mutations (

<.001). Thus, patients with persistent mutations were more than 3.5 times more likely to relapse.

OS was a median of 10.5 months in patients with persistent mutations versus 42.2 months in those with cleared mutations (

= .003), and those with persistent mutations were almost 3 times more likely to die.

Looking at 32 intermediate-risk cases (a gray area for determining prognosis), the presence of persistent mutations after induction chemotherapy was also significantly associated with EFS and OS.

EFS was a median of 8.8 months among 14 intermediate-risk patients with at least one persistent mutation versus 25.6 months for those with cleared mutations (

= .003); patients with persistent mutations were more than 3 times likely to relapse compared with those who have cleared mutations. OS was a median of 19.3 months versus 46.9 months (

= .02). Patients with mutations were almost 3 times more likely to die.

Ley said that future plans are to conduct a prospective comparison of mutation clearance, using the deep-exome sequencing method versus a flow cytometric method, for assessment of residual disease in first remission, focusing initially on patients with intermediate-risk AML, who usually have a normal karotype. The investigators want to compare both assays and determine which is best for risk assessment, and ultimately, for selection for allogeneic stem cell transplant.

Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia.

314(8):811-22. doi: 10.1001/jama.2015.9643.

Washington University in St. Louis. Relapse, poor survival in acute leukemia linked to genetic mutations that persist in remission.

https://news.wustl.edu/news/Pages/Relapse-poor-survival-in-acute-leukemia-linked-to-genetic-mutations-that-persist-in-remission.aspx

. Accessed September 2, 2015. â€‹â€‹â€‹

A new study suggests that the presence of persistent genetic mutations, 30 days after induction chemotherapy, predicted relapse and survival in patients with acute myeloid leukemia (AML), as well as intermediate-risk patients.

Prognostic Information in AML Gleaned From Timing of Genetic Mutations

It is well known that having multiple moles (ie, >50) is a risk factor for developing melanoma. A new study shows, however, that melanoma can also develop in people with fewer than 50 moles, and when it does, it typically has a more aggressive course.

The study, to be reported at the upcoming 2015 Summer Meeting of the American Academy of Dermatology, suggests that melanomas originating from patients with high nevus (mole) density (HND) and those with low nevus density (LND) may represent two different entities with distinct biologic pathways and aggressive potential.

"While we know having more than 50 moles is a risk factor for developing melanoma, paradoxically patients with fewer moles may develop more aggressive disease," said senior author Caroline C. Kim, MD, director, Pigmented Lesion Clinic and associate director, Cutaneous Oncology Program; Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston.

"The results of our study are important, because people with many moles may be more likely to be educated about their risk for melanoma and referred for skin cancer screening. However, we may be missing patients with fewer moles who may not know that they too are at risk for melanoma, while unaware of warning signs, and may be at risk for more aggressive disease. All patients should be aware of how melanoma is present on the skin and, in particular, patients should look for 'ugly duckling' lesions any lesion that appears different from anything else on their skin, especially if the lesions are changing," Kim explained in an interview with

"It is important to note that melanomas not only present as darkly pigmented lesions, but can also present as pink and skin-colored lesions. In addition, having a baseline skin examination with a dermatologist will give patients a better understanding of their skin and risk factors for melanoma. Early detection of melanoma is very important, as this relates to a better prognosis, " Kim said.

The study is based on a retrospective chart review of 281 patients with melanoma seen at BIDMC between 2013 and 2014. Of these, 89 had >50 moles (HND) and 192 had <50 moles (LND).

Patients with LND on average had thicker melanomas than those patients with HND (Breslow depth 1.8 mm versus 1.2 mm, respectively;

=.012) and were diagnosed at an older age (51 years versus 41 years, respectively,

<.001). Patients with LND on average had higher mitotic rates (4 mits/mm

= .05), and their tumors were less likely to be of the superficial spreading subtype and more likely to be of the nodular subtype (

In addition, patients with both HND and aplastic/dysplastic nevi (another risk factor for melanoma) when compared with patients with LND were more likely to have a family history of melanoma and to have a melanoma with dark pigmentation, without ulceration, and with a truncal location. Patients with HND and atypical/dysplastic nevi trended toward having a lower incidence of a nonmelanoma skin cancer.

Kim said that this study corroborates findings from a recent study (Ribero S, Davies JR, Requena C, et al. High nevus counts confer a favorable prognosis in melanoma patients.

2015;doi10:1002/ijc.29525), which also found that patients with melanoma and multiple moles had improved survival compared with those with fewer moles.

Future studies are needed to validate this finding and to explore genetic mutations.

"It is likely that the difference between melanomas in patients with more moles versus fewer moles lie within different genetic pathways leading to different aggressive potential. In addition, the role of the immune system in these two patient populations would be another important area to explore, as well as the role of earlier detection for the HND population if they were referred for screening earlier.  However, earlier screening is not likely to account for all of the differences found between the tumors of both populations, as the tumors had differences beyond Breslow depth," Kim said.

"Further understanding of the relationship between patient phenotype and tumor genotype could play a role in more accurate patient selection for melanoma screening, help with melanoma diagnosis, and could also play a role in therapeutic decisions," she added.

Kim hopes to continue to further analyze the study findings with genetic profiling of tumors in her patient population.

It is well known that having multiple moles (ie, >50) is a risk factor for developing melanoma. A new study shows, however, that melanoma can also develop in people with fewer than 50 moles, and when it does, it typically has a more aggressive course. 

Fewer Moles May Be Related to Aggressive Melanoma

Patients with bladder cancer who undergo robot-assisted radical cystectomy (RARC) appear to have acceptable 5-year survival, according to the largest multi-institutional series to date to collect data on RARC outcomes in this population.

The outcomes in this series appear to be comparable with those of historical controls who underwent open radical cystectomy (ORC), according to the authors of this study.

"We found that robot-assisted radical cystectomy, an advanced surgical procedure used to treat bladder cancer that has spread to the bladder wall or recurred despite local treatment in the bladder, provides similar early oncologic outcomes [to open radical cystectomy], while reducing operative blood loss," said senior author of the paper, Khurshid Guru, MD, director of robotic surgery at Roswell Park Cancer Institute, Buffalo, NY.

"The importance of this study is that it provides good evidence that you can treat patients with RARC without compromising oncologic outcomes. Before we jump on the bandwagon [of robotic surgery], we want to make sure we can provide oncologic efficacy," Guru stated in an interview with

The retrospective study was based on a review of prospectively treated patients entered on the International Robotic Cystectomy Consortium (IRCC) multi-institutional database. The study was not designed as a direct comparison of RARC and ORC; the authors cited data from four earlier studies of ORC to compare outcomes with more recent studies of RARC.

The study included 743 patients with clinically localized bladder cancer treated with RARC at least 5 years ago or longer. Patients who underwent palliative RARC were excluded, and some patients had missing data. The final analysis was based on 702 patients from 11 different institutions in 6 countries.

Median age was 69 years, 569 (82%) were male, and median time in the operating room was 7.3 hours. Almost two-thirds of patients (62%) had pathologic organ-confined (OC) disease. Eight percent had positive surgical margins. Seventy-five percent of patients were node negative. Positive lymph nodes were found in 137 (21%). One hundred thirty-four patients (24%) received adjuvant chemotherapy, and 507 patients (72%) had extended lymph node dissection, which is thought to contribute to improved staging, and outcomes.

At a median follow-up of 67 months, 5-year rates of relapse-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were 67%, 75%, and 50%, respectively.  Overall recurrence rate was 29%, which included an 11% local recurrence rate.&nbsp; Median time to cancer-specific death and noncancer-specific death was 14 months and 10 months, respectively.

A multivariate analysis showed that nonorgan-confined disease and positive surgical margins were predictors of poorer RFS, CSS, and OS. Age was a significant predictor of CSS and OS. Adjuvant chemotherapy and positive surgical margins were significant predictors of RFS. As would be expected for patients with bladder cancer, poorer survival was associated with positive surgical margins, positive lymph nodes, and nonorgan-confined disease.

In the discussion section of the published study, Guru et al compared 5-year outcomes in the IRCC patients with historical outcomes in previous studies of ORC. Although the ORC studies had different patient characteristics, it would appear that in general, RFS, CSS, and OS are comparable with those of LARC.

RARC is only available at about 1000 or more centers in the United States, Guru said.  Advocates of robotic-assisted surgery cite potential advantages such as fewer complications and less blood loss compared with conventional open surgery. However, the robotic technology is expensive. Currently, the cost of the Da Vinci knife is about $2 million or more, and the robotic equipment needs to be maintained and updated. RARC is estimated to cost about $1500 more than ORC.

"The world is evolving and the times are changing. As more companies come out with robotic technology, the cost is likely to decrease," Guru said.

Small studies to date have shown mixed results on whether or not robotics produce superior outcomes versus open surgery. The present study suggests that outcomes may be similar between the two techniques, but not superior, with robotics.

Guru and colleagues acknowledge the limitations of this retrospective analysis and the inherent differences in experience of surgeons, operative volume, patient selection, and reporting bias of their study. They hope that the information gleaned from this series will prompt randomized trials to compare RARC and ORC directly and provide more definitive data.

1) Raza SJ, Wilson T, Peabody JO, et al. Long-term oncologic outcomes following robot-assisted radical cystectomy: Results from the International Robotic Cystectomy Consortium.

. 2015. doi: 10.1016/j.eururo.2015.04.021.

http://www.roboticoncology.com/pr/IsTheCostOfRoboticSurgeryJustified/

Alice Goodman | Authors

Articles

Metastatic Hormone-Sensitive Prostate Cancer Should Include Docetaxel Alongside ADT

Prognostic Information in AML Gleaned From Timing of Genetic Mutations

Fewer Moles May Be Related to Aggressive Melanoma

Robot-Assisted Surgery Shows Good Survival and Less Blood Loss in Bladder Cancer