Docetaxel Rechallenge in Patients with Castration-resistant Prostate Cancer – A Review
findings in clinical practice that some patients respond to docetaxel and discontinue treatment after receiving the planned courses without experiencing disease progression. However, the response is not durable, and all of the patients who discontinue first-line chemotherapy in the absence of progression eventually relapse. In the SWOG trial, the time to progression was 6.3 months5
and in the
most successful arm of the TAX327 trial, the duration of the PSA response was 7.7 months.4
of advanced cancers: systemic treatment controls the disease only temporarily, meaning that further lines of therapy are required. The need for additional treatment options is more urgent for oncology patients who fail to achieve disease control with first-line therapy and require different drugs.
Some studies have explored the possibility of overcoming docetaxel resistance by adding a second drug, but often at the cost of an unmanageable toxicity profile.12–14
In the case of CRPC, the problem of the lack of a second-line therapy became increasingly relevant after docetaxel became the cornerstone of first-line treatment, because many docetaxel-resistant patients require further treatment and therapeutic options for nonresponders were very limited. Mitoxantrone is only moderately active as second-line treatment, with biochemical response rates of 6–20 %,7–10 and the new-generation drugs have failed to improve patient survival.9,11
Two large-scale randomised
phase III trials have recently tested the efficacy of new drugs that are expected to become available during 2012 as second-line treatment after docetaxel failure. Cabazitaxel is a new taxane associated with better survival rates than mitoxantrone15
and abiraterone is a new
cytochrome 17 alpha-hydroxylase – C(17,20)-lyase (CYP17) – inhibitor that was superior to placebo in terms of survival.16
The scenario for patients who fail to respond to first-line docetaxel has been very discouraging. On the other hand, although it is clear that their docetaxel sensitivity is different from that of those who stop first-line treatment because of disease progression, all of those who respond will experience disease progression some time after discontinuing docetaxel. In these cases, the question is whether they are still sensitive to docetaxel when they relapse: in other words, is it possible to repeat docetaxel-based treatment and achieve a new response capable of prolonging disease control?
Rationales for Chemotherapy Rechallenges and Intermittent Therapy in Oncology
Rechallenges refer to all situations in which a systemic treatment is resumed in the hope of exploiting its potential activity after it has been discontinued because of the completion of the planned number of courses (usually determined on the basis of median cumulative toxicity) and not because of the development of resistance (disease progression).
The strategy is strictly related to the concept of the sensitivity/resistance of a specific tumour to a specific drug, and has been particularly applied in the case of ovarian cancer. The standard first-line chemotherapy for women with advanced ovarian cancer is a combination of paclitaxel and a platinum analogue (cisplatin or carboplatin), which is usually administered for not more than six courses in the absence of progression. Upon relapse, patients with a progression-free interval of more than six months are considered platinum sensitive, and platinum-based retreatment can lead to an additional 30–50 % response rate.17
Patients who have experienced a EUROPEAN ONCOLOGY & HAEMATOLOGY This type of finding is common to all kinds
In the case of a true intermittent strategy, chemotherapy is stopped for a defined period of time after the administration of a limited number of cycles, and then resumed in an attempt to reduce toxicity and improve patient compliance. It would probably be more appropriate to use the word ‘rechallenge’ when speaking of a situation in which a patient who has completed a predefined number of chemotherapy courses without experiencing disease progression subsequently progresses after any period of time and then receives another course of the same treatment. As the two terms have often been used interchangeably, it may sometimes be difficult to identify which strategy has been used in a given study.
A number of randomised studies have tested an intermittent/ rechallenge strategy in patients with metastatic breast cancer19–22 metastatic colorectal cancer.23–26
or Although the results of these studies
conflict in terms of the quality of life advantages for intermittent over continuous therapy, and their equivalence in terms of disease control, they provide evidence that a new response may be achieved when treatment is resumed. For example, the patients with metastatic breast cancer who received cyclophosphamide, fluorouracil and epirubicin (FEC) at the time of progression after four courses of the same combination showed an overall response rate of 41 %,22
and the patients
with metastatic colorectal cancer who resumed treatment with fluoropyrimidines achieved a response in 21 % of cases.23
The rechallenge and intermittent strategies may hypothetically delay the appearance of drug resistance.
Rechallenges and Intermittent Therapy in Castration-resistant Prostate Cancer In the absence of an active second-line treatment for CRPC, it was debated whether the patients responding to first-line docetaxel who discontinued the treatment without experiencing progression would still be sensitive to docetaxel or not.
In prostate cancer, the concept of intermittent treatment developed in the context of advanced hormone-sensitive disease. Patients with hormone-sensitive disease undergo androgen deprivation for extended periods of time but, as this leads to a number of side effects that impair their quality of life, phase II and phase III studies were designed to investigate a strategy in which treatment was stopped after prolonged PSA normalisation and resumed at the time of biochemical progression (usually PSA values of 10–20 ng/ml). This approach has led to improved tolerability and quality of life27
but, because of the limited availability of
mature data concerning OS, conflicting conclusions have been drawn as to whether intermittent androgen deprivation should be considered experimental28
or not.29 However, as androgen deprivation in the
intermittent strategy is not discontinued after a pre-planned treatment duration but once a biochemical response is achieved, and is resumed at the time of biochemical progression, it would be more appropriate to call it a rechallenge.
In the field of CRPC, a truly intermittent strategy with planned early treatment interruption followed by a predefined rest period designed
37
progression-free interval of less than six months are considered platinum resistant, and the reintroduction of platinum should not be considered. Similarly, a platinum-based rechallenge can be proposed for patients with advanced small cell lung cancer and a progression-free interval of at least three months after discontinuation of first-line treatment.18
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