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Cabazitaxel side effects: Prevention and management
British Journal of Medical and Surgical Urology (2011) 4S, S21—S27
ORIGINAL ARTICLE
Cabazitaxel side effects: Prevention and management Anna Lydon ∗ Department of Oncology, South Devon Foundation Healthcare Trust, Lawes Bridge, Torquay, Devon TQ2 7AA, UK
Summary The publication of phase III data on cabazitaxel in the management of metastatic castrate-resistant prostate cancer in men previously treated with docetaxel demonstrated, for the first time, that a survival benefit can be achieved in this patient group. Optimal use of cabazitaxel will depend on appropriate patient selection and on effective management of the side effects, which have been shown to be predictable and preventable/treatable using interventions that are already familiar to chemotherapy clinics. © 2011 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction Treatment for patients with metastatic castrateresistant prostate cancer (mCRPC) underwent a paradigm shift in 2004 with the publication of the TAX 327 [1] and SWOG 99-16 [2] clinical trials. For the first time, a survival benefit, as well as an improvement in quality of life, was seen when using a chemotherapy regimen to treat patients whose metastatic prostate cancer was refractory to hormone therapy. As a result, docetaxel became the standard of care in this setting [3]. However, there is as yet no gold standard for treatment after docetaxel-based chemotherapy, or for patients whose disease is no longer sensitive to this approach [3]. Of note, the National Institute for Health and Clinical Excellence (NICE) has not approved repeated courses of docetaxel [3], and there is evidence that patients develop ∗
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resistance to this agent, which also impairs their response to the related compound paclitaxel [3,4]. However, the findings of the TROPIC trial in 2010 demonstrated that in patients with mCRPC who had already received docetaxel, treatment with cabazitaxel improved overall survival (compared with mitoxantrone recipients) [5]. Furthermore, while cabazitaxel is, like docetaxel, a taxane, it has little affinity for the multidrug resistance proteins associated with resistance to this drug class, and it has been shown to be effective in cell lines that do not respond to other taxanes [6]. In light of the TROPIC data (which are considered in detail elsewhere in this supplement: Malik, S14—S20), and the subsequent decision by the European Medicines Agency to license cabazitaxel [7], a new line of active treatment is now available for our patients, bringing the prospect of another major shift in the management of mCRPC. When any new drug is introduced into clinical practice, healthcare professionals will be
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S22 concerned about toxicity and treatment safety. Like docetaxel, cabazitaxel will be used without curative intent, so effective prevention and management of side effects will be crucial to helping our patients obtain optimal benefit. Oncologists will need to feel confident in their ability to deliver the drug safely, nurses will need to know what advice and support to offer, and patients will need a clear understanding of which side effects are potentially life-threatening and warrant urgent intervention. Although only a small number of UK centres thus far have experience of using cabazitaxel, the TROPIC trial itself has generated excellent data on the safety profile of the drug [5]. It has shown that the side effects of cabazitaxel are largely predictable, and can be managed effectively through appropriate selection of recipients, and education of patients and health professionals in the prevention and treatment of the documented toxicities. This article considers the potential role of cabazitaxel in the care of men with mCRPC, and the management of its side effects, from the perspective of an oncologist with clinical experience of the agent.
Patient selection Treatment indication Cabazitaxel is licensed in Europe [7] and the USA [8] for patients with mCRPC who have progressed during or following prior treatment with docetaxel. Before being prescribed cabazitaxel, patients in the TROPIC trial had received a median of 7.4 cycles of docetaxel and 35% had undergone palliative radiotherapy [5,9]. In our experience, this history of myelosuppressive treatment is typical of the population likely to be considered for cabazitaxel in routine clinical practice (see case studies below).
Assessment of performance status As with docetaxel, pre-chemotherapy assessment of performance status will help to predict which patients are likely to benefit from treatment with cabazitaxel. I generally consider cabazitaxel only for patients with a performance status of 60% or higher on the Karnofsky scale (Table 1) [10]— –i.e. the cut-off used in the TAX 327 [1] and TROPIC trials [5], and specified in NICE guideline TA101 [3].
A. Lydon
Selection in practice Case study 1 A 67-year-old retired farmer was diagnosed with locally advanced high-grade prostate cancer in 2002. He was treated with neoadjuvant hormonal treatment and radical pelvic radiotherapy, followed by 3 years of adjuvant hormonal therapy. He developed prostate-specific antigen (PSA) failure (by the ASTRO definition [11]) 18 months after cessation of adjuvant hormonal therapy. He commenced a luteinising hormone-releasing hormone (LHRH) agonist in January 2008, and had a PSA response lasting 10 months. Bicalutamide 50 mg was added in November 2008 when he developed a rapidly rising PSA. After falling initially, his PSA rose again in April 2009, and the anti-androgen was stopped. By June 2009, the patient was becoming symptomatic, with pain in his back and left hip, and he was referred to the oncology department. His PSA was 115 ng/ml, with a doubling time of less than 6 months. A bone scan showed multiple bone metastases. However, he remained well; he was still helping his son on the farm, and he played bowls regularly. He was treated with 10 cycles of docetaxel chemotherapy, with excellent improvement in his pain and an 80% fall in PSA. However, by April 2011, 15 months after completing docetaxel, his PSA began to rise, and he was aware of new pain in the thoracic area of his back. A bone scan confirmed progression of bone metastases, although he was still reasonably well and active—–he no longer played bowls, but he continued to take an active interest in the farm, and remained independent and self-caring. He was assessed as suitable for cabazitaxel chemotherapy, and has received 2 cycles. He has coped well, and his back pain has significantly improved.
Case study 2 A 78-year-old man diagnosed with metastatic prostate cancer in November 2008 responded reasonably well to a LHRH agonist for 12 months. By January 2010, his PSA had risen, and radiological investigations confirmed progression of para-aortic and pelvic nodal disease and bone metastases. Addition of an anti-androgen had little effect, and in April 2010 he commenced treatment with docetaxel chemotherapy. His disease improved symptomatically, radiologically and biochemically, but he was troubled with side effects, particularly fatigue and an altered sense of taste. Docetaxel was stopped after 8 cycles.
Cabazitaxel side effects: Prevention and management Table 1
S23
Karnofsky performance status [10]—–an essential guide to patient selection for cabazitaxel.
Karnofsky performance status (%)
Functional capacity
100
Normal No evidence of disease Normal activity Minor signs or symptoms of disease Normal activity with effort Signs or symptoms of disease Able to self-care Unable to perform normal activity or active work Occasional assistance required, but largely able to self-care Considerable assistance and frequent medical care required Disabled, requiring special care and assistance Severely disabled Hospitalisation indicated, but death not imminent Very sick Hospitalisation and active supportive treatment required Moribund, with rapid progress of fatal processes Dead
90 80 70 60 50 40 30 20 10 0
He had a good Christmas with his family, but by February he had become less well, with further pain in his lumbar spine, fatigue and left-leg oedema. When reviewed in the oncology clinic in March, he was less active than he had been, relying on his daughter for all of his shopping and having his meals delivered. He was no longer able to attend church on a Sunday—–indeed he rarely left his ground floor flat. He received a short course of palliative radiotherapy to his lumbar spine, and started dexamethasone 0.5 mg/day. However, in light of the deterioration in his performance status, the multidisciplinary team felt that the patient would not cope with cabazitaxel chemotherapy. He remains in his own home, where he is cared for by the community palliative care team. His pain control is good, and a package of social care has been arranged.
Common side effects of cabazitaxel The side effects of cabazitaxel are broadly similar to those of docetaxel [6], and indeed several other chemotherapy agents. They are manageable if anticipated, prevented where appropriate, and identified and treated should they present. Patients should be given clear instructions on how to recognise side effects and, where appropriate, the steps they can take themselves to minimise the development of symptoms. However, they should also be actively encouraged to contact their oncology unit early should side effects occur, and they must be able to recognise symptoms that warrant urgent assessment. A diary, or similar resource, may
help patients to remember the details of symptoms experienced between cycles. The most common adverse events in the TROPIC trial were haematological (Table 2), with neutropenia reported in 94% of cabazitaxel recipients and 88% of those in the mitoxantrone arm [5]. Febrile neutropenia was not a common side effect in the trial, but was seen more frequently with cabazitaxel than with mitoxantrone (7.4% versus 1.3%). Neutropenia and its consequences were cited as the cause of seven deaths in the cabazitaxel arm and one death in the mitoxantrone arm. However, all of the neutropenic deaths occurred early in the trial, i.e. before a protocol amendment requiring primary
Table 2 Common adverse events with cabazitaxel in the TROPIC trial (selection based on an incidence of ≥1% at grade ≥3) [5]. Adverse event
Anaemia Leukopenia Neutropenia Thrombocytopenia Diarrhoea Fatigue Nausea Vomiting Asthenia Haematuria Back pain Abdominal pain Febrile neutropenia
Incidence (%) All grades
Grade ≥3
97 96 94 47 47 37 34 23 20 17 16 12 8
11 68 82 4 6 5 2 2 5 2 4 2 8
S24 prophylaxis with granulocyte colony-stimulating factor (G-CSF) and, where indicated, cabazitaxel dose reduction. Furthermore, in a comment on the trial, it was noted that considerable variation between investigators in the management of febrile neutropenia may have contributed to the associated mortality, and that provision of preventive and supportive care, as appropriate, should be considered mandatory for patients receiving cabazitaxel [12]. Diarrhoea, fatigue/asthenia, nausea and vomiting were the most common non-haematological side effects of cabazitaxel (Table 2) [5].
Management of neutropenic toxicity Primary prophylaxis Primary prophylaxis with G-CSF should be considered for patients with high-risk clinical features that will predispose them to the complications of neutropenia, e.g. age over 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports and poor nutritional status. Evidence-based guidelines on the use of G-CSF have been published by the European Organisation for Research and Treatment of Cancer [13], the American Society of Clinical Oncology [14] and the National Comprehensive Cancer Network [15].
Cabazitaxel dose modification The patient’s full blood count should be monitored on days 1, 8 and 15 during cycle 1 of cabazitaxel treatment, and before each subsequent cycle. If the patient has grade ≥3 neutropenia, i.e. an absolute neutrophil count (ANC) of 1500/mm3 or lower, G-CSF treatment should be offered, and the next cycle of cabazitaxel should be delayed until the ANC threshold is exceeded. If grade ≥3 neutropenia persists for longer than 7 days despite G-CSF, or is complicated by fever or infection, the cabazitaxel dose should be reduced from 25 mg/m2 to 20 mg/m2 for the rest of the chemotherapy course. Prophylactic G-CSF may also be considered before subsequent deliveries of cabazitaxel. Cabazitaxel-based chemotherapy should be discontinued if grade ≥3 neutropenia develops at the reduced dose.
Neutropenic complications All oncology units that treat patients with cabazitaxel and other myelosuppressive chemotherapy
A. Lydon agents should have a clear, locally agreed protocol and care pathway for the management of individuals who present with febrile neutropenia and/or its life-threatening sequela neutropenic sepsis. Suspected febrile neutropenia or neutropenic sepsis is a medical emergency, analogous to meningococcal septicaemia, and should be treated as quickly as possible. Education—–of patients and healthcare professionals—–is essential to make sure patients and/or carers are aware that they must contact the hospital early, and that hospital staff act appropriately. Patients should check their temperature twice daily from day 5 of each cycle, and seek urgent attention if the reading is >37.5◦ C or <36◦ C or if they feel generally unwell, e.g. with flu-like symptoms. In such an eventuality they need to make contact with the hospital immediately via the number specified by their oncology team—–they should not seek help via their GP, NHS Direct, NHS24 or the 999 emergency service. They must not take paracetamol, wait for their symptoms to resolve or, if experiencing symptoms out of hours, delay until the next clinic session. As well as being discussed between the oncology team and the patient, and handed out in written form, this advice can be supported by displaying key information in the oncology waiting room. For example the TEA (Take Early Action) campaign launched in South Devon Healthcare Trust [16], includes a display reminding patients of the risk of febrile neutropenia, the warning signs and the points of emergency contact. On presentation, the patient will require urgent admission to hospital and rapid assessment (including blood culture). Intravenous antibiotic therapy must be administered as soon as possible, without waiting for the results of investigations. Suitable broad-spectrum antibiotics for initial use include piperacillin 4.5 g and gentamicin 260—400 mg. Drug modifications can be made subsequently, depending on the results of investigations and the patient’s clinical progress. Patients will require intravenous fluid support, and should be nursed in isolation according to local policy.
Management of diarrhoea Diarrhoea typically occurs 24 h or more after administration of a chemotherapy cycle. Almost half of the recipients of cabazitaxel in the TROPIC trial reported some degree of diarrhoea [5]. However, grade ≥3 diarrhoea (see Table 3) affected only 6% of the group. Patients who develop diarrhoea should be encouraged to inform their local chemotherapy
Cabazitaxel side effects: Prevention and management
S25
Table 3 Grading of diarrhoea according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events [17]. Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Increase of <4 stools per day over baseline
Increase of 4—6 stools per day over baseline
Increase of ≥7 stools per day over baseline; incontinence hospitalisation indicated; limiting self care and activities of daily living
Life-threatening consequences; urgent intervention indicated
Death
unit, so that their symptoms can be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (Table 3) [17]. The urgency of the assessment depends on the frequency of bowel movements. If a patient has more than four bowel movements in 24 h, they should contact the oncology unit by phone urgently, even if out of hours, so that an over-the-phone assessment can be made by a chemotherapy/oncology nurse. In the case of less frequent bowel movements, a phone call the next day should suffice.
Outpatient care Many of those with relatively mild diarrhoea (grade 1—2) can be managed as outpatients, with advice on medication, diet and fluid intake. They should be encouraged to drink 2—3 l of fluids per day—–high-energy drinks such as weak tea with sugar, and salt replacement fluids may be helpful. Some patients also find it helpful to avoid spicy or fatty foods, raw or high-fibre vegetables, and iced or caffeinated drinks. An absorbent medication, such as loperamide, should be prescribed—–4 mg initially and a further 2 mg with each episode of diarrhoea (maximum 16 mg per 24 h). If diarrhoea fails to resolve with these measures, the patient should be urgently assessed in hospital. Note also that diarrhoea can be a symptom of febrile neutropenia [18]. Therefore, if there is deemed to be a risk that the patient is neutropenic, e.g. they report diarrhoea symptoms 7—14 days after receiving a cycle of chemotherapy, a full blood count should be ordered and assessed urgently, and the patient admitted to hospital.
Inpatient care Hospital admission is required if the patient has grade ≥3 diarrhoea, or if any of the follow-
ing is present: fever, neutropenia, dehydration, abdominal cramping, rectal bleeding or reduced performance status. Any associated neutropenia and fever should be treated according to the local neutropenic care pathway. A stool sample should be analysed for Clostridium difficile toxin. If the result is positive, appropriate treatment should be initiated, again in line with local protocols. In other cases, the mainstay of treatment is loperamide plus codeine phosphate, with fluid and electrolyte replacement if required. A subcutaneous infusion of octreotide 300 mcg per 24 h can be used if the patient does not respond to the initial medication. If grade ≥3 diarrhoea persists despite these measures, the next cycle of cabazitaxel should be delayed until the symptoms resolve or improve, and subsequent doses should be reduced from 25 mg/m2 to 20 mg/m2 . Cabazitaxel-based chemotherapy should be discontinued if grade ≥3 diarrhoea develops at the reduced dose.
Fatigue/asthenia Fatigue and asthenia are associated with several chemotherapy agents, including cabazitaxel [5], and many patients benefit from understanding that they are experiencing expected side effects. Patients can be advised to take plenty of rest when they need to, but also to find opportunities for gentle exercise when they feel well enough. It is often helpful to suggest that they concentrate on activities that are essential to them and on those that give pleasure, but avoid feeling that they should maintain all routine activities. In some patients, asthenia may be related to a cause other than chemotherapy, e.g. depression, thyroid dysfunction or poor nutrition, and assessment of potential underlying factors may give useful pointers to management. Many patients ben-
S26 efit from understanding that fatigue and asthenia are expected side effects.
Nausea and vomiting Some patients experience nausea and vomiting after their cabazitaxel infusion [5]. The symptoms are generally mild, and resolve with antiemetic drugs. As with diarrhoea, advice on diet may be helpful; for example, patients may find it helpful to eat frequent small portions rather than more widely spaced large meals, and bland foods may be a better choice than spicy alternatives.
A. Lydon
Conflicts of interest I have received an honorarium from sanofi-aventis for a lecture, and an educational grant from Ipsen.
Acknowledgements My thanks to Succinct Healthcare Communications for editorial support. This supplement is sponsored by an educational grant from sanofi-aventis, which had no influence on the content of the article.
References Other adverse effects Haematuria and back pain were reported in the TROPIC trial [5], but, in my judgement, are likely to be related to the disease process rather than cabazitaxel. Other side effects associated with cabazitaxel, such as alopecia, stomatitis and onycholysis, are similar to those seen with docetaxel [19]. Although troublesome for the patient, these rarely result in stopping or reducing chemotherapy. Work is ongoing to help with some of these symptoms, e.g. use of iced gloves to reduce onycholysis [20]. Alopecia is rarely total, and patients can be reassured by knowing that their hair is likely to re-grow within 3 months of completion of chemotherapy. Stomatitis can be a nuisance, but is often helped by regular use of a mild mouthwash, and gentle tooth hygiene. Also, some patients find that soreness of the mouth is reduced by eating cold foods such as ice-cream during the course of the chemotherapy. However, it is important to examine the patient for signs of oral candida infection, which can be easily treated using conventional agents.
Conclusion With the introduction of cabazitaxel, we have the opportunity to improve the survival of patients with mCRPC who have progressed during or following docetaxel treatment and retain good performance status [5]. The drug is well tolerated, and healthcare professionals who look after patients with prostate cancer already have a wealth of expertise in the management of its side effects, which are predictable, and similar to those of docetaxel and various other chemotherapy agents [6]. With cabazitaxel, there is hope for a new paradigm shift in the battle with prostate cancer.
[1] Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisolone or mitoxantrone plus prednisolone for advanced prostate cancer. N Engl J Med 2004;351:1502—12. [2] Petrylak DP, Tangen CM, Hussain MHA, Lara PN, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisolone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513—20. [3] National Institute for Health and Clinical Excellence. Docetaxel for the treatment of hormone-refractory metastatic prostate cancer. [Technology Appraisal 101). http://www.nice.org.uk/nicemedia/pdf/TA101guidance.pdf accessed April 2011]. [4] Fojo AT, Menefee M. Microtubule targeting agents: basic mechanisms of multidrug resistance (MDR). Semin Oncol 2005;32:S3—8. [5] de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels J-P, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised openlabel trial. Lancet 2010;376:1147—54. [6] Mita AC, Denis LJ, Rowinsky EK, de Bono JS, Goetz AD, Ochoa L, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-h infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 2009;15:723—30. [7] Sanofi-aventis. Press release: JEVTANA® (cabazfor prostate cancer recommended for itaxel) approval in the European Union [http://en.sanofiaventis.com/binaries/20110121 JEVTANA en tcm2830090.pdf; accessed April 2011]. [8] US Food and Drug Administration. Cabazitaxel. [http://www.fda.gov/AboutFDA/CentersOffices/CDER/ ucm216214.htm; accessed April 2011]. [9] Sartor AO, Oudard S, Ozguroglu M, Hansen S, Machiels JH, Shen L, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). Presented at ASCO GU, San Francisco, March 2010; Abstract 9 (presentation). [10] Cancer Research UK. Performance status cancer/cancer[http://www.cancerhelp.org.uk/about accessed April questions/performance-status?vie; 2011]. [11] Roach M, Hanks G, Thames H, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following
Cabazitaxel side effects: Prevention and management
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radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOGASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965—74. Beuzeboc P. Re: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate progressing after docetaxel treatment: cancer a randomised open-label trial. Eur Urol 2011;59: 658. Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, Ellis M, et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 2006;42:2433—53. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187—205. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Myeloid growth factors. Version 1.2011. National Comprehensive Cancer Network; 2011 [http://www.nccn.
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org/professionals/physician gls/pdf/myeloid growth.pdf; accessed April 2011]. South Devon Healthcare, NHS Foundation Trust. Torbay Hospital’s Cancer Services team receives national recognition for life saving campaign [http://www.sdhct.nhs. uk/aboutus/newsandpublications/pressreleases/2011/ 110209 cancerteamrecievesnationalrecognition.php; accessed April 2011]. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). (Version 4.0) [http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-0614 QuickReference 5x7.pdf; accessed April 2011]. Aksoy DY, Tanriover MD, Uzun O, Zarakolu P, Ercis S, Erguven S, et al. Diarrhea in neutropenic patients: a prospective cohort study with emphasis on neutropenic enterocolitis. Ann Oncol 2007;18:183—9. Minisini AM, Tosti A, Sobrero AF, Mansutti M, Piraccini BM, Sacco C, et al. Taxane-induced nail changes: incidence, clinical presentation and outcome. Ann Oncol 2003;14:333—7. Scotte F, Tourani JM, Banu E, Peyromaure M, Levy E, Marsan S, et al. Multi-centre study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand. J Clin Oncol 2005;23:4424—9.
Available online at www.sciencedirect.com
ORIGINAL ARTICLE
Cabazitaxel side effects: Prevention and management Anna Lydon ∗ Department of Oncology, South Devon Foundation Healthcare Trust, Lawes Bridge, Torquay, Devon TQ2 7AA, UK
Summary The publication of phase III data on cabazitaxel in the management of metastatic castrate-resistant prostate cancer in men previously treated with docetaxel demonstrated, for the first time, that a survival benefit can be achieved in this patient group. Optimal use of cabazitaxel will depend on appropriate patient selection and on effective management of the side effects, which have been shown to be predictable and preventable/treatable using interventions that are already familiar to chemotherapy clinics. © 2011 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction Treatment for patients with metastatic castrateresistant prostate cancer (mCRPC) underwent a paradigm shift in 2004 with the publication of the TAX 327 [1] and SWOG 99-16 [2] clinical trials. For the first time, a survival benefit, as well as an improvement in quality of life, was seen when using a chemotherapy regimen to treat patients whose metastatic prostate cancer was refractory to hormone therapy. As a result, docetaxel became the standard of care in this setting [3]. However, there is as yet no gold standard for treatment after docetaxel-based chemotherapy, or for patients whose disease is no longer sensitive to this approach [3]. Of note, the National Institute for Health and Clinical Excellence (NICE) has not approved repeated courses of docetaxel [3], and there is evidence that patients develop ∗
Tel.: +44 01803 655376; fax: +44 01803 655386. E-mail address: [email protected]
resistance to this agent, which also impairs their response to the related compound paclitaxel [3,4]. However, the findings of the TROPIC trial in 2010 demonstrated that in patients with mCRPC who had already received docetaxel, treatment with cabazitaxel improved overall survival (compared with mitoxantrone recipients) [5]. Furthermore, while cabazitaxel is, like docetaxel, a taxane, it has little affinity for the multidrug resistance proteins associated with resistance to this drug class, and it has been shown to be effective in cell lines that do not respond to other taxanes [6]. In light of the TROPIC data (which are considered in detail elsewhere in this supplement: Malik, S14—S20), and the subsequent decision by the European Medicines Agency to license cabazitaxel [7], a new line of active treatment is now available for our patients, bringing the prospect of another major shift in the management of mCRPC. When any new drug is introduced into clinical practice, healthcare professionals will be
1875-9742/$ — see front matter © 2011 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjmsu.2011.05.005
S22 concerned about toxicity and treatment safety. Like docetaxel, cabazitaxel will be used without curative intent, so effective prevention and management of side effects will be crucial to helping our patients obtain optimal benefit. Oncologists will need to feel confident in their ability to deliver the drug safely, nurses will need to know what advice and support to offer, and patients will need a clear understanding of which side effects are potentially life-threatening and warrant urgent intervention. Although only a small number of UK centres thus far have experience of using cabazitaxel, the TROPIC trial itself has generated excellent data on the safety profile of the drug [5]. It has shown that the side effects of cabazitaxel are largely predictable, and can be managed effectively through appropriate selection of recipients, and education of patients and health professionals in the prevention and treatment of the documented toxicities. This article considers the potential role of cabazitaxel in the care of men with mCRPC, and the management of its side effects, from the perspective of an oncologist with clinical experience of the agent.
Patient selection Treatment indication Cabazitaxel is licensed in Europe [7] and the USA [8] for patients with mCRPC who have progressed during or following prior treatment with docetaxel. Before being prescribed cabazitaxel, patients in the TROPIC trial had received a median of 7.4 cycles of docetaxel and 35% had undergone palliative radiotherapy [5,9]. In our experience, this history of myelosuppressive treatment is typical of the population likely to be considered for cabazitaxel in routine clinical practice (see case studies below).
Assessment of performance status As with docetaxel, pre-chemotherapy assessment of performance status will help to predict which patients are likely to benefit from treatment with cabazitaxel. I generally consider cabazitaxel only for patients with a performance status of 60% or higher on the Karnofsky scale (Table 1) [10]— –i.e. the cut-off used in the TAX 327 [1] and TROPIC trials [5], and specified in NICE guideline TA101 [3].
A. Lydon
Selection in practice Case study 1 A 67-year-old retired farmer was diagnosed with locally advanced high-grade prostate cancer in 2002. He was treated with neoadjuvant hormonal treatment and radical pelvic radiotherapy, followed by 3 years of adjuvant hormonal therapy. He developed prostate-specific antigen (PSA) failure (by the ASTRO definition [11]) 18 months after cessation of adjuvant hormonal therapy. He commenced a luteinising hormone-releasing hormone (LHRH) agonist in January 2008, and had a PSA response lasting 10 months. Bicalutamide 50 mg was added in November 2008 when he developed a rapidly rising PSA. After falling initially, his PSA rose again in April 2009, and the anti-androgen was stopped. By June 2009, the patient was becoming symptomatic, with pain in his back and left hip, and he was referred to the oncology department. His PSA was 115 ng/ml, with a doubling time of less than 6 months. A bone scan showed multiple bone metastases. However, he remained well; he was still helping his son on the farm, and he played bowls regularly. He was treated with 10 cycles of docetaxel chemotherapy, with excellent improvement in his pain and an 80% fall in PSA. However, by April 2011, 15 months after completing docetaxel, his PSA began to rise, and he was aware of new pain in the thoracic area of his back. A bone scan confirmed progression of bone metastases, although he was still reasonably well and active—–he no longer played bowls, but he continued to take an active interest in the farm, and remained independent and self-caring. He was assessed as suitable for cabazitaxel chemotherapy, and has received 2 cycles. He has coped well, and his back pain has significantly improved.
Case study 2 A 78-year-old man diagnosed with metastatic prostate cancer in November 2008 responded reasonably well to a LHRH agonist for 12 months. By January 2010, his PSA had risen, and radiological investigations confirmed progression of para-aortic and pelvic nodal disease and bone metastases. Addition of an anti-androgen had little effect, and in April 2010 he commenced treatment with docetaxel chemotherapy. His disease improved symptomatically, radiologically and biochemically, but he was troubled with side effects, particularly fatigue and an altered sense of taste. Docetaxel was stopped after 8 cycles.
Cabazitaxel side effects: Prevention and management Table 1
S23
Karnofsky performance status [10]—–an essential guide to patient selection for cabazitaxel.
Karnofsky performance status (%)
Functional capacity
100
Normal No evidence of disease Normal activity Minor signs or symptoms of disease Normal activity with effort Signs or symptoms of disease Able to self-care Unable to perform normal activity or active work Occasional assistance required, but largely able to self-care Considerable assistance and frequent medical care required Disabled, requiring special care and assistance Severely disabled Hospitalisation indicated, but death not imminent Very sick Hospitalisation and active supportive treatment required Moribund, with rapid progress of fatal processes Dead
90 80 70 60 50 40 30 20 10 0
He had a good Christmas with his family, but by February he had become less well, with further pain in his lumbar spine, fatigue and left-leg oedema. When reviewed in the oncology clinic in March, he was less active than he had been, relying on his daughter for all of his shopping and having his meals delivered. He was no longer able to attend church on a Sunday—–indeed he rarely left his ground floor flat. He received a short course of palliative radiotherapy to his lumbar spine, and started dexamethasone 0.5 mg/day. However, in light of the deterioration in his performance status, the multidisciplinary team felt that the patient would not cope with cabazitaxel chemotherapy. He remains in his own home, where he is cared for by the community palliative care team. His pain control is good, and a package of social care has been arranged.
Common side effects of cabazitaxel The side effects of cabazitaxel are broadly similar to those of docetaxel [6], and indeed several other chemotherapy agents. They are manageable if anticipated, prevented where appropriate, and identified and treated should they present. Patients should be given clear instructions on how to recognise side effects and, where appropriate, the steps they can take themselves to minimise the development of symptoms. However, they should also be actively encouraged to contact their oncology unit early should side effects occur, and they must be able to recognise symptoms that warrant urgent assessment. A diary, or similar resource, may
help patients to remember the details of symptoms experienced between cycles. The most common adverse events in the TROPIC trial were haematological (Table 2), with neutropenia reported in 94% of cabazitaxel recipients and 88% of those in the mitoxantrone arm [5]. Febrile neutropenia was not a common side effect in the trial, but was seen more frequently with cabazitaxel than with mitoxantrone (7.4% versus 1.3%). Neutropenia and its consequences were cited as the cause of seven deaths in the cabazitaxel arm and one death in the mitoxantrone arm. However, all of the neutropenic deaths occurred early in the trial, i.e. before a protocol amendment requiring primary
Table 2 Common adverse events with cabazitaxel in the TROPIC trial (selection based on an incidence of ≥1% at grade ≥3) [5]. Adverse event
Anaemia Leukopenia Neutropenia Thrombocytopenia Diarrhoea Fatigue Nausea Vomiting Asthenia Haematuria Back pain Abdominal pain Febrile neutropenia
Incidence (%) All grades
Grade ≥3
97 96 94 47 47 37 34 23 20 17 16 12 8
11 68 82 4 6 5 2 2 5 2 4 2 8
S24 prophylaxis with granulocyte colony-stimulating factor (G-CSF) and, where indicated, cabazitaxel dose reduction. Furthermore, in a comment on the trial, it was noted that considerable variation between investigators in the management of febrile neutropenia may have contributed to the associated mortality, and that provision of preventive and supportive care, as appropriate, should be considered mandatory for patients receiving cabazitaxel [12]. Diarrhoea, fatigue/asthenia, nausea and vomiting were the most common non-haematological side effects of cabazitaxel (Table 2) [5].
Management of neutropenic toxicity Primary prophylaxis Primary prophylaxis with G-CSF should be considered for patients with high-risk clinical features that will predispose them to the complications of neutropenia, e.g. age over 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports and poor nutritional status. Evidence-based guidelines on the use of G-CSF have been published by the European Organisation for Research and Treatment of Cancer [13], the American Society of Clinical Oncology [14] and the National Comprehensive Cancer Network [15].
Cabazitaxel dose modification The patient’s full blood count should be monitored on days 1, 8 and 15 during cycle 1 of cabazitaxel treatment, and before each subsequent cycle. If the patient has grade ≥3 neutropenia, i.e. an absolute neutrophil count (ANC) of 1500/mm3 or lower, G-CSF treatment should be offered, and the next cycle of cabazitaxel should be delayed until the ANC threshold is exceeded. If grade ≥3 neutropenia persists for longer than 7 days despite G-CSF, or is complicated by fever or infection, the cabazitaxel dose should be reduced from 25 mg/m2 to 20 mg/m2 for the rest of the chemotherapy course. Prophylactic G-CSF may also be considered before subsequent deliveries of cabazitaxel. Cabazitaxel-based chemotherapy should be discontinued if grade ≥3 neutropenia develops at the reduced dose.
Neutropenic complications All oncology units that treat patients with cabazitaxel and other myelosuppressive chemotherapy
A. Lydon agents should have a clear, locally agreed protocol and care pathway for the management of individuals who present with febrile neutropenia and/or its life-threatening sequela neutropenic sepsis. Suspected febrile neutropenia or neutropenic sepsis is a medical emergency, analogous to meningococcal septicaemia, and should be treated as quickly as possible. Education—–of patients and healthcare professionals—–is essential to make sure patients and/or carers are aware that they must contact the hospital early, and that hospital staff act appropriately. Patients should check their temperature twice daily from day 5 of each cycle, and seek urgent attention if the reading is >37.5◦ C or <36◦ C or if they feel generally unwell, e.g. with flu-like symptoms. In such an eventuality they need to make contact with the hospital immediately via the number specified by their oncology team—–they should not seek help via their GP, NHS Direct, NHS24 or the 999 emergency service. They must not take paracetamol, wait for their symptoms to resolve or, if experiencing symptoms out of hours, delay until the next clinic session. As well as being discussed between the oncology team and the patient, and handed out in written form, this advice can be supported by displaying key information in the oncology waiting room. For example the TEA (Take Early Action) campaign launched in South Devon Healthcare Trust [16], includes a display reminding patients of the risk of febrile neutropenia, the warning signs and the points of emergency contact. On presentation, the patient will require urgent admission to hospital and rapid assessment (including blood culture). Intravenous antibiotic therapy must be administered as soon as possible, without waiting for the results of investigations. Suitable broad-spectrum antibiotics for initial use include piperacillin 4.5 g and gentamicin 260—400 mg. Drug modifications can be made subsequently, depending on the results of investigations and the patient’s clinical progress. Patients will require intravenous fluid support, and should be nursed in isolation according to local policy.
Management of diarrhoea Diarrhoea typically occurs 24 h or more after administration of a chemotherapy cycle. Almost half of the recipients of cabazitaxel in the TROPIC trial reported some degree of diarrhoea [5]. However, grade ≥3 diarrhoea (see Table 3) affected only 6% of the group. Patients who develop diarrhoea should be encouraged to inform their local chemotherapy
Cabazitaxel side effects: Prevention and management
S25
Table 3 Grading of diarrhoea according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events [17]. Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Increase of <4 stools per day over baseline
Increase of 4—6 stools per day over baseline
Increase of ≥7 stools per day over baseline; incontinence hospitalisation indicated; limiting self care and activities of daily living
Life-threatening consequences; urgent intervention indicated
Death
unit, so that their symptoms can be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (Table 3) [17]. The urgency of the assessment depends on the frequency of bowel movements. If a patient has more than four bowel movements in 24 h, they should contact the oncology unit by phone urgently, even if out of hours, so that an over-the-phone assessment can be made by a chemotherapy/oncology nurse. In the case of less frequent bowel movements, a phone call the next day should suffice.
Outpatient care Many of those with relatively mild diarrhoea (grade 1—2) can be managed as outpatients, with advice on medication, diet and fluid intake. They should be encouraged to drink 2—3 l of fluids per day—–high-energy drinks such as weak tea with sugar, and salt replacement fluids may be helpful. Some patients also find it helpful to avoid spicy or fatty foods, raw or high-fibre vegetables, and iced or caffeinated drinks. An absorbent medication, such as loperamide, should be prescribed—–4 mg initially and a further 2 mg with each episode of diarrhoea (maximum 16 mg per 24 h). If diarrhoea fails to resolve with these measures, the patient should be urgently assessed in hospital. Note also that diarrhoea can be a symptom of febrile neutropenia [18]. Therefore, if there is deemed to be a risk that the patient is neutropenic, e.g. they report diarrhoea symptoms 7—14 days after receiving a cycle of chemotherapy, a full blood count should be ordered and assessed urgently, and the patient admitted to hospital.
Inpatient care Hospital admission is required if the patient has grade ≥3 diarrhoea, or if any of the follow-
ing is present: fever, neutropenia, dehydration, abdominal cramping, rectal bleeding or reduced performance status. Any associated neutropenia and fever should be treated according to the local neutropenic care pathway. A stool sample should be analysed for Clostridium difficile toxin. If the result is positive, appropriate treatment should be initiated, again in line with local protocols. In other cases, the mainstay of treatment is loperamide plus codeine phosphate, with fluid and electrolyte replacement if required. A subcutaneous infusion of octreotide 300 mcg per 24 h can be used if the patient does not respond to the initial medication. If grade ≥3 diarrhoea persists despite these measures, the next cycle of cabazitaxel should be delayed until the symptoms resolve or improve, and subsequent doses should be reduced from 25 mg/m2 to 20 mg/m2 . Cabazitaxel-based chemotherapy should be discontinued if grade ≥3 diarrhoea develops at the reduced dose.
Fatigue/asthenia Fatigue and asthenia are associated with several chemotherapy agents, including cabazitaxel [5], and many patients benefit from understanding that they are experiencing expected side effects. Patients can be advised to take plenty of rest when they need to, but also to find opportunities for gentle exercise when they feel well enough. It is often helpful to suggest that they concentrate on activities that are essential to them and on those that give pleasure, but avoid feeling that they should maintain all routine activities. In some patients, asthenia may be related to a cause other than chemotherapy, e.g. depression, thyroid dysfunction or poor nutrition, and assessment of potential underlying factors may give useful pointers to management. Many patients ben-
S26 efit from understanding that fatigue and asthenia are expected side effects.
Nausea and vomiting Some patients experience nausea and vomiting after their cabazitaxel infusion [5]. The symptoms are generally mild, and resolve with antiemetic drugs. As with diarrhoea, advice on diet may be helpful; for example, patients may find it helpful to eat frequent small portions rather than more widely spaced large meals, and bland foods may be a better choice than spicy alternatives.
A. Lydon
Conflicts of interest I have received an honorarium from sanofi-aventis for a lecture, and an educational grant from Ipsen.
Acknowledgements My thanks to Succinct Healthcare Communications for editorial support. This supplement is sponsored by an educational grant from sanofi-aventis, which had no influence on the content of the article.
References Other adverse effects Haematuria and back pain were reported in the TROPIC trial [5], but, in my judgement, are likely to be related to the disease process rather than cabazitaxel. Other side effects associated with cabazitaxel, such as alopecia, stomatitis and onycholysis, are similar to those seen with docetaxel [19]. Although troublesome for the patient, these rarely result in stopping or reducing chemotherapy. Work is ongoing to help with some of these symptoms, e.g. use of iced gloves to reduce onycholysis [20]. Alopecia is rarely total, and patients can be reassured by knowing that their hair is likely to re-grow within 3 months of completion of chemotherapy. Stomatitis can be a nuisance, but is often helped by regular use of a mild mouthwash, and gentle tooth hygiene. Also, some patients find that soreness of the mouth is reduced by eating cold foods such as ice-cream during the course of the chemotherapy. However, it is important to examine the patient for signs of oral candida infection, which can be easily treated using conventional agents.
Conclusion With the introduction of cabazitaxel, we have the opportunity to improve the survival of patients with mCRPC who have progressed during or following docetaxel treatment and retain good performance status [5]. The drug is well tolerated, and healthcare professionals who look after patients with prostate cancer already have a wealth of expertise in the management of its side effects, which are predictable, and similar to those of docetaxel and various other chemotherapy agents [6]. With cabazitaxel, there is hope for a new paradigm shift in the battle with prostate cancer.
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