The site of metastasis has a substantial affect on the survival of patients with prostate cancer, confirms a US multistudy analysis that may help guide treatment decisions and future trial designs.
Data on almost 9000 men with castration-resistant prostate cancer (mCRPC) indicated that patients with lymph node–only disease survive the longest, at a median period of survival of more than 30 months, whereas those with liver metastases survive for the shortest period, at less than half that time.
Bone metastases and lung metastases, which were identified in approximately 70% of patients, were associated with a survival period between the two extremes.
Lead author Susan Halabi, PhD, a biostatistician at Duke University, Durham, North Carolina, told Medscape Medical News that the findings could be used to direct treatment and inform patient-clinician discussion.
She said: "If clinicians know that a patient has certain metastases, they may consider giving them more aggressive therapy, because they have more advanced and more difficult metastases to treat.
"For instance, if a patient had liver metastases, the clinician may decide to give them chemotherapy, which is much more aggressive and historically has worked with liver metastases, than, let's say, some of the novel therapies."
The findings could also inform the design of clinical trials. Dr Halabi explained: "If you know that your patients are heterogeneous, you will want to stratify the patients according to their heterogeneity, and you will want to make sure that whatever experimental therapies you are testing are not going to be confounded by the site of metastasis."
The study was published online March 7 in the Journal of Clinical Oncology.
The researchers conducted a search of PubMed and ClinicalTrials.gov for phase 3 clinical trials of docetaxel (multiple brands) in men with chemotherapy-naive mCRPC. The primary endpoint of the trials was overall survival.
They requested demographic, disease, and treatment data on all participants from the trial sponsors, and sites of metastases at baseline were collated from the case report forms.
Metastases were classified as visceral and nonvisceral disease. Nonvisceral disease was categorized as lymph node–only or bone metastases with or without nodal involvement. Visceral disease was classified as liver, lung, or nonlung, nonliver disease.
The categories were mutually exclusive. Visceral disease took priority over nonvisceral disease; liver disease took precedence over lung disease; and lung disease was noted ahead of nonlung, nonliver visceral disease.
Data were available from nine clinical trials and involved a total of 8820 men treated between 1999 and 2012. The median age of the patients was 68 years, and 94% of the patients had performance status of 0-1.
The majority (72.8%) of patients had bone metastases; 29.8% also had lymph node involvement. In addition, 9.1% had lung metastases, 8.6% had liver metastases, 6.4% had lymph node–only disease, and 3.0% had nonlung, nonliver visceral disease.
Median overall survival on Kaplan-Meier analysis was 31.6 months for lymph node–only disease, 21.3 months for bone metastases, 19.4 months for lung metastases, and 13.5 months for liver metastases.
The risk for death was significantly greater for men with lung metastases than for those with bone metastases, at a pooled hazard ratio of 1.14 (P = .007). Men with liver metastases had a significantly increased risk for death in comparison with those with lung metastases, at a hazard ratio of 1.52 (P < .0001).
Dr Halabi pointed out that it was not possible in the current study to determine the order in which patients developed their metastases. She said: "For instance, I did not know whether patients had first bone or liver metastases, because we don't have the dates."
Dr Halabi noted that the order in which metastases occur cannot be determined from retrospective studies. Such a determination requires the prospective collection of data.
It was also not possible from the current dataset to determine the impact of multiple metastases on survival. However, Dr Halabi said that previous, smaller studies have "alluded to the importance of number of metastases" for overall survival.
The new study is "very good" because it has "a large yet at the same time very granular dataset," said Daniel M. Geynisman, MD, from the Fox Chase Cancer Center, Philadelphia, Pennsylvania, who was not involved with the research.
Although previous investigations have looked at survival relative to site of metastases in prostate cancer, Dr Geynisman said that the sample sizes have been smaller and that they have used pooled data from only one or two trials. In contrast, the current analysis used data on almost 9000 patients, which was "the major strength of the study."
He added: "At the same time, because all patients were on clinical trials, they had very granular, very specific information on them. There was not really a lot of missing data, and so they can really say with very good certainty that the results they are getting are valid and correct."
However, Dr Geynisman told Medscape Medical News that probably the greatest weakness of the study is that several of the studies included in the analysis were conducted before patients had access to newer treatments, and so it is "not quite the same population that would be receiving chemotherapy now."
It is probably most useful to categorize prostate cancer patients as those with liver metastases, bone metastases, and lymph node–only disease, he said.
Dr Geynisman also pointed out that because all of the men in the study were taking part in clinical trials and most were white, "this is not real life.
"There are men with liver disease or lung disease who would never qualify for these clinical trials because they're too ill, so I think the real-life numbers will probably be lower than what they reported," he commented.
Dr Geynisman nevertheless observed that, overall, the current study helps clinicians and trial designers to be "more thoughtful" in choosing treatments, potentially reserving chemotherapy for men with liver metastases and directing immunotherapy toward, for example, patients with lymph node–only disease.
He added: "It really helps with sitting in front of a patient and guiding them. You can say: 'Look, I have a huge sample size, and I can actually be pretty certain as to the numbers I'm giving you in regards to prognosis.' "
This research received support from the National Institutes of Health and the US Department of Defense. The Alliance for Clinical Trials in Oncology, AstraZeneca, Bristol-Myers Squibb, Celgene, Oncogenex, Regeneron, Sanofi, and SWOG provided data. The authors have disclosed no relevant financial relationships.
J Clin Oncol. Published online March 7, 2016. Abstract
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