Cyclophosphamide administration routine in autoimmune rheumatic diseases: a review^☆

Abstract

Cyclophosphamide is an alkylating agent widely used for the treatment of malignant neoplasia and which can be used in the treatment of multiple rheumatic diseases. Medication administration errors may lead to its reduced efficacy or increased drug toxicity. Many errors occur in the administration of injectable drugs. The present study aimed at structuring a routine for cyclophosphamide use, as well as creating a document with pharmacotherapeutic guidelines for the patient. The routine is schematized in three phases: pre-chemotherapy, administration of cyclophosphamide, and post-chemotherapy, taking into account the drugs to be administered before and after cyclophosphamide in order to prevent adverse effects, including nausea and hemorrhagic cystitis. Adverse reactions can alter laboratory tests; thus, this routine included clinical management for changes in white blood cells, platelets, neutrophils, and sodium, including cyclophosphamide dose adjustment in the case of kidney disease. Cyclophosphamide is responsible for other rare - but serious - side effects, for instance, hepatotoxicity, severe hyponatremia and heart failure. Other adverse reactions include hair loss, amenorrhea and menopause. In this routine, we also entered guidelines to post-chemotherapy patients. The compatibility of injectable drugs with the vehicle used has been described, as well as stability and infusion times. The routine aimed at the rational use of cyclophosphamide, with prevention of adverse events and relapse episodes, factors that may burden the health care system.

Keywords:
Cyclophosphamide; Antiemetics; Chemotherapy; Cystitis

Resumo

A ciclofosfamida (CFM) é um agente alquilante vastamente usado para o tratamento de neoplasias malignas e pode ser usado no tratamento de diversas doenças reumatológicas. O erro de administração de medicamentos pode levar à diminuição da eficácia ou ao aumento da toxicidade medicamentosa. Diversos erros ocorrem na administração de medicamentos injetáveis. O trabalho objetivou a estruturação de uma rotina do uso de ciclofosfamida, bem como a criação de um documento de orientações farmacoterapêuticas para o paciente. A rotina foi esquematizada em três fases, a pré-quimioterapia (pré-QT), a administração da ciclofosfamida e a pós-quimioterapia (pós-QT), que levaram em consideração os medicamentos que devem ser administrados antes e depois da ciclofosfamida para prevenção aos efeitos adversos, incluindo náusea e cistite hemorrágica. As reações adversas podem alterar os exames laboratoriais e a rotina incluiu manejo clínico para alteração clínica dos leucócitos, das plaquetas, dos neutrófilos e do sódio incluindo o ajuste de dose de ciclofosfamida em caso de insuficiência renal. A ciclofosfamida é responsável por outras reações adversas raras, mas sérias, como hepatotoxicidade, hiponatremia severa e falência cardíaca. Outras reações adversas incluem perda de cabelo, amenorreia e menopausa. A rotina foi composta também por orientações ao paciente pós-QT. A compatibilidade dos medicamentos injetáveis com o veículo foi descrita, bem como o tempo de estabilidade e o tempo de infusão. A rotina visou ao uso racional da ciclofosfamida e prevenir os efeitos adversos e os episódios de recidiva, os quais podem onerar o sistema de saúde.

Palavras-chave:
Ciclofosfamida; Antieméticos; Quimioterapia; Cistite

Introduction

Cyclophosphamide (CPM) is an alkylating agent widely used for the treatment of malignancies such as breast cancer,¹ multiple myeloma,² renal diseases including nephrotic syndrome refractory to corticosteroid and focal segmental glomerulonephritis, and this drug can be used in the treatment of multiple rheumatic diseases,^3-5 including cicatricial pemphigoid (also called pemphigoid mucous membrane),⁴ rheumatoid arthritis,⁵ juvenile dermatomyositis,⁶ systemic sclerosis,^7,8 interstitial lung disease,⁷ lupus vasculopathy,⁹ systemic vasculitis, and refractory treatment of lupus-associated thrombocytopenic purpura.¹⁰ In addition to other indications of cyclophosphamide, the treatment of neuromyelitis optica can also be included.¹¹

In children, cyclophosphamide may be used in the treatment of nephrotic syndrome and systemic lupus erythematosus.^12,13

Cyclophosphamide can be administered by oral or intravenous route.¹⁴ The intravenous administration is more frequent in the field of rheumatology, taking into account studies showing an efficacy similar to that of oral treatment, but with less toxicity, for example, a decrease in premature ovarian failure, less severe infection, and lower overall exposure of the urinary tract to acrolein, a toxic metabolite of cyclophosphamide.¹⁵ Cyclophosphamide is orally administered QD (24-24 h), while the intravenous route is administered in pulses, and the dose is adjusted according to hematologic and renal toxicities.¹⁶

The administration of cyclophosphamide in pulses may follow a weekly or monthly basis, in combination with a corticosteroid and other chemotherapeutic agents, provided that the attending physician takes into account the minimum blood count (NADIR) for the administration of cyclophosphamide.^16-18 Cyclophosphamide may cause some adverse events, and when these effects are related to the drug, are classified as an adverse drug reaction.¹⁹ The adverse drug reaction can be conceptualized as an unintended and harmful reaction into the body, occurring in those routinely used doses in humans for prophylaxis, diagnosis, disease therapy, or for changes of physiological functions.¹⁹

A reaction that occurs in a small percentage of the population, but that, if not avoided, may cause irreversible damage to the patient, such as death, congenital abnormalities, birth defects or conditions that require permanent hospitalization, is classified as "severe reaction".¹⁹

Some adverse reactions related to the administration of cyclophosphamide are bone marrow suppression, susceptibility to infections, sterility and amenorrhea,¹⁸ as well as nephrotoxicity and cystitis,^18,19 and also cardiovascular complications, for instance, sinus bradycardia, pericarditis, myocarditis and heart failure.²⁰ Children and adolescents treated with high doses of cyclophosphamide are more likely to develop dental disorders and a decreased salivary flow. Cyclophosphamide is also teratogenic.²¹ A long term reaction of cyclophosphamide is malignacies.¹⁸ One can observe an increase in the incidence of bladder cancer and esophageal and lung adenocarcionoma, which customarily occur after two years of treatment.¹⁸

In addition to adverse drug reactions of cyclophosphamide, it is critical that the physician adopt all precautionary measures, because these adverse reactions may be more important in cases where cyclophosphamide is administered intravenously, given that, with this route of administration, the drug is not absorbed, the onset of its action is faster and, because the drug does not undergo first-pass metabolism, the bioavailability, i.e. the bioavailable concentration to exert a pharmacological action, becomes proportionally higher versus oral administration of cyclophosphamide.^22,23 Another important aspect to consider concerns the errors associated with the administration of injectable drugs.²⁴

It is known that the use of injections is often associated with medication errors classified as serious events.²² Intravenous-route administration errors represent 21.1% of all errors, with possible risk of errors of contamination, administration rate, and dilution.²⁵ Such parenteral drug administration errors, especially those by intravenous route, can cause an adverse drug reaction.¹⁹

In addition to health-related problems, it is required that the costs resulting from drug administration errors are taken into account. In Brazil, it is estimated that the annual cost with the use of chemotherapeutic drugs exceed 1.1 billion reais, and this value can increase in cases of injectable drug administration errors.²⁴

Thus, one must bear in mind that these costs may be magnified by the occurrence of adverse events.²⁶ An adverse event is any untoward medical occurrence that affects the patient being medicated, but without a direct causal relationship with his/her treatment.¹⁹

Thus, it is important to standardize the administration of parenteral drugs and provide their rational use, which can be defined as the patient's need to receive the appropriate drug in the correct dosage for an adequate length of time and with the lowest cost.²⁷

Taking into account the rational use of drugs, it is important to standardize rules for the parenteral administration of cyclophosphamide. The objectives of this study are proposing a cyclophosphamide administration routine in Rheumatology units, and the creation of a document containing pharmacotherapeutic guidelines for the patient, in order to maximize the efficiency of treatment based on a literature review.

Methods

Cyclophosphamide routine

An infusion routine for cyclophosphamide was developed in order to increase the bioavailability (effectiveness) of this drug while minimizing adverse reactions, thus rendering the treatment more tolerable for the patient. The protocol was divided into stages to facilitate the comprehension of the health staff and the replication of the cyclophosphamide dosing schedule. The drugs of the first (pre-ChT) and third (post-ChT) steps correspond to the administration of pharmaceuticals in order to prevent the main adverse reactions resulting from the administration of cyclophosphamide (second phase), including nausea, vomiting, and hemorrhagic cystitis. The clinical management of adverse reactions that change laboratory tests was described, as well as the clinical management of cyclophosphamide in renal failure. The rare, but serious, adverse reactions were also highlighted.

The most common adverse reactions were emphasized so that the attending physician could provide guidance with respect to the main care that the patient should take in his/her home, after administration of cyclophosphamide. These precautions are essential to prevent or minimize adverse effects and increase treatment adherence.

In addition, the compatibility of these injectable drugs with the vehicle, stability time, and infusion time was ascertained. The sequence of administration of these drugs has been prepared in order to increase the efficacy of cyclophosphamide and diminish the onset of adverse reactions to the drugs administered.

Results

The routine administration of cyclophosphamide was developed in three phases: pre-ChT, cyclophosphamide administration, and post-ChT. With a view to the prevention of hemorrhagic cystitis, intravenous hydration with a blood volume expander (a crystalloid: 0.9% saline) was standardized.²⁸ In addition, the drug administration sequence, the amount of diluent, the need (or otherwise) for dilution, infusion and administration times, and laboratory tests which should be monitored before and after the infusion of cyclophosphamide were indicated, as well as the guidelines to the patient.

Fig. 1^3,5,20,29-42 , lists the routine data, and Fig. 2 ^44-50 describes the guidelines for the patient. Severe and uncommon adverse reactions which should be monitored are hepatotoxicity,³ hyponatremia⁴⁵ (in this case, serum sodium level = 135 mmol/L [sodium is an univalent element; thus, 1 mmol/L = 1 mEq/L)],⁴⁵ and cardiovascular failure due to cyclophosphamide cardiotoxicity.³⁶

Fig. 1
Cyclophosphamide administration routine in autoimmune rheumatic diseases.Sources: ^aShepherd et al.²⁹; ^bHawthorn; ^eCunningham³⁰; ^cJordan et al.³¹; ^dTurner et al.³²; ^eTrissel³³; ^fHaubitz et al.³⁴; ^gMardegan et al.³⁵; ^hDi Lisi et al.³⁶; ⁱSalido et al.³⁷; ^jCalixto-Lima et al.³⁸; ^kLotan et al.²⁰; ^lZahn et al.³⁹; ^mMilman⁴⁰; ⁿMota et al.⁵; ºMcDermid and Lönnerdal⁴¹; ^pCentro de Oncologia Unimed Birigui⁴²; ^qSubramaniam et al.³; ^rMota et al.⁴³

Fig. 2
Guidelines for the patient taking cyclophosphamide.Sources: ^aInstituto Estadual de Hematologia Arthur de Siqueira⁴⁴; ^bBruining et al.⁴⁵; ^cGonzález et al.⁴⁶; ^dOtero López⁴⁷; ^eMedeiros-Souza et al.⁴⁸; ^fMesna⁴⁹; ^gTaketomo et al.⁵⁰.

Other adverse reactions from cyclophosphamide are amenorrhea,¹⁸ early menopause,⁴⁶ and hair loss.³

Discussion

Drug administration errors can decrease the effectiveness of the pharmacological treatment and increase both the occurrence of adverse reactions and the financial costs of treatment.²⁴ A retrospective study conducted in hospitals in Spain between 2008 and 2010 evaluated the incidence of cost and adverse event. 245,320 episodes were identified, with an overall cost of 1,308,791.97 euros. Approximately 6.8% of patients experienced adverse events, representing a rise of 16.2% in costs. Six of the ten adverse events that burdened more significantly the hospital system occurred in the operating room, corresponding to an increase of expenses around 6.7% to the health system.²⁶

A prospective study conducted between August and November 1999 and between January and May 2000 notified 1800 errors in 1663 patients. The number of notifications resulting from drug-related problems (including those probable and possible ones) was 215 (11.9%). Of these notifications, 108 (50.2%) were filled up due to adverse reactions, 100 (46.5%) came out of therapeutic failure related to dosing, and seven (3.3%) were due to intoxication. According to the criteria (modified) of Schumock and Tornton, 68.4% of drug-related problems are considered as preventable.⁴⁷

The cyclophosphamide dosing schedule took into account the most common adverse reactions, the administration's strategy in the case of kidney failure, and the sequence in the administration of pre-ChT drugs, cyclophosphamide, and post-ChT drugs; to this end, the dosage of all medications used, their dilution and infusion time also were included.

The main clinical strategies in the face of adverse reactions from cyclophosphamide use included the care of hemorrhagic cystitis, nausea, and vomiting.¹⁸ The administration of these drugs corresponds to what is defined as a qualitative polypharmacy, wherein the administration of a medication is performed to correct the adverse reaction of another medication.⁴⁸

Several clinical strategies have been proposed to avoid hemorrhagic cystitis, including increased hydration of the patient and the administration of mesna and furosemide.^28,29 In those cases in which the patient suffers of a severe kidney impairment, it is preferable to administer mesna in place of hydration, due to the patient's water restriction.^20,29

For the prevention of hemorrhagic cystitis, mesna is administered in a dose equivalent to 60% of cyclophosphamide, divided into three doses - 20% 15 min before the administration of cyclophosphamide, 20% after cyclophosphamide, and 20% 4 or 8 h after cyclophosphamide.²⁸ Mesna reduces the deposit of acrolein (a metabolite of cyclophosphamide) in the bladder, thus preventing hemorrhagic cystitis and bladder cancer.¹⁸

In order to decrease the exposure of the urinary tract to acrolein, the patient should be well hydrated before, during and after the administration of cyclophosphamide. Thus, at the time of his/her admission, the patient should receive, through a venous access, 1 L of a blood volume expander (a crystalloid: saline 0.9%) for 1 h, 60 min before the administration of cyclophosphamide.⁵¹

Cyclophosphamide per se can be administered at any time. In turn, the infusion of mesna depends on the administration of cyclophosphamide.²⁸ Mesna may be administered by oral or parenteral (subcutaneous or intravenous) route.²⁸

The oral administration of mesna has the advantage of a convenient dosage schedule; however, its use brings some disadvantages, for instance, a higher frequency of nausea and vomiting.^49,50 Another limiting factor of the use of this drug orally is the decreased bioavailability versus parenteral route, due to first-pass metabolism, in addition to the potential decrease in its absorption as a result of frequent episodes of vomiting caused by the treatment with cyclophosphamide.³¹ Taking into account the concepts that guide the rational use of pharmaceuticals, including the reduction of treatment costs for both the patient and society, oral administration of mesna would have also the advantage of a likely decrease in expenses, due the lower bed occupancy time and less workload of the nursing team.⁵¹ Still in this context, another possible disadvantage is the patient's non-compliance; thus, one cannot be sure that the patient has taken, or otherwise, the last dose of mesna PO.⁵²

The advantage of the use IV mesna is that there is no need of absorption, and the onset of action of this drug is faster, compared with oral administration.^22,23,53 The disadvantage of the parenteral route is the greater risk of contamination, administration errors, less dosing convenience, and increase of the patient's hospital stay.^23,53

However, mesna administration with a view to the prevention of hemorrhagic cystitis in patients using cyclophosphamide in therapeutic doses for rheumatic diseases is controversial; thus, mesna may be replaced by a suitable hydration with 6 L of water per day, plus a diuretic drug, or the use of hydration with a volume of 3 L/m² per day.⁵⁴

Furosemide is administered after cyclophosphamide infusion at a dose of 20 mg, in order to stimulate diuresis that, in synergism with mesna, decreases the exposure of urothelium to the action of acrolein.⁵⁵ The maximum concentration of furosemide is 10 mg/mL administered in bolus, achieving a therapeutic concentration of 10 mg/mL per minute.⁵⁵ The second dose of mesna (20% of cyclophosphamide dose) is administered in the interval between 15 and 30 min after the administration of cyclophosphamide.²⁸

Nausea and vomiting are considered as common adverse reactions in chemotherapy, and this also occurs with cyclophosphamide³¹ which, in turn, participates of many chemotherapeutic regimens. In this case, a routine has been proposed for the treatment of rheumatic diseases. Nausea caused by the exclusive administration of cyclophosphamide (without a therapeutic scheme) is classified as a late-onset nausea.⁵⁶ Thus, ondansetron was not required to prevent this effect.⁵⁶ A decrease in effectiveness is another reason for not using ondansetron prior to cyclophosphamide.⁵⁷

This reduction in efficacy occurs because ondansetron is an inhibitor of CYP2B.⁵⁸ This occurs because cyclophosphamide is a prodrug that must be activated by CYP2B, resulting in 4-hydroxycyclophosphamide and aldophosphamide. These metabolites are transported to the site of action, where they undergo spontaneous cleavage, producing phosphoramide mustard, responsible for the pharmacological effects of the drug.⁵⁸

Moreover, dexamethasone was added prior to chemotherapy, as a prophylactic agent to anaphylactic shock and also as an antiemetic.⁵⁹ Preferably, dexamethasone should be administered so that its peak coincides with the peak of physiological corticosteroids, which normally occurs at 8 a.m. and 16 p.m.⁵⁸ A peak in dexamethasone plasma concentration occurs within 60 min, and its action begins in 30 min.^55,60 Thus, the administration of dexamethasone should be started in the morning, 30 min before the administration of cyclophosphamide, preferably at 7:30 a.m.⁵⁸

After the emesis caused by cyclophosphamide was classified as a delayed-type,⁵⁶ and in view of the decrease of cyclophosphamide efficacy when ondansetron is administered prior to this chemotherapeutic agent, ondansetron (8 mg PO^31,61 administered at 6 and 14 or 8 and 16 h post-ChT, and with a maximum dose of 16 mg after chemotherapy, not exceeding 32 mg per day) was the last drug used for the prophylaxis of emesis caused by cyclophosphamide.³¹

Other important adverse effects of cyclophosphamide include hematologic toxicity,¹⁸ kidney failure,²⁰ hyponatremia,^45,62 neurological impairment,⁴⁵ amenorrhea,¹⁸ early menopause,⁴⁶ hair loss,³ hepatotoxicity (rare),³ and late-onset cancer.¹⁸ The dose of cyclophosphamide for the treatment of systemic lupus erythematosus, including those patients with neuropsychiatric and/or hematologic disorders, with class IV lupus nephritis, and with other serious manifestations of systemic lupus erythematosus, is 0.5-1 g/m² IV monthly,^5,62 with dosage adjustment in patients with hematological toxicity and kidney failure.^20,63 Adverse hematologic reactions caused by cyclophosphamide are classified as serious, as they cause high morbidity.^19,64 NADIR is the minimum hematologic counting that must be observed to see if the patient may or may not embark on another chemotherapeutic cycle.⁶⁵ The main hematological tests include platelets, neutrophils, white blood cells and neutrophil counts. Neutropenia is defined as a decrease in absolute neutrophil count <1500 cells/µL.⁶⁵ The main causes of neutropenia include hematologic disorders, autoimmune diseases, infection, adverse drug reaction, chemotherapy, and radiotherapy.⁶⁵ Thrombocytopenia occurs when the platelet count is <100,000/mm³.⁶⁵ In a patient with a platelet count <81,000/mm³ concomitantly experiencing leukopenia, the treatment should be discontinued until the platelet count increase to 99,000/mm³.⁶⁵ However, cyclophosphamide can be used in the treatment of refractory thrombocytopenic purpura, and in this case, among the hematologic disorders, thrombocytopenia, and microangiopathic hemolytic anemia are included. Leukopenia¹⁰ is defined as a white cell count <3500/mm³.⁶⁵

Hepatotoxicity is an adverse reaction caused by cyclophosphamide that normally occurs at high doses.³ When hepatotoxicity occurs at low doses, the reaction is classified as a rare, but serious, event.^19,64 Acute liver failure with low-dose cyclophosphamide (200 mg) was described in a case report of a male Chinese aged 48 years with progressive glomerulonephritis secondary to Wegener's granulomatosis, 24 h after the administration of cyclophosphamide.³ The diagnosis of granulomatosis with polyangiitis was established by pathological examination and c-ANCA.³ The patient was being treated with high-dose methylprednisolone, plasmapheresis, intermittent hemodialysis and low intravenous doses of cyclophosphamide.³ Other factors that may be associated with hepatotoxicity have been excluded, including antifungals, HIV, and hepatitis B and C.³ Alanine transaminase increased from 41 U/L to 336 U/L at the day of administration of 200 mg of cyclophosphamide; in the next day, a peak of 566 U/L was reached.³ Two weeks later, the patient was treated with another pulse of 200 mg of cyclophosphamide (second dose), and the concentration of alanine transaminase reached 1253 U/L.³ A liver biopsy was not possible, because the patient had a clotting disorder.³ Another laboratory parameter to be monitored is sodium concentration. Hyponatremia is considered as an electrolyte disorder identified in clinical practice.⁴⁵ Although many cases are mild or relatively symptomatic, hyponatremia is regarded as a clinically important finding, with high morbidity and mortality. Neurological symptoms of hyponatremia occur at sodium levels <125 mmol/L.⁶⁶ Among the complications of hyponatremia, one can mention central nervous system disorders such as seizures, and even a permanent damage to the central nervous system, and death.⁶⁶ Syndrome of inappropriate antidiuretic hormone secretion (SIADH) was described in a case report in which this syndrome was associated with the use of IV cyclophosphamide in a dose of 500-1000 mg/m², with a serum sodium level <120 mmol/L in a patient presenting neurological complications.⁶²

Cyclophosphamide may also cause cardiotoxicity. Routinely, echocardiography, a noninvasive method, is used to monitor cardiovascular function in patients treated with immunosuppressants.³⁶ Other non-invasive methods most widely used are electrocardiography and 24-h (ECG) Holter monitoring.³⁶ Invasive methods such as scintigraphy, magnetic resonance imaging and cardiac biopsy are also procedures that can be used in cases of adverse reactions classified as serious.³⁶

Other adverse reactions caused by cyclophosphamide include amenorrhea, menopause, and late-onset cancer, including esophageal, lung and bladder adenocarcinoma.^18,46 Cyclophosphamide was administered at a dose of 750-1000 mg/m² body surface in LUMINA (Lupus in minorities, nature versus nurture), a multicenter study performed including 567 women aged under 51 years.⁴⁶ A decrease in gonadal function was found, and gonadal failure was defined as the occurrence of amenorrhea for more than six months without a history of hysterectomy.⁴⁶ Cyclophosphamide has also been associated with teratogenicity.¹⁸

As to cyclophosphamide dose adjustment in patients with kidney failure, this is only done in severe cases, that is, with a creatinine clearance <10 mL/min. The therapeutic regimen of cyclophosphamide should be modified, its dose should be reduced by 25%, and supplemented with 50% after dialysis.³⁴

The dilution of the drugs used in cyclophosphamide routine was carried out with the goal of maintaining the highest possible concentration of the drug in its non-ionized form.⁵⁸ Thus, two parameters were taken into account: drug compatibility with the vehicle (saline, dextrose or ringer lactate) and its stability time in the vehicle; preference was given to those drugs whose stability time was longer, in order to ensure a more effective treatment.³³

When the drugs used have proved compatible and stable with the same vehicle, preference was given to the choice of the same vehicle, as this facilitates their administration by the nursing staff and prevents pharmacokinetic interaction, which would cause ionization of the drugs and a decrease in their efficacy.⁶⁷

Another important aspect that should be addressed is the education of the patient on the treatment to what he/she is being submitted. A study in the city of Natal with 40 women diagnosed with systemic lupus erythematosus at the Hospital Onofre has shown that patients showing greater adherence were those who understood correctly the treatment and also the disease; thus, these women satisfactorily understood the adverse events and the clinical management, in order to minimize these adverse drug reactions.⁶⁸

Publications on adverse events are important tools for drug safety monitoring after their release for marketing purposes by the health authorities of each country.⁶⁹ This review of medication administration intended to standardize the administration of cyclophosphamide by health professionals, in order to minimize the adverse events caused by drugs, the so-called adverse drug reaction.¹⁹

Conclusion

The routine was developed in order to increase the area under the curve (AUC) for cyclophosphamide, and to attain an appropriate clinical management to minimize the adverse drug reactions that, if not properly prevented, will cause damage to the patient, for instance, an increased prevalence of vomiting, and acrolein deposition in the bladder. The clinical management of adverse reactions that alter laboratory tests was described in order to guide the application of these tests. Adverse reactions, even being rare, were highlighted because these events can cause high morbidity. Thus, the rational use of cyclophosphamide increases the safety of the treatment and reduces the cost of administration of this chemotherapeutic agent, since our goal is to avoid error.

• ☆
  Study conducted at the Serviço de Reumatologia, Hospital Universitário, Universidade de Brasília, Brasília, DF, Brazil.

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Publication Dates

• Publication in this collection
  Nov-Dec 2017

History

• Received
  2 Aug 2013
• Accepted
  7 Apr 2016