We currently use very small margins around the prostate gland of mm. Gold seeds fiducials Image above right : Solid gold markers, also called fiducials, are placed by the Urologists under ultrasound guidance just like the biopsies. These can be imaged with stereoscopic x-rays images, and an accurate 3-dimensional position determined instantly.
Figure Novalis Tx : The Novalis Tx linear accelerator is shown illustrating how a prostate patient would be set up for treatment. The image-guidance system is also shown the x-ray tubes located in the floor and the detectors near the ceiling and is able to automatically detect the gold seeds fiducials and correct for position and movement. Note how well the bladder and rectum can be spared with the technique of RapidArc using the Novalis Tx. Our experience shows that this is a very safe approach, and one that spares the rectum and bladder to a degree not seen with other radiotherapy techniques.
King began using SBRT for prostate cancer in and was one of the first in the world to do so. He has also been the first to publish results of his clinical program. Torre 1,2,3 , M. Grob 4 , J. Stojadinovic 1,6,7 , Y. Man 1,6,8. South Hospital of Nanjing, Nanjing, China. Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm in men in the United States and the second leading cause of cancer mortality. One in 7 men will be diagnosed with prostate cancer during their lifetime. As a result, monitoring treatment response is of vital importance.
The cornerstone of current approaches in monitoring treatment response remains the prostate-specific antigen PSA. However, with the limitations of PSA come challenges in our ability to monitor treatment success. Defining PSA response is different depending on the individual treatment rendered potentially making it difficult for those not trained in urologic oncology to understand.
Furthermore, standard treatment response criteria do not apply to prostate cancer further complicating the issue of treatment response. Historically, prostate cancer has been difficult to image and no single modality has been consistently relied upon to measure treatment response. However, with newer imaging modalities and advances in our understanding and utilization of specific biomarkers, the future for monitoring treatment response in prostate cancer looks bright.
It is estimated that , men will be diagnosed with prostate cancer in making it the most commonly diagnosed non-cutaneous neoplasm in men in the U. Between and , the median age at diagnosis of prostate cancer was 66 years. The age-adjusted incidence rate is African American men have the highest incidence of disease at The importance of treating this disease and monitoring the success of these treatments cannot be overstated with regard to the impact it has on the healthcare system. There are many effective treatment options in the definitive treatment of prostate cancer.
Prior to the PSA-era, the effectiveness of treatment was judged by a lack of clinical progression or a resolution of symptoms. With the advent of PSA in the s, monitoring of therapeutic success after completion of primary treatment for prostate cancer, while imperfect, was vastly improved over monitoring of clinical signs and symptoms as was historically solely relied upon. For all of the recent controversy surrounding PSA as a screening tool leading to sweeping changes in the recommendations for its use for the purpose of early detection, PSA remains the standard of practice in monitoring the state of disease in the post-treatment setting.
Furthermore, as imaging techniques improve, more effective monitoring of disease response on the basis of anatomical and functional indicators is becoming possible. The purpose of this manuscript is to examine the current approaches, challenges and the future of monitoring treatment responses for patients with prostate cancer.
Treatment for prostate cancer, like all cancers, is optimized according to stage of disease. While TNM staging is important, it is not well suited for deciding the best treatment for a patient with prostate cancer. The reason for this limitation is the considerable heterogeneity of prognosis within each stage category. Table 2 shows the stratification of the groups according to risk: very low risk, low risk, intermediate risk, high risk and very high risk disease. The treatment options for the risk stratified subgroups may consist of active surveillance, surgery both radical prostatectomy and robotic assisted laparoscopic prostatectomy , brachytherapy, external beam radiation therapy photon IMRT, protons, cyberknife etc.
The treatment decision depends on the patient's risk group assigned at diagnosis, the patient's projected survival and the patient-specific preferences. Department of Health and Human Services, were designed to provide an accessible mechanism for obtaining objective, detailed information on clinical practice guidelines for the treatment of prostate cancer and to further their dissemination, implementation and clinical use [ 3 ].
Both the American Urological Society and the European Association of Urology EUA offer detailed guidelines for the diagnosis and treatment of men with prostate cancer [ 5 , 6 ]. Table 3 lists standard treatment options based on tumor stage recommended by all mentioned guidelines. A repeat prostate biopsy should also be performed at least as often as every 12 months. The main goal of treatment in a patient with low-risk disease is cure. The main goal of treatment for a patient diagnosed with intermediate-risk prostate cancer is cure. There is debate about the preferred management of this disease as few randomized trials have compared effectiveness between primary treatments.
Treatment choice may also be influenced by the functional impact of treatment including potential loss of erectile dysfunction, urinary incontinence or other side effects from treatments, which have been documented in the literature [ 7 ]. The main goal of treatment in a patient diagnosed with high-risk prostate cancer is cure. Radiation therapy given in combination with androgen deprivation for years has shown to significantly improve disease-free survival [ 8 - 10 ]. Radical prostatectomy plus pelvic lymph node dissection may be considered in highly selected patients with low-volume disease without fixation to the pelvic musculature or skeleton [ 2 ].
The use of systemic chemotherapy in combination with radiation therapy and androgen suppression is under investigation, but currently plays no role in locally advanced high-risk prostate cancer. If a patient is not a good surgical candidate or if he is not a good candidate for radiation therapy including inflammatory bowel disease or prior radiation therapy , isolated androgen deprivation therapy may be used.
Very high risk disease is defined as clinical stage T3b to T4 locally advanced disease. The treatment options for patients with very high-risk disease are the same as those for patients with high-risk disease, noted above.
Tumor Response Monitoring and Treatment Planning | SpringerLink
The main goal of the treatment for metastatic prostate cancer is palliation of symptoms. The primary treatment of choice for metastatic prostate cancer is androgen deprivation with an LHRH agonist or antagonist. Patients will usually receive a nonsteroidal anti-androgen e. It has been shown that the addition of a first-generation bisphosphonate improves overall survival in men with metastatic prostate cancer [ 12 ]. It is also recommended that an intravenous bisphosphonate e.
A randomized trial showed that toremifene, a selective estrogen receptor modulator, significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for metastatic prostate cancer [ 14 ]. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.
A newer agent, Denosumab Xgeva which is a human monoclonal antibody that inhibits RANK ligand, has been found to be superior to the bisphosphonate zoledronic acid in preventing skeletal-related events in patients with advanced prostate cancer and bone metastases [ 15 ]. Systemic chemotherapy should be reserved for castrate-resistant metastatic disease.
Docetaxel chemotherapy is the current standard of care for metastatic castrate-resistant prostate cancer [ 16 , 17 ]. In patients with metastatic castrate-resistant prostate cancer experiencing progression after initial chemotherapy with a docetaxel-based regimen, oral satraplatin has been shown to delay progression of disease as well as disease-related pain [ 18 ].
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Alternative regimens for disease nonresponsive to preferred chemotherapy include abiraterone, mitoxantrone or carbazitaxel [ 2 ]. Sipuleucel -T is recommended for asymptomatic or minimally symptomatic patients with castrate-resistant metastatic disease and an ECOG performance status of External beam radiation therapy in palliative doses can be given to sites of painful bony metastases.
Radiation may include a single fraction or a more protracted 1- or 2- week course depending on normal tissue toxicity and patient convenience. Systemic radiation therapy e. Recently Radium has been FDA-approved for use in the treatment of metastatic castrate-resistant prostate cancer. It is a calcium mimetic that localizes to bone and delivers radiation directly to bone metastases by emitting an alpha particle. It has shown efficacy at both preventing skeletal-related events and prolonging overall survival [ 21 ]. Cryotherapy is a technique whereby, under ultrasound guidance, special metal rods are inserted through the perineum into the prostate.
Highly purified argon gas is used to cool the tips of the rods and freeze the surrounding tissue, thereby killing the prostate cancer. A catheter filled with warm saline prevents the urethra from freezing during cryotherapy. The method has been studied as a salvage therapy after primary treatment failure [ 22 ], but also is now being studied in the primary treatment of organ-confined prostate cancer [ 23 ]. The poor quality of available studies makes it difficult to determine the relative benefits of this modality.
Randomized trials are needed to fully evaluate the potential of cryotherapy in patients with prostate cancer [ 24 ]. In HIFU therapy, high-intensity ultrasound beams are precisely focused on diseased tissue, raising the temperature within the target tissue to between 65 o C and 85 o C, destroying the diseased tissue by coagulation necrosis. This treatment is currently being studied in the United States. There have been a number of studies in Asia showing a potential benefit to HIFU in localized prostate cancer, but this is not currently an accepted standard of practice [ 25 - 28 ]. Focal treatment in prostate cancer has been shown to be a potential treatment of recurrent disease [ 29 - 31 ].
Definitive focal therapy is an emerging treatment modality for localized prostate cancer that aims to reduce the morbidity seen with radical therapy, while maintaining cancer control. Focal therapy treatment strategies attempt to minimize damage to normal tissue, especially anatomic structures that are important functional determinants: the neurovascular bundles, external sphincter, bladder neck and rectum. There are a number of ablative technologies that can deliver energy to destroy cancer cells as part of a focal therapy strategy.
The most widely investigated are cryotherapy and high-intensity focused ultrasound, as mentioned above [ 30 , 31 ]. Existing radical therapies, such as brachytherapy and external beam radiotherapy, also have the potential to be applied in a focal manner [ 29 ]. The Index Study was proposed this year and represents the first prospective multicenter trial to evaluate the outcomes of a tissue preserving strategy for localized prostate cancer [ 33 ].
It is important to monitor patients after definitive treatment for prostate cancer in order to identify locally recurrent disease at a point where further curative treatments may be employed. Equally important is the need to identify and treat complications of the initial therapy. The cornerstone of follow-up in monitoring for treatment response after definitive treatment for prostate cancer is the PSA. It has also been shown that a serum PSA recurrence nearly always precedes a clinical recurrence [ 35 ]. Therefore, the current standard for monitoring includes serum PSA every 6 to 12 months for the first five years of post-treatment surveillance and then annually after that [ 2 , 6 ].
PSA testing every three months may be recommended for men at high risk of recurrence. Because, on rare occasions, a local recurrence may occur in the absence of an elevated PSA, digital rectal examinations should be done annually [ 2 , 6 ]. Any new nodule felt on physical exam should raise suspicion of recurrent disease. Prostate cancer is unique among cancers in that it usually has no associated symptoms and is rarely measured radiographically. The use of PSA to monitor treatment response, although not perfect, has for years been the gold standard by which various curative approaches are compared.
Tumour Response Monitoring and Treatment Planning : Advanced Radiation Therapy
Transrectal Ultrasound TRUS and biopsy are not a part of the recommended routine monitoring after treatment for prostate cancer. A bone scan is not routinely used in monitoring treatment response in asymptomatic patients. It is, however used to further evaluate a rising serum PSA in the absence of symptoms or to evaluate new symptoms in the presence or absence of a detectable PSA.
Furthermore computed tomography CT and magnetic resonance imaging MRI currently have no well-defined role in monitoring for routine treatment response after definitive treatment in the absence of symptoms or a detectable PSA. Multiparametric prostate MRI is, however gaining increased acceptance for the assessment of response to treatment and will be discussed later in this manuscript. A CT scan may be used as a secondary staging study to further evaluate for potential salvage treatments after a diagnosis of recurrence has been made.
Current approaches and challenges, in addition to the potential future directions, for monitoring treatment responses will differ slightly depending on which specific therapeutic modality was used in the initial phase of treatment of the disease and will be looked at separately. Objective response criteria in oncology are important as they represent the standard by which the efficacy of therapeutic agents is determined in cancer trials.
Measuring response to treatment of prostate cancer can be both subjective and objective. The subjective relief of pain, neurologic deficits or obstructive symptoms can be more important to the patient than an objective response to treatment however, measuring an objective tumor response is important when measuring and comparing effectiveness of treatments.
Since those criteria were published, the quality and diagnostic accuracy of imaging modalities have improved tremendously and have been replaced with more up-to-date response criteria. However, none of them, even today, apply to prostate cancer, as they remain inefficient.
These criteria focus predominantly on the physical measurement of solid tumors. In the RECIST criteria, bone metastases are considered too difficult to measure objectively and are designated as unmeasurable [ 39 ]. Therefore the majority of bone metastases from prostate cancer are still considered unmeasurable according to these updated criteria and their response to treatment cannot be measured quantitatively.
Other criteria have been developed that consider the difficulty in evaluating bone metastases objectively. In one study retrospectively comparing the MDA criteria with the WHO criteria, the MDA criteria were shown to better differentiate responders from nonresponders [ 42 ]. A recently published prospective comparison showed that both the WHO criteria and MDA criteria predicted progression free survival PFS at six months based on the binary classification of progressive disease or non-progressive disease, but these rates, as well as overall survival did not differ at 3 months [ 43 ].
Taking advantage of the functional measurement of FDG-PET and the increased glucose metabolism in most solid tumors, an effort was made to publish updated objective response criteria aimed at standardizing with increasing accuracy functional response of metastatic lesions to treatment [ 44 ]. In one publication, patients enrolled on institutional review board-approved trials were assessed [ 45 ]. More significant was the fact that there were no target lesions defined in patients with a rising PSA and localized disease.
Another challenge in the application of the RECIST criteria to prostate cancer patients is that the presence or absence of symptoms is not considered an eligibility criterion [ 41 ]. While overall survival is usually the desired endpoint in most studies, the palliation of pain [ 46 ] and the reduction in the risk of skeletal metastases [ 47 ] have also been used to measure the success of treatment regimens in prostate cancer.
With the increased number of treatment options for prostate cancer, both localized and castrate-resistant disease, one must be able to measure success of treatment according to the treatment objective for the individual agent and in the individual patient to whom it is offered. A recent cohort study published in showed, at a median follow-up of 6. At 10 years, the disease-specific survival was The biggest challenge in monitoring patients under active surveillance is, knowing when to make the decision to offer definitive treatment, and when to continue surveillance.
Generally there are three reasons that a person will proceed with treatment: 1 Gleason score progression, 2 a rapidly rising PSA increasing PSA velocity or 3 patient anxiety. PSA doubling time was not significantly associated with subsequent adverse biopsy findings and PSA velocity was only marginally significant suggesting that PSA kinetics do not reliably predict disease biology [ 49 ].
Furthermore, a potential challenge in monitoring during active surveillance is a rising PSA in the presence of a consistently negative biopsy. It has more recently been suggested that the psychosocial aspect or burden of living with prostate cancer plays a substantial role in adherence to active surveillance and outcomes of men with the disease [ 52 ].
Effective clinician education and counseling as well as early referral to supplemental support services should be implemented to alleviate these fears that may precipitate unnecessary treatment. Another challenge of active surveillance may be the discordance between a rising PSA and a continued negative biopsy. Caution also needs to be taken when using guidelines for surveillance. It was shown recently that these criteria should not be used when counseling men in the United Kingdom with regard to active surveillance [ 53 ]. Seven hundred consecutive men treated for prostate cancer from by robot-assisted laparoscopic prostatectomy RALP were included.
In all, patients Several surgical options are available for removal of the prostate gland. Whether an open retropubic radical prostatectomy, a DaVinci robotic prostatectomy or robot-assisted laparoscopic prostatectomy , or radical perineal prostatectomy is performed, the goal is the complete removal of the prostate gland and all cancerous cells. Pathologic analysis of prostatectomy specimens is the first tool used to measure surgical outcome and plays an important role in predicting 'biochemical-free survival'. Adverse prognostic indicators such as high Gleason scores, positive surgical margins, extracapsular extension, and seminal vesicle involvement are independent risk factors for recurrent disease and are the standard measures used to determine outcome and the need for adjuvant or salvage therapy [ 34 , 54 - 59 ].
Three randomized trials to include SWOG , EORTC , and ARO have documented significant improvements in biochemical recurrence-free survival when adjuvant radiotherapy following prostatectomy was compared with prostatectomy alone [ 60 - 63 ]. Gleason score is another pathologic measure used following surgery. A Gleason score of 8 or greater has been associated with a higher incidence of biochemical relapse and reduced prostate cancer specific survival [ 34 ]. This is not a surprise as high risk Gleason scores are one of the strongest indicators of metastatic disease.
Micro-metastatic disease in this setting is considered to be the primary reason for a rising PSA. Some controversy exists regarding the value of lymphovascular invasion LVI in assessing radical prostatectomy specimens, but most recent studies have found LVI to be important.
Clear evidence of tumor in endothelial spaces was required to designate a tumor specimen as having lymphovascular invasion LVI. LVI was shown to correlate with other well-established predictors of biochemical relapse such as Gleason score, extracapsular extension and nodal involvement. In multi-variate analysis, the presence of LVI was minimally helpful; the authors suspected that follow-up was too short for an additional variable to contribute much to accuracy of estimating prognosis over that provided by standard pathologic features [ 64 ].
LVI was associated with extracapsular extension beyond the prostate, seminal vesicle involvement and positive surgical margins. On univariate analysis, LVI significantly correlated with biochemical relapse but was not found to be an independent prognostic factor for biochemical relapse on multivariate analysis.
LVI was, however, associated with both metastases and death. These same researchers found that while peri-neural involvement was also associated with other worrisome pathological features, it was not independently prognostic for metastases or death [ 65 ]. Unlike most other studies, however, LVI was also associated with biochemical relapse on multi-variate analysis [ 66 ]. Older studies did not show LVI to be an independent predictor of relapse, but in , the Association of Directors of Anatomic and Surgical Pathology finally changed their recommendations to include reporting of LVI.
Prior to that, LVI reporting was considered optional [ 67 ]. The presence of lymph node metastases at the time of radical prostatectomy has long been regarded as a poor prognostic sign. Early in the PSA era and prior to the PSA era, if a positive lymph node was identified at the beginning of a radical prostatectomy, the prostatectomy was often aborted. The disease was then treated without curative intent.
The incidence of positive nodes has certainly declined in the PSA era. Some centers such as the Mayo clinic however, have taken an aggressive treatment approach to lymph node positive disease. Cheng et al were among the first to demonstrate that radical prostatectomy including bilateral pelvic lymphadenectomy plus orchiectomy was superior to orchiectomy alone.
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The early reports were not randomized trials and the level of evidence did not meet today's standards to broadly impact clinical practice [ 68 ]. Messing et al reported a prospective trial on behalf of the Eastern Cooperative Oncology Group that immediate androgen deprivation was superior to a delayed approach in node positive patients [ 69 ]. The initial study was criticized for lack of centralized review among other issues but the results were confirmed with follow-up analysis [ 70 ]. Despite these studies, there is no definite consensus on what is the best approach for lymph node positive disease.
In addition to pathologic review, serum PSA is obtained to measure surgical outcome. If the PSA rises slowly or if the rise occurs after being undetectable for two or more years then this predicts a local only recurrence within the prostatic bed [ 34 , 73 ]. Numerous retrospective studies have shown the benefits of salvage radiation therapy once biochemical recurrence after prostatectomy is present [ 74 ]. Defining the optimal PSA level to be used as the threshold for initiation of the therapy is much more complicated.
There exists controversy over when a biochemical failure represents clinically significant disease that requires salvage treatments and if earlier therapy provides superior outcomes. King from UCLA performed a systematic review of over 60 published salvage radiation therapy studies of which 41 met the selection criteria looking at biochemical relapse as related to the PSA level at the start of radiation. He found that relapse free survival was compromised on an average 2. The range of PSA was 0. When he extrapolated, he found that when radiation was initiated with a PSA level of 0.
Stephenson et al. One study has shown a somewhat surprising association between PSA doubling time after radical prostatectomy and response to salvage irradiation. The implication is that men with longer doubling times may have biologically less aggressive disease [ 77 ]. A recent study by Karlin et al. Outcome measures after prostatectomy are multi-factorial and should include pathologic features, PSA parameters such as supersensitive PSA and PSA kinetics, and need to be considered collectively when used to predict for biochemical recurrence.
These measures can help determine those candidates that are more likely to benefit from adjuvant or salvage therapies as well as help determine the best time to initiate the therapy in order to maximize patient outcomes. There are many challenges of monitoring treatment response in prostate cancer, mainly which center around the use of PSA as the marker of disease.
Whether prostate cancer is treated with surgery, radiation or other forms of therapy, PSA is really the only current tool that is readily available, standardized, and utilized in the community setting. All prostate cells produce PSA; however, not all prostate cancer cells produce PSA in a direct correlation with tumor volume.
Poorly differentiated tumors may lack the expression of PSA; therefore it may not measure accurately the burden of disease [ 79 ]. Another problem with PSA as a leading indicator of disease is that the presence of PSA does not reveal the location of disease. Distinguishing between locally persistent disease vs. Often patients are given the benefit of the doubt and offered salvage treatment with the hopes that the observed PSA elevation represents local disease. The practitioners are faced with trying to incorporate multiple variables such as pathologic factors, PSA kinetics, and patient factors including age, co-morbidities, and expected longevity.
Although PSA can potentially detect the presence of cancer cells, it can also detect the presence of normal prostate cells. Detectable PSA after radical prostatectomy is universally felt to be due to residual or recurrent prostate cancer. There is a small possibility that detectable but very low and stable PSA, may be due to retained benign tissue. To date, there are no published reports that conclusively demonstrate a higher rate of PSA recurrence to be associated with specimens with benign glands at the margin.
Godoy et al wrote that in a properly performed radical prostatectomy, measurable PSA attributed to retained benign prostatic tissue should be an extraordinarily rare event [ 81 ]. Other normal tissue cells may also produce PSA. PSA immunoreactivity has been found in some non-prostatic tissues in small amounts such as parotid gland, apocrine glands of the skin, bladder, ovary, pancreatic tissues and breast [ 82 - 85 ].
In fact, efforts have been made to investigate PSA utilization as a marker of breast cancer but with little success [ 85 ]. Diagnostic dilemmas have been reported in the setting of treated prostate cancer and the development of a parotid oncocytoma. Contribution to serum PSA from any other source other than prostate tissues should be an extremely rare event, but as PSA assays become more sensitive, it is prudent to keep in mind that PSA is not only produced by prostatic tissues [ 83 ].
One disadvantage with radiotherapy as definitive management of prostate cancer is the lack of pathologic analysis. Pathology is a strong tool used to help predict which patients may need additional interventions and when salvage treatments should be administered. Current post-radiation therapy outcome measures lack pathologic analysis and must rely only on PSA response as a biochemical predictor of prostate cancer death.
An increase in oxygen availability may favor oxygenation of hypoxic cells 7. The effect appears to be preferentially in diffusion-limited, chronic hypoxia 13 , Whether the radiosensitizing effect outlasts the time frame of increased perfusion remains so far unclear. Other studies could not reproduce this result As hypoxia is a central causative factor for radioresistance, a decrease in hypoxia by HT may be responsible for the observed radiosensitization.
Hyperthermia has been shown to confer cell death by apoptosis or mitotic catastrophe 18 , It has been reported that HT triggers unfolding of especially heat-labile non-histone nuclear proteins leading to aggregation, due to exposition of hydrophobic groups, with surrounding proteins and subsequent association with the nuclear matrix. As consequence, basic nuclear matrix-dependent functions such as transcription, replication, or DNA repair are impaired 20 , Malfunction of DNA replication finally causes chromosome aberrations, genome instability, and cell death by mitotic catastrophe Apoptosis may be mediated by cell death membrane receptor activation and subsequent caspase 3 activation The extent of apoptosis appears to differ among different tumor types Both mechanisms may further enhance protein instability and apoptosis 25 — As mentioned above, there is sufficient evidence showing inhibition of DNA repair mechanisms upon HT.
Krawczyk et al. Further on, HT impairs the function of the Ku heterodimer by reducing its DNA-binding capacity and preventing the initiation of non-homologous end joining at DNA double-strand breaks sites In addition, base excision after cell radiation has been shown to be reduced upon heat administration In summary, HT acts on multiple levels including excision repair, non-homologous end joining, and homologous recombination influencing the repair of DNA lesions as well as single-strand and double-strand breaks 29 — A more detailed review was recently published discussing existing evidence Besides direct effects on cell metabolism, HT appears to trigger multiple immune responses on local and systemic levels.
Toraya-Brown and Fiering published a thorough review covering this aspect After binding intracellular proteins, HSPs get secreted stimulating the activity of NK cell- and antigen-presenting dendritic cells 36 , Tumor antigens are also provided by increased release of exosomes In addition, immune cell trafficking is enhanced by increased perfusion and permeability Following elevated intratumoral IL-6 signaling, it may further be facilitated by increased cell adhesion molecule expression such as ICAM-I Heating techniques can be divided by the size, penetration depth, and region of energy deposition.
Alternatively, hyperthermic isolated limb perfusion to administer CT agents is performed. Whole-body hyperthermia WBHT has been applied either alone or in combination with CT for the treatment of metastatic disease. Different approaches including capacitive, radiative, infrared-A, or ultrasound have been used for clinical HT treatments The clinically most relevant methods are described in the following. Capacitive heating systems work with two electrodes positioned on both sites of the body with direct body contact using a water bolus. Heat is induced by the resulting currents and is directed toward the smallest electrode On the contrary, in obese patients, therapy-limiting local hot spots can occur causing painful subcutaneous burns Radiative heating systems work with frequencies ranging from 75 to MHz spectrum of radiowaves and microwaves and use a water bolus for electromagnetic coupling.
Compared to capacitive heating, radiative systems appear to yield better power disposition and temperature distribution leading to better target coverage The applicable temperature is sometimes limited due to local temperature hot spots. The accuracy of such systems depends on construction details such as the number, positioning and design of antennas or properties of the water bolus In recent years, increasingly complex systems have been introduced comprising multiple antennas such as the commercially available Sigma applicators, build in a circular arrangement, or the AMC-8 phased array HT system 50 , Site-specific systems such as the HYPERcollar3D system, which was developed for the treatment of carcinomas of the head and neck, take into account local characteristics of target areas to optimize temperature coverage Alternatively, antennas can be interstitially implanted or used for endocavitary HT in direct approximation to tumors In order to perform superficial or interstitial HT, heating systems are used applying higher frequencies such as MHz Walter-filtered infrared-A-based systems have successfully been used for the treatment of superficial tumors 54 , Infrared-A radiation is generated by a halogen lamp, passing through a water filter.
The range of therapeutically relevant temperatures is limited to a depth of 15—20 mm [with good therapeutic temperature coverage 56 ]. Due to the technical setup a very short interval between HT and RT combined with heat isolation procedures enables quasi-simultaneous RTHT, optimizing the synergistic effect see below. Pretherapeutic hyperthermia treatment planning can be used to optimize tumor temperatures. It uses dielectric models created on the basis of segmented CT or MRI data assigning literature-based dielectric properties to distinct tissue types. So, the specific absorption rate SAR of the respective tissue can be calculated and used for a finite element-based prediction of temperature distributions.
In clinical studies, calculated SAR values correlated well with measured SAR values, relative temperature increase and clinical data regarding hot spots in patients with pelvic tumors 57 — However, in the clinical setting, temperatures above While trying to reach targeted temperatures, therapy-limiting hotspots occurred causing substantial side effects. In these cases, this led to a reduction of target temperatures or early termination of HT 60 , This was regarded as failure of delivering adequate thermal doses, which lead to a rapid decline in HT-usage in the mid-to-late s.
It took several more years until the beneficial effects of mild HT Nowadays, mild HT has become the standard in modern clinical trials and daily clinical usage 5.
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Modern HT technology has been developed and optimized for minimal hot spot occurrence as a main focus 51 , As a consequence, therapy-limitation due to focal hot spots has not been an issue in many recent HT trials 62 — As important as heat generation, measurement of the actual tissue temperature distribution is crucial for effective heating of tumors. A homogenous temperature distribution is necessary for optimal treatment effects. Local dose-limiting hotspots have to be avoided. Originally, temperature assessment was restricted to single-point measurements.
It can be performed either invasively by insertion of intratumoral catheters or, as applicable in tumors with close proximity to natural cavities such as rectal, cervical, vaginal, urethral or vesical tumors, equally efficient by endoluminal catheters.
Insertion of catheters inherits the risk of complications such as pain, inflammation, or abscess formation Thus, the latter option should be used if possible.
In superficial tumors, surface skin measurements by contact electrodes constitute a further alternative. In addition, by using infrared thermography cameras, two-dimensional data can be obtained for superficial tumors even though calibration with contact electrodes is necessary for absolute temperature assessment A promising method for deep temperature monitoring is MRI-guided thermometry capable of measuring three-dimensional temperature distributions non-invasively. Temperature can be measured by exploiting either T1w-imaging, diffusion weighted imaging or proton resonance frequency shift-imaging Proton resonance frequency shift-imaging appears to be the most accurate method in the clinical setting.
By combining HT with online MRI thermometry, direct changes of temperature delivery can be performed to optimize temperature distribution and suppress hot spots To this end, an adaptive iterative algorithm has been developed First studies have confirmed its applicability in the clinical setting In general, a dose—effect relationship of HT has been shown The interval of administration of HT relative to RT has great influence on its effectiveness.
However, biological aspects of HT react differently to the extent of heating sequence of HT. In the clinical setting, the maximal achievable TER should be combined with the most limited TER for healthy tissue to retain a tumor-specific effect reducing toxicity. However, inhibition of DNA repair mechanisms is not tumor specific since it is also present in normal tissues 71 , In contrast, direct cell killing is specific to malignant tissue at target temperatures. The respective TER is estimated at 1. To summarize, optimal effects can be achieved by simultaneous RTHT treatment with no tumor-directed specificity.
Treatment selectiveness would completely depend on accuracy of radiation delivery. In the time frame of 1—4 h before or after radiation, a maximal selective TER can be achieved by adding up DNA repair inhibition and direct cell damage. For optimization of the oxygenation-effect, RT should be applied shortly after HT When considering time schedules and fractionation schemes, one should also take into account two phenomena termed cellular and vascular thermotolerance.
The underlying mechanisms remain incompletely understood 74 — For this reason, detailed description of these phenomena is not performed in the context of this review. Most probably, thermotolerance in currently used clinical HT schedules i. In the following, key studies providing evidence for a clinical benefit of a combined treatment with HT and RT is presented, sorted by tumor entity and the extent of existing evidence see Tables 1 — 3 for a detailed overview.
In the following paragraph, existing clinical evidence of combined HT with CT is summarized see Table 4. Table 1. Summary of cited meta-analyses and randomized trials for breast cancer and cervical cancer. Table 2. Summary of cited meta-analyses and randomized trials for head and neck cancer and rectal cancer. Table 3. Breast cancer constitutes the most widely investigated malignant entity.
Vernon et al. The effect was most prominent in preirradiated recurrent lesions. Skin toxicities such as blisters, ulceration, and necrosis were higher in the HT group, however with low impact on the patients well-being and generally treatable with conservative measures In cases of locoregional recurrence, breast surgery is recommended if possible. Thus, RT constitutes a significant alternative, and depending on the time interval between first and second RT and other pretreatment characteristics offers substantial clinical benefit.
Since nowadays most patients receive RT in the primary situation, HT may help to enhance the effects of reirradiation in the recurrence scenario, especially since in some clinical situations only reduced radiation doses may be prescribed. A recent meta-analysis by Datta et al. CR was similar between one-arm studies CR: In preirradiated patients patients , a CR of Among the analyzed studies, there was great heterogeneity in RT dose, HT fraction schedules, total number of HT fractions, HT duration, or average achieved temperatures.
However, no prognostic treatment variables could be identified in a subgroup analysis and meta-regression. Similar results were recently published by Linthorst et al. Notter et al. In summary, there is sustained evidence demonstrating a value of adjunct HT in locoregional, recurrent breast cancer as definitive or adjuvant treatment. Several randomized trials have been conducted to test HT in combination with RT. A Cochrane database meta-analysis was performed analyzing six trials involving a total of patients No difference was found regarding acute and late toxicity rates.
Therefore, the authors conclude that the results do not suffice for a definitive recommendation to apply HT along standard treatment regimen. All studies have in common that concurrent CT was not included in the treatment regimen. A recently published meta-analysis has revised all relevant publications including 23 articles with a total patient number of 1, All studies, but one, included patients with locally advanced disease.
The same six trials with minor updates were included. In coherence, a recent randomized phase III trial, which was closed early due to poor accrual with only 87 of planned patients, did not show any significant difference in event-free survival and pelvic recurrence-free survival between RTHT and RTCT By combining all three modalities, the best treatment effect may be possible.
To evaluate the effect of HT in head and neck carcinomas, a meta-analysis was recently performed including six 2-armed studies encompassing patients. Five of the six studies were randomized trials. One study included exclusively nasopharyngeal carcinomas, whereas all other studies considered all cancer sites of the head and neck.
However, all studies involving surgery or concurrent CT were excluded. Three other randomized trials with a total of patients recently analyzed the effects of trimodal treatment combing RT, CT, and HT in patients with nasopharyngeal carcinomas 88 — The same patients had an increased OS in two of the studies.
Patients with higher tumor temperatures and higher HT fraction numbers showed a better outcome In all three studies, no difference in treatment-related toxicity has been described. Patients receiving HT showed even better quality of life scores after completion of therapy These studies demonstrate that trimodal therapy including RT, CT with different agents, and HT constitute an effective and safe treatment alternative.
To our knowledge, no other randomized studies have been published in other head and neck sites investigating trimodal therapy. As shown in other malignancies, re-treatment may constitute a further clinical situation in which HT may be a valuable treatment option. To conclude, HT constitutes a valuable treatment option in cancers of the head and neck. However, due to relatively high perfusion rates and fast adaptation to local temperature changes, HT delivery appears to be especially challenging. By using a site-tailored radiative heating device, treatment outcomes may be better in the future HT could be used in multimodal treatment schemes further improving treatment outcome.
Alternatively, it may constitute a toxicity-sparing alternative for concurrent CT in elderly or multimorbid patients. Further clinical studies are necessary to evaluate the true clinical value. In , a Cochrane analysis of six phase II and III randomized-controlled trials including patients with locally advanced rectal carcinomas was performed.
Patients received neoadjuvant RT with or without HT. Increased CR RR 2. The survival benefit, however, could not be measured for any later time point. No difference in acute toxicity was found in the two studies reporting on this side effect A positive impact on pathologic complete response pCR could as well be shown in a retrospective study of patients.
Sphincter-sparing surgery was higher for tumors in close proximity to the anal verge In a further retrospective study encompassing patients, HT appeared to confer better downstaging of the primary tumor and involved lymph nodes Additional HT appears to be well tolerated without increased impairment of quality of life To conclude, the Cochrane analysis demonstrated a fundamental possibility of increased response by applying adjunct HT. However, further randomized prospective trials are necessary to evaluate the true value of neoadjuvant RTHTCT as well as of treatment of recurrent disease.
For the treatment of bladder carcinomas, HT has been predominantly applied in combination with intravesical CT. However, a few trials have evaluated RTHT. In an early study, 56 patients with bladder carcinomas were treated with intravesical CT bleomycin simultaneously to RTHT with reduced total dose 40 Gy or RT alone with higher dose prescription 50—70 Gy.
HT was delivered by intravesical infusion of warmed saline solution containing bleomycin. The high temperature cohort showed significantly better downstaging compared to both other groups indicating the importance of adequate temperature delivery The Dutch deep HT trial also included bladder carcinomas besides cervical and rectal carcinomas.
However at 3y, LC and OS were not significantly different. There was no difference in toxicity Taken together, some studies exist demonstrating a clinical benefit for adjunct HT with no additional toxicity. However, the patient cohorts in the different studies appeared to be quite heterogeneous by mixing locally restricted and advanced tumors. The treatment regimens used differed among studies impairing adequate comparisons. Randomized studies are necessary with clearly defined risk profiles and adequate direct comparisons with guideline-based treatment regiments.
One multicentric randomized trial analyzed the benefit of adjunct HT in melanomas treated with RT. There was no significant difference in toxicity. As these results are very promising, more randomized trials would help to establish a distinct role for RTHT in the treatment of melanomas, for example in combination with less hypofractionated treatment schemes. No significant difference of OS, local response, or treatment-related toxicity could be observed. However, with a significantly higher 1y-PFS, a certain benefit was apparent In a small case—control study encompassing 13 patients with direct bone invasion treated with RTHT 60—70 Gy showed a possibly high efficacy in LC and survival under this unfavorable condition Median doses used initially and for reirradiation were 70 and 50 Gy, respectively.
All three studies employed radiofrequency capacitive heating systems. More studies are necessary to explore potential areas of application. Toxicity was limited to grades 2 and 3, respectively. Quality of life was not significantly changed by addition of HT to RT treatment A HT-dependent burn occurred in one patient indicating critical temperature delivery , Hurwitz et al. Currently, a phase II study examines the safety of combining HT and dose-escalated external salvage RT for recurrent prostate cancer Another study is examining salvage BT combined with interstitial HT In a retrospective analysis of patients, no significant difference was found between patients receiving HT or not.
The authors discussed that this might be due to insufficient heat delivery, since a significant difference was apparent for patients receiving a high thermal dose To summarize, a set of phase II studies show promising results. However, randomized phase III trials are necessary to evaluate the actual value of adjuvant HT in the treatment of prostate carcinomas.
In , Sneed et al. After patient exclusions, 68 patients were randomized to BT with or without HT HT was administered 30 min before and after a BT boost via placement of helical-coil microwave antennas. In recent years, efforts were made to optimize HT delivery by improving interstitial catheters or applying focused ultrasound , No data exist so far validating these new techniques or the combination with temozolomide.
Randomized trials have shown a significant benefit of HT in addition to CT However, evidence of combined RTHT in sarcoma treatment remains scarce. Toxicity was mild except one grade 4 adverse event First clinical results show general feasibility of applying RTHT to sarcoma treatment. However, randomized trials are necessary to assess whether a similar benefit exists as it has been shown for neoadjuvant HTCT. Nakajima et al. A general response rate of Described toxicities were limited to grade 2 and grade 3. R0 resection was possible in all patients with mild toxicity. Treatment was tolerated well with mild toxicity rates maximum grade 2 Apart from the described entities, in multiple trials, RTHT has been applied to rather rare RT indications with only low levels of evidence see Table 4 for a detailed summary of the cited trials.
Klaver et al. All patients demonstrated partial response or complete response as well as complete symptom relief However, two of eight preirradiated patients developed grade IV toxicities. Moreover, the influence of adjunct HT for the treatment of liver lesions has been assessed. Vaginal cancers have been chosen as target for HT in small prospective Dutch trial. Patients with vaginal carcinomas with a tumor size larger than 4 cm were treated with RTHT, whereas smaller tumors were primarily treated with RT showing no significant difference in 5y-survival In a more general approach, Jones et al.
Only tumors that appeared to be heatable on a pretest were randomized. Despite the limited amount of evidence, substantial benefits of RTHT, especially for preirradiated, locally advanced and recurrent tumors, became apparent. Since there is a lack of randomized trials, definite recommendations for treatment cannot be made. In addition, HT centers should work more closely together for the establishment of multicenter trials capable of gathering critical patient numbers.
Thermochemotherapy has been evaluated in multiple clinical trials. A limited number of phase II studies have shown feasibility of applying WBHT to CTHT treatment of various entities such as recurrent ovarian cancer, malignant pleural mesothelioma, metastatic STS, melanoma, and pretreated metastatic colorectal cancer — Up to date, no phase III trials exist.
General feasibility of local CTHT has also been shown in other entities such as refractory or recurrent non-testicular germ cell carcinomas, recurrent or persistent ovarian cancer, breast carcinoma, or peritoneal carcinomatosis in several phase II studies — As alternative to regional HT, hyperthermic isolated limb perfusion has been established for the treatment of STS and unresectable melanomas showing favorable results , In summary, the few existing randomized trials suggest substantial benefit by adding HT to CT.
More randomized trials are necessary to broaden the spectrum of CTHT. Review of the current literature has shown various retrospective and prospective trials exploring the value of adding HT to RT or RTCT regiments in multiple tumor entities.