Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients

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1 (2004) 7, & 2004 Nature Publishing Group All rights reserved /04 $ Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients P Rodrigues 1, F Hering 1 & JC Campagnari 1 1 Beneficência Portuguesa Hospital of São Paulo and Santa Helena Hospital of São Paulo, São Paulo, SP, Brazil Introduction: Approximately 85% of patients who die from prostate cancer present the spread of bone metastases. Even though the radiological appearance of such metastases is osteoblastic, it is now known that these lesions coexist in their microenvironment with blastic and lytic lesions. The process always begins with bone lysis by osteoclast proliferation, paralleling nearby bone deposition. The treatment options are palliative and have poor clinical response with short-lived improvement. We have studied the clinical effect of bisphosphonates (clodronate) in the treatment of skeletal complications from prostate cancer. Materials and Methods: In an open prospective study, 58 patients with hormonerefractory prostate cancer with bone metastases were assessed from November 2000 to September The mean age was 70.3 y (range: y). Bone scintigraphy, plain X-ray, assaying of prostate-specific antigen (PSA) and biochemical tests were requested before and following treatment. Patients were previously and subsequently assessed using the visual pain scale (0 10) and Karnofsky s index after the first and second intravenous (i.v.) infusions (administration of i.v. clodronate every 28 days) and every 4 6 months thereafter. Student s t-test was used for statistical analysis. Results: A total of 53 patients (91.4%) showed improvement after the first and/or second cycle, which persisted for at least 4 months (average 6.3 months). The averages on the visual pain scale improved from 7.4 (range: 2 8) to 2.4 (0 7) and on Karnofsky s index from 43 (32 58) to 73 (50 82). The radiological appearance of the metastases improved in 27 patients (46.5%) and there were few relapses (six patients; 10.3%). Conclusions: Clodronate was effective in the treatment of skeletal complications from prostate cancer. There was an objective response in 91.4% of treated patients, with a marked improvement in the subjective visual pain scale evaluation as well as on Karnofsky s index, with low side effects. (2004) 7, doi: /sj.pcan Published online 9 November 2004 Keywords: prostate carcinoma; prostate metastasis; bone metastasis, bisphosphonates; pain palliation Introduction The incidence of prostate carcinoma has greatly increased over the last decade and it is now the most Correspondence: P Rodrigues, Rua Maestro Cardim andar, Paraíso- São Paulo, SP, CEP , Brazil. paulortrodrigues@aol.com Received 9 December 2003; revised 15 May 2004; accepted 22 June 2004; published online 9 November 2004 common type of noncutaneous cancer found in men over 50 y. Today, even with all the efforts towards early detection, 20% of patients already present bone metastases at the time of diagnosing prostate cancer. Considering that about 30% of patients who receive treatment for localised prostate cancer present a relapse, the number of patients with advanced disease is significantly high. Most of such patients who are undergoing hormone treatment become refractory to hormonal management

2 after a time of months, despite the therapy, and 85 95% of them will present bone metastases and their complications such as pain, fractures and paralysis. 1,2 Patients with bone metastases have an average survival of 30 months, which is a very long time and requires therapies directed towards treating the pain from the metastases or the complications related to pathological fractures. 2 4 Bone metastases from prostate cancer are viewed via plain radiography as osteoblastic lesions. However, this concept is outdated, since it is known that lytic lesions are always present in the microenvironment and are caused by tumoral prostatic cells that interrupt normal bone remodelling through irregular stimulation of osteoclasts and osteoblasts. Following the formation of the lytic lesion, excessive deposition of lamellar bone in the lacunae takes place, thus giving rise to the osteoblastic appearance. This mechanism results in osteosclerosis, thereby increasing the bone volume and destroying the normal bone. 5,6 Bisphosphonates have been widely employed in treating bone metastases caused by breast cancer and multiple myeloma, with excellent results. They are potent inhibitors of both normal and pathological bone reabsorption, exerting a depressant effect on mature osteoclasts and inhibiting the stimulation of osteoblasts, thereby decreasing skeletal complications. 7 The present study has evaluated the clinical effect of bisphosphonates (clodronate) in patients with bone metastases due to hormone-refractory prostate adenocarcinoma. Materials and methods Between November 2000 and September 2003, 58 patients with bone pain due to metastases from advanced hormone-refractory prostate adenocarcinoma were prospectively evaluated and treated with clodronate in an open study. This study was preceded by a review of the literature and approval of the study protocol from the Ethics Committees of the hospitals involved. The patients mean age was 70.3 y (range: 51 87) and they presented progressive bone disease confirmed radiologically or by scintigraphy, or they presented increasing bone pain. Before these patients were enrolled on this treatment protocol, 16 had undergone orchiectomy. A total of 19 patients were using cyproterone acetate, 13 used LH-RH analogues, two used bicalutamide and eight use oestrogens. All the patients presented castrated levels of testosterone (o50 ng/dl). Mitoxantrone and corticoids were being administered to nine patients following hormonal blockade failure. Six patients were receiving estramustine phosphate, four used ketoconazole with corticoids and three used PC- SPES to control pain and disease progression, as measured by increasing prostate-specific antigen (PSA) or pain. A total of 38 patients were taking nonopioid analgesics due to pain at the time of enrolment. These medications were all suspended when the clinical or biochemical response ceased. Patients were considered to be hormone-refractory after three consecutive increases in PSA, despite the above-mentioned therapy, over 6 months of follow-up. After patients were enrolled, the various drugs they had been using were suspended and bisphosphonates were administered alone with no other analgesics. Further analgesic usage was carefully evaluated by the authors. Before the administration of the first clodronate dose, patients underwent skeletal mapping to record the quantity and location of metastases. Every point with hypercaptation highly suggestive of metastases was radiographed. Improvements seen via radiological imaging were subjectively evaluated by the authors on the basis of the intensity and quantity of metastasis seen on bone scintigraphy. Skeletal events necessitating radiotherapy for pain palliation of fracture treatment were deemed to be evidence of failure and/or progression. All patients were asked to estimate their pain on a visual pain scale from 0 to 10 (no pain to very strong pain), at every visit, and their general condition was assessed via Karnofsky s index. Patients were deemed responsive to clodronate if the visual pain scale diminished by more than five points, irrespective of the initial pain measurement. The patients were contacted every 14 days: either they revisited or they were called by telephone). After 4 6 months of treatment, the patients underwent bone scintigraphy again, for comparison with the initial result. Radiographs of metastasis locations were also taken. Monthly determinations of PSA, phosphatases, calcium, creatinine and transaminases were made, and hemograms with the erythrocyte sedimentation rate were produced. Clodronate was administered intravenously every 28 days at a dosage of 1500 mg (five vials of 300 mg diluted in 500 ml of saline solution infused over two hours). The procedure was carried out as at an outpatient basis without requiring admission to hospital. Following the infusion, the patient was released for his normal activities. For parametric and nonparametric statistical analysis of variations in the pain scale and Karnofsky s index, Student s t-test was used for comparing data before and during treatment. Results According to the visual pain scale, 53 patients (91. 4%) responded to treatment with intravenous bisphosphonate. The average value on the visual pain scale before treatment was 7.4 (range: 2 9) and after treatment it decreased to 2.4 (range: 0 7) (Table 1). Predominantly, osteoblastic lesions were observed in 46 cases (79.2%), while osteolytic lesions were observed in the remaining 12 cases (20.8%). A radiological improvement in the metastases was observed in 27 patients (46.5%) after the first 6 months. Osteoblastic patients showed a response in 47.8% of the cases (22 out of 46), while only 8.6% of the osteolytic lesions (five cases out of 12) presented radiological improvement (Table 2). The pelvic bones were the site most frequently affected by metastases (29.3%; 17 cases), followed by the lumbar column (15.5%; nine cases) and hips (5.1%; three cases). However, scattered lesions were the predominant type (50%; 29 cases). 351

3 352 Table 1 Improvement in pain according to visual scale after two cycles of bisphosphonate in 58 treated patients Pain scale level following clodronate administration Patients % Diminished Z5 points after treatment Diminished o5 points after treatment Without improvement Total with improvement Table 2 Improvement in radiological imaging in 27 responsive patients after treatment with clodronate Type N Radiological response according to the type of the lesion (% of whole group) Osteoblastic Osteolytic Total Table 4 Exclusively biochemical response in 14 patients with advanced hormone-refractory prostate cancer whose PSA was diminished after 6 months of treatment with intravenous clodronate Patient Before treatment After treatment Average Among the 53 responsive patients, the average Karnofsky s index score improved from 43 (range: 32 58) to 71 (range: 50 82) (Table 3). Four patients (6.8%) did not respond to clodronate and required opioids just after the first two intravenous administrations of clodronate. A total of 22 patients (37.9%) completely stopped using analgesics during the first 6 months of this protocol, while 24 (41.4%) controlled their pain with nonsteroidal nonopioid antiinflammatory drugs during these initial 6 months but exclusively after 2-months of analgesic-free period. Disease progression led to the use of narcotics by eight of the 25 patients who completed more than 24 months of follow-up. The patients completed an average of 8.8 cycles (range: 2 32) before progression became evident. The median PSA was 54 (mean: ; range ). The comparable PSA response before and after treatment did not show any trend, with only 14 cases (24.1%) presenting objective reduction that was not related to radiological response (not shown) (Table 4). There were minimal side effects. Four patients had mild digestive disorders and two had superficial phlebitis in the infused arm (Table 5). Discussion Bone metastases are the most frequent event in advanced prostate cancer. It is known that approximately 85% of patients who die from prostate carcinoma have skeletal Table 5 Side effects reported by 58 patients treated with clodronate for advanced hormone-refractory prostate cancer Type Patients % Superficial phlebitis Diarrhoea Slight digestive disorders Abdominal pain Total lesions and related complications such as pain, pathological fractures or spinal compression. 4 On the basis of clinical and experimental studies, it can be concluded that bone metastases in prostate and breast cancer have similar behaviour. Bisphosphonates are widely employed and accepted as an adjuvant treatment for breast cancer, with excellent clinical and radiological results. 6,8 Recent research has demonstrated that, both in multiple myeloma and in prostate or breast cancer, the key to the formation of lesions is increased osteoclastic activity that promotes bone lysis. Subsequently, there will be excessive and disordered deposition of sclerotic bone because of the increased osteoblastic activity (osteoblastosis). In prostate cancer, such deposition is what most often confers the radiological appearance of an osteoblastic lesion. 7 Cancerous cells detach from the prostate, reach the blood circulation and are attracted to bone by local and distant chemotactic factors inside bones. PSA, bone sialoprotein (BSP), thymidine phosphorylase (TP) and bone morphogenetic protein-6 (BMP6) share a biochemical specificity towards bone, thereby predisposing Table 3 Summary of data on 58 patients who underwent treatment with clodronate scored by Karnofsky s index Parameters No. of patients Before treatment After treatment Average on pain scale for patients with no response Average Karnofsky s index score for patients with no response (38 69) 60.4 (38 72) Average on pain scale for responsive patients Average Karnofsky s index score for responsive patients (32 58) 73.3 (50 82)

4 detached cells to land on fertile soil where metastasis can develop The release of local paracrine factors that promote the initial bone absorption is triggered by osteoclast activation, thereby initiating the lytic lesion. Factors that promote increased osteoblastic activity are subsequently released in anarchic patterns that allow excessive bone deposition over the initial lytic lesion. Bisphosphonates cause a decrease in osteoclast activity, thereby inhibiting bone lysis. They also cause decreased osteoblast activity, which prevents the hyperactivity among these cells (osteoblastosis) that would culminate in excessive bone formation. Direct cytotoxic action on the tumour has also been described, with the inhibition of angiogenesis and promotion of direct apoptosis of cancerous cells, in addition to inhibition of metalloproteases and cytokines. 1,6,8,11,12 Bisphosphonates can be divided into two large groups: aminobisphosphonates (NBPs: pamidronate, ibandronate, alendronate and zoledronate) and nonamino bisphosphonates (non-nbps: clodronate and etidronate). Differently from non-nbps, NBPs do not have a nitrogen atom in their formulation, which give them a different mechanism of action at the molecular level. While NBPs act inside cells, inhibiting the mevalonate cycle, non- NBPs act by promoting direct cytotoxicity towards osteoclasts and osteoblasts, thereby inducing apoptosis and inhibiting the ATP/ADP translocase enzyme. 13,14 The differences in pharmacological action between the groups determine their effects on the inflammatory process. Non-NBPs such as clodronate have anti-inflammatory action and antirheumatic activity, whereas this is not well established in NBPs. 14 Preclinical studies have demonstrated that osteolytic lesions always precede the abnormal bone deposition (osteoblastosis) that gives the osteoblastic appearance to the majority of metastatic skeletal lesions from prostate cancer. 7 It has been shown through biopsies of metastatic skeletal lesions that excessive bone absorption occurs at these sites, in the same way as it occurs in breast cancer. 6,7 The rationale for using bisphosphonates in the treatment of prostate cancer comes from studies that have demonstrated their beneficial effects in inhibiting the invasion of prostatic cancerous cells as well as their adherence to and lysis of bone matrix. As already mentioned, bisphosphonates have been used in the treatment of breast cancer and multiple myeloma since the early 1980s, with excellent clinical results. However, it was only at the beginning of the 1990s that the first studies using bisphosphonates in the treatment of prostate cancer appeared. 8,13 The first study using bisphosphonate in the treatment of prostate cancer was conducted with clodronate by Adami et al in In this study, 17 patients with osteoblastic metastases were treated by administering 300 mg of intravenous clodronate daily for 14 days and 3200 mg orally for a further 4 11 weeks. A significant improvement in 16 patients (94.1%) was observed, in relation to pain and Karnofsky s index, for 4 8 weeks. 14 Vorreuther 15 administered intravenous clodronate to 41 patients with skeletal lesions due to prostate cancer, at a dosage of 300 mg daily for 8 days, along with 1600 mg orally. It was observed that 20 patients (71%) presented significant reduction in pain as early as the first 3 5 days, with nine patients continuing to show response thereafter. Heidenreich et al 16 treated a larger group of 85 patients with skeletal complications due to metastatic prostate cancer. The dose was 300 mg of intravenous clodronate daily for 8 days and 1600 mg daily by oral route for maintenance. A response rate of 75% was observed in the group, with an improvement in Karnofsky s index from 45 to 70%, while 19 patients (22%) persistently showed no response. The studies mentioned above corroborate our results. The results from Adami et al 14 were reproduced in our study: more than 90% of our patients had a significant reduction in pain, with 49 patients improving by more than five points on the pain scale and an improvement in Karnofsky s index from 42% (range: 32 55%) to 71% (range: 50 82%) following intravenous treatment with clodronate. 14 In our study, we used intravenous clodronate in bolus at a dose of 1500 mg (five vials containing 300 mg), diluted in 500 ml of saline solution and applied over a 2-h period every 28 days, performed on an outpatient basis. Side effects were observed in only 10.3% of cases and these were mild and transitory drawbacks. They did not preclude further administration, as occurred in Vorreuther s series. 15 The intravenous route was chosen because previous studies 17 showed that the oral route was highly correlated with adverse gastrointestinal effects that led to reductions in the drug dose. Following intravenous administration, 70 80% of the active substance is cleared via the urine within 24 h. An additional advantage claimed for clodronate is precisely the possibility for oral usage, as demonstrated in clinical scenarios. 15,16,18 However, when Smith 19 used oral etidronate, he did not observe an improvement in patients in relation to the placebo group, possibly because the low absorption by this route became ineffective and failed to reproduce the improvement observed by others. In a more recent series, Dearnaley et al 17 also failed to show an improvement among 311 patients who were randomly assigned to oral clodronate (2080 mg/day) or a matching placebo group, after 59 months of follow-up. An average increase of 8.7 months in survival was observed in the group with the active drug. Patients who were free of symptomatic bone progression also showed a favourable trend in the group with the active drug, with a 21% reduction in bone metastasis. This did not, however, reach statistical significance or have an impact on the overall survival. This effect may be explained by the direct action that clodronate exerts over metastatic tumoral cells, as shown by others. 8,12 However, a deeper look into Dearnaley et al s 17 study reveals that it was composed of subjects with an average PSA of 5.0 ng/dl, while our series essentially consisted of more advanced cases (average PSA of 54), which may explain the lack of clinical response in Dearnaley s study. Moreover, the oral route (which has around 2% bioavailability) is associated with a marked effect from food intake on clodronate absorption, and this may favour the intravenous route when this drug is considered. This may also explain the pain control obtained in a randomised controlled trial that favoured intravenous pamidronate over oral clodronato. 20 The severity of the disease may be an important issue for debate when 353

5 354 studying the effect of bisphosphonates in the treatment of metastatic prostate cancer. Patient characteristics may influence the clinical response, as pointed out by Ernst et al, 21 who failed to show improvement in pain control after adjuvant clodronate vs mitoxantrone. He had an analgesic response (450% decrease in analgesic intake from baseline) in 33% out of 104 cases using clodronate and 30% in the placebo group. However the response rate was quite different when only the subgroup of patients with moderate pain was analysed, with a 58% response in the treated group and 26% in the placebo group. This revealed that the patients with high baseline pain were more prone to respond to bisphosphonates than the mild cases. The use of bisphosphonate in metastatic prostate cancer cases has been gaining wide attention from urologists, who have been tracking the results from breast cancer and myeloma, where its usage is largely accepted, established and consensual. 8 From this, a randomised multicentre clinical study using the new generation of bisphosphonates (zoledronic acid) showed statistically significant differences that favoured its use in comparison with placebo in preventing skeleton-related events after 15 months of follow-up, and with no impact on clinical disease progression, quality-of-life index or performance status. 22 In this study, the patients were comparable to ours (median PSA of 88.2 ng/dl), and the pain relief was dramatic in the first 6 months of administration. However, the pain relief did not reach statistical significance at 15 months, probably because the disease did not stop progressing. Pain control was not the primary assessment in this study as skeletal-related event (fractures) was, but its consistently verified effect had not been previously confirmed in a double-blind randomised trial. In conclusion, it can be seen that clodronate can dramatically reduce pain in advanced hormone-refractory prostate cancer patients, with prompt effects on pain, few side effects and a significant improvement in performance status, as measured by Karnofsky s index. References 1 Berruti A et al. Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline. JUrol2000; 164: Greenlee RT, Murray T, Bolden S. Cancer statistics, American Cancer Society, January/February 2000; 50: Parker SL, Tong T, Bolden S. Cancer statistics Cancer J Clin 1997; 47: Issacs JT. The biology of hormone refractory prostate cancer. Why does it develop? 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