Quality of life in the treatment of prostate cancer

The concept of "quality of life" is closely related to the definition of health adopted by the World Health Organization. In its framework, not only physical, but also mental and social aspects of human life are considered. In a more narrow medical framework, the concept of "health-related quality of life" is used that does not address cultural, social or political factors and allows to focus on the impact of the disease and its treatment on the quality of life of the patient. The quality of life depends on the patient's personal qualities, internal perception of the disease, psychological well-being, severity of the symptoms of the disease and / or the consequences of his treatment. All these components form a personal representation of the patient about his illness, sometimes different from the doctor's vision. Practice shows that the absence of instrumentally recorded deviations does not detract from the importance of subjective perception of the patient and does not always correspond to the latter.

[1], [2], [3], [4], [5], [6], [7], [8],

Comparative characteristics of the influence of modern methods of treatment of localized prostate cancer on the quality of life

The complexity of the choice of the method of treatment of localized prostate cancer is explained by the lack of randomized comparative studies of the three main methods: RPE, remote radiation therapy and brachytherapy. In addition to studying the effectiveness of each method, it is important to assess their impact on patients' quality of life, since it often serves as a key factor in the selection of a specific treatment strategy.

Using the questionnaire 5P-36 showed the advantages of radical prostatectomy before the remote radiation therapy and brachytherapy. During the first month, there is a significant decrease in the QoL indicator characterizing a more severe postoperative period, but after 4 months, it is noted that it has increased to the initial level. It should be noted that the initial QOL in patients undergoing RP was 7-10 points higher than in the other groups. This is explained by the fact that the age of patients who chose surgical treatment is on average 6 years less.

Despite the low incidence of postoperative complications, brachytherapy is considered the least favored method in terms of impact on the quality of life . In comparison with the control group (patients without treatment), after brachytherapy, urinary disorders (irritative symptoms and decreased voiding rate), sexual function, disorders of the gastrointestinal tract were observed. When applying remote radiation therapy, the signs of radiation damage of the intestine come to the fore: diarrhea, bleeding, obstruction. Often there is damage to the rectum: often observe the incontinence of stool due to radiation damage to the nerves that innervate the anal sphincter. The same mechanism underlies the development of erectile dysfunction.

Patients undergoing radical prostatectomy show incontinence and sexual disorders, but in general, the quality of life is considered to be the highest after surgical treatment. This can be explained by the fact that surgery is the only guaranteed way to remove a localized tumor, which gives an additional psychological stimulus for overcoming the difficulties associated with postoperative complications.

[9], [10], [11], [12], [13]

Neoadjuvant hormonal therapy and quality of life

Currently, the issue of the need for neoadjuvant hormonal therapy before RPE in patients with localized PCa remains open. Numerous studies have shown that the use of neoadjuvant hormone therapy does not increase life expectancy and does not significantly reduce the risk of relapse after surgery. At the same time, its long-term use (more than 6 months) leads to a decrease in the quality of life, deterioration in overall well-being, the development of tides, decreased libido and sexual function.

On the other hand, the use of gonadoliberin agonists (tryptorelin) with a short course of up to 3 months can significantly reduce the volume of the prostate gland, since its considerable size complicates the operation. In addition, treatment with triltorelin helps reduce intraoperative blood loss. It is important to note that the appointment of triptorelin a short course does not cause a significant decrease in libido and sexual function, patients easily transfer it. In addition, the use of tryptorelin allows you to delay the operation (without the risk of progression of the disease) and choose the most convenient time for it. The decision on the appointment of a long course is taken on an individual basis. It is indicated at a high risk of local spread of the tumor.

Hormone resistance

Antiandrogen therapy creates good conditions for the development of resistant cells, which eventually occupy most of the tumor. Obviously, in the development of stability, the key role is played by the violation of signal transmission through androgen receptors. Possible mutations of the androgen receptors that affect the expression of the genes encoding them and the sensitivity of receptors to ligands are possible. However, such mutations are found only in the part of tumor cells, and it is hardly possible to relate all cases of resistance to hormone therapy with them. Protein growth factors play an important role in the progression of the tumor. The epidermal growth factor dramatically increases the proliferation of the epithelium and prostatic stroma. It is actively produced by the tumor and acts as a paracrine growth stimulant. With resistance to hormone therapy, the importance of autocrine stimulation increases, and this protein supports uncontrolled tumor growth.

Tumors resistant to hormone therapy (hormone-resistant, hormone-independent or androgen-independent PCa) constitute a very heterogeneous group and the prognosis is different,

There are two levels of resistance to hormone therapy. It is necessary to distinguish resistance to anti-androgen therapy alone, when hormone therapy of the second line (estrogens, glucocorticoids, and anti-androgen withdrawal) can help, and resistance to all types of hormone therapy.

Criteria for resistance to hormone therapy: 

• Postastratsionny level of testosterone; 
• three consecutive elevations of the PSA level at intervals of 2 weeks, leading to a doubling of the minimum value; 
• an increase in PSA levels in the second line of hormone therapy and the concomitant withdrawal of antiandrogenic drugs for at least 4 weeks; 
• an increase in tumor foci; 
• reduction of antitumor effect.

The antitumor effect should be assessed according to standard criteria (RECIST). 80-90% of patients do not have measurable tumor foci, suitable for the application of these criteria, and the number of bone metastases in them is difficult to quantify. In patients with predominance of extraosteal metastases, the prognosis is usually worse than in patients with bone metastases. Therefore, there is no unequivocal opinion about the evaluation of the effectiveness of hormone therapy. Finally, in patients with PCa it is difficult to establish the cause of death, so it is desirable to consider the overall survival, rather than the risk of dying from a tumor.

Sometimes the effect of treatment is assessed by the dynamics of PSA level, although there are no single criteria for remission (the magnitude and duration of PSA reduction). Dynamics of PSA content allows you to quickly assess the effectiveness of new drugs. Data on the adequacy of the evaluation of remission by PSA level are contradictory, sometimes the treatment causes sharp fluctuations in the PSA level, which indicates the transitory effect of drugs on the production of PSA. Thus, in order to conclude about the effectiveness of the drug in terms of the dynamics of the PSA content, it is necessary to know how it affects the production of PSA, as well as to take into account other clinical data. Despite these limitations, it has been shown that a decrease in the initial PSA level by a factor of two or more significantly increases survival. Molecular prediction factors (eg, PSA mRNA level) are known, determined by polymerase chain reaction with reverse transcription. To reduce the pain associated with metastases in the bone, you can assess the palliative effect of treatment.

Increasingly, subjective criteria are used to evaluate the therapeutic effect. In clinical trials, it is necessary to include a sufficient number of patients, use clear criteria for efficacy and take each of them into account separately (for example, do not combine partial and complete remissions), assess the dynamics of PSA levels only in combination with other parameters, and in patients with symptom retention to determine the quality of life.

Clinical recommendations for assessing efficacy

With a PSA reduction of 50% or more for 8 weeks, survival is significantly higher than in the remaining patients.

In the presence of extraosteal metastases, the effect of treatment should be evaluated according to the criteria of REECTI.

With the expressed symptoms, the effectiveness of treatment can be assessed by their change.

[14], [15], [16]

Continuation of antiandrogen therapy

Resistance to hormone therapy means growth of the tumor against the background of castration. In such cases, it is necessary, first of all, to make sure whether the post-stress level of testosterone is determined (not higher than 20-50 ng%). Usually the effect of continuing antiandrogen therapy is small. There are no clear data on the increase in survival with prolonged treatment, however, in the absence of randomized trials, life-long anti-apoptosis therapy should be recommended, since its possible benefit is greater than the incidence and severity of side effects.

[17], [18], [19], [20], [21]

Second line hormone therapy

Hormone therapy with the progression of the process against the background of anti-androgen therapy includes the abolition or addition of anti-androgens, estrogens, inhibitors of the synthesis of steroid hormones and experimental drugs.

Abolition of antiandrogens

In 1993, the phenomenon of reducing PSA after flutamide withdrawal was described. This discovery has great theoretical and practical significance. Approximately 301 patients with progression on the background of the use of antiandrogenic drugs, their withdrawal causes remission (PSA reduction of 50% or more), lasting about 4 months. The remission is also described when bicalutamide and megestrol are discontinued.

[22], [23], [24],

Treatment after first-line hormone therapy

In addition to those cases when the level of testosterone is higher than gestational, it is impossible to predict the effectiveness of hormone therapy of the second line. For bicalutamide, the dependence of the effect on the dose has been proved: in tumors sensitive to hormone therapy, at a dose of 200 mg / day, it reduces PSA to a greater extent than at a dose of 50 mg / day. However, with the growth of PSA content against the background of castration, the appointment of antiandrogens, flumigamide or bicalutamide is effective only in a small part of the patients.

The adrenal glands produce about 10% of androgens. Despite the progression after castration, some tumors remain dependent on androgen levels and an additional reduction in their concentration with adrenalectomy or drugs that suppress the synthesis of steroid hormones sometimes causes remission. So do aminoglutetimad, ketoconazole and glucocorticoids: in a quarter of patients they cause a two-fold decrease in the level of PSA lasting about 4 months.

Tumor cells contain estrogen receptors. In animal experiments, castration has been shown to enhance their expression. In vitro experiments have shown that estrogens can stimulate mutant androgen receptors isolated from tumors resistant to anti-androgen therapy. Antiestrogens cause remission in 10% of patients. The cases of remission are described against the background of high doses of estrogens. Their action is associated with a violation of mitosis and a direct cytotoxic effect, probably due to the induction of apoptosis. However, even at low doses, dysylsgilbestrol can cause deep vein thrombosis in 31% of patients and myocardial infarction - in 1% of patients.

Clinical recommendations for symptomatic therapy

To prevent complications with metastases in the bone, bisphosphonates (zoledronic acid) are recommended.

Symptomatic therapy (introduction of isotopes, remote radiation, analgesics) should be prescribed at the first occurrence of pain in the bones.

[25], [26], [27], [28], [29], [30]

Disorders of urination in patients after radical prostatectomy

Among urinary disorders after radical prostatectomy, urinary incontinence is dominant. According to the study, Karakevich et al. (2000), this complication is a major factor in the decline in the quality of life after radical prostatectomy. It is met in 15-60% of cases. Such a large range of values is explained by the fact that in many cases urinary incontinence is a temporary phenomenon that occurs on its own after a few weeks or months.

Unlike the nerve-preserving variant, the application of the traditional RP technique doubles the duration of the recovery period of the function of the sphincter apparatus.

[31], [32], [33]

Control of the bladder

Another important factor affecting the frequency of urinary incontinence is the age of the patient. The incidence of prolonged incontinence (more than two years) in patients aged 60-69 years is 5-10%, in patients older than 70 years - 15%. Only 61% of patients one year after treatment are able to retain urine at the preoperative level, but after 6 months 90% of patients do not use pads. Thus, despite the preservation of functional disorders from the sphincter apparatus 6 months after the operation, this does not cause patients significant concern.

If urinary incontinence persists for an extended period, collagen injections or artificial sphincter implantation are possible, but only 3% of patients use such measures. It is important to note that the longest incontinence is observed in patients who have noted such a symptomatology before the operation.

[34], [35], [36], [37], [38], [39]

Sexual disorders after radical prostatectomy

Impotence (erectile dysfunction) is a frequent complication of RP, which significantly affects the quality of life of patients. This confirms the fact that many men in choosing a method of treatment of prostate cancer are not focused on a large expected life expectancy, but on preserving potency. The vast majority of patients face this problem in the first months after the operation. The subsequent restoration of normal sexual function is variable and depends on the presence of sexual disorders before surgery, hormonal status, the use of the nerve-sparing technique of radical prostatectomy. However, even with the preservation of the neurovascular bundles, the restoration of the erectile function may take months or even years. It is considered justified to enhance the erection with the use of medications: tableted phosphodiesterase-5 inhibitors, urethral suppositories, intracavernous injections of prostaglandin preparations, and the use of vacuum devices. Endoprosthetics of the penis is considered a highly effective method of correcting erectile dysfunction. Unfortunately, the majority of men aged 65 years and older do not complete a full self-restoration of erectile function compared to the preoperative level, but a significant number of patients adapt or apply the above-mentioned means to achieve a satisfactory level of sexual activity. The younger patients (40-60 years) after performing nerve-sparing RP are much more likely to have a full sexual intercourse without using any additional therapy. Talcott et al. (1997) showed that, despite the lower frequency of erectile dysfunction after performing nerve-sparing RP in comparison with the traditional technique, the level of dissatisfaction with sexual activity in such patients is the same.

Practice shows that sexual disorders provide patients with significantly less inconvenience than micturition disorders. This can be explained by the elderly age of patients, many of whom did not live a sexual life before the operation, and the absence of an erection in the postoperative period does not negatively affect the quality of their life. According to the study, 75% of patients were satisfied or adapted to postoperative changes in sexual functions, only 12% of patients noted a full erection. This fact must be taken into account when choosing a method of treatment.

Quality of life in the treatment of patients with localized prostate cancer

In modern literature, much attention is paid to the quality of life problem in patients with prostate cancer (PCa) after completion of treatment.

All modern methods of treating prostate cancer entail serious and prolonged complications, while it is impossible to single out the most effective method among others. For most cancers, 5-year survival rate often serves as a cure indicator, while mortality from localized PCa in the first 5 years, on the contrary, is a rare phenomenon.

Thus, a significant life expectancy dictates the need to take into account the patient's opinion when choosing therapeutic tactics, and the consequences of treatment should not be heavier than the disease itself. In connection with this, more and more attention in recent years has been paid not only to the effectiveness of the method of treatment, but also to its influence on the patient's quality of life.

Chemotherapy for prostate cancer and quality of life

Some chemotherapy regimens have shown efficacy in prostate cancer, which is resistant to hormone therapy. In two recent trials with docetaxel therapy, the median survival was increased by approximately 2 months compared with the mitoxantrone + prednisolone regimen. The TAH-327 trial included 1006 patients who received mitoxantrone (12 mg / m ² every 3 weeks-the first group) or docetaxel (75 mg / m ² every 3 weeks - the second group, 30 mg / m ³ weekly for 5 consecutive weeks with a break for 1 week - the third group), the median survival was 16.5, respectively; 18.9 and 17.4 months; the frequency of remission (PSA decrease by 2 times and more) - 32, 45 and 48%; the proportion of patients with marked reduction of pain 22, 35 and 31%. Side effects in all three groups were similar, but the quality of life against docetaxel was significantly higher.

In the SWOG 99 trial, 16,674 patients received mitoxantrone (12 mg / m ² every 3 weeks) or docetaxel (60 mg / m ² every 3 weeks) with estramustine. The median survival was 15.6 and 17.5 months, respectively; the median time to progression was 3.2 and 6.3 months; the frequency of remissions (PSA reduction) is 27% and 50%. Reduction of pain in both groups was the same, but side effects on the background of docetaxel appeared significantly more often.

The optimal time to start chemotherapy is unknown, since its effectiveness at only an increase in the level of PSA on the background of hormone therapy has not been studied. The decision to switch to chemotherapy is taken individually, sometimes it is recommended to start it after two consecutive elevations of the PSA level and reaching its level more than 5 ng / ml.

In tests on the combined use of gaxans with antisense oligonucleotides, calcitriol, excisulind and thalidomide, the remission rate reaches 60%. In a small randomized trial with a combination of docetaxel (30 mg / m ² weekly for 3 consecutive weeks with a break for 1 week) and thalidomide (200 mg / day inwards), the remission rate was higher (53%) than with monotherapy with docetaxel (37% ); the median time to progression was 5.9 and 3.7 months, respectively; year survival of 68% and 43%. However, the addition of thalidomide therapy increased the risk of complications (including thromboembolic) from 0 to 28%.

Much attention is paid to the combination of mitoxantrone with glucocorticoids for bone pain associated with metastasis. In the "SALGV 9182" test, 244 patients received hydrocortisone or hydrocortisone with mitoxantrone (12 mg / m ² every 3 weeks). The frequency of remission, the time to progression and the quality of life with the addition of mitoxantrone were significantly higher. In another study, which included 161 patients, the addition of mitoxantrone to prednisolone significantly increased the analgesic effect (29 and 12%) and the duration of the symptomatic effect (43 and 18 weeks). The frequency of remission and the median survival coincided with those without the use of mitoxantrone. Although none of these tests showed an increase in survival, in connection with the reduction of pain, the quality of life against mitoxanthropic background was significantly improved.

In preliminary trials, conjugated doxorubicin, paclitaxel + carboplatin plus estramustine, vinblastine + doxorubicin in combination with isotopes, docetaxel + mitoxantrone showed good results. Randomized trials were not conducted.

[40], [41], [42], [43]

Forecast

Despite numerous attempts to use tissue and serum markers, the degree of differentiation of tumor cells and the stage of the disease are considered to be the most important factors in predicting tumor disease. In patients with a highly differentiated tumor, a high tumor-specific survival is noted. In patients with a low-grade tumor or with localized prostate cancer with germination of the prostatic capsule (T ₃ ), the prognosis is extremely unfavorable.

[44], [45], [46], [47], [48]