|Year : 2003 | Volume
| Issue : 1 | Page : 54-58
Monotherapy with docetaxel in treatment of hormone resistant cancer of the prostate - our results
NK Mohanty, Vineet Malhotra, Rajiba L Nayak, RP Arora
Department of Urology, VM Medical College and Safdarjang Hospital, New Delhi, India
N K Mohanty
C-II/124, Moti Bagh-1, New Delhi - 110 021
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objectives: Management of hormone resistant prostate cancer (HRCaP) is always a challenge to urologist. Microtubule inhibitors have been in focus as chemotherapeutic agents in carcinoma prostate, docetaxel being the most active among such drugs. The present study aims to evaluate the efficacy and safety of docetaxel as a single agent in the management of HRCaP.
Methods: Twenty patients of HRCaP between 58-82 years of age were enrolled to receive docetaxel 75mg/sq.m. intravenously every 3'd week with a minimum 6 dose schedule. A total number of 136 doses were used. All patients were D3 stage disease and symptomatic. Median prostate specific antigen (PSA) at the time of entry was 180ng/ml and the median follow up was for 28 months.
Results: An objective response in PSA reduction by = 80% was observed in 5 patients (25%) and more than 25% reduction seen in 12 patients (60%). Seventy percent of the patients showed improvement in symptoms on treatment. In 12 patients (60%), the disease was stable and showed response for a median period of 18 months. The median overall survival was 22 months. Adverse reaction in the form of anaemia, neutropenia, leucopenia was seen in 20 patients (100%), stomatitis, fever and alopecia was seen in 12 patients (60%). Four developed oral thrush (20%). Mortality occurred in 5 patients (25%) during the study, 2 died from pulmonary metastasis and 3 had cerebral metastasis with paraplegia.
Conclusions: The response seen in this study is very encouraging and suggests substantial durable activity of docetaxel as a single therapy in HRCaP
Keywords: Hormone resistant, docetaxel, cancer prostate.
|How to cite this article:|
Mohanty N K, Malhotra V, Nayak RL, Arora R P. Monotherapy with docetaxel in treatment of hormone resistant cancer of the prostate - our results. Indian J Urol 2003;20:54-8
|How to cite this URL:|
Mohanty N K, Malhotra V, Nayak RL, Arora R P. Monotherapy with docetaxel in treatment of hormone resistant cancer of the prostate - our results. Indian J Urol [serial online] 2003 [cited 2023 Jan 28];20:54-8. Available from: https://www.indianjurol.com/text.asp?2003/20/1/54/37126
| Introduction|| |
Prostate cancer is the most common malignancy among elderly males  and the second leading killer cancer in men. All initially hormone sensitive malignancy virtually become hormone resistant over a period of time.
Management of hormone resistant prostate cancer (HRCaP) remains a challenge to the urologist. Although many treatments are available for localized disease, hormone therapy remains the best treatment option for metastatic or advanced prostate cancer, but unfortunately hormone therapy is not curative, with a median duration of response varying between 18=24 months.  Previous chemotherapy trials in HRCaP have resulted in low response rate with minimal survival impacts - less than 20%.
In HRCaP, mutation in p53 tumor suppressor gene takes place resulting in greater expression of bCl, and over expression of multi-drug resistance protein. Transfection of bCl 2 gene into hormone sensitive tumor cells confers resistance to both hormone and chemotherapy. Efforts to abrogate bCl 2 in prostate tumors are therefore approaches to improve clinical results. ,,,,
Microtubule inhibitor agents (txane) have been in recent focus of investigation as chemotherapeutic agents in advanced cancer prostate. Docetaxel appears to be the most active of these drugs. Docetaxel, one of the taxanes, has shown promising results in management of HRCaP. Taxane (docetaxel) initiates the apoptotic process by binding to 2-tubulin  and promoting its polymerization, stabilizes the microtubular network preventing the usual remodeling of intracellular structure required for cell growth and division. This inhibition of formation of bCl, protein will cause arrest in the G2-M phase  of the prostate cancer cell leading to programmed cell death or apoptosis. It is 25 times more soluble than paclitaxel and has 2-5 fold higher affinity for microtubules then paclitaxel. It appears to work by stabilizing the microtubular network, preventing the usual remodeling of intracellular structure required for cell growth and division. Studies have shown docetaxel is two to four times more potent than paclitaxel. ,,,,
Joel Picus  in his study showed 7 patients having PSA reduction more than 80% and 5 patients had PSA decline over 90% with 2 of these patients sustaining concentration below 1 ng/ml and 1 sustaining it below 4 ng/ml. Most of these responses showed reduction in the requirement for pain medication. In 1 patient PSA level decreased from baseline 2070 ng/ml to 95 ng/ml and stayed below 100 ng/ml for over 2 years. Their median overall survival period was 27 months.
David Friedland et al  in their study using docetaxel for HRCaP showed an objective response of more than 50% reduction in PSA in seven patients (38%) and more than half of the patients with symptomatic disease at the initiation of therapy had improvements on treatment.
We undertook this open labeled non-randomized study using docetaxel (Docetere) in patients with HRCaP to explore the activity of this drug as a single agent using at a dose of 75 mg/sq.m of body surface and to evaluate its safety, efficacy (response rate) and survival time in these patients.
| Patients and Methods|| |
A total number of 20 patients (stage D 3 ) were enrolled in our study. All these patients had a pathologically proved cancer prostate. Patients who failed to respond to total hormone ablation therapy with documented disease progression radiologically and by serum PSA rise even after antiandrogen withdrawal with or without symptoms were included in this study. Inclusion and exclusion criteria as detailed below, was strictly followed in selection of our patients. Patients' characteristics are mentioned in [Table - 1].
A baseline value of hemogram, kidney function tests, liver function tests, serum PSA, CT abdomen, isotope bone scan and skeletal X-ray survey was done in all cases. Patients with WBC >4000/cu.mm, platelet >100,000/cu.mm and hemoglobin =10 gm% were prerequisites with normal liver function and kidney function tests. Patients qualifying with above criteria were asked to give a written consent before the trial.
- HRCaP with failure to previous hormone therapy.
- No history of previous taxane or any chemotherapy received.
- Last radiation therapy at least 8 weeks earlier.
- WHO performance status score 0-2.
- Adequate renal/hepatic/bone marrow functions.
- History of hypersensitivity reaction to taxane therapy.
- Patients with active infection and not on adequate antibiotic therapy.
- Medically uncontrolled hypertension, congestive cardiac failure and myocardial infarction, arrhythmia within last four months.
- Concurrent treatment with any other active cancer therapy.
Docetaxel (Docetere) at a dose of 75 mg/sq.m of body surface was given intravenous slowly every 3rd week for at least 6 dose cycles. Patients who showed improvement were continued with further cycles. Dose modifications were allowed for fever, severe neutropenia and neurotoxicity.
Any delay for more than three weeks from scheduled dose were removed from the study. Hemogram/liver and kidney functions was done before each cycle.
Premedication was given before each cycle with injection dexamethasone (16 mg), phenergan (20 mg), metoclopramide (10 mg), ranitidine (150 mg) and ondansetron (16 mg) followed by injection of docetaxel (Docetere) slowly with 5% Dextrose in glass bottle followed by oral therapy with ondansetron (8 mg) twice daily, metoclopramide (10 mg) twice daily, ranitidine (150 mg) once daily for next four days. Patients were followed by hemogram, liver and kidney function tests before next dose. Serum PSA was done every 6th week and radiological assessment done at every 24th week. Median follow up was for 28 months (ranging from 12-36 months).
Complete response (CR) rate was defined as normalization of PSA level. Partial response (PR) rate was defined as PSA decline by > 80% for at least three consecutive evaluation.
Stable disease (SD) was defined as PSA decline by 8025% in three consecutive evaluation. Progressive disease (PD) was defined as increase in PSA by > 50% in three consecutive evaluation. The patients who did not fall in any of the above response groups were classified as indeterminate. Transient PSA decline in only one evaluation was not considered as partial response. Period prevalence rate was used for calculating the median survival rate.
| Results|| |
A total number of 20 patients entered into the trial, all were of stages D 3 disease and were symptomatic. The average age of our patients was 67 (58 to 82 years). A total number of 136 dose cycles were given with a minimum of 6-dose cycle per patient (range 6-10) at three weeks interval. Median serum PSA was 180 ng/ml varying from 30-1220 ng/ml. There were no dropouts from the study during follow-up period. Median follow-up period was 28 months (12-36 months). After 24 months follow-up, we achieved the following results.
- > 80% reduction in serum PSA was observed in 5 of our patients (25%) (PR).
- > 25-80% reduction in serum PSA was observed in 12 of our patients (60%) (SD).
- > 50% increase in serum PSA was observed in 3 of our patient (15%) (PD).
- There were no patients falling in the indeterminate group.
Response rate was established when the reduction in PSA was observed in all patients of the respective category on three consecutive estimations.
All 17 patients who showed PSA reduction more than 25% of baseline value continued to have durable reduction as follows. Five patients who showed PSA reduction>80% continued to have the same low PSA range for an average of 22 months while the remaining 12 showing reduction in PSA 25-80% also continued to have the same low PSA range for average 18 months and were categorized as stable disease. The 3 patients in whom PSA level showed transient decrease of PSA less than 25% on one or two evaluation, repeat PSA estimation of these patients showed increase in PSA value to more than 50% on three consecutive evaluation and were designated as progressive disease with distant metastasis like pulmonary and cerebral metastasis.
All the 20 patients designated as HRCaP in our series were symptomatic initially having backache, bone pain, reduced mobility, loss of appetite and leading to a low quality of life. Improvement in pain relief and better mobility was observed in 70% (14 patients) of these patients. There was considerable reduction in use of pain-killer medicines. Many taking earlier injectable painkiller drugs were better off with reduced oral therapy.
In our study no scale for evaluating pain, mobility or quality of life was followed. Our clinical assessments before and after therapy, with a few questions like how much pain relief is achieved, how much mobility the patient has gained, has there been any improvement in quality of life and is there any reduction in the dose and frequency of painkiller medicines, were used to assess improvement in pain mobility and quality of life.
- The median overall survival was 22 months in our study. Five patients (25%) died. Two died of pulmonary metastasis/ embolus/pneumonitis and 3 died of cerebral metastasis.
- Out of 5 mortalities in our series 3 belonged to progressive disease group and 2 belonged to stable disease group; the latter died after 18 months of follow-up. Two patients had fracture of the femur due to advanced bone metastases.
The most common toxicity was neutropenia, leucopenia followed by anemia [Table - 2]. Four patients developed oral thrush and stomatitis.
| Discussion|| |
Till date no single chemotherapeutic agent or combination therapy has improved survival in metastatic HRCaP.  In such HRCaP patients, the physician is left with a very few therapeutic options like empirical radiotherapy, suramin, antifungal agents or nitrogen mustard with estrogen, all with limited efficacy. The theoretical concept of mechanism of action of taxane (docetaxel) sounds very encouraging and logical as a treatment options in management of HRCaP. A trend towards improved survival has been seen with docetaxel either alone or in combination with estramustine. In our study 5 patients (25%) showed disease stability for 22 months and 12 patients (60%) showed the same for 18 months. In 14 patients (70%) clinical improvement in pain relief, better mobility, reduction in the use and frequency of painkiller drugs and improved quality of life was observed. The median overall survival period was 22 months.
Our data is comparable with those data observed by workers like Picus et al  and Friedland et al  in their studies.
Significant response was observed in our study using docetaxel for management of HRCaP, which suggests substantial durable activity of this taxane molecule in treatment of HRCaP. Although toxicity was observed in our study, the degree was acceptable for completion of therapy cycle.
| Conclusions|| |
From this small, single center study, as a single agent, the response of docetaxel (Docetere) in management of HRCaP was found to be very promising and encouraging, but awaits a larger multicentric clinical trial for establishing its efficacy and dose schedule.
| Acknowledgement|| |
We are grateful to Mr. Mahendra Joshi for his help in preparing and typing the manuscript.
| References|| |
|1.||Landis SH. Murray T. Bolden S et al. Cancer statistics. Cancer J Clin 1999; 49(8): 31. |
|2.||Picus J, Schultz H et al. Docetaxel (Taxotere) as monotherapy in the treatment of Hormone Refractory Prostate Cancer : Preliminary results. Semin. 1999; 26(5): 14-18. |
|3.||Friedland D, Cohen J. Miller R et al. A phase II trial of Docetaxel (Taxotere) in hormone refractory cancer : correlation of antitumor effect of phosphorylation of BCl_,. Semin Oncol 1999; 26(5): 19-23. |
|4.||Mc Donnell TJ. Troncoso P, Brisbay SM et al. Expression of the protoncogene bCl, in the prostate and its association with emergence of androgen independent prostate cancer. Cancer Res 1992: (52): 6940-6944. |
|5.||Ti S, McConnell K, Marin Me et al. Combination of adriamycin and suramin induces apoptosis in bCl,_ expressing prostate cancer cells. Cancer Lett 1995: 93: 147-155. |
|6.||Levine AS. p53. the cellular gatekeeper for growth and division. Cell 1997: 88: 323-331. |
|7.||Sullivan CT, Amenta PS, Villanneva JD et al. The expression of drug resistance gene products during progression of human prostate cancer. Clin Cancer Res 1998: 4: 1393-1403. |
|8.||Rigel I, Horowitz S. Studies with RP 56976 (Taxotere) : A semi synthetic analogue of Taxol. J Natl Cancer Inst 1991; 83: 288-291. |
|9.||Jordan M, Toso R, Thrower D et al. Mechanism of mitotic block and inhibition of cell proliferation by Taxol at low concentration. Proc Natl Acad Sci USA 1993; 90: 9552-9556. |
|10.||Jordan M, Wendell K, Gardiner S et al. Mitotic block induced in hela cells by low concentration of paclitaxel results in abnormal mitotic exit and apoptotic cell death. Cancer Res 1996; 56: 816-825. |
|11.||Kelland LR, Abel G et al. Comparative in vitro cytotoxicity of Taxol and Taxotere against cisplatin - sensitive and resistance human ovarian carcinoma cell lines. Cancer Chemother Pharmacol 1992; 30: 444-450. [PUBMED] |
|12.||Vogel M, Hiklsebeck SG, Depenbrock H et al. Preclinical activity of Taxotere (RP56976, NSC 628503) against freshly explanted clonogenic human cell. Comparison with Taxol and conventional antineoplastic agents. Eur J Cancer 1993: 29A: 2009-2014. |
|13.||Horowitz S. Taxol (Paclitaxel) : Mechanism of action. Ann Oncol 5, 1994 (suppl 6): 53-56. |
|14.||Stein CA. Mechanism of action of Taxanes in prostate cancer. Semin Oncol 1999, Vol. 26, No. 5, (suppl 17): 3-7. |
|15.||Vaishampayan U et al. Taxanes : An overview of the pharmacokinetics and pharmacodynamics. Urology 1999; 54: 77-79. |
[Table - 1], [Table - 2]