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RESEARCH ARTICLE
Year : 2003  |  Volume : 20  |  Issue : 1  |  Page : 54-58
 

Monotherapy with docetaxel in treatment of hormone resistant cancer of the prostate - our results


Department of Urology, VM Medical College and Safdarjang Hospital, New Delhi, India

Correspondence Address:
N K Mohanty
C-II/124, Moti Bagh-1, New Delhi - 110 021
India
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Source of Support: None, Conflict of Interest: None


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   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 2019 Aug 20];20:54-8. Available from: http://www.indianjurol.com/text.asp?2003/20/1/54/37126



   Introduction Top


Prostate cancer is the most common malignancy among elderly males [1] 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. [2] 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. [3],[4],[5],[6],[7]

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 [13] 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 [14] 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. [8],[9],[10],[11],[12]

Joel Picus [2] 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 [3] 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 Top


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.

Inclusion criteria:

  • 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.


Exclusion criteria:

  • 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.


Dose Schedule:

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).

Response Rate:

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 Top


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.

Pain

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.

Survival

  • 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.


Toxicity

The most common toxicity was neutropenia, leucope­nia followed by anemia [Table - 2]. Four patients devel­oped oral thrush and stomatitis.


   Discussion Top


Till date no single chemotherapeutic agent or combina­tion therapy has improved survival in metastatic HRCaP. [15] 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 [2] and Friedland et al [3] 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 Top


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 Top


We are grateful to Mr. Mahendra Joshi for his help in preparing and typing the manuscript.

 
   References Top

1.Landis SH. Murray T. Bolden S et al. Cancer statistics. Cancer J Clin 1999; 49(8): 31.  Back to cited text no. 1    
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.  Back to cited text no. 2    
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.  Back to cited text no. 3    
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.  Back to cited text no. 4    
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.  Back to cited text no. 5    
6.Levine AS. p53. the cellular gatekeeper for growth and division. Cell 1997: 88: 323-331.  Back to cited text no. 6    
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.  Back to cited text no. 7    
8.Rigel I, Horowitz S. Studies with RP 56976 (Taxotere) : A semi synthetic analogue of Taxol. J Natl Cancer Inst 1991; 83: 288-291.  Back to cited text no. 8    
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.  Back to cited text no. 9    
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.  Back to cited text no. 10    
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.  Back to cited text no. 11  [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.  Back to cited text no. 12    
13.Horowitz S. Taxol (Paclitaxel) : Mechanism of action. Ann Oncol 5, 1994 (suppl 6): 53-56.  Back to cited text no. 13    
14.Stein CA. Mechanism of action of Taxanes in prostate cancer. Semin Oncol 1999, Vol. 26, No. 5, (suppl 17): 3-7.  Back to cited text no. 14    
15.Vaishampayan U et al. Taxanes : An overview of the pharmacoki­netics and pharmacodynamics. Urology 1999; 54: 77-79.  Back to cited text no. 15    



 
 
    Tables

  [Table - 1], [Table - 2]



 

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    Abstract
    Introduction
    Patients and Methods
    Results
    Discussion
    Conclusions
    Acknowledgement
    References
    Article Tables

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