Σάββατο, 24 Δεκεμβρίου 2016

VPT FOR TREATMENT OF LOW RISK PROSTATE CANCER

A new approach to the treatment of low-risk prostate cancer, which involves injecting a light-sensitive drug into the bloodstream and then activating it with a laser to destroy tumor tissue in the prostate, has been shown to achieve complete remission in half of the men who were treated in a phase 3 trial.
"These results are excellent news for men with early, localized prostate cancer, offering a treatment that can kill cancer without removing or destroying the prostate," says senior author Mark Emberton, FMedSci, dean of medical sciences and consultant urologist at University College London in the United Kingdom. He has been a leading proponent of the use of high-intensity focused ultrasound to ablate a section of the prostate, rather than removal of the whole gland.
The new approach, known as vascular-targeted photodynamic therapy (VTP), is "truly a huge leap forward for prostate cancer treatment," Dr Emberton said in a press release issued by the institution.
The VPT study was published online December 19 in the Lancet Oncology.
The results have made headlines all over the United Kingdom, with some proclaiming the research "truly transformative," but none have reported the rather less enthusiastic comments made by an expert in an accompanying editorial.
"Vascular-targeted photodynamic therapy is a novel, interesting treatment for prostate cancer with potential modest tumour control and modest short-term side-effects," writes editorialist Stephen Freedland, MD, Cedars-Sinai Medical Center, Los Angeles, California, but he warns that the results do not justify the routine use of the photodynamic approach for all men with low-risk prostate cancer.
Study Details
The study was carried out in 10 European countries and included 413 men with low-risk prostate cancer. The patients were randomly allocated to be followed by active surveillance or to receive VPT.
The researchers, with first author Abdel-Rahmene Azzouzi, MD, Angers University Hospital, France, and colleagues, describe the participants as having low-risk (but not very-low-risk) prostate cancer. The patients had localized prostate cancer that was diagnosed with the use transrectal ultrasound–guided biopsy. Patients were eligible for the study if one core of cancer that was free of Gleason patterns 4 or 5 was present, provided that the cancer core length was between 3 mm and 5 mm. In other words, patients were eligible if only one core was positive, only Gleason pattern 3 was present, and the length of the cancer core was ≥3 mm and was ≤5 mm. Men with two or three positive cores were also included, but for those patients, cancer core length could not exceed 5 mm, and Gleason patterns 4 or 5 were excluded.
Patients were included only if their cancer was of clinical stage T2a or higher and their prostate-specific antigen (PSA) values were 10 ng/mL or less.
Patients randomly assigned to the active surveillance group underwent a protocol-directed biopsy at 12-month intervals, and PSA levels were measured every 3 months. In addition, a digital rectal examination was performed every 3 months. 
Men in the experimental arm received padeliporfin VPT (Aptuit LLC) at a dose of 4 mg/kg intravenously over a 10-minute interval. Optical fibers were placed in the prostate in the designated treatment area and were activated by laser light for 22 min, 15 sec.
The researchers note that men with bilateral disease could receive a second course of treatment for the contralateral tissue, and men could also undergo a second treatment in the event that tissue was positive for prostate cancer when the first biopsy was performed at 12 months.
A transrectal, ultrasound-guided, 12-core biopsy was performed at both the 12-month point and at study endpoint at 24 months.
Details of the Results
"Median time to progression from low-risk to moderate or high-risk prostate cancer was longer in the VPT group [at] 28.3 months...than in the active surveillance group [at] 14.1 months (< .0001)," the researchers report.
Moreover, 66% fewer patients in the experimental arm experienced disease progression at study endpoint compared with those in the active surveillance group (28% vs 58%, < .0001).
More than 3.5-fold more men in the VPT group also had a negative biopsy result at month 24 than those in the active surveillance group (< .001), the researchers comment. In addition, 49% of patients in the VPT arm were found to be in complete remission at month 24, vs 13.5% in the control group.
Only 6% of men in the experimental group required either surgery or radiotherapy during the study period, compared with 29% of men in the active surveillance group (< .0001). The interval between randomization and initiation of radical therapy was also significantly longer in those treated with VPT than in those in the active surveillance arm (< .0001).
"For men whose prostate cancer did not progress during the study, vascular-targeted photodynamic therapy was associated with clinically and statistically significant decreases at month 24 in all mean tumour burden measurements compared with active surveillance," the researchers report.
Table. Mean Tumor Burden Measurements: VPT vs Active Surveillance
 VPTActive SurveillanceP Value
Total no. of positive cores0.92.3P < .0001
Total cancer core length2.6 mm6.8 mmP < .0001
Maximum cancer core length1.6 mm3.4 mmP < .0001

Safety Profile
"As expected, both the frequency and severity of adverse events and serious adverse events were higher in the VPT group than in the active surveillance group," the investigators acknowledge.
Most adverse events were mild or moderate in nature, they comment, and occurred either during the procedure or immediately after it. Most resolved quickly without consequence, they add.
During the study, participants were evaluated using both the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function questionnaire (IIEF-15). Quality of life was established using the EuroQol-5D questionnaire.
"In the VPT group, IIEF-15 and IPSS assessments showed transient deterioration in erectile and urinary function, but the result at month 24 was similar between the two groups," the team reports.
Scores on the EQ-5D questionnaire also suggested that men in the experimental arm did not experience any decrease in quality of life at study endpoint, Dr Emberton said.
"These results are excellent news for men with early localized prostate cancer, offering a treatment that can kill cancer without removing or destroying the prostate," Dr Emberton said in a statement. "The success of this new tissue-preserving treatment is welcome news indeed," he added
Reservations From Editorialist
However, in his editorial, Dr Freedland comments that "any treatment that leaves residual cancer in more than half the men (as in this study) is not ideal.
"Moreover," he adds, "more than a quarter of men 'progressed' within 2 years, again suggesting a non-ideal treatment."
Dr Freedman also points out that the benefits seen with PDT compared with active surveillance did not come without cost in terms of side effects.
He indicates that 30% of those in the VPT group experienced a serious adverse event, compared with only 19% in the control group. In addition, more than 25% of men in the experimental arm reported some degree of dysuria or hematuria, and more than one third of the patients in the VPT group reported erectile dysfunction.
However, the overarching concern that Dr Freedland appears to have with this new approach is with the level of risk associated with prostate cancer.
"First, for men with very low-risk versus low-risk prostate cancer, the risk of progression is very low," Dr Freedland states.
"For these men, the benefits of early treatment, even a less toxic treatment, are hard to justify," he adds.
On the other hand, when treatment is warranted, the new approach may not be sufficient. Dr Freedland argues that because approximately half of the patients still had evidence of cancer, as determined on the basis of the results of biopsy performed 2 years after the patients underwent the procedure, VPT may well be inferior to radiation or surgery, and that "upfront aggressive treatment" should be considered in men who are at higher risk for progression, though still considered to be low-risk.
Commenting further on what he thought of the new tissue-preserving strategy, Dr Freedland told Medscape Medical News he is not convinced the right kind of patient can be found who would be an appropriate candidate for this new approach.
"Either you have very, very low-risk men for whom basically any side effects are too many because their risk of progressing or needing treatment or dying of their disease is very, very low," Dr Freedland said.
"Alternatively, you have men with worse disease that need real treatment, and any treatment in my books that leaves cancer still in the prostate 50% of the time is not an ideal treatment," he added.
"So while this therapy is better than doing nothing — it kills cancer cells, it has side effects, so it's real — for many patients, it's not enough, and for others, it's too much," he said.
Dr Freedman also pointed out that the benefits seen with the photodynamic strategy did not come without costs in terms of side effects.
Relative to active surveillance, for example, an additional 1 of 4 patients in the photodynamic group complained about erectile dysfunction, and one quarter of patients in the experimental arm developed irritative voiding symptoms or blood in the urine.
"Both of these effects seemed to be relatively short-lived, so they did not have a major impact on patients, and they are certainly less than side effects we see from surgery or radiation, but the treatment is not devoid of side effects," Dr Freedman observed.
"I think this is a very intriguing study, but the challenge with any new technology is to find the right patient, and to me, it is not clear who this procedure is appropriate for," Dr Freedland concluded.
"So it has modest cancer efficacy with modest side effects, so perhaps there is a group of men with modest disease for whom a modestly effective treatment with modest side effects might be appropriate. Probably there is, but it just doesn't readily come to mind," he said.
Trial Planned at MSKCC
On the other hand, Jonathan Coleman, MD, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, is more than enthusiastic about using the technique — but in higher-risk prostate cancer patients.
"The Memorial Sloan Kettering Cancer Center is going to be utilizing the vascular-targeted photodynamic technique to treat patients with Gleason 7 prostate cancer with the intention of trying to cure these patients without the need for further therapies with either surgery or radiation," he told Medscape Medical News.
Preclinical research done in small and large animals at MSKCC showed that this type of treatment can be successfully applied in the setting of localized advanced and even systemically advanced cancers, Dr Colemen noted.
"We've worked with a number of different ablative techniques for treating cancer, and we've found that this approach has some major advantages over all of the other therapies that are out there," he said.
"And we're developing this treatment for use in a variety of other cancers, including breast cancer, esophageal cancer, and different forms of kidney cancers," he added.
MSKCC recently partnered with Merck to use a number of their agents to try to enhance the effectiveness of the photodynamic approach.
The study was funded by Steba Biotech. Dr Azzouzi received payment from Steba as an investigator on this study. He has also served as a consultant and proctor for that company. Neither Dr Freedland nor Dr Coleman has disclosed any relevant financial relationships.
Lancet Oncol. Published online December 19, 2016.

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