Focal cryotherapy of localized prostate cancer: a systematic review of the literature

Radical/whole gland treatment for prostate cancer has significant side-effects. Therefore focal treatments such as cryotherapy have been used to treat localized lesions whilst aiming to provide adequate cancer control with minimal side-effects. We performed a systematic review of Pubmed/Medline and Cochrane databases' to yield 9 papers for primary focal prostate cryotherapy and 2 papers for focal salvage treatment (radio-recurrent). The results of 1582 primary patients showed biochemical disease-free survival between 71–93% at 9–70 months follow-up. Incontinence rates were 0–3.6% and ED 0–42%. Recto-urethral fistula occurred in only 2 patients. Salvage focal cryotherapy had biochemical disease-free survival of 50–68% at 3 years. ED occurred in 60–71%. Focal cryotherapy appears to be an effective treatment for primary localized prostate cancer and compares favorably to radical/whole gland treatments in medium-term oncological outcomes and side-effects. Although more studies are needed it is also effective for radio-recurrent cancer with a low complications rates.     

Focal therapy in prostate cancer: A review of seven common controversies

Radical treatments such as prostatectomy and radiotherapy have demonstrated success in terms of biochemical and disease-specific survival for localised prostate cancer. However, whilst the end goal of any cancer treatment is to control or cure disease it must also do so by minimising any side effects that may be experienced by the patient. Focal therapy as a concept aims to redress this established therapeutic ratio by treating areas of the prostate affected by significant disease as opposed to treating the entire gland. However, there are a number of common criticisms of focal therapy – we deem the seven sins – that require further interrogation.     

Evolution from active surveillance to focal therapy in the management of prostate cancer

Organ-preserving therapies are widely accepted in many facets of medicine and, more recently, in oncology. For example, partial nephrectomy is now accepted as a preferred alternative over radical nephrectomy for small (up to 4 cm or T1) tumors. Focal therapy (FT) is another organ-preserving strategy applying energy (cryotherapy, laser ablation and/or high-intensity focused ultrasound) to destroy tumors while leaving the majority of the organ, surrounding tissue and structures unscathed and functional. Owing to the perceived multifocality of prostate cancer (PCa) technology limitations, in the past PCa was not considered suitable for FT. However, with the rise of active surveillance for the management of low-risk PCa in carefully selected patients, FT is emerging as an alternative. This is owing to technology improvements in imaging and energy-delivery systems to ablate tissue, as well as the realization that many men and clinicians still desire tumor control. With the postulated ability to ablate tumors with minimal morbidity, FT may have found a role in the management of PCa; the aim of FT a being long-term cancer control without the morbidity associated with radical therapies. Data for FT in PCa have been derived from case series and small Phase I trials, with larger cohort studies with longer follow-up having only just commenced. More data from large trials on the safety and efficacy of FT are required before this approach can be recommended in men with PCa. Importantly, studies must confirm that no viable cancer cells remain in the region of ablation. FT might eventually prove to be a 'middle ground' between active surveillance and radical treatment, combining minimal morbidity with cancer control and the potential for retreatment.     

Prospective study of external radiotherapy with and without intraluminal brachytherapy for esophageal cancer in Japan. JASTRO Study Group

To improve the results of treatment of patients with esophageal cancer, it is important to achieve good local control. Since the esophagus is adjacent to highly radiation-sensitive organs such as the lungs, bone marrow, etc., it is difficult to irradiate tumors with high doses. Although irradiation techniques have improved as a result of advances in treatment-planning equipment and irradiation equipment, there are still some patients for whom radical radiation therapy within doses that the bone marrow and lungs can tolerate is difficult with external irradiation alone. On the other hand, intraluminal brachytherapy allows high-dose irradiation of esophageal cancer with little risk to adjacent organs. However, intraluminal brachytherapy, in which the dose sharply declines with the distance from the radiation source, is suggested to be a useful technique for tumors with relatively shallow invasion. With the aim of improving the results of esophageal cancer treatment, we designed this study to establish the optimal irradiation method in radical radiation therapy for esophageal cancer by clinically evaluating external irradiation alone and in combination with intraluminal brachytherapy.     

Minimally invasive approaches to localized prostate carcinoma

Prostate cancer is an increasing medical problem. Radical prostatectomy and radiation therapy are effective treatments, but have the risk of significant morbidity. Clinicians have strived to develop new modalities of treatment that can maintain the excellent treatment outcomes of radical prostatectomy, but diminish the morbidity. Improved instrumentation, optics, and robotic technology have allowed the application of laparoscopic techniques to radical prostatectomy. Patients can have less blood loss and expect more rapid recovery. Intermediate oncologic outcomes appear similar to radical prostatectomy with good functional results. Cryotherapy and HIFU are tissue ablative approaches rather than extirpative approaches to prostate cancer treatment. They attempt to use nonsurgical methods to treat prostate cancer with the hope of providing oncologic control comparable to surgery and radiation while minimizing morbidity.     

Emerging minimally invasive procedures for focal treatment of organ-confined prostate cancer

Prostate cancer is the most common malignancy amongst American men. However, the majority of prostate cancer diagnoses are of low risk, organ-confined disease. Many men elect to undergo definitive treatment, but may benefit from focal therapy to maintain continence and potency. This review reports the mechanism of action and outcomes of emerging focal therapies for prostate cancer. We report the mechanism of action of focal cryotherapy, high intensity focused ultrasound, focal laser ablation, and irreversible electroporation. In addition, we reviewed the largest studies available reporting rates of urinary incontinence, erectile dysfunction, biochemical recurrence-free survival (ASTRO), and post-operative adverse events for each procedure. Each treatment modality stated has a unique mechanism in the ablation of cancerous cells. Genito-urinary symptoms following these studies report incontinence and erectile dysfunction rates ranging from 0–15% and 0–53%, respectively. Biochemical disease-free survival was reported using the ASTRO definition. Some treatment modalities lack the necessary follow-up to determine effectiveness in cancer control. No focal therapy studies reported serious adverse events. These minimally invasive procedures are feasible in a clinical setting and show promising functional and disease control results with short to medium-term follow-up. However, each treatment requires additional robust prospective studies as well as its own unique domain to determine biochemical recurrence free survival to properly determine their role in treatment of organ-confined prostate cancer.     

Interference with EGFR signaling: paradigm for improving radiation response in cancer treatment

The introduction of biologically active agents that interfere with the epidermal growth factor receptor (EGFR) provides a promising opportunity to improve cancer treatment outcomes. Several EGFR-selective agents, such as humanized monoclonal antibodies and small molecule, orally available tyrosine kinase inhibitors have shown antitumor activity in early clinical trials in advanced cancer patients. Preclinical studies have demonstrated enhanced radiation- and chemotherapy-induced tumor cytotoxicity when EGFR antagonists are implemented. More broadly, recent clinical trials have confirmed improved survival with combinations of HER-2 (a member of the ErbB family of receptors) targeted antibodies and chemotherapy in patients with advanced breast cancer. A landmark trial combining C225 antiEGFR antibody with radiation therapy for patients with locally advanced head and neck cancer has just completed accrual. Thus, emerging rapidly are cancer treatment strategies based on an improved understanding of the specific cellular and molecular abnormalities of individual tumors.     

Locally advanced prostate cancer

Opinion statement Standard therapy for clinically localized prostate cancer includes radical prostatectomy, external beam radiotherapy, or transperineal interstitial brachytherapy. Patients eligible for standard therapy are those with low risk features as defined by various risk group classifications, which generally include clinical stage T1 or T2a, serum prostate-specific antigen (PSA) less than 10 ng/mL, and biopsy Gleason sum of 6 or less. Although there has been important evolution in the performance of these techniques, particularly with respect to functional outcomes, these approaches for low-risk disease are relatively mature, and the cure rates with each of these therapies are similar in this patient population; locally advanced disease is more difficult to cure, however. Biochemical disease-free survival rates in men undergoing radical prostatectomy are clearly related to the pathologic stage. Prognostic groups can be defined based on pathologic stage with increasingly worse outcomes based on extracapsular extension (ECE), margin status, and the status of the lymph nodes and seminal vesicles. In patients with low risk features, the positive margin rate is generally low, making the presence or absence of ECE the dominant variable in predicting the likelihood of treatment failure. These observations suggest that more aggressive therapy is needed to cure those who are likely to have ECE or other adverse histologic features. Several nomograms predicting the likelihood of ECE or 5-year biochemical failure rates are now in routine clinical use, and can be used to select men at high risk of failure with single modality therapy for more aggressive treatment strategies. However, the optimal form of aggressive therapy for these patients is unknown.     

Interference with EGFR signaling: paradigm for improving radiation response in cancer treatment

The introduction of biologically active agents that interfere with the epidermal growth factor receptor (EGFR) provides a promising opportunity to improve cancer treatment outcomes. Several EGFR-selective agents, such as humanized monoclonal antibodies and small molecule, orally available tyrosine kinase inhibitors have shown antitumor activity in early clinical trials in advanced cancer patients. Preclinical studies have demonstrated enhanced radiation- and chemotherapy-induced tumor cytotoxicity when EGFR antagonists are implemented. More broadly, recent clinical trials have confirmed improved survival with combinations of HER-2 (a member of the ErbB family of receptors) targeted antibodies and chemotherapy in patients with advanced breast cancer. A landmark trial combining C225 antiEGFR antibody with radiation therapy for patients with locally advanced head and neck cancer has just completed accrual. Thus, emerging rapidly are cancer treatment strategies based on an improved understanding of the specific cellular and molecular abnormalities of individual tumors.     

Minimally-invasive technologies in uro-oncology: The role of cryotherapy, HIFU and photodynamic therapy in whole gland and focal therapy of localised prostate cancer

The use of minimally-invasive ablative therapies in localised prostate cancer offer potential for a middle ground between active surveillance and radical therapy. This article reviews the evidence for cryotherapy, high intensity focused ultrasound (HIFU) and photodynamic therapy in the treatment of localised prostate cancer. These ablative technologies can deliver a minimally invasive, day case treatment with effective early cancer control and low genitourinary morbidity. In addition, all have the ability to deliver focal therapy of only the malignant lesions within the prostate.     

Health technology assessment in evolution – focal therapy in localised prostate cancer

Focal therapy in prostate cancer aims to treat only the part of the gland harboring clinically significant disease while preserving the rest of the tissue. This approach may substantially reduce treatment-related toxicity without compromising disease control outcomes. Short- to medium-term functional and oncological results in prospective interventional studies are promising, but comparative effectiveness research against standard of care is required to incorporate focal therapy among standard options. In this review, we discuss the actual stage of assessment and results of sources of energy commonly used to deliver focal therapy. We also provide our viewpoint on how the field will evolve in the near future.     

Focal or Subtotal Therapy for Early Stage Prostate Cancer

Opinion statement Focal treatment for prostate cancer is highly intriguing, but poorly supported by the published literature. Further studies, preferably randomized controlled trials, are needed before this can be considered standard therapy. Focal treatment should be reserved for patients with focal disease. Even “clinically insignificant” synchronous tumors are malignant, and carry risk of progression if not treated with the index lesion. Whether these are likely to progress in this setting compared to those managed with active surveillance is unknown. The limited data regarding subtotal or focal cryotherapy suggest that patients properly evaluated for presence of satellite tumors have a low risk of having large unknown satellite tumors. The author requires office-based saturation biopsy prior to considering focal cryotherapy. Observation of prostatic intraepithelial neoplasia (PIN), atypical findings (ASAP), or cancer on the contralateral biopsy cores excludes the patient from consideration of subtotal therapy. MRI offers a potential additional ability to detect occult contralateral tumors. Younger men paradoxically seem to have greater interest in focal therapy while having a higher risk of future malignancy in the untreated areas based on the years of potential risk. However, no age cutoff is established. Without published data to support its use, lumpectomy or freezing only the focus where cancer is believed to exist, will remain limited. Hemispheric or subtotal treatment decreases the amount of untreated tissue. As a result, the local failure rate would be predicted to be lower but is unknown. When performing subtotal treatment, the author freezes almost the entire gland, sparing only the aspect adjacent to the contralateral neurovascular bundle, and has found this practice to be of highly limited utility based on the issues described. Biopsy should be performed following any treatment that fails to target the entire gland. A positive biopsy should be dealt with based on clinical factors as if the patient had not been treated, and a positive biopsy should not preclude active surveillance if deemed appropriate.     

Engineering T cell response to cancer antigens by choice of focal therapeutic conditions

Focal thermal therapy (Heat), cryosurgery (Cryo) and irreversible electroporation (IRE) are increasingly used to treat cancer. However, local recurrence and systemic spread are persistent negative outcomes. Nevertheless, emerging work with immunotherapies (i.e., checkpoint blockade or dendritic cell (DC) vaccination) in concert with focal therapies may improve outcomes. To understand the role of focal therapy in priming the immune system for immunotherapy, an in vitro model of T cell response after exposure to B16 melanoma cell lysates after lethal exposures was designed. Exposure included: Heat (50?°C, 30?min), Cryo (?80?°C, 30?min) and IRE (1250?V/cm, 99 pulses, 50 µs pulses with 1?Hz intervals). After viability assessment (CCK-8 assay), cell lysates were collected and assessed for protein release (BCA assay), protein denaturation (FTIR-spectroscopy), TRP-2 antigen release (western blot), and T cell activation (antigen-specific CD8 T cell proliferation). Results showed IRE released the most protein and antigen (TRP-2), followed by Cryo and Heat. In contrast, Cryo released the most native (not denatured) protein, compared to IRE and Heat. Finally, IRE dramatically outperformed both Cryo and Heat in T cell activation while Cryo modestly outperformed Heat. This study demonstrates that despite all focal therapies ability to destroy cells, the ‘quantity’ (i.e., amount) and ‘quality’ (i.e., molecular state) of tumor protein (including antigen) released can dramatically change the ensuing priming of the immune system. This suggests protein-based metrics whereby focal therapies can be designed to prime the immune system in concert with immunotherapies to eventually achieve improved and durable cancer treatment in vivo.     

Minimally invasive surgical modalities in the management of localized prostate cancer

Localized prostate cancer is one of the success stories of modern oncology, with radical treatments offering long-term cancer-specific survival for most patients. In fact, most men with this condition die from nonprostate cancer diseases rather than from their prostate cancer. Open radical prostatectomy has been the gold standard radical treatment for localized prostate cancer, but a new dawn is emerging. Novel minimally invasive modalities are now available, and include both minimally invasive prostatectomy as well as newer energy sources such as high-intensity focused ultrasound. This review summarizes these newer technologies, in terms of technique, as well as both oncological and functional outcomes to date. The ultimate goal of such novel minimally invasive modalities is to continue to improve on the functional outcomes without compromise to the oncological results of the gold standard.     

Minimally invasive surgery in prostate cancer: current and future perspectives

Prostate cancer is a leading cause of death for men. Its prevalence increases substantially with advancing age, which coincides with increased incidence of comorbidities. The mainstay therapy for early prostate cancer remains radical surgery and radiotherapy. In the era of prostate-specific antigen and the newly emerging highly specific screening tests, more men are diagnosed earlier in their life and with confined disease. The application of minimally invasive approaches, such as the laparoscopic/telerobotic approach and focal treatments, is becoming more popular, yielding shorter hospital stays and faster recovery, with minimal complications. In part, this is possible due to groundbreaking advances in laparoscopic equipment, prostate imaging modalities, and gained urologic expertise in minimally invasive treatment. In this review we critically discuss the current knowledge and future perspectives of minimally invasive treatment in prostate cancer.     

Controversy over treatment options in clinical T3 prostate cancer

Clinical stage T3 prostate cancer is a locally advanced disease at risk of having micrometastasis.Since clinical T staging is potentially inaccurate, PSA and Gleason score are also added at biopsy for risk stratification. The recurrence rate after radical prostatectomy alone or radiotherapy alone is generally high. Therefore, multimodal treatment is required. Recent multiple randomized trials have shown survival benefits of radiotherapy combined with long-term hormonal therapy. Dose escalation utilizing intensity modulated radiotherapy (IMRT) or brachytherapy has the potential benefit of exerting local control. Since previous trials used conventional external radiotherapy, the optimal duration of hormonal therapy combined with dose escalated radiotherapy remains unknown. On the other hand, some patients can be cured by radical prostatectomy alone, and approximately half of patients with adverse features after surgery can be rescued by adjuvant radiotherapy. Primary hormonal therapy is used widely and has shown favorable results in patients with T3 prostate cancer, particularly in Japan. Based on the life expectancy and comorbidity of an individual patient, hormonal therapy can be chosen as a primary treatment. There are controversies over treatment options such as surgery, radiotherapy, and hormonal therapy in clinical T3 prostate cancer. The clinical results of these treatments are reviewed and several unresolved issues are addressed here.     

Curiethérapie de la prostate : évolutions des indications et des techniques

Prostate brachytherapy has been for a long time one of the standard treatments for low risk prostate cancer, with high rates of biochemical control and low levels of urinary and sexual late toxicity compared to other available techniques, namely external beam radiotherapy and radical prostatectomy. The aim of this article is to review the recent innovations of prostate brachytherapy, which suggest a bright future for the technique. We will discuss the extension of indications of permanent implant brachytherapy to favorable intermediate-risk patients, the use of novel isotopes such as Palladium 103 and Cesium 131, and the benefit of brachytherapy as a boost following external beam radiotherapy for intermediate and high-risk patients. We will also discuss the rise of high dose rate brachytherapy, as a boost or monotherapy, the increasing use of MRI for patient selection and treatment planning, as well as the development of brachytherapy as a means of focal therapy.     

Total neoadjuvant therapy for rectal cancer

While outcomes for patients with locally advanced disease have improved considerably with combined modality therapy, there is now an emphasis on developing risk-adapted treatment strategies. Moreover, the primary cause of death from locally advanced rectal cancer is related to distant progression, which now exceeds the rate of local failure. Thus, the necessity to optimally address micrometastatic disease has led to increasing interest in delivering chemotherapy in the neoadjuvant setting rather than in the postoperative setting. This review critically appraises the emerging literature on the options for sequencing of therapy, focusing on the total neoadjuvant therapy paradigm as well as emerging options for omitting components of multimodality therapy.     

Targeted focal therapy: a minimally invasive ablation technique for early prostate cancer

The morbidities associated with prostate cancer treatments have improved over the years. However, potential overtreatment and the risks of adverse events associated with radical treatment still pose a considerable challenge. Targeted focal therapy (TFT) of prostate cancer appears to be part of a logical continuum in the quest to improve upon the management of early organ-confined disease. TFT is a procedure in which only the cancer in the gland is ablated. The normal gland, sphincter, and in most cases the neurovascular bundles are preserved. Therefore, this approach averts some of the common complications of more radical therapy. Initial experience has been encouraging; however, long-term data and full implementation of emerging advances in imaging are urgently needed before the widespread adoption of this approach. In this review, we present the current status of our knowledge about this procedure and the most important challenges that need to be addressed. We also present the initial results with this approach at our center.