Adverse side effects associated to metronomic chemotherapy
Elisabetta Munzone, MD Division of Medical Senology Istituto Europeo di Oncologia
Milano, Italy
LDM: the optimal biological dose
• 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.
• This would indicate that the lack of severe
acute toxicity could be used to optimize LDM
chemotherapy dosing in individual patients
Therapeutic index
• The benefit of cancer therapies can be characterized by the therapeutic index: a balance between
antitumor activities and treatment‐
associated toxicities.
• 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
metronomic chemotherapy seems particularly beneficial given the combination of excellent antitumor activity with a toxicity profile that is considered to be superior to MTD chemotherapy.
Therapeutic window
Hypothetical dose‐response curves for different effects of cyclophosphamide
• When given at the optimal biological dose, metronomic CTX results in antiangiogenic and immunostimulatory effects.
• Higher CTX doses increase the risk of immuno/myelosuppression, likely without added benefit (MTD dose range)
• Metronomic schedule may optimize the beneficial therapeutic side effect and minimize host toxicity
Metronomics in breast cancer
Endocrine mechanism • immunogenic cell death
• Enhanced APC through DC
• Depletion of Tregs
• MDSC modulation
• Enhanced tumor specific Tcells and γδT cells
• Reduced tumour endothelial
• cell proliferation
• Reduced angiogenic potential
• of endothelial cells
• Increased THBS‐1 expression
• Inhibition of CECs
• Blockade of EPC mobilization
• Vessel normalization
• Increased tumour perfusion
• Reduced tumour‐
initiating cells
• HIF‐1 inhibition
• Modulation of clonal evolution
• cytotoxic drugs directly suppress ovarian function
• plasma estrogens decline, with a corresponding increase in gonadotropins
Multi-mechanism of action of metronomic chemotherapy in breast cancer
Nat Rev Clin Oncol. 2015 Nov;12(11):631‐44.
Immuno side‐effects on Tregs
• metronomic CTX strongly
decreases immunosuppressive
regulatory T cells (preserving other lymphocyte subsets in number and function), favoring a better control of tumor progression.
• these data support CTX regimen as a valuable treatment for reducing tumor‐induced immune tolerance before setting to work anticancer immunotherapy aimed at
improving T cell or NK cell functions.
Metronomic CTX selectively depletes regulatory T cells (Treg) in cancer patients
Ghiringhelli F et al (2007) Cancer Immunol Immunother 56(5):641–648
Critical issues to be considered…
• LDM chemotherapy is primarily being studied in advanced disease stages, LDM drug administration is sometimes
limited to a few months.
• The overall prognoses of such patients are poor, which could explain why side effects associated with cumulative doses of chemotherapeutics are rarely reported
• Many of the side effects (i.e., grade 1 or 2) reported in LDM trials may be related to the underlying neoplastic condition rather than to LDM therapy itself.
• Low‐grade symptoms could negatively impact adherence to
treatment itself, particularly to oral regimens administered
over prolonged periods of time.
Reports on side effects in a frail population
• Patients initially treated within clinical trials of metronomic chemotherapy were often
heavily pretreated or elderly
– High‐grade toxic effects were either rare or absent – the most common toxic effects were: grade 1
nausea and/or vomiting, grade 1 and 2 anemia, neutropenia, leucopenia, as well as low‐grade fatigue.
– Alopecia grade 1 was rarely reported.
Toxicity of mCT: a systematic analysis
• A recent systematic review of 80 published phase I/II LDM
chemotherapy trials included 3,688 patients (only studies with at least 20 patients)
• Varying cancer types and different LDM regimens reported overall
low toxicity rates
Metronomic drugs used
Most frequently used in breast cancer
Reported cumulative toxicities
• Severe (grade 3 or 4) side effects were rare and limited to less than 10 % of patients.
• Severe lymphopenia and neutropenia were the most frequent side effects reported, occurring in 6.44 % and 5.71% of patients.
• Elevated transaminases, a known side effect of
methotrexate administration, were the most prevalent non‐
hematological side effect.
Comparative studies: LDM versus an MTD treatment arm in parallel
Three comparative studies reporting the rates of adverse events associated with LDM versus MTD regimens indicate superior tolerance and safety of LDM chemotherapy, while still displaying comparable antitumor effects.
Risk of secondary cancers
• Prolonged metronomic chemotherapy may lead to high total cumulated doses of anticancer agents, which can be associated with secondary diseases
• High cumulated dose of etoposide,
cyclophosphamide or temozolomide can lead to the development of secondary leukemia.
• Because of its alkylating properties,
cyclophosphamide has been shown to increase the
risk of secondary malignancies such as leukemia and
urothelial cell carcinomas
The issue of cumulative doses
• A cumulative CTX dose of >10 g/m2 (approximately 200 days of treatment with 50 mg of CTX po daily in a patient with 1.8 m2) is considered to increase the leukemia risk
• Some increased risk was associated with total CTX doses up to 30,000 mg, the relative risk was 4.7 (N Engl J Med. 1992).
• 972 patients evaluated from IBCSG Trials I‐III, only one case of leukemia was observed. The patients, who received 12 cycles of CMF (cumulative total CTX dose 25,000‐33,600 mg), had a median follow‐up of 18 years.
• The long‐term effect of prolonged exposure to metronomic chemotherapy on normal endothelial and vascular tissues is unknown.
Cumulative doses in autoimmune disorders
• Oral CTX regimens are used for the treatment of autoimmune disorders, albeit at higher daily doses than 50 mg (168 pts; time frame:25 yrs)
Swiss Med Wkly. 2014;144:w14030
Commonly used metronomic drugs
toxicities
MetroCapecitabine toxicity
• The daily doses of capecitabine varied from 500 mg flat‐dosed twice daily to 2,250 mg once daily (1,250 mg/m2), assuming an average body surface of 1.8 m2
• The most frequently observed severe hematological side effects were neutropenia, and anemia.
• Non‐ hematological side effects were reported with a higher
frequency, including fatigue, hand–foot syndrome, stomatitis,
elevated transaminases, and diarrhea
MetroVinorelbine Toxicity
• Oral vinorelbine at 70 mg/m2, fractionated on days 1, 3, and 5, for 3 weeks on and 1 week
off, every 4 weeks;
• 50 mg given three times a week
• Main toxicities: neutropenia and anemia,
nausea
MetroEtoposide Toxicity
• Daily oral etoposide, ranging from 50 to 100 mg daily
• LDM etoposide had myelosuppressive profile
comparable to cyclophosphamide. No incidence of severe lymphopenia was observed
• LDM etoposide was associated with some severe non‐hematological toxicities: renal failure,
hemoptysis, thromboembolic complications,
mucositis, fatigue/asthenia.
MetroCyclophosphamide toxicity
• Most studies used an oral cyclophosphamide flat dose of 50 mg
• Neutropenia and anemia were the most frequently reported side effects reflecting the known
myelosuppressive potential of cyclophosphamide
• Most commonly reported non‐hematological
adverse events included skin rash, fatigue, nausea,
and hypertension
CM toxicity
• Roughly 10 studies were published with CM mainly in breast cancer
• Overall, the rate of severe hematological side effects was well below 10 % in the majority of studies
• Elevated transaminases, a known side effect of methotrexate, were the most prevalent non‐
hematological side effect.
vinorelbine, cyclophosphamide plus capecitabine (VEX) combination
Montagna E et al. Eur J Cancer 2015;51:S291‐S292
Strenghts and weakeness of oral CT
• Surveys have shown that most patients prefer oral to i.v. 1
• A minority prefer i.v. due to possible less effectiveness of oral therapies (last resort) 2
• Robust data are required to convince the full benefit of oral chemotherapy 3
• Adherence 4
1J Clin Oncol 1997; 15: 110–115
2Ann Oncol 2006; 17: 205–210
3Breast Cancer Res Treat 2005; 92: 265–272
4CA Cancer J Clin 2009;59(1):56-66
Patients’ perception on efficacy of oral chemotherapy
oral chemotherapy is well accepted by patients and makes them feel less sick than if they were given intravenous therapy
Breast Cancer Research and Treatment (2005)
Patients’ belief
In the overall population the majority of patients tended
not to believe in fewer side effects due to oral
administration
Schott et al. BMC Cancer 2011
Acceptance of oral chemotherapy in breast cancer patients: oral vs. iv
• 224 patients completed the questionnaire: 164 (73.2%) and 60 (26.8%) patients received i.v. and p.o. chemotherapy,
respectively
• Significant differences were especially found in terms of:
– personal benefit (55% i.v., 92% p.o.)
– reduced feeling of being ill due to p.o. treatment (26% i.v., 65% p.o.) – better coping with disease due to p.o. therapy (36% i.v., 68% p.o.).
• Side effects were significantly less often reported under p.o.
treatment (19% p.o. vs. 53% i.v.).
Schott et al. BMC Cancer 2011
Patient adherence and persistence with oral anticancer treatment
CA: A Cancer Journal for Clinicians
Volume 59, Issue 1, pages 56‐66, 16 JAN 2009
Reasons for non adherence are complex in most situations.
A large meta‐analysis of 76 studies demonstrated that adherence is adversely proportional to medication dosing frequency (prescribed number of doses per day )
complexity of the treatment regimen and symptom severity were the primary factors affecting adherence.
Spoelstra S et al. CJON 2013,
Factors associated with non adherence to prescribed oral chemotherapy
JNCI, 2002; 94: 652‐661
