“By making treatments more tolerable and accessible to a broader range of cancer patients, mCT is an example that less can sometimes be more.”
These are the words of Elisabetta Munzone of the Division of Medical Senology at the European Institute of Oncology in Milan. She was recently speaking at a series of continued professional development events in SA, hosted by Pierre Fabre, France’s third largest pharmaceutical laboratory. The topic of discussion was, “New era of breast cancer treatment: the role of oral vinorelbine with the metronomic schedule.”
According to Munzone, mCT can be described as “the chronic administration of chemotherapy, at low doses, with a frequent schedule of administration at close, regular intervals and with no extended interruption.”
“The results from a national survey conducted in Italy indicated a significant interest in metronomic therapy, with 72% of responders having been administered a regimen of MT at least once. The largest number of published studies are phase II trials with a relatively low number of patients,” said Munzone.
Briasoulis et al states that systemic therapy of metastastic cancers has moderately progressed over the last decade. “Conventional chemotherapy appears to have reached a plateau in efficacy for most major cancers and a number of promising targeted therapeutics have failed to meet their objectives.”
Metronomic chemotherapy (mCT) has been developed as a patient-friendly therapy on the concept to induce prolonged cancer control without significant side effects, even in frail patients.
According to the conventional chemotherapy regimens, anticancer drugs are administered in cycles near or at the MDT and they alternate with long drug-free period to allow the patient to recover from adverse drug reactions. This strategy is successful in controlling the disease process in a significant number of patients, but leads to some complications.
In addition, despite initial improvement, recurrence is a common problem in metastatic and high-risk cancers. The rationale and effectiveness of conventional MTD-based chemotherapy regimens and dose modification strategies have been questioned for many years, especially in patients with poor-prognosis and scientifically convincing research data were needed to support the potential of an alternative therapeutic strategy.
In the late nineties, Browder et al published such much-awaited preclinical data from Judah Folkman’s laboratory and it was confirmed in Robert Kerbel’s laboratory. For demonstrating the anti-angiogenic effect of low-dose chemotherapy, both the teams used transplantable tumours and xenograft models. The first study revealed that metronomic regimen of cyclophosphamide (CPA) was more effective than conventional therapy and could overcome drug resistance; whereas, the second study explored the existence of synergism between continuous treatment with low-dose vinblastine and anti-VEGF receptor (VEGFR) therapy.
The scientific basis for metronomic chemotherapy is that conventional anti-neoplastic drugs target vascular endothelial cell proliferation but the anti-angiogenetic effect cannot be sustained because endothelial cells get a chance to recover during treatment breaks and this may be overcome by frequent treatment at low doses.
Hanahan et al invented the term ‘metronomic’, which is derived from the word “metronome”, a musical instrument that produces regular, metrical ticks representing fixed, regular aural pulse. Metronomic chemotherapy is the frequent administration of chemotherapy drugs at doses below the MTD and with no prolonged drug-free break. It therefore achieves a sustained low blood level of the drug without significant toxic side effects.
According to the authors of a review, Metronimic oral vinorelbine in advanced breast cancer and non-small-cell lung cancer: current status and future development, mCT has multiple actions against cancer cells, including inhibition of angiogenisis and modulation of the immune system. A number of studies led support to the clinical efficacy of mCT in advanced breast cancer and non-small-cell lung cancer.
According to Cardoso et al, “Although advanced breast cancer is a treatable disease, it is still generally incurable and the goal of care is to optimise both length and quality of life.”
Summary of mechanisms of action of metronomics
LDM: the optimal biological dosage
“If drug exposure needs to be chronic, the traditional system of defining the MTD based on toxicity limitations no longer applies, since it is based on peak exposure. Although there is no definite clinical data, preclinical studies suggest that the optimal biological LDM dose in terms of anticancer activity appears to coincide with very limited toxicity,” said Munzone.
“This would indicate that the lack of severe acute toxicity could be used to optimise LDM chemotherapy dosing in individual patients.”
The therapeutic index
The benefit of cancer therapies can be characterised by the therapeutic index: a balance between antitumor activities and treatment.
“TD50 is the dose of drug that causes a toxic response in 50% of the population and ED50 is the dose of drug that is therapeutically effective in 50% of the population. The therapeutic index of mCT seems particularly beneficial given the combination of excellent antitumour activity with a toxicity profile that is considered to be superior to MTD chemotherapy,” said Munzone.
Recommendations on the use of mVNB in the treatment of breast cancer
|50 mg dd 1,3,5/wk||30-40 mg dd 1,3,5/wk|
“In the era of biological drugs, mCT is a valid option to take advantage of desired modes of action with oral agents. mCT by optimal biological dose increases the therapeutic index with a better toxicity profile than classical MTD schedule. MTAs such as mVNB are the most promising classes of chemotherapeutic drugs currently used for metronomic schedules in cancer treatment.
mCT single agent or combination?
“In the past four years, more than 2500 patients with different advanced/refractory, metastatic and/or relapsed cancers have been treated with metronomics,” said Munzone.
“The combination was either metronomic CT and hormone therapy or; metronomic CT and targeted therapy; or metronomic CT alone.
“The summary of the studies shows that the choice is dependent on age, PS, comorbidities and previous treatment,” states Munzone.
Munzone states that the results of available data and clinical trail outcomes can be summarised accordingly:
- MTD combinations CT demonstrate to be superior to single agent MTD CT in terms of ORR, PFS but not in OS
- MTD combinations CT is characterised by a worse safety profile than single agent MTD CT
- mCT combination has been evaluated in selected first-line MBC patients demonstrating to be active and feasible for a prolonged time without increasing toxicities and without impairing QoL
- mCT combination could be offered in patients not requiring a rapid tumour response
- indolent disease: HR+, DFI > 1y, PS≥0
- mCT single agent has been evaluated as active and safe in frail/elderly and pre-treated patients.
Treatment of advanced breast cancer
According to the ASCO guidelines for HER-2 negative advanced breast cancer, “Advanced breast cancer remains an incurable disease, and the general goals of therapy are to prolong survival, palliate symptoms and to optimise quality of life (QoL).”
“It has often been difficult to demonstrate an OS advantage from any given regimen in this setting, partly because of the opportunity for women to cross over to other treatments after a study, partly because of the heterogeneity of prior treatment and of the disease itself,” states the guidelines.
“QoL, together with efficacy and patient’s preference, is a major parameter to consider choosing a therapy for incurable disease,” said Munzone.
“All of the treatment options should be discussed with the individual patient with a clear explanation of the risk-to-benefit ratio. The subjective attitude of the patient is one of the major factors, which influence the choice and acceptance of a therapeutic programme. Personal preference and considerations about quality of life, rather than data from clinical trials, should guide the treatment choice,” emphasised Munzone.
The ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC), reiterates Munzone’s statements.
“Advanced breast cancer is a treatable, but still generally incurable disease. The goals of care are to optimise both length and quality of life.”
“Anthracycline- or taxane-based regimens, preferably as a single agent, would usually be considered as first-line CT. Other options are available and effective, such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient. The main recommendation relates to the sequential use of single agents, with combination chemotherapy reserved for situations of visceral crisis, rapidly progressive or highly symptomatic disease,” states the guidelines.
Metronomics in a frail population
Patients initially treated within clinical trials of metronomic chemotherapy were often heavily pre-treated or elderly:
- High-grade toxic effects were either rare or absent, the most common toxic effects were: grade one nausea and/or vomiting, grade one and two anemia, neutropenia, leucopenia, as well as low-grade fatigue.
- Alopecia grade one was rarely reported.
- Reported cumulative toxicities
“Metronomic chemotherapy is an alternative treatment, especially for palliative indications and for the elderly and/or frail patients that otherwise would not be candidates for MTD chemotherapy,” said Munzone.
“The low burden of personal costs to the patient and the possibility to continue the treatment for several months support the use of metronomic CT as an additional therapeutic tool.”
Metronomic chemotherapy in perspective: is there any future?
“Currently the main criticism is the lack of data from randomised trials,” states Munzone.
A randomised phase II trial of metronomic oral vinorelbine plus cyclophosphamide and capecitabine (VEX) versus weekly paclitaxel as first-line or second-line treatment in patients with ER-positive/HER2-negative advanced or metastatic breast cancer, is currently underway to address the concern.
This is a multi-centre, randomised phase II trial that will randomise women with ER-positive, HER2-negative (Human Epidermal Growth factor Receptor 2-negative) metastatic or locally relapsed breast cancer in a ratio of 1:1 to receive a metronomic regimen of vinorelbine plus cyclophosphamide and capecitabine, or the conventional paclitaxel monotherapy.
Further study details as provided by International Breast Cancer Study Group, “Time to treatment failure (TTF) compared between treatment groups. From date of randomisation until the date the final dose of trial treatment was given due to documented progression, lack of tolerability or until further treatment is declined, assessed up to 36 months from enrolment of the first patient.”
Efficacy and tolerability, measured by time to treatment failure of metronomic oral vinorelbine plus cyclophosphamide and capecitabine (VEX), versus weekly paclitaxel, using an intent-to-treat analysis approach.
The estimated enrolment of the trail is 160 with an anticipated study start date of May 2017; the estimated study completion date is October 2020.
“The prognosis for patients with locally advanced or metastatic disease (ABC) remains poor, with a median survival of two to four years. About 10% of newly diagnosed BC patients present with ABC, and 30% to 50% of patients diagnosed at earlier stages will subsequently develop metastatic disease,” states the study group.
In the first-line treatment of HER2 (Human Epidermal Growth factor Receptor 2) negative ABC patients, various chemotherapy regimens can be used including taxanes, which are among the most active agents in BC. Single agent response rates range from 20% to 50%.
“However, eventually all patients will progress with a median time to progression of five to seven months. A weekly (qw) over a three-weekly (q3w) administration schedule of paclitaxel has been shown to be more effective in the metastatic as well as in the adjuvant setting after standard chemotherapy
The VEX regimen was recently investigated within a phase II trial currently on-going at the European Institute of Oncology (IEO): “A phase II study of metronomic oral chemotherapy with cyclophosphamide plus capecitabine and vinorelbine in metastatic breast cancer patients”). Patients received vinorelbine 40 mg orally on days one, three and five every week, cyclophosphamide 50 mg daily and capecitabine 500 mg three times a day,” the study material states.
Given the promising activity of the VEX regimen in a pre-treated population of advanced breast cancer patients and the good tolerability, the aim of the present trial is to investigate whether the VEX schedule may improve efficacy and tolerability as compared to standard paclitaxel treatment in advanced or metastatic ER-positive/HER2-negative breast cancer patients.
“The concept of the VEX metronomic treatment is to administer the combination for as long as the patient has the possibility of deriving a benefit from it. The time to treatment failure (TTF) has been chosen as primary endpoint for this trial. TTF is defined as time from the date of randomisation to the date when the final dose of trial treatment is administered. Chemotherapy may need to be stopped due to lack of tolerability, lack of efficacy or patient preference through subjective symptom assessment. TTF is a composite endpoint combining all these feasibility aspects of a treatment. It is therefore uniquely suited to the research question of the current trial. The secondary endpoints progression-free survival, disease control and safety will allow further assessment of the feasibility of the VEX metronomic treatment versus the paclitaxel monotherapy regimen,” the Breast Cancer Study Group said.
How to select a patient for mCT?
- Consider the patients’ preference
- Consider tumour/disease characteristics
- IV or oral?
- Patients and their physicians must weigh the risks and benefits of all therapeutic options
- Lack of validated predictive or pharmacodynamics markers of metronomic chemotherapy
- Additional clinical studies are warranted to further improve the therapeutic index of metronomic chemotherapy
- What subtype benefits most?
- Who benefits?
“Increased attention to patients’ quality of life favours the use of active oral treatments,” Munzone concluded.
Briasoulis et al: Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer, a Hellenic cooperative oncology group clinical translational study. BMC Cancer 2013: 263
Metronomic oral vinorelbine in advanced breast cancer and non-small-cell lung cancer: current status and future development. Marina E Cazzaniga*, Andrea Camerini, Raffaele Addeo, Franco Nolè, Elisabetta Munzone, Elena Collovà, Alessandro Del Conte, Manlio Mencoboni, Paola Papaldo, Felice Pasini, Silvana Saracchini & Guido Bocci
E Montagna, et al: Safety and efficacy study of metronomic vinorelbine, cyclophosphamide plus capecitabine in metastatic breast cancer: A phase II trial. Cancer Letters (2017)
International Breast Cancer Study Group: http://www.ibcsg.org/Public/Health_Professionals/Open_Trials/Pages/ibcsg54-16_meteora.aspx