Κυριακή, 30 Απριλίου 2017

CURE FOR METASTATIC PROSTATE CANCER? NOT YET THE CASE

Metastatic prostate cancer is considered to be incurable. But now a pilot trial, in 20 selected men with early-stage metastatic prostate cancer, has shown that aggressive multimodality treatment with hormone therapy, surgery, and radiation "can eliminate detectable disease."
Overall, 20% of the patients treated reached the primary endpoint — undetectable prostate-specific antigen (PSA) and noncastrate levels of testosterone at 20 months, which the authors described as "no evidence of disease" (NED).
This endpoint "could not have been achieved with any single therapy alone," they note.
"Although longer follow-up is needed to assess durability, this binary end point represents a first step toward establishing a paradigm of cure in patients with low-volume metastatic disease," they conclude.
First author is Matthew J. O'Shaughnessy, MD, PhD, from the urology service, Department of Surgery, and senior author is Howard Scher, MD, chief of the genitourinary oncology service, both at Memorial Sloan Kettering Cancer Center in New York City.
The study was published in the April issue of Urology.
"The paradigm outlined here represents an important step forward in attempting to cure patients who have previously been viewed as being incurable," comments Oliver Sartor, MD, from Tulane University School of Medicine, New Orleans, Louisiana, in an accompanying editorial comment.
…an important step forward in attempting to cure patients who have previously been viewed as being incurable. Dr Oliver Sartor
This comment was highlighted in a press release issued by Urology, which said, "the results suggest that some men who have previously been considered incurable can possibly be cured," even though it also quotes both the senior author and the editorialist as saying that a longer-term follow-up is needed.
It is this talk of cure that has rankled an outside expert contacted by Medscape Medical News.
"The news release seems misleading — particularly in bandying about the word 'cure'," commented Richard Hoffman, MD, MPH, professor of internal medicine and epidemiology and director of the Division of General Internal Medicine at the University of Iowa Carver College of Medicine in Iowa City.
He pointed out that in the paper, the authors' conclusion "seems more circumspect.... I don't see them as claiming that they've cured cancer — [they say] it's just a 'first step'."
The results show that 4 of 15 patients achieved the primary endpoint of having an undetectable PSA at 20 months after testosterone recovery, and 2 patients continued having undetectable PSA for a further 27 and 46 months.
"This represents a surrogate endpoint, not a cure," Dr Hoffman commented to Medscape Medical News. 
"Oncologists usually speak of cancer cure when there is no evidence of disease 5 years after treatment," he pointed out. "We do not know whether this treatment approach cures prostate cancer or even extends life.  This article reminds me of the reports about HIV patients who seemed to have been cured with bone marrow transplant only to have the virus reappear years later."

High Praise for the Study 

However, another outside expert contacted by Medscape Medical News was full of praise for the study, while also pointing to the need for long-term follow-up.
"Even with substantially lower-risk, nonmetastatic patients, we often do not know  if cure has been achieved for decades — yes, decades — post therapy," said Marc Garnick, MD, professor of medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, and editor-in-chief of Harvard Medical School's Annual Report on Prostate Diseases.
But he was very enthusiastic about the results that had been achieved. This study "has profound implications and represents the upheaval of current-day prostate cancer thinking," he told Medscape Medical News.  
…upheaval of current-day prostate cancer thinking. Dr Marc Garnick
There is already a trend "to do 'more' for more disease," he said.
"Only about 10 years ago, many practitioners would generally not consider surgery in the form of a radical prostatectomy for men with Gleason 9-10 cancers due to the overwhelming likelihood of such patients harboring micrometastatic disease. Now we consider that. Moreover, we now even consider lymphadenectomy for men with suspected  and clinical evidence of metastatic nodal disease, and some retrospective data suggest excellent outcomes in this approach even with the finding of microscopic nodal metastases," he commented.
The approach taken in the new study "is transformative in that a truly multimodality treatment approach is coming to the fore as acceptable in terms of risk benefit. Such forward thinking has been in the works, but the data proposed here is motivational for the properly selected patient," Dr Garnick said.

Aggressive Treatment 

The pilot study by Dr O'Shaughnessy and colleagues was conducted in 20 selected men, 5 of whom had oligometastatic M1a disease (extrapelvic nodal disease) and 15 had M1b disease (bone disease) at diagnosis. The median number of bone metastases was 3 (range, 1 - 7).
The Gleason score was 9 or 10 in 13 patients (65%), and 14 (70%) primary tumors were classified as T3a or greater. Clinically positive pelvic nodes (N1) were seen in all 5 (100%) of the M1a patients and in 6 of the 15 (40%) of the M1b patients.
These patients underwent aggressive multimodal treatment, including androgen deprivation therapy (ADT), radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease or to the primary site.
"Aggressive resection of visible disease performed by experienced surgeons was critical to the outcome," Dr O'Shaughnessy commented.
Treatment was completed in approximately 8 months and was "well tolerated," the authors report.
In comments to Medscape Medical News, Dr Hoffman noted that these  aggressive treatments all have important side effects, and the authors did not fully address the effects of treatment on quality of life — either physical or psychosocial function.  Another consideration is the cost of these treatments and whether the multimodal approach would be covered by insurance or considered experimental, he added.
In the paper, the authors note that one of the patients with bone disease was denied insurance coverage for radiotherapy and was treated later for symptoms.  

Each Therapy Contributed 

Each treatment modality contributed to the outcome, they note.
Nearly everyone (19 of 20 men, 95% of the cohort) achieved an undetectable PSA with multimodal treatment, including 25% of patients after ADT alone; an additional 50% achieved this after surgery and 20% more did so after radiotherapy.
"This is consistent with reports demonstrating the inability of systemic therapy alone to eliminate disease in either the primary or metastatic sites, and highlights the need to treat each site of disease in order to reach the 'no evidence of disease' end point," the authors comment.
However, while nearly everyone achieved an undetectable PSA, in many patients, testosterone and PSA levels then began to rise, once the effects of ADT began to wear off.  
Overall, only 4 patients (20%) achieved the primary endpoint of an undetectable PSA (<0 .05="" and="" levels="" ml="" ng="" noncastrate="" of="" testosterone="">150 ng/dL) at 20 months after the start of ADT. All 4 of these patients had been classified as having M1b disease (bone disease) at presentation.
These undetectable PSA and testosterone levels (which the authors described as "NED") persisted further for a variable amount of time — for 5, 6, 27+, and 46+ months in these 4 patients, respectively.
So, 1 of these patients has had "NED" for more than 5 years (20 + 46 = 66 months) while not receiving any further therapy, the authors note in a reply to the editorial comment.
In an email to Medscape Medical News, Dr O'Shaughnessy said that patients with early-stage metastatic prostate cancer similar to the participants in this trial would have a median survival of 42 months (as, for example, patients in the control group of the STAMPEDE trial [Eur Urol. 2015;67:1028-1038]).
He also noted that only 2 patients in this pilot trial died of prostate cancer, and there no other deaths. "Because of the size of the trial we cannot draw definite conclusions about how overall survival is impacted...but there are no other reports to our knowledge showing complete elimination of disease in these patients," he said.

Early Relapse After Not Achieving Undetectable PSA  

Failure to achieve an undetectable PSA was associated with early relapse, the authors note.
None of the 5 men with M1a disease (extrapelvic nodal disease) achieved the primary endpoint. With a median follow-up of 34 months, castration-resistant disease developed in 2 patients (40%) at 18 and 32 months, respectively. Two (40%) progressed radiographically: in the prostate bed and retroperitoneum in 1 patient and in bone and lung in the other. One of these patients with M1a disease died of prostate cancer at 24 months after the start of therapy.
Among the 15 men with M1b disease (bone disease), 4 achieved the primary endpoint. Overall, with a median follow-up of 47 months, castration-resistant disease has been documented in 8 patients at a median of 23 months. One of these patients with M1b disease died of prostate cancer at 56 months after the start of therapy.

Novel Endpoint 

The authors acknowledge that the endpoint they used (an undetectable
PSA with noncastrate testosterone level is equivalent to no evidence of disease) is novel. Whether it will translate into a durable oncologic benefit is an open question, they add, and this will require validation in phase 3 clinical trials.
But they also argue that use of this novel endpoint "will ensure the timely evaluation of multiple strategies so that only the most promising ones are moved forward. Regimens that do not result in an NED state are unlikely to translate into durable responses and can be de-prioritized."
At the same time, achieving and then maintaining this NED  endpoint "begins to establish the possibility of cure," Dr O'Shaughnessy and colleagues write.
Commenting on the study in the journal press release, Dr Sartor said, "The end point deserves special mention, as the end point of undetectable PSA after testosterone recovery has been previously discussed but rarely studied. The authors proposed that this end point may serve as a first step toward establishing a curative paradigm."
"Many in the field agree, but note that the longevity of effect is essential to prove the point of curability," Dr Sartor continued.
The longevity of effect is essential to prove the point of curability. Dr Oliver Sartor
"Regardless, the movement toward a curative paradigm is much needed, and the investigators are to be congratulated for setting forth a paradigm that can be used to assess the possibility of cure in a reasonable period of time," he said.
In his comments to Medscape Medical News, Dr Garnick echoed this sentiment. "Commendation is in order to the authors for providing physicians who care for this patient population with a significant alteration in treatment choices," he said.   

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