Prostate Cancer Radiation Therapy Threatment - Literature review Example

Abstract. Prostate cancer (PC) is the third leading cause of death among men in the developed world. Usually this cancer is not seen in men younger than forty years. More than 50% of the cases reported are in men older than 75 years of age. Diagnosis of PC is generally by histology with serum prostate specific antigen (PSA) serving as the disease progression marker. Radiotherapy (RT) is perhaps the most common treatment of choice in patients with PC. However, results of treatment of PC are rather disappointing. A probable explanation for this could lie in the fact that more than 50% of PCs are seen in men 75 years of age. Mortality in such cases is attributed to be a consequence of the adverse effects of treatment rather than cancer per se. Hence, treatment is contraindicated in such cases. Compounding this problem is the imaging or scanning of tumours to their exact locations. In this context, we decided to identify the lacunae in the current management strategies of PC. For the same, a review of literature was done with the key words “Prostate cancer, bladder volume, patient compliance, organ motion, set-up error, UK” in speciality databases like the BiomedCentral (www.biomedcentral.com), Open Access Journal Database (www.openj-gate.com), PubMed (www.pubmed.gov), Science Direct (www.sciencedirect.com) apart from literature search in regular libraries. The results were scanned for relevancy to the present research interests. While a significant amount of work was done the world over in the directions mentioned in the keywords, very little information was available from England. Based on this review, we conclude that perhaps, the higher mortality observed, and attributed because of the failure of treatment on older men, may, in reality and in part, be a consequence of failure to effectively map the exact tumour locations, owing to which targeting the affected tissue may not be achievable, leading to unwarranted adverse consequences. List of Abbreviations Used. 3D-CRT: Three Dimensional Conformal Radiotherapy; CHART: Continuous hyper-fractionated Accelerated Radiotherapy; CT: Computer(d) Tomography; DVH: Dose volume histogram; EB: Empty-bladder; FACT: Functional assessment of cancer therapy; FB: Full-bladder; GTV: Gross Target Volume; GU: genitourinary; HAD: Hospital Anxiety and Depression; HDR: High dose rate; IMRT: Intensity modulated radiation therapy; IPSS: International Prostate Symptom Score; MRC: Medical Research Council; MSKCC: Memorial Sloan Kettering Cancer Centre; PC: Prostate cancer; PC: Prostate cancer; PET: Positron Emission Tomography; PSA: Prostate specific antigen; PTV: Planning target volume; PVR: post void residual urine; QOL: Quality of Life; RT: Radiotherapy; RTTP: Radiotherapy treatment planning protocols; TVP: Transurethral electro vaporization of the prostate; UK: United Kingdom; Other abbreviations carry their usual significance. Keywords. Bladder volume, Organ motion, Patient compliance, Prostate cancer, Set-up error, UK Introduction. Defined as the cancer of prostate gland, Prostate Cancer (PC) is the third most common cancer in males, with greater than 50% of the cases being documented in men older than 75 years of age. Approximately, 10000 new cases are diagnosed each year in the United Kingdom (UK). No clear aetiological agent has been identified, although mutations in the BRCA II and pTEN genes are found to be associated with PC. Frequently asymptomatic, patients may show symptoms of prostatism, nocturia, dribbling, increased frequency, with metastatic symptoms like bone pain, etc. Diagnosis of PC is generally by histology, particularly of a trans-rectal biopsy with the serum prostate-specific antigen (PSA) serving as tumor marker. Radio nucleotide bone scans, MRI, reveal metastases. Because PC affects mostly older men, management of the disease leads to a tricky situation. The elderly patients may die from complications associated with treatment of PC. Perhaps a safer option in such situations is to keep the patient under a ‘Wait and Watch’ policy (Bott et al., 2003, p580). In situations wherein, treatment is possible, the median survival following surgery is 4.5 years, following radiotherapy is approximately 10 years, while in patients with metastatic disease it is 2.5 years. Elevated levels of PSA are associated with poorer prognosis (Hall et al., 1998, p216; Gronberg, 2003, p 864; Jani & Hellman, 2003, p1045; Radiotherapy in cancer management – A practical manual, 1997, p175). With radiotherapy being given to greater than 35% of patients in UK each year (Hall et al., 1998, p 216), quality of life (QOL) becomes topmost priority. Among the numerous definitions for QOL, one definition says that QOL is an indicator of well-being ness of the patient and a monitor of the treatment outcome. In PC, QOL becomes vital for the simple reason that PC afflicts mostly elderly men wherein treatment is contraindicated. Given this situation, an accurate measurement of QOL becomes the topmost priority for the medical personnel. Where treatment is possible, radiotherapy (RT), apart from surgery, has been the treatment of choice for PC. When RT is given after surgical resection, it is referred to as ‘Adjuvant’ RT, and if performed pre-operatively, it is referred to as ‘Neo-adjuvant’ RT. Radiotherapy can be delivered as an external beam, using X-rays, -rays, etc., or as brachytherapy wherein radioactive sources are placed near the tumor to deliver a localized high dose of radiation or as radio nucleotides. In addition to this, increased usage of Continuous hyper-fractionated Accelerated Radiotherapy (CHART) and Positron Emission Tomography (PET) scanning can be seen (Hall et al., 1998, p 216; Radiotherapy in cancer management – A practical manual, 1997, p175). Irrespective of the type of RT given or adopted, because RT involves imaging, ‘motion’ of the organs, ‘status’ of bladders, ‘patient’ compliance and ‘set-up’ errors are indeed a cause for concern and hence are of utmost importance. In the present review, with an aim at identifying the lacunae in the current management strategies of PC, a literature search was done in various speciality databases like the BiomedCentral (www.biomedcentral.com), Open Access Journal Database (www.openj-gate.com), PubMed (www.pubmed.gov), Science Direct (www.sciencedirect.com) apart from literature search in regular libraries. The results were scanned forrelevancy to the keywords like organ motion, status of bladder, patient compliance, and set-up errors, UK. However, before we discuss the results of the literature search, first, a note on how QOL is assessed or measured and its clinical significance. Quality of Life (QOL). Because this is a measurement of the feelings of patients, it is best done through questionnaires and psychometric assays. For cancer patients examples of some of the psychometric assays include functional assessment of cancer therapy (FACT) scale, Hospital anxiety and Depression (HAD) scale, etc., (Hall et al., 1998, p216). Such a testing has profound clinical implications and may be an effective indicator of the success or failure of a particular therapy. Thus aiding in decision making for the medical personnel, for example, Hanlon et al., (2001, p59) found that men treated with three-dimensional conformal radiotherapy (3DCRT) enjoy QOL related to bladder function on par with the normal population. To arrive at this conclusion, Hanlon and colleagues (2001, p59) conducted two health surveys that included AVA symptom problem index and the BPH impact index. For both the surveys, 195 PC patients were included and were divided into two groups. The first group of 95 patients were treated to the prostate alone while the remaining 100 patients were treated to the whole pelvis followed by a boost to the prostate and were referred to as group II. The bowel and bladder QOL measures were in turn compared to those of the normal population of men of similar age distribution. Likewise, in a study involving 46 patients treated at Memorial Sloan Kettering Cancer Centre (MSKCC), Reinstein et al., (1998, p214), found that inverse planning utilizing intensity – modulated radiation therapy (IMRT) is a promising technique in the treatment of prostate cancer. However, Reinstein et al., (1998, p214) noted that owing to planning target volume (PTV) and bladder contours, exceptions were observed, necessitating studies on set-up errors and errors owing to organ motion and organ contour variations. More recently, Akimoto et al., (2005, p478), upon grading the severity of the acute genitourinary (GU) toxicity, concluded that urethral dose in high-dose-rate (HDR) brachytherapy should be kept low. Such a conclusion was based on Dose Volume Histogram (DVH) parameters, one among the numerous QOL assessment methods. In a perhaps first of its kind study, Do et al., (2002, p67) studied the effect of RT on urodynamics function, three months after the treatment. Based on the results, Do et al., suggest that most patients tolerate RT well, an inference that is in-line with the findings of Hanlon et al., (2001, p 59). Needless-to-day, this study was conducted on 17 patients and involved International Prostate Symptom Score (IPSS), QOL assessment index, and urinary functional enquiry. Status of Bladder. As already stated ‘status’ of bladder is a determining factor be it in imaging or in assessment of QOL. While Do et al., (2002, p67) found significant changes in bladder volume at capacity, at first sensation when supine and post void residual volume; occurrences of changes in bladder volumes and in the location of various organs during the course of treatment is well-documented (Akimoto et al., 2005, p 478; Beekman et al., 2005, p 1270; Drzymala et al., 1991, p78; Fiorino et al., 2005, p 195; Hille et al., 2005, p795; Hoogeman et al., 2005, p 3597; Jani 2003, p246; Lee et al., 2005, p625; Oozer et al., 1999, p 340; Peeters et al., 2005, p1152, Pinkawa et al., 2006a, p 841; Pinkawa et al., 2006b, p861; Roeske et al., 1995, p 1329; Sheng et al., 2005, p1286; Stam et al., 2006; Ten Haken et al., 1991, p 1324; Weber et al., 2001, p97; Zhu et al., 2005, p404). Because such changes are a common occurrence in patients with PC, exact nature and extent of change being unpredictable, Roeske et al., (1995, p1329) suggest that the uncertainties must also be taken into account when designing treatment plans and in dosage trials. However, an earlier study by Drzymala et al., (1991, p78) suggests that loss of organ positional information should not be the sole criterion for plan evaluation. Additionally, Drzymala et al., (1991, p78) advise that inclusion of DVHs can be one useful input data to estimate and compare treatment plans in specific patients. Continuing the discussion in similar lines, Fiorino et al., (2005, p195) state that a significant uncertainty creeps in due to rectal wall motion and variations in bladder volume. In their study Fiorino et al., also found variations in DVH due to variations in bladder volume. Apart from documenting these systemic uncertainties, Fiorino et al., do not recommend any remedial measures. These variations get more pronounced in Computer Tomography (CT) scans. In addition, Oozer et al., (1999, p340) mention that CT image interpretation can vary from one radiation oncologist to another. This observation has a profound significance when important differences in bladder and rectal volumes receiving different amounts of radiations are noted in two CT scans in the same patient due to a variation in bladder or rectal filling. Based on these findings, Oozer et al., suggest that to ensure good reproduction of the planned treatment, the treatment must preferably be delivered on an empty bladder and rectum. As tissue opacification is often included in CT-based treatments, viz., 3D-CRT, it would be interesting to see whether the presence or absence of contrast affects the treatment regimen. Whereas Ten Haken et al., (1991, p1324) did find indirect evidence for prostate gland movement with dosimetric consequences; no significant influence on prostate or rectal dose distribution was found by Weber et al., (2001, p97). Thus to increase reproducibility in bladder filling Jani (2003, p246) suggests asking the patient to void before treatment to ensure an empty bladder. Furthermore, usage of balloons has been reported to assist immobilization of the prostate gland (Jani, 2003, p246; Watcher et al., 2002, p100). However, it is worth mentioning at this stage that rectal balloons are not used in England. Whatever might be the case, one can infer from the above discussion that to ensure reproducibility of results of treatment in PC patients, imaging must preferably done with bladder and rectum either naturally filled or empty. In this context to ensure a better reproducible bladder filling, Stam et al., (2006) investigated the usage of bladder ultrasound scanner. The results were compared with CT. Daily bladder volume variation was evaluated using a biofeedback protocol. Whereas a strong correlation between bladder scanner volume and CT-volume was observed, the researchers found a high variation in the daily bladder volume. Basing on their results, Stam et al., conclude that while bladder scanner is an accurate and easy-to-use tool, biofeedback protocol yielded little reduction in bladder volume variations. When achieving a reproducible bladder volume itself becomes a matter of concern to achieve reproducibility of results, development of new protocols that can accomplish a pre-set target volume becomes imperative. In this context, the works of Seddon et al., (2000, p83) and Zhu et al., (2005, p404) gain prominence. Whereas Zhu et al., compared three RT treatment planning protocols (RTTP) including a novel procedure, Seddon et al., demonstrated an adequate consistency of gross target volume (GTV) as per the UK Medical Research Council (MRC) definition. Nevertheless, Seddon et al., did note clinician uncertainties in various methods of analysis. Moreover, Hille et al., (2005, p795) state that it is prudent to inform the patients about the higher risk, viz., chronic rectal toxicity and bladder complications, associated with irradiation of the entire seminal vesicles. Beekman et al., (2005, p1270) found that if the bladder post void residual urine (PVR) is less than 100mL, a better QOL is achieved in terms of resolution, catheter dependency and post brachytherapy surgical intervention. Similar observations using close volume parameters were reported by Lee et al., (2005, p625). In a pair of related studies on patient’s ability to fill the bladder, Pinkawa et al., (2006a, p841; 2006b, p861) observed i. A major impact of the patient’s ability to fill the bladder on DVH and urinary toxicity (number of patients studied = 80), and ii. Despite a significant variability in bladder filling, prostate position stability was the same with full bladder (FB) and empty bladder (EB) (number of patients studied = 30). Based on the above observations, Pinkawa et al., (2006a, p841; 2006b, p861) conclude their study by stating that in a scenario wherein the patient’s ability to fill the bladder profoundly impacts the DVH, and urinary toxicity, treatment plans with empty bladder resulted in an increased amount bladder volume in the high dose region and a higher dose to bowel loops. In those patients with bladder outlet obstruction, Sheng et al., (2005, p1286) suggest that transurethral electro vaporization of the prostate (TVP) plus castration and endocrine therapy is a safe and effective treatment option. This conclusion was made in a study involving eighty advanced prostate cancer patients with bladder outlet obstruction. Using data from 17 patients who received eleven repeat CT scans, and a planning CT scan, Hoogeman et al., (2005, p3597) evaluated the impact of bladder filling changes on the four-histogram types. They found an absolute dose-surface histogram was the most representative one for the actual treatment, a result that concurs with those of Peeters et al., (2005, p1152). Thus, it is clear that bladder volume profoundly impacts the results, interpretations and inferences of imaging and treatment. Unsurprisingly, naturally filled or empty bladders yielded the best results. This situation gets complicated when the patient voids the bladder without informing the medical personnel. Escalating this error-prone state of affairs is the organ motion. Organ Motion. When repeat imaging is involved, owing to organ motion, there may be a loss of information. Obviously, precision radiotherapy depends on the accurate definition of the location of the target organ, its volume, and its motions (Schild et al., 1993). This is where the possibility of additional errors setting in crops up, and coupled with differences in visual interpretation of the data, expands the repertoire of miscalculations. Traditionally, motion of an organ is evaluated by repeat imaging taking into account its relative position, within specified landmarks located on the organ and the bony anatomy. In an attempt to quantify the organ motion, van Herk et al., (1995, p1320) made four repeat CT scans of eleven patients with PC. Using 3D image registration, van Herk and colleagues could accurately quantify the motion of organs. They further add that uncertainties in contouring and visual interpretation of scans have much smaller influence with their method of measurement of organ displacement. Thus the method developed by van Herk et al., (1995, p1320) gains significance when considered in the context of the findings of Roeske et al., (1995, p1329), Oozer et al., (1999, p340), and Fiorino et al., (2005, p195), who reported that even small uncertainties in contouring, organ motion and differences in visual interpretation profoundly affect the treatment outcome. In this situation an effective solution, perhaps, would lie in the usage of rectal balloon tubes as internal immobilization device, although not used in England, reduces organ motion thereby enhancing the quality of results yielded (Jani, 2003, p246; Watcher et al., 2002, p100). To overcome this problem of organ motion, incremental collection of information throughout the course of the patient treatment in the form of daily assessments has been suggested by various researchers (Chinnaiyan et al., 2003, p458; Little et al., 2003, p1224; Mackay et al., 1999, p49; Mah et al., 2002, p575; Millender et al., 2004, p10). However, procedures involving instruments and complicated planning taking into account bladder volumes, organ motions, etc., invite ‘Set-up error’ thereby complicating already obscure procedures for deliverance of effective treatment. Nevertheless, man’s quest, since time immemorial, has been to evolve effective procedures that extend the misery of individual existence by lengthening the human life span against all odds. For an exhaustive review of organ motion and its management, readers are advised to refer to the article by Langer and Jones (2001, p278). Set-up Error. This particular aspect of management of any disease is perhaps the most significant. Set-up error usually manifests itself in the form of lack of imaging quality (Meertens et al., 1990, p1181), incorrect imaging owing to organ motion (Bedford et al., 2005, p292; Chinnaiyan et al., 2003, p458; Hedelin et al., 2005, p 159; Little et al., 2003, p 1224; Mackay et al., 1999, p49; Mah et al., 2002, p575; Nichol et al., 2005, p468; Yoshioka et al., 2005, p 317), metal artifacts (Yazdi et al., 2005, p1231), patient positioning (Chung et al., 2004, p334; Mubata et al., 1998, p231;) and lack of target definition (Millender et al., 2004, p10; Rasch et al., 2005, p145). Sometimes, variations in bladder volume can contribute to set-up error (Zhu et al., 2005, p404). Whatever might be the reason for set-up error, such errors become a major impediment in dispensing the correct therapeutic or management strategy for the patient. Despite numerous reports documenting set-up error as a possible cause for failure of treatment or management strategy, some of which have been cited in the present review, not many of them offer suggestions to overcome the same. This in part could be because the mentioned set-up errors are consequences of either patient non-compliance or lack of genuine procedures that can overcome the mentioned set-up errors. In this context, development of treatment strategies on a patient-to-patient basis becomes imperative. Conclusions. The present review of literature, although not exhaustive, achieves in documenting at least three possible sources of error in the prognosis of PC. Although the current review does not offer an effective solution to overcome the identified errors, mere documenting all of the impediments in one place aids researchers in developing novel protocols that can overcome the same. In addition, because of these impediments, viz., bladder volume, organ motion, set-up error, and perhaps patient non-compliance, apparently it seems that variations in the interpretations of results by physicians is an expected natural consequence. This results in a significant impact in the management and treatment of PC, for the simple reason that the tumours may not be mapped to their exact locations, occurrence of dosage misinterpretation, etc. Thus, there is every possibility of normal tissue being destroyed. Taking all of these together it would be prudent to suggest that 1. PC cases be treated on an individual basis, and 2. In elderly patients, perhaps, the best strategy would be to ‘Wait and Watch’. References (in alphabetic order). 1. Akimoto T, Katoh H, Noda SE, Ito K, Yamamoto T, Kashiwagi B, Nakano T. Acute genitourinary toxicity after high dose rate (HDR) brachytherapy combined with hypofractionated external beam radiation therapy for localized prostate cancer: second analysis to determine the correlation between te urethal dose in HDR brachytherapy and the severity of acute genitourinary toxicity. Int J Radiat Oncol Biol Phys, 2005; 63(2): 472 – 478. 2. Bedford JL, Henrys AJ, Dearnaley DP, Khoo VS. Treatment planning evaluation of non-coplanar techniques for conformal radiotherapy of the prostate. Radiother Oncol, 2005; 75 (3): 287 – 92. 3. Beekman M, Merrick GS, Butler WM, Wallner KE, Allen ZA, Gallerath RW. Selecting patients with pre-treatment post void residual urine volume Read More