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versión impresa ISSN 0004-0614
Arch. Esp. Urol. v.62 n.7 Madrid sep. 2009
Outcomes of maximal androgen blockade in prostate cancer patients at a health area with type 2 reference hospital (2nd part). Quality of life: application of EORTC QLQ-PR25 instrument and global results. Quality-of-life adjusted survival. Pharmaceutical expenses and cost-utility
Resultados del uso en cáncer de próstata del bloqueo androgenico completo en área de salud con Hospital de Referencia Tipo 2 (2a Parte). Calidad de Vida: Aplicación del instrumento EORTIC QLQ-PR25 y resultados globales. Supervivencia ajustada a la calidad de vida. Gasto farmaceútico y coste-utilidad
Nicolás Alberto Cruz Guerra
Department of Urology. Complejo Asistencial de Zamora. Zamora. España.
Objectives: To study quality of life in patients from the health area of Zamora diagnosed of prostate adenocarcinoma between 2000-2005 treated with maximal androgen blockade (MAB). To evaluate the pharmacoeconomics of the treatment.
Methods: Basal, 12-month, 24 -month and 36-month application of the health-related quality of life measurement instrument EORTC QLQ-C30 to the population sample (n= 111) as well as a control sample (n= 100). Comparative study of outcomes: between groups; between different time measurements in MAB patients; and inter-categories/-intervals of some variables in patients with hormonal deprivation therapy (third year of follow-up). Analysis of health-related quality of life global outcomes (QLQ-C30 + QLQ-PR25). Description of the pharmaceutical expenses in androgen blockade patients. Cost-utility analysis by means of quality-adjusted life years (QALYs) obtained using preference-based weighted index from the EUROQOL 5-D tool.
Results: Hot flushes and sexual field worsening as mean expressions related to hormonal suppression. Treated patients had worse subjective perception of health condition and quality of life, in opposition to non-tumoral individuals. Positive bone scan, was a negative-influence factor on quality of life. Most patients undergoing MAB needed cost-utility figures of less than 5000 Euros/QALY.
Conclusions: There was a negative initial repercussion of MAB on quality of life, although tinged according to the different fields studied. The economic impact of this therapy on overall pharmaceutical expenses is relative.
Key words: Prostate cancer. Hormonal therapy. Quality of life. Health economics.
Objetivo: Estudiar la calidad de vida en los pacientes diagnosticados entre los años 2000-2005 de adenocarcinoma de próstata en el área de salud de Zamora tratados con bloqueo androgénico completo (BAC). Repercusión farmacoeconómica.
Métodos: Aplicación basal, al mes 12, mes 24 y mes 36, del instrumento de medición de calidad de vida relacionada con la salud EORTC QLQ-PR25 a la muestra poblacional (n= 111) citada, así como a una muestra de sujetos control (n= 100). Estudio comparativo entre ambos grupos; entre las diferentes determinaciones temporales para los pacientes con BAC; e inter-categorías/ -intervalos de determinadas variables en pacientes con terapia de deprivación hormonal (tercer año de seguimientoj. Análisis de los resultados globales de calidad de vida relacionada con la salud (QLQ-C30 + QLQ-PR25). Descripción del gasto farmacéutico en bloqueo androgénico. Análisis coste-utilidad a través del cálculo de los años de vida ajustados a la calidad (AVACs) obtenidos mediante el uso de los índices de ponderación preferencial correspondientes al instrumento EuroQol 5-D.
Resultados: Aparición de sofocos y deterioro de la esfera sexual como manifestaciones más significativas relacionadas con la hormonosupresión. Peor percepción subjetiva del estado general de salud y calidad de vida en pacientes tratados, frente a los sujetos no neoplásicos. La positividad gammagráfica, como factor de influencia negativa sobre la calidad de vida. La mayor parte de los pacientes sometidos a BAC presentan cifras de coste-utilidad menor de 5000 Euros/ AVAC.
Conclusiones: Repercusión negativa inicial del BAC sobre determinados aspectos calidad de vida, aunque matizable en función de cada esfera estudiada. Relativización del impacto económico de dicho tratamiento sobre el gasto farmacéutico total.
Palabras clave: Cáncer de próstata. Terapia hormonal. Calidad de vida. Economía de la salud.
HEALTH-RELATED QUALITY OF LIFE - HRQoL - (II).
A. Descriptive parameters corresponding to outcomes from use of the EORTC QLQ-PR25 instrument.
Outcomes for the micturition field result from the sum of items 1 to 9 from QLQ-PR25. The field of intestinal symptoms is obtained from the addition of items 10 to 13, and 17 to 18 from the instrument mentioned before. Score of item 14 from QLQ-PR25 corresponds to presence of hot flushes.
Values obtained in relation with the sexual sphere have been calculated adding items 19, 23, 24 and 25 from QLQ-PR25, and substracting to its outcome the sum of items 20 to 22, which has an scale of opposite interpretation. Items 22 to 25 are valid only in those patients with sexual activity during the last four weeks, thus, individuals who do not fulfill this premise have not been included. At basal measurement, 37.84 % of patients diagnosed of neoplasm had sexual intercourse during the last four weeks, compared to 36 % of non-cancer individuals. At measurements corresponding to months 12, 24 and 36 values of 17.12, 16.22 and 16.22 % were obtained, respectively, in maximal androgen blockade - MAB -patients; while outcomes in non-neoplasic individuals, on the other hand, kept constant during the three measurements - 37 % -.
The complete list of mean, standard deviation and median values for each one of those mentioned HRQoL fields is shown at Tables I-IV.
B. Values corresponding to global Quality of Life.
Mean value obtained for the total sum of QLQ-C30 and QLQ-PR25 instruments, with those considerations expounded before, was 52.2 points (standard deviation - SD = 8) for patients diagnosed of prostate adenocarcinoma, and 53,9 for non-neo-plasic individuals (SD= 11.29). After 12 months of follow-up a mean value of 57.4 points (SD= 10.18) is seen for MAB patients, compared to 54.2 (SD= 11.51) in non-cancer individuals. At month-24 measurement the outcomes are 57.2 points (SD= 10.95) in cancer patients, and 55.2 (SD= 12.31) for those males without it. Values at 36 months of follow-up are 55.2 points (SD= 9.4) and 56.9 (SD= 14.64), respectively.
The complete list of mean, standard deviation and median values for the total sum of QLQ-PR25 instrument in an individual fashion, and QLQ-C30 plus QLQ-PR25 jointly is shown at Tables I-IV.
The complete list of mean and standard deviation values for items 29 - self-perception of general health state - and 30 - self-perception of quality-of-life degree - from QLQ-C30 instrument is shown at Tables V-VI.
C. Quality-of-life outcomes according to categories/ intervals of some variables (month 36 of follow-up).
The list of mean, standard deviation and median values - corresponding to the month-36 measurement in patients undergoing MAB - for the total sum of QLQ-PR25 instrument in an individual fashion and QLQ-C30 plus QLQ-PR25 jointly according to the different categories/ intervals of "academic level" and "home location" variables is shown at Table VII.
The list of mean, standard deviation and median values - corresponding to the month-36 measurement in patients undergoing MAB - for the total sum of QLQ-PR25 instrument in an individual fashion and QLQ-C30 plus QLQ-PR25 jointly according to the different categories/ intervals of "basal age", "DRE prostatic characteristics", "basal PSA value", "prostatic morphology with transrectal ultrasonography", "uni- o bilateral positiveness of prostatic transrectal biopsy", "Gleason score", "bone scintigraphy positiveness", and "type of MAB (according to antiandrogen used)" variables is shown at Tables VIII-IX.
D. Descriptive parameters corresponding to outcomes from application of preferential ponderation system belonging to the EuroQol 5-D instrument.
Mean value obtained corresponding to total quality-of-life adjusted survival calculated by means of preferential ponderation from EuroQol 5-D instrument was 2.1 Quality-Adjusted Life Years - QALYs - (SD= 0.63) for MAB patients, compared to 2.27 (SD= 0.34) for non-cancer individuals (Table IV).
The list of mean, standard deviation and median values - corresponding to the month-36 measurement in patients undergoing MAB - for total quality-of-life adjusted survival according to different categories/intervals of "basal age", "DRE prostatic characteristics", "basal PSA value", "prostatic morphology with transrectal ultrasonography", "uni- o bilateral positiveness of prostatic transrectal biopsy", "Gleason score", "bone scintigraphy positiveness", and "type of MAB (according to antiandrogen used)" variables is shown at Tables X-XI.
Figure 1 shows the distribution corresponding to outcomes of total quality-of-life adjusted survival, distinguishing between MAB patients and nonneoplasic individuals.
E. Comparative study of outcomes from application of QLQ-PR25 instrument and of global quality-of-life scores.
1. MAB patients versus non-neoplasic individuals.
Sigificant differences were seen regarding the micturition field at basal measurement, as well as at those corresponding to months 24 and 36. The outcomes were better for the group of non-cancer individuals.
The comparison of outcomes on the field of intestinal symptoms showed significant differences between month-12 and month-24 measurements, worse outcomes belonging to MAB patients.
The comparative assessment of outcomes from scores of item 14 from QLQ-PR25 instrument - presence of hot flushes - evidenced significant differences at all measurements except for the basal one, and worse outcomes being seen for the group of MAB patients compared to non-neoplasic individuals.
The comparison of values obtained for the sexual sphere gave statistically significant differences at month-12, -24 and -36 measurements. The worst outcomes corresponded to the group of prostate cancer patients. Significant differences were also seen when comparing - for month-12, -24 and -36 measurements - the percentages of neoplasic patients who had sexual intercourse during the last four weeks, compared to values corresponding to non-cancer individuals.
The comparison of total QLQ-PR25 scores, -with those considerations mentioned before -, evidence statistically significant differences at month-12, and -24 measurements, with worse outcomes obtained for patients undergoing hormone deprivation therapy.
On the other hand, when comparing the sum of total scores from QLQ-C30 plus QLQ-PR25 instruments, significant differences are seen at month-12, and -24 measurements, with worse outcomes obtained for prostate cancer patients undergoing hormone blockade.
The comparison of outcomes corresponding to item 29 - self-perception of general health state -and 30 - self-perception of quality-of-life degree - from the QLQ-C30 instrument in patients with prostatic neoplasm compared to those disease-free individuals evidenced statistically significant differences for all measurements - basal, month-12, -24 and -36 -. These differences were always favorable to cancer-free indviduals.
The complete list - for each measurement - of p values obtained from the comparative study between MAB patients and non-neoplasm individuals for each HRQoL field mentioned, for the total sum of QLQ-PR25 instrument in an individual fashion and QLQ-C30 plus QLQ-PR25 jointly, as well as for items 29 and 30 from QLQ-C30 is shown at Tables I-VI.
2. Inter-categories/ -intervals comparison for some variables in MAB patients (month 36 of follow-up).
Significant differences were seen regarding the sum of values from QLQ-C30 plus QLQ-PR25 instruments between the soubgroup with basic or primary studies and those with intermediate or higher ones, with more satisfactory outcomes for the latter. Differences assessment did not give statistical significance for the independent value obtained from QLQ-PR25 instrument.
Statistically significant differences were seen as well when comparing between the subgroups of patients with and without positive bone scintigraphy the outcomes corresponding to the sum of values from QLQ-C30 plus QLQ-PR25 instruments, as well as those from QLQ-PR25 instrument in an individual fashion.
The complete list of p values obtained from the comparative assessment of different categories/ intervals corresponding to the variables mentioned before for the total sum from QLQ-PR25 instrument in an individual fashion and QLQ-C30 plus QLQ-PR25 jointly - at month-36 measurement, in MAB patients - is shown at Tables VII-IX.
3. Inter-measurement comparisons (MAB patients).
Significant differences were seen on micturition field between basal and month-12 measurements only.
With regard to the field of intestinal symptoms, differences were significant when comparing the basal measurement values with those from month 12, as well as between the former and month-36 measurement.
Regarding the values belonging to item 14 from QLQ-PR25 instrument - presence of hot flushes -, significant diferences were seen between basal measurement and those corresponding to months 12 and 36.
The comparison of values of the total score from QLQ-PR25 instrument evidenced significant differences between basal and month-12 measurements, as well as between the former and that one corresponding to month 36.
The assessment of inter-measurement differences between values of total sum from QLQ-C30 plus QLQ-PR25 instruments let see statistical significance between basal and month-12, the latter and month-24, as well as between basal and month-36 measurements.
Comparison of measurement outcomes corresponding to item 29 - self-perception of general health state - and 30 - self-perception of quality-of-life degree - from QLQ-C30 instrument evidenced statistically significant differences between basal and month-12, the latter and month-24, as well as basal and month-36 measurements.
Statistically significant differences were not seen when comparing the different measurements on sexual field, although worse outcomes were verified for month-12 value compared to the basal one, remembering that only patients with sexual intercourse during the last four weeks before each application of HRQoL-measurement instruments are compared.
The complete list of p values obtained for the inter-measurement comparative assessment of each HRQoL field mentioned, for the total sum from QLQ-PR25 instrument in an individual fashion and QLQ-C30 plus QLQ-PR25 jointly, as well as for items 29 and 30 from QLQ-C30 is shown at Tables XII-XV.
F. Comparative assessment of outcomes from the application of the preferential ponderation system belonging to the EuroQol 5-D instrument.
Significant differences were not seen at mont-36 of follow-up on quality-of-life adjusted survival between cancer patients and non-neoplasic (Table IV).
The complete list of p values obtained from the comparative assessment of different categories/intervals corresponding to the assessed variables, for total quality-of-life adjusted survival at month-36 measurement, in MAB patients is shown at Tables X-XI. Statistically significant differences were obtained for no one of them.
PHARMACEUTICAL EXPENSES. COST-UTILITY
A. Evolution in time (years 2000-2005) of total and relative pharmaceutical expense on androgen blockade at Zamora´s health area.
Regarding the total pharmaceutical expense on those drugs used for prostate cancer hormonal therapy, at Zamora's health area is obtained a value of 1348820.04 Euros - € - for year 2000, with a 3.85 % decrease in 2001, to a level of 1296956.38 €. In 2002 there is an 6.69 % increase, reaching 1383779.87 €, decreasing 1.23 % in 2003 again with a corresponding value of 1366702.77 €. During 2004 that expense shows a 1.76 % growth up to 1 390812.12 €, finally decreasing in 2005 merely 0.27 %, equivalent to a total expense of 1386988.5 €.
If we analize, on the other hand, the evolution of the relative percentage of pharmaceutical expense on androgen blockade at Zamora's health area compared to its total one, a progressive decrease in these values between years 2000 and 2005 is obtained, from 3.82 to 2.63 % (Figure 2).
B. Cost-utility outcomes.
Data obtained relating cost of MAB to quality-of-life adjusted survival - in Euros/ QALY gained - are shown at Figure 3. Mean value of pharmaceutical expense on MAB per QALY gained is 4768.52 € (SD= 3509.86).
LOWER URINARY TRACT SYMPTOMS
The effect of androgen deprivation on lower urinary tract symptoms - LUTS - has been assessed in a benign hiperplasia as well as in prostate carcinoma.
In experimental studies with rats undergoing castration an increase in density of prostatic alfa-1 receptors was seen, that outcome being explained by a relative growth of stromal components compared to the epitelial one during androgen deprivation - reversible after administration of testosterone supplements -, and not due to positive self-regulation phenomena (1).
In patients with benign prostatic hiperplasia it has been seen a 29 % decrease in ultrasonography-measured prostatic volume after 12 weeks of busere-lin or ciproterone acetate therapy; together with rise of maximum urinary flow, and reduction of daytime micturitional frequency as well as in residual urine volumes (2). Some increase was seen in detrusor contractile capacity but changes in urethral resistance values were not reported. After suspension of that mentioned therapy, new rise of prostatic volume was verified starting from a variable period of 3-36 weeks, as well as reversibility in those clinical and urodynamic reported before.
In one study with 61 patients diagnosed of locally-advanced or metastatic prostate adenocarcinoma, differences between outcomes from application of International Prostate Symptom Score - IPSS - and Symptom Problem Index - SPI - were assessed in a prospective and retrospective fashion at three and six months from starting therapy with a GnRH analog (3). Using the prospective method a statistically significant improvement of 2.9 points was reported for the first measurement at the end of the first term, with a non-significant decrease of 0.9 points after six months of follow-up. When tests are applied in a retrospective fashion - "then-test" method -, the increase of scores at three months was 4.2 points, while at six-month measurement an improvement of 1.8 points was seen. The improvement on quality of life obtained at three months and shown by means of SPI was 4 compared to 2.2 points, by means of the retrospective and prospective method, repectivvely. At six months of follow-up non-significant worsening was seen by means of prospective measurement, while with the prospective one significant improvement was evidenced.
Outcomes obtained with retrospective measurements must be interpreted cautiously, due to a potential effect of "answer shift" which explains their differences with those got by means of "test/pre-test" method, because patients are susceptible to change their standards when judging levels of internal functioning and therefore their symptoms/ quality of life (4). Some reports defend that variations of those standards must be accepted and incorporated into the outcomes of quality-of-life assessments (5,6).
The fact of evidencing significant unfavorable differences in our study regarding the micturition field for non-neoplasic males compared to those undergoing androgen deprivation at most measurements, and considering the age rank of the population sample, can be linked to a higher influence of symptoms that processes like benign prostatic growth exert in an isolated fashion on that HRQoL sphere. Stabilization of scores after an initial unfavorable outcome at month 12 compared to basal measurement can be set in relation to a therapeutical effect of the blockade on those symptoms.
In the context of MAB, antiandrogens are frequently associated to gastrointestinal adverse effects such as abdominal pain, intestinal rhythm disturbances and anorexia. The precise mechanism is yet unknown. Some studies report up to a 22 % incidence (7), suggesting the possibility that local toxicity of flu-tamide is not the only responsible factor. It must be emphasized, in any case, that symptoms related to the intestinal tract more frequently manifest in patients undergoning combination of GnRH analog plus antiandrogen (8).
Use of opioids conditions the presence of constipation as main adverse effect of this therapy, cause of its influence on gastrointestinal tract and specific spine pathways, leading to decrease in secretory and peristaltic capacities. This manifestations persist in time, since a slow tolerance experienced by patients, specially in a context of usually chronic therapies. Use of laxatives and increase in dietary fiber constitute the initial therapeutical step, and lactulose-like osmotical cathartics must be associated in refractarial cases (9).
Significant differences seen in our study regarding intestinal symptoms between non-neoplasic individuals and cancer patients at month-12 and -24 measurements, unfavorable for patients undergoing hormone blockade agree with what has been exposed before, although the fact of a stabilization of scores from month 12 could be set in the context of higher rationalization on complementary medication - opioid-like, for example -, together with adoption of appropriate hygienical-measures.
Influence exerted by presence of hot flushes on physical well-being in a context of androgen deprivation for prostate cancer has been evidenced in some studies (10), by means of application of HRQoL-measurement FACT instrument. A significant relation was as well demonstrated between the clinical assessment of that manifestation and patient-expressed wish for therapy. Hot flushes have been described as "extremely distressing" symptom in 27 % of patients undergoing hormone therapy (11).
The presence of statistically significant differences between non-neoplasic individuals and cancer patients in our study, with regard to manifestation of hot flushes, at all measurements from month 12, is an expected finding, as well as inter-measurement differences found when comparing the basal one and those of months 12 and 36, and later stabilization of outcomes for objetivation of that symptoms during the period between the last two measurements mentioned before.
Sexuality is a complex and multidimensional phenomenon that comprises biological, psycological, interpersonal and behovioural aspects. Variants of normal sexual behaviour are defined by each patient and his couple, and being influenced by some factors like genus, age, personal attitudes and religious and cultural values.
Calculus of sexual disfunction incidence after antineoplasic therapies shows a range between 40-100 % (12). The commonest sexual problems of these patients are lack of sexual desire and erectile disfunction. Other possible manifestations are anejaculation, retrograde ejaculación and anorgasmia - although regarding the latter, its delay is more frequent, of pharmacological origin or secondary to anxiety disorders (13) -.
Unlike many other physiological adverse effects related to cancer therapy, sexual problems do not trend to resolve during the first or second year of disease-free survival (14). It has been seen that post-therapy quality of life in prostatic neoplasms vary in a significant fashion, even in those aspects like quality of sexual privacy, daily relationships with the other sex, his capacity of sexual dreaming, and masculinity self-perception (15).
Sexual dysfunction in an oncological context has a multifactorial origin. Physical factors include functional worsening, fatigue and pain. Analgesic therapy with opioids can lead to libido decrease, erectile dysfunction, and low testosterone index. It is believed that two mechanisms are responsible: GnRH-production inhibition and hyperprolactinemia, which causes negative feed-back on LH release and reduces testosterone production (16). It is known that opioids alter the normal function of hypothalamic-pituitarygonadal axis. These effects usually disappear after opioid suspension. Other cases of patients undergoing opioid therapy for relief of chronic pain, confirm these findings (17).
Psycological factors vary (13). Wrong beliefs on neoplasm origin and possible feelings of guilt related to them exert a significant negative influence on sexual field; and it is frequent the conviction that any past sexual intercourse, extramatrimonial relationship, or sexually-transmitted disease has been able to cause his cancer, and even that sexual activity can promote recurrence of his tumor - specially in those individuals with pelvic or genital neoplasms -. Coexistent depression - 15-25 % more prevalent in cancer patients than in healthy population (18) -, changes of corporal self-image and tensions linked to interpersonal relationships - sometimes in association with fear to rejection - are also other decisive factors of pycological sexual dysfunctions.
Selective serotonin-reuptake inhibitors - SSRIs - block the re-storage mechanism of that neurotransmitter at post-stimulus synaptosomic vesicle, leading to serotonin accumulation at synaptic space (19), causing a down-regulation in hypothalamic postsynaptic receptors, which also lead to a decrease in release of stimulating neurotransmitters at erectogenic centers. Sexual dysfunction due to SSRIs is considered to affect about 8-20 % of all patients. Percentages of sexual dysfunction related to each SSRI were the following ones: sertralin - 16-56 % -, fluoxetin - 20-54 % -, paroxetin - 22-65 % -, fluvoxamin - 59 % -, and venlafaxine - 38% -. The most common sexual symptoms were delayed orgasm or anorgasmia, followed by decreased libido (20). Paroxetin caused significantly higher delays of orgams or ejaculation - 48 % -, and laid to erectile dysfunction mor frequently than sertralin - 37 versus 16 % -, fluvoxamin - 31 versus 10 % -, or fluoxetin - 34 versus 16 % -, respectively.
Aging is not necessarily related to decrease of libido, and thus, in some studies with age-advanced males, they agreed that sex influence on their quality of life, that age-adjusted yield can yet be maintained and that sexual disorders are worrysome (21).
Androgen deprivation in prostate cancer therapy entails a parallel decrease of male sex hormones activity on brain to promote desire, together with erectile dysfunction and difficulty to reach orgasm (22). It has been estimated that serum testosterone levels lower than 5-8 nmol/ L (23) are linked to a fall of sexual function, so that the decrease in that hormona levels would cause a reduction of its positive feed-back effect preferently on cortical temporal areas (24).
An increasing number of young males diagnosed of advanced asymptomatic prostate cancer - together with the fact that they sometimos go on enjoing a suitable sexual function -, have promoted to give more and more attention to prevention of sexual morbidity from that therapy, and in this sense some authors have tried to delay hormonal therapy until the start of symptoms (25), intermittently administered (26) or using a combination of 5-alfa reductasa inhibitor and antiandrogen instead of MAB (27) although the assessment the influence of these options have on survival is has not been finished yet.
Several models of assessment/ intervention on sexual sphere exist, some of them specifically designed for neoplasic patients (28). Kaplan's model provides guidelines on interview, focused on the main complaint, sexual and psiquiatric states, family and psycosocial history, with later assessment of relationships, case summary, and recommendations (29). PLISSIT - permission degree, limited information, specific suggestions, and intensive therapy -, is another assessment/ intervention model regularly used as framework for sexual rehabilitation in oncological care (30).
General factors affecting sexual function which must be considered during assessment are varied, and among them the following can be emphasized:
Premorbid sexual function. Sexual development prior to diagnosis of disease, as well as preferencies and experience are essential in order to sexual state assessment. The degree of sexual function, interest on sex, satisfaction and importante of relationship influence on patient's possible anguish related to the moment of present sexual function. Thus, individuals who have already suffered sexual difficulties may have an enhanced vulnerability towards therapy effects (31).
State of relationship. Duration, quality and stability of relationship must be considered prior to diagnosis. Furthermore, as many patients fear to be rejected or abandoned, the clinician must inquire into couple's response to disease and into patient's worries about consequences of therapy on it (32). Couples share many reactions with patients because their most important worries are usually related to loss and fear to death.
Psycological state. Anxiety and depression are two common affective interruptions among cancer patients, and they must be assessed because of their influence on sexual field, as seen before. Couple's social role frequently changes during therapy. Individual identity and self-esteem may be threatened when these functions vary (28); and couple's involvement on patient's physical care may also entail a potencial negative influence on his sexuality feeling.
Sexuality assessment is complemented from a medical point of view with application of questionnaries (33) like the International Index of Erectile Function - IIEF -, and the Brief Male Sexual Functioning Inventory - BMSFI -, validated scales which measure aspects on male's sexual function and satisfaction. There is also the possibility of using abbreviated scales, like the Sexual Health Inventory for Men - SHIM -.
Non-coital pleasure "sensorial approach" (34), offer an option to express intimate feelings without presence of pressure and/ or anxiety that obligation to complete coitus entails, representing a non-necessarily excluding alternative with regard to other therapeutic approaches - 5-fosfodiesterasa inhibitors, prostaglandin E-1 intracavernosal injection, etc -, which act on the erectogen aspect of sexual dynamics.
In a study (35), patients undergoing intermittent androgen blockade presented significant differences compared to continuous therapy regarding sexual activity, so that 41 % of the former reported to maintain it at nine, 40 % at 15, and 35 % at 21 months of follow-up.
Regarding outcomes obtained in our study, the finding of significant differences in sexual sphere, infavorable to patients undergoing androgen deprivation therapy - as well as decrease of their percentage with sexual activity during the last four weeks - at all measurements, except for the basal one, can be explained by the negative effect exerted on that field by hormonal blockade. Lack of inter-measurement significant differences between all pairs of compared values in MAB patients is remarkable; and although a trend towards worse scores at months 12 and 24 has been seen, the limited amount of these differences may suggest a relatively early adaptation of patient's behaviour and sexual habits to the new situation created from the start of therapy.
GENERAL ASSESSMENT OF TOTAL HRQoL IN ANDROGEN BLOCKADE
Measurement of total HRQoL in patients with diagnosis of prostate adenocarcinoma and undergoing androgen blockade has been reported in some publications. Thus, better global scores have been obtained - after 6 and 12 months of follow-up - in patients with non-metastatic disease (36), whom an expectant attitude was indicated compared to those with early onset of hormonal therapy, with significant differences to the detriment of the latter group regarding global HRQoL values as well as those from subscales of physical activity, fatigue, and sexual dysfunction. The psycological component of anguish also turned out to be in those patients undergoing androgen blockade. Other authors (37) have reported worsening of sexual function, as well as in playing social roles and subjective cognitive function, in spite of improvements observed in physical and micturitional functions.
Outcomes from a randomized study with assessments based on administration of psychosocial questionnaries - one week prior to start of androgen deprivation in the group undergoing active therapy -, have not achieved to demonstrate a clear advantage compared to expectant attitude. Oscillations - increases or decreases - in global HRQoL scores were lower in the observation group compared to that one undergoing hormonal therapy (38).
In a 91-patient series with histological diagnosis of lymph-node positive prostate cancer (39) a worse global HRQoL was seen in the group of immediate-onset hormonal deprivation compared to that one of delayed start, the former presenting as well worse scores for sexual, emotional, and physical spheres, apart from showing higher frequency of hot flushes. Time until clinical progression was significantly shorter in the group of delayed therapy compared to that one of immediate hormonal blockade - 33 versus 62 months -, and without significant differences seen regarding total survival.
In a study based on application of SF-36 instrument to patients undergoing androgen deprivation therapy during less than six months compared to a group treated for a longer period of time, and to another one with no therapy, in the latter significant differences were seen regarding better physical function and global HRQoL score. These differences were not observed with regard to the mental health field (40).
Other reports have shown HRQoL outcomes from a global point of view as well. An example of that is the assessment of 173 patients diagnosed of clinically asymptomatic metastatic prostate cancer (41) whom it was given the option of therapy with leuprorelin plus flutamide, GnRH analog as monotherapy, orquiectomy, diethylestilbestrol, flutamide, or therapeutical abstention. HRQoL values were significantly better in patients who chose the latter option. MAB linked to higher fatigue and emotional disturbance when comparing to the other forms of androgen deprivation, influencing not only on decrease of serum testosterone levels, but also on the daily-memory-of-disease psycological component which antiandrogen administration entails.
In a report (22), derived from the Prostate Cancer Outcomes Study - PCOS -, a follow-up of 661 patients was done, in order to make a comparison between a hormonal suppressive therapy and therapeutical abstention. Five domains were assessed - pain, depression/anxiety, vitality, physical limitations and those related to emotional state -, as well as a global item on general health condition, obtained from the RAND SF-36 generic questionnaire. It was observed that those patients undergoing pharmacological therapy presented significant differences at one year of follow-up regarding loss of libido, percentage of impotence, and sexual inactivity compared to the group of expectant attitude. Prevalence of gynecomastia, as well as that of hot flushes - and weekly presence of the latter - was also higher in the group of hormonal therapy. Significant differences were seen regarding physical discomfort in the subgroup of patients with low risk of presenting with non-organconfined disease and undergoing therapy; and happening in the same form with regard to limitation in daily activity for the high-risk subgroup undergoing hormonal blockade, although significant differences were obtained in the latter regarding satisfaction with the therapy administered.
In an observational cohort study named Cancer of Prostate Strategic Urological Research Effort -CaPSURE -, based on a questionnaire which includes the RAND 36 item Health Survey 1.0, UCLA PCI, and other questions to measure self-esteem as well as general impact of prostate cancer on individual and his family, it has been observed a discreet improvement in HRQoL domains during the first year of hormonal therapy, except for that one related to sexual function and bothers linked (42) (43), while patients who chose an expectant attitude presented reduced scores obtained for general health, physical activity and social relationship spheres.
Krongrad, with simultaneous use of UCLA-PCI and RAND SF-36 points out that up to 41 % of variations in global HRQoL values can be attributed to non disease-specific component, whereas percentages of 16, 15 and 14 % would correspond to urinary, sexual and intestinal spheres, respectively (44).
In a study with a sample of 288 prostate cancer males (45) CARES questionnaire was used to discriminate between different clinical stages of disease, demonstrating the usefulness of this instrument to quantitatively document the progressive worsening as the neoplasm advances. These findings have also been confirmed in other reports (46) by means of using EORTC instruments, assessing patients as well as their partners, demonstrating that as disease progresses, HRQoL decline in the former comes accompanied with a parallel increase in emotional stress of the latter. In the same sense it must be pointed out the outcomes from a cross-sectional study (47), according to which those patients with hormonosensitive disease present better outcomes compared to those from hor-monorresistant ones on HRQoL domains corresponding to pain, energy, social interaction and mental health.
Improvement in quality of life during periods of therapy rest in intermittent androgen blockade has not been confirmed yet - in most series - in a statistically significant fashion by means of validated questionnaires (48), and in those assessed with the latter, outcomes are not coincident. Thus, it has been reported (49) an improvement in general well-being values during periods of therapeutical pause. In other publications (50) it is observed an improvement of general state in 37.5 % of cases, asthenia in 42 %, 62 % in hot flushes incidence and erection recovery, and 75 % in libido recovery during no-therapy periods. Other authors (51), using the EORTC QLQ-C30 questionnaire only find improvement in those typical adverse effects of hormone therapy, but not in social and occupational activities, emotional state or sexual function. In a randomized study (52), preliminary outcomeas were obtained where better scores on quality of life for the intermittency group, but with no significant improvement on sexual activity. In other reports (53), using the SF-36 and PCI, clinical significant immprovement has been observed during no-therapy periods regarding asthenia, sexual function, and libido, compared to a lesser one on physical function and micturitional disturbances.
In spite of psicosocial intervention in patients diagnosed of prostate cancer - supported in some publications (54) - has not demonstrated survival improvements, some authors make reference to the role of self-administered HRQoL questionnaries as a complementary factor when predicting that parameter in terms of time (55).
For the development of the study we present, telephone communication was chosen - due to logistic reasons - for patients' assessment of HRQoL. The use of this kind of interview for acquisition of HRQoL-related data by means of questionnarie-type measurement instruments with scaled values has demonstrated to be a reliable method (56) if it is compared with their obtention by means of presential interview with the individual, the differences between both methods not being significant.
In order to facilitate the practical interpretation of outcomes from HRQoL studies it must be obtained the lowest number of measurements which can give most quantity of information on changes happened. Time intervals must be as similar as possible between study and control groups, taking as initial point of reference those values obtained at the moment of diagnosing the neoplasic process - for the first group mentioned -, given the difficulty to have non-retrospective basal data, prior to tumor confirmation.
There are no universally accepted "threshold" values aceppted as cut points which difference significant changes in HRQoL, however, many authors consider acceptable to describe in this form to those ones which represent a 5-10 % variation from the prior figure.
Specifically regarding physical, emotional and social spheres, as well as in relation with the global HRQoL scale from QLQ-C30 instrument, patients themselves whom it was presented considered that variations between 5-10, 10-20, or > 20 points entail mild, moderate or important changes on prior personal condition, respectively (57). Other authors, however (58) consider that definition of "great difference" comparing the prior value differs according to each sphere - for example, 7 for the emotional function, 27 for the physical one, and 16 for global HRQoL -. However, there is no lack of attempts for a standardized classification of outcomes according to age and sex (59).
Findings from our study of an evolution towards worse scores in measurements until month 24 for total values from QLQ-C30 instrument as well as for those from the sum of QLQ-C30 plus QLQ-PR25 in patients undergoing MAB are in the line of informations mentioned before on HRQoL worsening after start of taht therapy. All come reinforced with significant differences obtained at months 12 and 24 when comparing total values from QLQ-PR25 instrument with those from sum of QLQ-C30 plus QLQ-PR25 between patients undergoing blockade and non-neoplasic individuals. Special features of those patients' outcomes on sexual field are one of the factors which condition to a most extent the evolution of total values from QLQ-PR25 instrument, presenting an earlier stabilization than that verified for the other instrument used in this study as well as for the sum of both ones.
It must be mentioned the finding - at month-36 measurement - of better total scores from QLQ-C30 instrument, as well as from the sum of the latter plus QLQ-PR25 in patients undergoing androgen blockade who have intermediate/ higher studies compared to those having no studies or basic ones. It could be attributed certain effect that comprehension of HRQoL multidimensionality by a patient with more upbringing exerted when he counteracts the potential negative influence of the prostatic neoplasm and its therapy.
The observation, on the other hand, of better total scores from QLQ-C30 and QLQ-PR25 instruments, as well as from the sum of both ones, in patients with positive bone scintigraphy compared to those who presented a negative one is set inside the field of what expectable.
SUBJECTIVE PERCEPTION OF OWN GLOBAL HEALTH STATE
According to data from the National Health Survey of Spain (60) corresponding to year 2003, 73 % of males and 63.2 % of women 16 years old and onwards value their health as good or very good. That accounts for 68 % of population belonging to this age rank, grouping both genders; discreetly lower figure compared to that corresponding to year 1993 - 68.5 % -. Spain occupies an intermediate position among European Union countries with regard to this perception.
In our study, descriptions of outcomes corresponding to the perception of own general health state as well as quality of life are coincident. It is observed that in all measurements after both assessments the scores are significantly favourable for those non-neoplasic individuals, in harmony with the previously reported existence of satisfactory figures in absence of disease. On the other hand, it is observed a progressive worsening in those subjective appreciations from males undergoing androgen deprivation until month-24 measurement; and in this sense, the later relative stabilization of values seen could be related with patients' multidimensional adaptation to emerging situations that the entity diagnosed - and its therapy started - cause.
There is no evidence on existence of significant differences in two-year survival when comparing MAB patients with those undergoing castration alone. At five years, that difference is 2.9 % - 27.6 % versus 24.7 % - favorable to the first therapeutical option. Values of mean survival are 33.3 versus 29.9 months, and it is observed that the advantage mentioned before which is attributed to maximal blockade would maintain in an independent fashion compared to age ranks or disease stages assessed (61). Other reports agree to accept the fact of higher survival in patients undergoing MAB compared with castration as mo-notherapy (62), and 10-22 % decrease of mortality risk being detected favoring the first type of therapy mentioned (63).
Survival outcome figures are also similar when comparing two non-steroidal antiandrogens - flutamide and nilutamide - which can be used in association with GnRH analog in MAB. The comparative assessment of those with ciproterone acetate shows shorter survivals, with unfavorable differences against the latter drug (61). On the other hand, the trial corresponding to assessment of bicalutamide versus flutamide - in association with analog - detected specific differences in patients' mean survival, which are favorable to the former, although with lack of statistical significance (64). Thus, the absence in our study of significant differences when comparing those different antiandrogens used in hormone blockade in keeping with the reports pointed out.
An increase in cancer-specific survival at five years of follow-up is obtained wtih MAB. Progression-free survival shows significant improvement with MAB around the end of the first year, but not at later follow-up intervals (62).
Some authors (65) have found significant differences regarding survival in patients undergoing MAB according to the latter has a fulfilment duration larger or lesser than 120 days, with more favorable outcomes for the former assumption.
HRQoL assessment is one of the focusing points of our study, and hence it has been priorized the assessment of survival outcomes after their adjustment by means of application of preferential ponderation values, and not from a net point of view, which would entail a subject of evaluation by other kind of reports, examples of which are bibliographic references mentioned in previous paragraphs of this section. Starting from this consideration, it must be pointed out the limited mention given until now in scientific literature to survival adjustment according to quality of life. In thsi context of scarcity it can be referred, however, some considerations of interest; and thus, for example, some authors report the lack of evidence on a potnetial assoiation existing between patients' sociodemographic - gender, age, socioeconomic status, marital status, race and religion - and ourcomes from preferential ponderation assessment (66), and in this sense it must be set the lack of statistically significant differences obtained in our study with regard to the variable of age assessed.
Regarding the rest of variables assessed in our study on quality-of-life adjusted survival, although certain outcome differences are obtained, more or less "a priori" expected if we would refer to net pre-adjustment values, - as it happens, for example when a higher one is observed in patients who present PSA values < 20 ng/ mL, non-suspicious prostatic transrectal-ultrasound morphology, unilateral positiveness of prostatic biopsy and negative bone scintigraphy, do not achieve to have enough entity. Given the lack of availability regarding specific bibliographic references which report reflections on the connection between those variable mentioned before and adjusted survival values, it is suggested the convenience of multicentric trials in order to a possible corroboration of statistical significance absence which is not linked to a limited available number of patients assessed.
In our study significant differences were not seen with regard to quality-of-life adjusted survival between individuals with and without neoplasm at month 36 of follow-up. Outcomes from preferential ponderation assessment usually manifest a trend towards giving better valuation on their health condition by patients who have presented or present any degree of worsening, compared to those ones from general population wtihout that experience (67).
The potential influence this aspect could exert on comparison between individuals with and without disease in our study, must be considered relativized given the use of an assistential-origined database as source for obtaining the comparative sample, therefore being persons with some degree of experience on health-altered conditions. Because of it, this consideration lets keep the validity of those adjusted survival outcomes mentioned before, making it necessary in the light of them to tinge the importance that disturbances caused by MAB on precise HRQoL spheres or fields have when evaluating preferential ponderation by patients.
A. Pharmaceutical expense.
Data corresponding to year 2003, set the public sanitary expense in Spain at 41199.7 million Euros - € -, what accounts for 71.4 % of country's total sanitary expense, which amounts to 57698.7 million Euros. Total sanitary expense in Spain expressed as percentage of Gross Domestic Product - GDP - sums up 7.7 %, discreetly lower figure compared to the European Union's mean, set at 9 %. Percentage from GDP of public sanitary expense is 5.5 % and that of private one is 2.2 %. According to data published by Ministerio de Sanidad y Consumo regarding expense composition, hospitalary and specialized services are those which represent higher percentage of it - 52 % -, followed by pharmaceutical - 22.3 % - and Primary Care ones - 16 % -, (68).
Actual yearly growth rate of public pharmaceutical expense in Spain has been 5.5% from year 1980 and 6.4 during the 90's (69). The increase of that expense is due to three main potential sources:
- Price levels. Price of drugs registered in Spain has grown considerably bellow Consumer Price Index -CPI -, especially considering that most novelties put on the market are not included in that index and they usually have higher prices because they incorporate an innovation bonus. At the same time, prices in Spain are among the lowest in Europe. The reduction of pharmaceutical profit margins introduced in 1997, the system of reference prices from december 2000, and promotion of generic drug use are the single measures which have let some expense restraint.
- Pharmaceutical expense and mean cost per prescription. Mean number of prescriptions per inhabitant has not significantly increased - it has raised from 12.2 to 14.4 prescriptions per inhabitant and year during the last 20 years -. The variable whicha has raised the most in Spain has been the mean cost per prescription, - 5 % yearly during the last decade -, above all due to an increase of last-generation products which replace those existing before and which have a higher price compared to the latter. These phenomenon would only have potentially positive repercussions on total sanitary expense if those replacements are based on cost-effectiveness criteria.
- Population's ageing. The number of prescriptions for patients on active service has not grown during the last five years, while those for pensioners have raised at a mean yearly rate of 2.5 %, higher increase compared to that belonging to the number of pensioners, which has yearly raised at 1.4 %. Ageing entails an increase of pharmaceutical expense, because elder people use to be the higher consumers of drugs. Thus, the co-payment formule has become from representing 19 % of total pharmaceutical consumption in 1981, to 11 % in 1990, and to little more than 7 % in year 2000. On the other hand, pensioners' expense represented 58 % of the pharmaceutical expense in 1981, 70 % in 1990, and more than 77 % in year 2000.
The present pattern of pharmaceutical consumption increase in Spain is, on the other hand, similar to that observed from the rest of European Union - although it must be considered that per capita net in our country are one of the lowest ones from it -. Spanish public pharmaceutical expense has raised 5.22 % in 2007 - 5.19 % in Castilla y León -, only one point over the inflation registered during that year, this latter figure representing during four years in a raw a lower value of actual growth of pharmaceutical industry compared to GDP, with a decreasing trend of the weight belonging to the pharmaceutical expense being observed on total sanitary expense as well as the GDP itself (70) (71), having been promoted from an institutional point of view by means of reduction on drug prices imposed by the Ministerio de Sanidad y Consumo in years 2005 and 2006. The more recent report from National Economic Research Associates shows a growth prediction regarding pharmaceutical expense in Spain for year 2008 of 5.37 % (72).
Future predictions on global pharmaceutical expense will be conditioned to the evolution of spanish population's growth during next years, and their ageing above all. However, the constant decrease shown by the amount of cost from drug association used in MAB compared to the total expense from the assessed health area, and observed from the assessment of Concylia database values (73), must make us think about the possibility of relativizing the economic weight attributed to this therapeutical option in particular.
B. Cost-utility of MAB.
Prostate cancer represented 5-6 % of global costs destined to tumor therapy, from the 90's being estimated in 12400 american dollars - US $ - the mean cost per patient from neoplasm diagnoses to exitus (74). Roughly 25 % of total expense was used during the first year post-diagnosis. Hospitalary costs represented 72 % of the total, while pharmaceutical expense was 15 %.
The proportion of patients "de novo" diagnosed of prostate cancer and subsidiary of hormone therapy whom it has not been initially administered has been progressively decreasing from the second half of the 80's (75), contributing to a constant raise of costs generated by that disease. If we consider canadian data from the Ontario Drug Benefit Program (76), total pharmaceutical expenses related to prostate cancer in males elder than 64 years increased from 0.2 to 15 million canadian dollars - $ - during the period 1985-1992 - 7500 % -, compared to a raise of 305 % in global drug expense. Estimated yearly cost per patient became from 77 to 1838 $ - incremento del 2.387 % -, frente al 240 % para el global de grupos farmacológicos.
In United States, mean yearly costs gnerated by the therapy of a patient with metastatic disease have been estimated between 1807-2225 US $ (77) (78). Most of those costs - 80.5 % - would be due to antiandrogen therapy. Nilutamide plus goserelin combination turns out to be the most expensive option - 41400 US $ as total amount during the survival period -, although it also obtains the best QALY value - 5.13 -, compared to 5.10 for orquiectomy only, 4.68 for diethylestilbestrol monotherapy, 4.89 with GnRH analog, and 4.61 with non-steroideal antiandrogen, respectively (79). Outcomes from cost-utility assessment comparing between non-steroideal antiandrogen plus orquiectomy and the latter alone were 43400-74800 US $/ QALY gained, while that value was 110900-196700 US $/ QALY when comparing MAB with non-steroideal antiandrogen to surgical castration alone.
In a recent report (80), cost-utility of MAB with bicalutamide is supported compared to GnRH analog monotherapy in patients with stage D2 prostate cancer - at five and ten years of follow-up, outcomes of incremental cost-utility ratio were 33677 y 20053 US $ per QALY gained, respectively -. Other authors (81) report as well favourable outcomes on cost-utility assessment when comparing MAB with bicalutamide compared to MAB with flutamide, obtaining a cost-utility ratio vlue of 22000 and 16000 US $ per QALY gained, respectively.
Other report (82) estimates the yearly cost of MAB ranking between 8717-12209 US $. That assessment showed an increasing trend towards its early onset, so that at year 1988 24.8 % of patients undergoing that therapy presented initially with metastasis, compared to 7.6 % of those ones started at 1996. After a mean follow-up of 10 years (83), MAB-related expense was 17.3-20.9 times more expensive than that one corresponding to surgical castration, the former being less costly only in those patients - 5.2 % of total - who had maximum survival of 2.7-3.4 months.
When comparing early versus late MAB onset, the lowest number of QALYs - 5.9 - is obtained when therapy starts coinciding with diagnosis while the highest value corresponds to a delayed therapy - 6.8 QALYs when the patient is with no symptoms and 7 if the latter are present -. Mean costs of therapy are slightly higher if it is onset when patients are without symptoms - 14700 US $ -, compared to 12200 if it is started when asymptomatic distant metastasis are detected. Start of MAB coinciding with symptomatic distant metastasis presents a cost-utility ratio of 14300 US $/ QALY gained. Other authors (84) also report favourable outcomes from cost-utility assessment for MAB onset at clinically advanced stages of disease. MAB estimations suggest that to fulfill cost-utility criteria, the combination of GnRH agonist plus antiandrogen should lead to a 20 % increase in survival compared to that obtained with orquiectomy alone (85).
MAB represents, therefore, a therapeutical option which may be considered expensive, favourable in terms of cost-utility for some cases only; however, the fact that in our study a significant percentage of patients undergoing that therapy present expense values per QALY which are set at lower extremes - < 5000 € -, of a wide rank of values, represents another element which makes appropriate at least a previous reflection before condemning on an economic context the combined use of GnRH analog and antiandrogen.
Presence of hot flushes and worse outcomes on sexual field represent two aspects of maintained differentiation between MAB patients and non-cancer individuals, to the detriment of the former; and the intestinal sphere presenting significant differences as well in an time-specific fashion.
It is observed - constantly expressed in time -a worse valuation regarding subjective perception of general health condition as well as quality of life by cancer patients undergoing MAB compared to non-neoplasic individuals.
It is seen no sphere or field that maintains a significant constant worsening through the study period in MAB patients, although at early phases it does exist - in higher or lesser degree - for all aspects on study, including the valuation of subjective perception of general health condition as well as quality of life. Improvement is observed regarding the micturitional field.
MAB patients' lower academic level persists as factor of negative differentiation for HRQoL outcomes belonging to this section of the study, happening in the same form for bone scintigraphy positiveness.
Quality-of-life adjusted survival is not influenced in an essential fashion by the aspects studied.
There are factors who let the relativization of the importance traditionally given to the economic impact exerted by MAB on the total pharmaceutical expense belonging to the health are on study.
To Dr. Juan Miguel Silva Abuín, Associate Professor at the Faculty of Medicine, University of Salamanca, and Director of the Doctoral Thesis Quality of life and pharmacoeconomy in patients from Zamora's health area, diagnosed of prostate adenocarcinoma undergoing maximal pharmacological androgen suppression, part from which the report presented here is derived; and in general to all people who contributed in any way to make it come true.
Nicolás Alberto Cruz Guerra
Av. de los Reyes Católicos, 5, bajo izda.
49021 Zamora. (Spain).
Accepted for publication: December 15th, 2008.
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