**4. Side effects of androgen suppression therapy**

The well-known side effects of CAS like sexual dysfunction, hot flushes, fatigue, cardiovascular complications, osteoporosis, weight gain and anemia have significant implications for quality of life (Malone, *et al.,* 2005; Freedland, *et al*., 2009; Galvão, *et al*. 2009). Since androgens are essential for the regulation of fat distribution, insulin sensitivity and lipid and bone metabolism, recent publications focussed on the concept that CAS may also be associated with an increase in overall and in particular cardiovascular morbidity and mortality (Corona, *et al*., 2011). A multivariate analysis by Saigal and colleagues evaluating over 22,000 men concluded that patients receiving CAS had a 20% higher risk of cardiovascular morbidity (Saigal, *et al*., 2007). CAS leads to increased incidence of osteoporosis and concomitant bone fractures (Kiratli, *et al*., 2001). Therefore, it was expected that off-treatment periods during IAS would allow for recovery of testosterone levels and cessation of bone material degradation. With regards to bone loss, a large, retrospective study evaluated more than 50,000 men with prostate cancer, showing increased occurrence of bone fracture in the CAS group (19.4% vs 12.6%). There was a significant relationship between the number of CAS doses and fracture risk (Shahinian, *et al*. 2005). In the elderly population of prostate cancer patients increased incidence of osteoporosis and resulting bone fractures are of major concern. Higano and colleagues observed loss of bone mineral density during 9 months of androgen suppression significantly greater than the expected 0.5%-1% annual loss in IAS; however, interruption of androgen suppression attenuated the rate of bone loss without full recovery (Higano, *et al*., 2004).

In the study by Malone and colleagues, general loss of potency occurred during the treatment period, but was regained by half of the evaluable patients when therapy was withdrawn (Malone, *et al*., 2005). There was no significant overall change in body mass index at the end of the treatment periods. Osteoporosis was documented for at least one site evaluated in one third of the patients. Quality of life and sexual function seem to follow testosterone normalization (Mearini, *et al*., 2011). Phase II clinical trials demonstrated improved sexual function and quality of life in men undergoing IAS (Dawson, 2000). The average percentage of time spent off androgen deprivation ranges from 37%-58% and most men were responsive to retreatment with hormonal therapy. While IAS seems feasible and holds the potential to improve quality of life of the patients, the degree of reversal of the long-term side effects of androgen suppression still remains to be confirmed.

#### **4.1 Bone matrix turnover and androgen suppression therapy**

Our group examined the effect of IAS on bone metabolism by determinations of CrossLaps levels, a biochemical marker of collagen degradation in blood samples of prostate cancer patients. These measurements revealed that increased bone degradation, which was associated with the androgen suppression phases, was rapidly reversed during treatment cessation periods, in good agreement with the clinical observations of reduced loss of bone mineral density (BMD) in IAS (Theyer, *et al.,* 2010). 140 patients have been recruited since 1993, with first patients reaching their seventh treatment cycle (Theyer & Hamilton, 1998). All patients with disseminated adenocarcinoma of the prostate fulfilling the inclusion criteria of a histologically confirmed tumor, stage ≥T2, not having received pretreatment by hormone ablation or chemotherapy and PSA >6 ng/ml were recruited for a nonrandomized open IAS trial consisting of an initial 8 months course of androgen suppression (goserelin acetate/Zoladex® and cyproterone acetate/ Androcur®), followed

The well-known side effects of CAS like sexual dysfunction, hot flushes, fatigue, cardiovascular complications, osteoporosis, weight gain and anemia have significant implications for quality of life (Malone, *et al.,* 2005; Freedland, *et al*., 2009; Galvão, *et al*. 2009). Since androgens are essential for the regulation of fat distribution, insulin sensitivity and lipid and bone metabolism, recent publications focussed on the concept that CAS may also be associated with an increase in overall and in particular cardiovascular morbidity and mortality (Corona, *et al*., 2011). A multivariate analysis by Saigal and colleagues evaluating over 22,000 men concluded that patients receiving CAS had a 20% higher risk of cardiovascular morbidity (Saigal, *et al*., 2007). CAS leads to increased incidence of osteoporosis and concomitant bone fractures (Kiratli, *et al*., 2001). Therefore, it was expected that off-treatment periods during IAS would allow for recovery of testosterone levels and cessation of bone material degradation. With regards to bone loss, a large, retrospective study evaluated more than 50,000 men with prostate cancer, showing increased occurrence of bone fracture in the CAS group (19.4% vs 12.6%). There was a significant relationship between the number of CAS doses and fracture risk (Shahinian, *et al*. 2005). In the elderly population of prostate cancer patients increased incidence of osteoporosis and resulting bone fractures are of major concern. Higano and colleagues observed loss of bone mineral density during 9 months of androgen suppression significantly greater than the expected 0.5%-1% annual loss in IAS; however, interruption of androgen suppression attenuated the

In the study by Malone and colleagues, general loss of potency occurred during the treatment period, but was regained by half of the evaluable patients when therapy was withdrawn (Malone, *et al*., 2005). There was no significant overall change in body mass index at the end of the treatment periods. Osteoporosis was documented for at least one site evaluated in one third of the patients. Quality of life and sexual function seem to follow testosterone normalization (Mearini, *et al*., 2011). Phase II clinical trials demonstrated improved sexual function and quality of life in men undergoing IAS (Dawson, 2000). The average percentage of time spent off androgen deprivation ranges from 37%-58% and most men were responsive to retreatment with hormonal therapy. While IAS seems feasible and holds the potential to improve quality of life of the patients, the degree of reversal of the

Our group examined the effect of IAS on bone metabolism by determinations of CrossLaps levels, a biochemical marker of collagen degradation in blood samples of prostate cancer patients. These measurements revealed that increased bone degradation, which was associated with the androgen suppression phases, was rapidly reversed during treatment cessation periods, in good agreement with the clinical observations of reduced loss of bone mineral density (BMD) in IAS (Theyer, *et al.,* 2010). 140 patients have been recruited since 1993, with first patients reaching their seventh treatment cycle (Theyer & Hamilton, 1998). All patients with disseminated adenocarcinoma of the prostate fulfilling the inclusion criteria of a histologically confirmed tumor, stage ≥T2, not having received pretreatment by hormone ablation or chemotherapy and PSA >6 ng/ml were recruited for a nonrandomized open IAS trial consisting of an initial 8 months course of androgen suppression (goserelin acetate/Zoladex® and cyproterone acetate/ Androcur®), followed

long-term side effects of androgen suppression still remains to be confirmed.

**4.1 Bone matrix turnover and androgen suppression therapy** 

**4. Side effects of androgen suppression therapy** 

rate of bone loss without full recovery (Higano, *et al*., 2004).

by treatment cessation and resuming of the therapy upon increases of PSA >4 and >20 ng/ml, respectively. Serum testosterone was measured using an ELISA assay (Biomar Diagnostics, Marburg, Germany) according to the manufacturer´s instructions. PSA was determined by the microparticulate enzyme immunoassay (MEIA, AxSYM PSA assay, Abbott, USA). CrossLaps ELISA was obtained from Nordic Bioscience Diagnostics, Herlev, Denmark, and used according to the manufacturer´s instructions (Rosenquist, *et al*., 1998). This assay is used for follow-up of anti-resorptive treatment of patients with metabolic bone diseases (Okabe, *et al*., 2004).

Amino-terminal propeptide of type I procollagen (PINP) and PSA were determined using the Elecsys 2010 Chemistry Analyzer (Roche Diagnostics, Vienna, Austria). All patients (n=75; mean age ±SD: 68±7 years, range: 53-84 years) exhibited progression of disease without metastases following radical prostatectomy and/or irradiation therapy. The lengths of the treatment cessation periods (mean ±SEM) for the respective off-treatment cycles (I–VI) in months were: 16±2 (n=75), 10±1 (n=31), 8±2 (n=18), 8±1 (n=12), 10±2 (n=8), 7±6 (n=2), respectively. The first treatment cessation period (PI) was significantly longer compared to the following breaks, which were not significantly different among each other. Individual time courses of testosterone and CrossLaps for a representative patient and four IAS cycles is depicted in figure 3A.

CrossLaps are elevated during androgen suppression phases indicating bone matrix degradation and normalize during treatment cessation periods on a regular basis (Theyer, *et al*., 2010). After a prolonged time without androgen suppression, CrossLaps values exhibited a gradual increase, most likely due to regrowth of the tumor (data not shown; Nguyen-Pamart, *et al*., 1997). Time courses of PINP and PTH were compared with PSA during the same IAS cycles in further measurements (figure 3B). The results show that PINP is a suitable alternative parameter for the assessment of bone matrix turnover during androgen suppression phases that are accompanied by low PSA levels. The parallel course of blood PTH indicates a participation of this hormone in androgen suppression-induced bone loss. This finding corroborates reports of decreased loss of BMD in bone scans in prostate cancer patients under IAS therapy. Since pretreatment concentrations of CrossLaps were restored within several months of therapy cessation and mean duration of the off-treatment periods ranged from 8–16 months in our patients, this protective effect of IAS is expected to be effective for several treatment cycles (Theyer, *et al*., 2010). The bone matrix synthesis product PINP was used to assess bone turnover in metastatic prostate and breast cancer among other malignancies (Jung, *et al*., 2011; Koopmans, *et al.,* 2007; Pollmann, *et al*., 2007). Studies in metastatic prostate cancer patients showed that both PINP and ICTP (carboxy-terminal telopeptide of type I collagen) were most indicative of predicting metastatic progression and skeletal complications, respectively. Although androgen deprivation has been associated with bone loss in patients with prostate cancer, its mechanism remains unclear. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1)/parathyroid hormone (PTH) axis that plays a critical role in bone synthesis was investigated during CAS (Isahaya, *et al*., 2010). PTH is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids and effects to increase the concentration of calcium in blood (Poole & Reeve, 2005). The serum PTH level was reduced after CAS by approximately 25% compared with baseline levels, concomitant with increases of bone resorption markers like blood and urinary N-telopeptides (NTx), in good agreement with our measurements during androgen suppression in IAS cycles.

Intermittent Androgen Suppression Therapy

**A**

**PSA (ng/ml)**

**Testosterone**

 **(ng/ml)**

**B**

**C**

**Erythrocytes**

**Hemoglobin**

 **(g/dl)**

**(x106/µl)**

**25**

**30**

**35**

**Hematocrit**

 **(%)**

**40**

**45**

**50**

for Prostate Cancer Patients: A Choice for Improved Quality of Life? 373

**<sup>40</sup> PSA Testosterone**

**Time point**

**Time point**

**Time point**

Fig. 4. (A) Time courses of testosterone and PSA, (B), hemoglobin and erythrocyte count and (C) and hematocrit are shown for 3 cycles of IAS for a typical prostate cancer patient.

**Erythrocytes Hemoglobin**

**Hematocrit**

Fig. 3. (A) Individual time courses of testosterone and CrossLaps levels for a representative patient under IAS. Values cover androgen suppression phases (I–IV) and treatment cessation periods (I/P-IV/P). (B) Time courses of PSA, PINP and PTH are shown for the same patient.

#### **4.2 Anemia and intermittent androgen suppression**

Anemia was previously reported as a common side-effect of CAS. In an IAS study involving 95 patients receiving 245 cycles the median duration of resting periods was 8 months and median time to treatment failure 47 months (Malone *et al*., 2005). Testosterone recovery during treatment cessation was observed in 60% of cycles with mild anemia, which was more frequently detected in successive cycles (33%, 44% and 67%). Thus, the observed anemia (hemoglobin level of < 30 g/l) was normochromic, normocytic, temporally related to the initiation of CAS and usually resolved after discontinuation of therapy in half of the cases. The improvement in hemoglobin during the off-treatment intervals probably contributes to improvements in the sense of well-being and vitality in these patients.

We collected data regarding anemia in our prostate cancer patients and a typical course of erythrocyte count, hemoglobin content and hematocrit is shown in figure 4. The data show that small decreases and increases in erythrocyte parameters coincide with IAS phases and levels of PSA. Such determinations can be used to assess the extent of anemia and the impact of treatment cessations on erythropoiesis.

**PINP PTH PSA**

**CrossLaps Testosterone**

**Time point**

Fig. 3. (A) Individual time courses of testosterone and CrossLaps levels for a representative patient under IAS. Values cover androgen suppression phases (I–IV) and treatment cessation periods (I/P-IV/P). (B) Time courses of PSA, PINP and PTH are shown for the same patient.

Anemia was previously reported as a common side-effect of CAS. In an IAS study involving 95 patients receiving 245 cycles the median duration of resting periods was 8 months and median time to treatment failure 47 months (Malone *et al*., 2005). Testosterone recovery during treatment cessation was observed in 60% of cycles with mild anemia, which was more frequently detected in successive cycles (33%, 44% and 67%). Thus, the observed anemia (hemoglobin level of < 30 g/l) was normochromic, normocytic, temporally related to the initiation of CAS and usually resolved after discontinuation of therapy in half of the cases. The improvement in hemoglobin during the off-treatment intervals probably

contributes to improvements in the sense of well-being and vitality in these patients.

We collected data regarding anemia in our prostate cancer patients and a typical course of erythrocyte count, hemoglobin content and hematocrit is shown in figure 4. The data show that small decreases and increases in erythrocyte parameters coincide with IAS phases and levels of PSA. Such determinations can be used to assess the extent of anemia and the

**Time point**

**A**

**B**

**CrossLaps**

**Testosterone**

 **(ng/ml)**

**(x10 ng/ml)**

**PINP, PSA (ng/ml)**

**PTH (pg/ml)**

**4.2 Anemia and intermittent androgen suppression** 

impact of treatment cessations on erythropoiesis.

Fig. 4. (A) Time courses of testosterone and PSA, (B), hemoglobin and erythrocyte count and (C) and hematocrit are shown for 3 cycles of IAS for a typical prostate cancer patient.

Intermittent Androgen Suppression Therapy

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