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 treatmentassociated 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
Multi-mechanism of action of metronomic chemotherapy in breast cancer Metronomics in breast cancer Endocrine mechanism immunogenic cell death Enhanced APC through cytotoxic drugs directly DC suppress ovarian function Depletion of Tregs plasma estrogens decline, with MDSC modulation a corresponding increase in Enhanced tumor gonadotropins specific Tcells and γδt cells Reduced tumour endothelial cell proliferation Reduced angiogenic potential of endothelial cells IncreasedTHBS 1 expression Inhibition of CECs Blockade of EPC mobilization Vessel normalization Increased tumour perfusion Reduced tumourinitiating cells HIF 1 inhibition Modulation of clonal evolution 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 nonhematological 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 nonhematological 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 1 J Clin Oncol 1997; 15: 110 115 2 Ann Oncol 2006; 17: 205 210 3 Breast Cancer Res Treat 2005; 92: 265 272 4 CA 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 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 ) CA: A Cancer Journal for Clinicians Volume 59, Issue 1, pages 56 66, 16 JAN 2009
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
Conclusions 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 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 Increased attention to patients' quality of life favors the use of active oral treatments
Future tools: how to select? Patients may have tumors, preferences and characteristics with little evidence supporting the use of i.v. single agent chemotherapy or polychemotherapy Patients and their physicians must weight the risks and benefits of all therapeutic options In the absence of validated predictive or pharmacodynamic markers of LDM chemotherapy, additional clinical studies are warranted to further improve the therapeutic index of LDM chemotherapy.
Less is more? A number of chemotherapy dose intensification strategies have either failed or resulted in only incremental benefits, they were often associated with increased toxicity By making treatments more tolerable and accessible to a broader range of cancer patients, LDM chemotherapy is an example that less can sometimes be more. a balance between beneficial therapeutic side effect and minimize host toxicity