Table 4 Studies reporting dose reductions as non-conventional dosing strategy

Binder et al (2010) Germany [34]

To assess efficacy and tolerability outcomes of dose-reduced erlotinib

Retrospective cohort study, sample = 53, indication: advanced NSCLC

Subgroup 1 (S1): n = 31:150 mg od. Subgroup 2 (S2):n = 9: 100 mg od. Subgroup 3 (S3): n = 9: 75 mg or 50 mg od

Licensed monotherapy starting dose:150 mg od

Median TTP months (S1: 3.1, S2: 6.2, S3 18.4). Median TTP among patients with no toxicity vs. with toxicity (1.0 vs. 5.4, P = 0.001).

Toxicity leading to discontinuation (8%). G3 rash (9/53), G2–3 nail toxicity (9/53), G2–3 diarrhoea (4/53), G3 conjunctivitis or keratitis in 2/53

Nil

Breccia et al (2010) Italy [18]

To determine if reduced dosing of imatinib is as effective as standard

Retrospective cohort study, sample = 45, indication: CML

Starting dose 400 mg od, reduced to 300 mg od (43 patients) and 200 mg od (2 patients).

Licensed monotherapy starting dose:400 mg od

MCyRs in 67% of patients at 6/12 from dose reduction, CCyR 58%, CMR 18%. All patients on MCyR reached CCyR at 12/12. CMR in 20% and MMR 22%.

Nil

Nil

Serpa et al (2010) Brazil [17]

To report in 4 cases the safety and efficacy of low doses of dasatinib

Case report, sample = 4, indication CML

Varied: range 20-140mg od, different durations and interruptions

Licensed monotherapy starting dose:100 mg od

Responses include CCyR or MMR or both.

High grade thrombocytopenia and neutropenia

Nil

Abbadessa et al (2011) Italy [39]

To report in four cases treated with sorafenib, the efficacy and tolerability of prolonged low dosing

Case report, sample = 4, indication: advanced HCC

Only case 4 has extractable dose data: 400 mg 10/7, withheld for 1/12, restarted at 50% for 4/12, withheld 9/7, restarted 400 mg e.o.d

Licensed monotherapy starting dose:400 mg bd

PR after 3 months. Stable response at 2 years. CR at 62 months.

G3 hand-foot skin reaction on full dose.

Nil

Hoon Sim et al (2014) S.Korea [35]

To evaluate the effect of gefitinib dose reduction on survival

Retrospective cohort study, sample = 263, indication: EGFR NSCLC

Subgroup 1(S1): n = 240: 250 mg od. Subgroup 2 (S2) n = 23: mean dose intensity index 0.84.

Licensed monotherapy starting dose:250 mg od

Median PFS S1 vs. S2 (10.8 vs. 14.0 months, P = 0.042). Median OS in S1 and S2 (29.6 vs. 54.5 months, P = 0.02).

Toxicities leading to dose reduction: skin (5/23), abnormal LFTs (11/23), both toxicities (6/23).

Nil

Jung Sung et al (2014) S.Korea [33]

To evaluate BSA as index in defining appropriate imatinib dosage

Retrospective cohort study, sample = 70, indication: CML

Subgroup 1(S1) n = 25: ≥ 400 mg od. Subgroup 2 (S2) n = 45: ≤ 300 mg od.

Licensed monotherapy starting dose:400 mg od

Dose/BSA important index of CCyR12. Higher CCyR12 probability if IM/BSA > 206.7 mg/m².

Toxicities leading to doe reductions: severe neutropenia or thrombocytopenia

Nil

Zipin et al (2014) US [19]

To describe a case of reduced dose of imatinib in terms of efficacy

Case report, sample = 1, indication: CML

400 mg od 4/52, withheld 7/52, restarted 100 mg od. At week 23, increased to 200 mg od 22/52 until date of report

Licensed monotherapy starting dose:400 mg od

FBC normalise on therapy. CCyR on 200 mg od.

Nil

Nil

Shinoda et al (2015) Japan [36]

To describe a case of reduced doses sorafenib (efficacy and toxicity)

Case report, sample = 1, indication: advanced HCC

Variable dose range: 800 mg od to 200 mg e.o.d

Licensed monotherapy starting dose: 400mg bd

Good response CT at month 8. No progression on last follow up.

G3 hypertension at 800 mg od.

Nil

Jamison et al (2016) US [37]

To report 2 cases of low dose of dasatinib (efficacy and toxicity)

Case report, sample = 2 indication: CML

Patient 1: 70 mg bd reduced gradually to 20 mg od. Patient 2: 70 mg bd reduced gradually to 50 mg od

Licensed monotherapy starting dose:100 mg od

BCR-ABL p 210 fusion transcript undetectable. Time to MMR: 9 and 10 months respectively.

Patient 1: grade 2-3 arthralgia, myalgia, and peripheral oedema. Patient 2: painful maculopapular rash and pancreatitis.

Nil