The first clinical experience in prostate cancer salvage cryotherapy

Correspondence to: Marius Snicorius, Institute of Oncology, Vilnius University, Santariškių 1, Vilnius, Lithuania. E-mail: Marius.Snicorius@gmail.com Introduction. Prostate cancer is the most common malignant neoplasia among men in Lithuania, though it presents a low mortality rate. In 2007 more than 3 500 Lithuanians were diagnosed with prostate cancer. Many patients were treated with radiotherapy. Unfortunately, after several years the number of cases of prostate cancer recurrence after radiotherapy started to grow. This new problem requires the following difficult decision to make: which treatment method to choose? Radical prostatectomy, high-dose radiotherapy, cryotherapy, high-intensityfocused ultrasound, active surveillance or hormone therapy – all are viable salvage methods. In 2012 we performed the first cryotherapy procedures. Now we want to present our first clinical experience in prostate cancer salvage cryotherapy. Materials and methods. Five patients diagnosed with prostate cancer were selected for prostate cryotherapy. Four patients were treated only with radiotherapy, one patient was treated with radiotherapy plus neoadjuvant hormonal treatment. Prostate cancer recurrences were diagnosed by multiparametric MRI and ultrasound guided transrectal or transperineal biopsies. MRI findings were validated with the Magnetic Resonance Prostate Imaging Reporting and Data System (PI-RADS). CT, MRI, ultrasound scanning, and bone scintigraphy were performed for patients before treatment. No pathological bone changes were detected. All patients received 2-cycle cryotherapy with real-time ultrasound guidance and temperature change tracking. Results. The described treatment scheme for these patients enables to deliver two freezing-thawing cycles with 10–12 probes and a urethra-warming catheter. All procedures were completed succesfully without any intraoperative complications. Urinal obstruction was observed after 1 week for 1 of 5 patients. He had to stay with epicystostomy and overwent prostate transurethral resection. After these procedures the patient could urinate normally. One patient had biochemical progression due to metastasis in parailiacal lymph nodes, and he got external beam therapy to lymph-node projection. After 6 months there was no cancer progresion signs on MRI and PSA was 1.77 ng/ml. No patients suffered from urinary incontinence. Conclusions. Our initial experience shows that cryotherapy can be a viable alternative for patients with disease progression after radiotherapy. Currently the biggest advantages of cryotherapy are as follows: possibility to treat patients not suitable for salvage prostatectomy, short hospitalization, low complication risk and lower overall cost than other methods. Short term data seems to be promising but longer follow-up is necessary to verify oncological and functional results.


INTRODUCTION
Prostate cancer is the most common malignant neoplasia among men in Lithuania, though it presents low mortality rate.In 2007 more than 3 500 Lithuanians were diagnosed with pro sta te cancer.Many patients were treated with ra dio therapy.Unfortunately, after several years the number of cases of prostate cancer recurrence after ra dio therapy started to grow.This new problem requires a difficult decision to make: which treat ment method to choose?Radical prostatectomy, highdose radiotherapy, cryotherapy, high-intensity-focu sed ultrasound, active surveillance or hormone therapy -all are viable salvage methods.In 2012 we performed the first cryotherapy procedures.Now we want to present our first clinical experience in prostate cancer salvage cryotherapy.

MATERIALS AND METHODS
Five patients diagnosed with prostate cancer were selected for prostate cryotherapy.Four patients were treated only with radiotherapy, one patient was treated with radiotherapy plus neoadjuvant hormonal treatment.
Prostate cancer recurrences were diagnosed by multiparametric MRI and ultrasound guided transrectal or transperineal biopsies.MRI findings were validated with the Magnetic Resonance Prostate Imaging Reporting and Data System (PI-RADS).CT, MRI, ultrasound scanning, bone scintigraphy were performed for patients before treatment.No pathological bone changes were detected.
All patients received 2-cycle cryotherapy with real-time ultrasound guidance and temperature change tracking.Figure 1 shows placement of free z ing probes during the procedure.
The first case: a 71-year-old patient with ini tially diagnosed cT1c N0 M0 prostate cancer, Gleason 3 + 3 = 6, PSA value 8.9 ng/ml.In May 2004 the patient received 70 Gy dose for prostate treatment volume with 3D conformal radiotherapy.In 2012 prostate cancer recurrence was diagnosed on MRI, with PSA 0.3 ng/ml.Prostate volume was 26 cm 3 .5 months after cryotherapy PSA was 0.07 ng/ml.

Fig. 1. Placement of freezing probes
The second case: a 68-year-old male, with initially diagnosed cancer cT2b N0 M0, Gleason 3 + 3 = 6, PSA value 17.6 ng/ml.In January 2007 the patient received 70 Gy dose treatment with radiotherapy.In 2012 prostate cancer recurrence was diagnosed on MRI, with PSA 2.7 ng/ml.Prostate volume was 28.5 cm 3 .Cryotherapy was used, but after 4 months PSA was 21.6 ng/ml.Metastasis was spotted in the parailiacal lymph node on MRI.The patient received 60 Gy dose radiotherapy.After 6 months there were no cancer progresion signs on MRI and PSA was 1.77 ng/ml.
The third case: A 64-year-old patient, initially diagnosed with cT3aN0M0, Gleason 3 + 3 = 6 prostate cancer.In 2004 the patient with initial PSA 44 ng/ml received 70 Gy dose 3D conformal radiotherapy with neoadjuvant hormonal treatment.In 2012 local recurrence was diagnosed with PSA 5.2 ng/ml.Prostate volume was 27.9 cm 3 .Cryotherapy was used and after 6 months PSA was 0.002 ng/ml.
The fourth case: In 2001 a 71-year-old pa tient with initial PSA 22 ng/ml had prostate treatment with 3D conformal radiotherapy.In 2012 biochemical recurrence occurred with PSA 5.9 ng/ ml.Prostate volume was 27 cm 3 .MRI showed extra-capsular extension.PSA was 0.21 ng/ml 6 months after cryotherapy.MRI showed no cancer progression signs.Figure 2 shows the MRI perfusion map before cryotherapy (prostate can cer recurrence) and Fig. 3 shows this map six months after the procedure.
The fifth patient, 66-year-old, was diagnosed with cT2b N0 M0 prostate cancer, Gleason 3 + 3 = 6, PSA value of 15.2 ng/ml.In 2007 the patient received 70 Gy dose treatment with 3D conformal radiotherapy.In January 2013 prostate cancer recurrence was diagnosed on MRT, with PSA 4.9 ng/ml.Prostate volume was 20.1 cm 3 .In February 2013 cryotherapy was applied and after 2 months PSA was 0.29 ng/ml.

RESULTS
The described treatment scheme for these patients enables to deliver two freezing-thawing cycles with 10-12 probes and a urethra-warming catheter.All procedures were completed succesfully without any intraoperative complications.
Urinal obstruction was observed after 1 week for 1 of 5 patients.He had to stay with epicystostomy and overwent prostate transurethral resection.After these procedures the patient could urinate normally.

Fig. 2. MRI perfusion map shows intensive blood flow, which is increased in prostate cancer cells
One patient had biochemical progression due to metastasis in the parailiacal lymph node, and he got external beam therapy to lymph-node projection.After 6 months there were no signs of cancer progression on MRI and PSA was 1.77 ng/ml.
No patients suffered from urinary incontinence.

DISCUSSION
Nowadays many urologists are trying to solve new dilemma: How to treat patients who were diagnosed with prostate cancer recurrence after radical radiotherapy?According to new literature, in eight years biochemical prostate cancer recurrence will be diagnosed for 15-20% low risk cases and about 40% high risk cases of prostate cancer (1,2).Data of the Cancer of the Prostate Strategic Urologic Research Endeavour comprising 2 336 patients with prostate cancer (4) demonstrated that 92% of patients who had initially been irradiated received ADT for the secondary treatment of PSA progression.In the absence of salvage procedures, the mean time interval from biochemical to clinical progression was approximately 3 years.After radiotherapy for prostate cancer, it has been demonstrated that up to one third of patients with biochemical failure will have a positive biopsy (5).
According to the 2008 American Urological Association (AUA) Best Practice Consensus Sta tement, ideal candidates for salvage cryoablation also should have absence of seminal vesicle invasion, a PSA less than 10 ng/mL (preferably <4 ng/mL), a PSA doubling time of 16 months or more, and at least a 10-year life expectancy.Factors such as gland volume larger than 50 to 60 cm 3 or prior transurethral resection may exclude patients in some cases (5)(6)(7).On the other hand, the Euro pean Association of Urology (EAU) guidelines state that ideal candidates for cryotherapy are those who have organ-confined prostate cancer and those identified as having minimal tumour extension beyond the prostate (1-3).The prostate should be <40 mL in size.Prostate glands >40 mL should be hormonally downsized to avoid any technical difficulty in placing cryoprobes under the pubic arch.Prostate-specific antigen (PSA) serum levels should be <20 ng/mL, and the biopsy Gleason score should be <7.It is important that patients with a life expectancy >10 years should be fully informed that there are no data, or only minimal data, on the longterm outcome for cancer control at 10 and 15 years (10).We analyzed and adapted these AUA and EAU statements for our hospital.In our opinion, excellent candidates for prostate cryotherapy are Fig. 3. MRI perfusion map after cryotherapy.There are no increased blood-flow spots in prostate diagnosed with local prostate cancer, no metastases (checked with CT, MRI or bone scintigraphy scans), The prostate-specific antigen (PSA) serum level is lower than 10 ng/mL, the biopsy Gleason score is <7 and the prostate volume should be lower than 50 mL.Patients with life expectancy longer than 10 years must be informed that there is no or there is only minimal data on the long-term outcome for prostate cancer control.
Currently there are many treatment alternatives for prostate cancer recurrence: prostate cryotherapy, high dose rate brachytherapy (HDR), prostatecto my, high-intensity focused ulrasound (HIFU).In rare cases active surveillance can be used.
In our experience surgery after radical radiotherapy is associated with high mortality rate and high risk of postoperative complications.EAU guidelines propose not to perform radical prostatectomy for patients who had radiation therapy because of high complications risk.Various authors reported that 30-67% of the patients, who had salvage prostatectomy after radiotherapy, suffered from urinary incontinence, anastomosis stenosis occurred in 11-30% and 1-10% had rectal injuries (8,9).Erectile dysfunction seems frequently not to be a major problem in this setting as it is often present after radiotherapy (10, 11).It is important to remember that many patients with prostate cancer recurrence are old with many comorbidities and are after radiotherapy.Quite often surgery cannot be applied in such settings.Other salvage treatment options are brachytherapy or external beam re-radiotherapy.Unfortunately, these treatment methods cannot be used in a lot of cases because of too high cummulative radiation dose (External beam therapy already brings at least 70 Gy radiation dose).In addition to this, experience with salvage brachyterapy for radiation failures is very limited.Hormonal therapy brings many ne gative side-effects and desperately decreases the quality of life.Hormonal treatment lasts for a long period of time and cost of the treatment is very high.The experience of High-intensity-focused Ultra sound (HIFU) for the treatment of locally recurrent prostate cancer after radiation therapy is limited to a few retrospective studies and nature of this treatment modality is still experimental due to the short follow-up periods reported.
On the other hand, cryotherapy is well known for a low complication rate, good quality of life, short procedure time and hospitalization.Cryosurgery may offer an option for treating cancers that are con sidered inoperable or that do not respond to stan dard treatment methods.Furthermore, it can be used for patients who are not good candidates for conventional surgery because of their age or other medical conditions.The technology of cryoablation devices has been improved, and the development of new-generation real-time ultrasound probes as a guide for freezing ablation allows safer and more precise treatments than in the first ex periences.Gas-driven miniaturized equipment, ultra sonographic ice-ball monitoring, and the use of thermal sensors have allowed more efficient free zing of the prostate gland while reducing collateral damage to surrounding tissues.Various studies re ported outcomes and complication rates of salva ge cryotherapy: 4.4-13% urinary incontinence, 1-3.4% rectal injuries.The same studies followed up patients for 3-10 years after salvage cryothera py and reported biochemical recurrence-free survi val rates varying from 39 to 66% (9).
Many doctors consider that cryotherapy is an expensive procedure.However, one study evaluated financial implications of localized prostate cancer treatment methods.Despite the relatively increased surgical expense of cryotherapy compared with con ventional surgical prostatectomy (open, laparos copic or robotic), the overall direct costs were offset by the significantly lower nonoperative hospital costs.The cost advantages associated with cryo therapy included a shorter length of stay in the hospital and the absence of pathologic costs and the need for blood transfusion (12).