Table 3 Studies reporting dose interruptions as non-conventional dosing strategy

Wick et al (2007) Germany [20]

To evaluate toxicity and efficacy of an alternating weekly regimen of temozolomide

Prospective non-randomized late phase trial, sample = 90, indication: recurrent glioma (64 glioblastoma)

150 mg/m² (days 1–7 and 15-21 every 4/52). Dose reductions/increases in steps of 25-50mg/m².

Licensed monotherapy starting dose: 150 mg/m ² od 5/7 of a 28 day cycle

6 month PFS rate in glioblastoma group 43.8%. Median PFS 24 weeks. Median OS from diagnosis of progression 38 weeks.

% per week neutropenia: G2 (7.6), G3(1.1), G4(0.1), Lymphopenia: G2(1.6), G3(1.1), G4(0.7), thrombocytopenia: G2(5.9), G3(8.5), G4(1.9)

Nil

Buti et al (2012) Italy [28]

To investigate the tolerability and efficacy of a modified schedule of sunitinib following ≥G2 toxicities

Retrospective cohort study, sample = 8, indication: metastatic RCC

Starting at 50 mg od 4/52 and 2/52 off. Modified schedule: daily on days 1-5 (weeks 1-5) and od on days 1, 3 and 5 (week 6)

Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break

Median PFS and OS 16.3 and 28.5 months. 70% of patients alive at 2 years.

Toxicity reduced with modified schedule

Nil

Mangiacavalli et al (2012) Italy [21]

To explore efficacy and peripheral neuropathy of low-dose intermittent thalidomide

Late phase randomised trial, sample = 23, indication: multiple myeloma

Arm A (n = 13: 100 mg daily days 1-21 plus 7 days break), Arm B (n = 10: 100 mg daily continuously)

Licensed starting dose: 200 mg od but it can start lower (50 mg–100 mg)

Median PFS and OS in arms A and B (7 vs. 42 months, p = 0.02), (24 months vs. not reached < 0.001).

Majority of patients (74%) suffered some peripheral neuropathy PN (G1 49%, G2 39%, G3 12%). Median time to PN occurrence 7.5 months. PN incidence in arms A and B (62% vs. 90%, P = 0.15).

Nil

Atkinson et al (2013) US [25]

To investigate the impact of alternative schedules of sunitinib on clinical outcomes

Retrospective cohort study, sample = 185, indication: metastatic RCC

Standard subgroup 1 (S1) n = 98: 50 mg od 4/52 on 2/52 off. Alternative dosing Subgroup 2 (S2) n = 87: 50 mg 2/52 on 1/52 off or other alternative schedule.

Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break

Median PFS in S1 and S2 was 4.3 vs. 14.5 months, p < 0.0001), median TOT (4.1 vs. 13.6 months, p < 0.0001), median OS (17.7 vs. 33.0 months, p < 0.0001).

63 patients experienced AE leading to schedule change. Rate of G3–4 fatigue 10%, hand-foot syndrome 8% and diarrhoea 5%. Incidence of AE in S2 < 30%. Incidence reduced on transition from S1 to S2 dose

Nil

Kondo et al (2013) Japan [26]

To compare efficacy and AE profile of an alternative sunitinib schedule with standard schedule

Retrospective cohort study, sample = 48, indication: metastatic RCC

Subgroup 1 (S1) n = 22: 50 mg od 4/52 and 2/52 off. Subgroup 2 (S2) n = 26: 50 mg od 2/52 and 1/52 off.

Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break

CR and PR rates S1 (5%, 45%) S2 (8%, 24%). Objective response in S1, S2 (50% vs. 32%, p = 0.12), median PFS S1 and S2 (9.1 vs. 18.4 months, p = 0.13).

No difference in incidence of most AEs between subgroups. More frequent hand–foot syndrome (HFS) and diarrhoea in S1 compared to S2

Nil

Neri et al (2013) Italy [29]

To determine if bi-weekly sunitinib dosing can maintain the same efficacy as standard schedule whilst reducing AE

Retrospective cohort study, sample = (31), indication: metastatic RCC

Alternative schedule: 50 mg od 2/52 and 1/52 off. Dose was reduced to 37.5 mg for ≥ G2 toxicity in 4 patients.

Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break

ORR 42%, CR 10%, PR 32%. Median PFS 16.4 months. Median OS 18.1 months.

Reported as important toxicities: anaemia, gastrointestinal effects, fatigue and hypertension but manageable.

Nil

Ohzeki et al (2014) Japan [30]

To report efficacy and toxicity outcomes of 2 sunitinib schedules: alternative and standard

Retrospective cohort study, sample = 54, indication: metastatic RCC

Standard dose subgroup 1(S1): 4/52 on 2/52 off (daily dose not specified). Alternative dose subgroup 2(S2): any schedule different to standard dose

Licensed monotherapy dose:50 mg od 28/7 plus 2/52 off

PR or stable disease in S1 and S2 (47.1% vs. 95.5%, P < 0.001). Median TTF (4.1 vs. 11.6 months, p = 0.04). Median PFS (4.1 vs. 11.3 months, p = 0.031). Median OS (12 vs. 32.1 months, p = 0.0018).

AE significantly less common in S2, including most high-grade AE.

Nil

Dooley et al (2014) UK [10]

To report efficacy and toxicity outcomes of 6 cases treated with intermittent vemurafenib

Case series, sample = 6, indication: BRAF V600E-mutant melanoma

Variation between 6 cases: range 240 mg–960 mg bd. Schedules: continuous, 2/52 on 2/52 off, 1/52 on 1/52. Different durations/interruptions

Licensed monotherapy starting dose:960 mg bd

Variation between 6 cases. Response range: stable disease to good response, progression in some cases.

Toxicity outcomes variable depending on case and dose

Nil

Koop et al (2014) Germany [32]

To report efficacy and toxicity outcomes of 1 case treated with intermittent vemurafenib

Case report, sample = 1, indication: metastatic BRAF V600E-mutated melanoma

Dose: 960 mg bd 6/52, off 12/52, on 8/52, off 11/52, on 6/52

Licensed monotherapy starting dose:960 mg bd

PR at 6 weeks, mixed response (progression on interruption and response on re-initiation)

acanthoma on the trunk, photosensitivity, loss of taste and fatigue

Nil

Russo et al (2015), Italy [23]

To investigate the effects of a non-standard, intermittent imatinib dose in elderly patients

Late phase trial, sample = 76, indication: CML

Schedule: 1/52 on 1/52 off (weeks 1-4), 2/52 on 2/52(weeks 5-12), 1/12 on 1/12 off thereafter. Daily dose: 400 mg (81%), 200-300 mg (17%), 600 mg (1 patient).

Licensed monotherapy starting dose:400 mg od

21% lost CCgR and MR3.0, 21% lost MR3.0 alone. No progression recorded. 9 patients died on remission.

Nil

Nil

Bracarda et al (2015) Italy [27]

To evaluate safety and efficacy outcomes of an alternative schedule of sunitinib

Retrospective multicentre cohort study, sample = 460, indication: metastatic RCC

Subgroup 1 (S1) n = 208: 50 mg od 4/52 on 2/52 off, switched to 2/52 on 1/52 off. Subgroup 2 (S2) n = 41: 50 mg od 2/52 on 1/52 off. External control group (E) n = 211: 50 mg od 4/52 on 2/52 off.

Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break

Median PFS in S1, S2 and E (30.2 vs. 10.4 vs. 9.7 months). Median OS (not reached vs. 23.2 vs. 27.8 months).

Incidence of G ≥ 3 in alternative schedule compared to standard (8.2% vs. 45.7%, P < 0.001).

Nil

Pan et al (2015) China [24]

To assess efficacy and tolerability and HRQoL of alternative vs. traditional sunitinib dosing

Retrospective cohort study, sample = 108, indication: metastatic RCC patient

3 subgroups: Subgroup 1(S1) n = 50: 50 mg od 4/52 on 2/52 off. Subgroup 2(S2) n = 26: 50 mg od 2/52 on 1/52 off. Subgroup 3 (S3) n = 32: starting as per S1 and switched as per S2

Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break

No difference in tumour response between S1–3. Median PFS S3 vs. S2 vs. S1 (11.2 vs. 9.4 vs. 9.5 months, respectively, P = 0.030).

Incidences of diarrhoea, fatigue, hand-foot syndrome, and neutropenia less common in S3 compared to S2 and S1 (P < 0.05).

HRQoL better in S3

Miyake et al (2015) Japan [31]

To investigate clinical significance of changing from standard to alternative sunitinib dosing

Retrospective cohort study, sample = 45, indication: metastatic RCC

50 mg od 4/52 on 2/52 off, then changed to 50 mg od 2/52 on 1/52 off

Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break

Nil

Toxicities occurred on both schedules. Statistically higher ≥G3 toxicities with schedule change.

HRQOL Better with reduced dose

Jonasch et al (2018) US [22]

To assess efficacy and toxicity of an alternative schedule of sunitinib

Late phase trial, sample = 59, indication: previously untreated RCC

Stating at Level 0, and reducing to other alternative schedules (Levels −1 to −5) if toxicities: Level 0: 50 mg od 2/52 on 1/52 off

Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break

ORR 56%, CR 2%, PR 54%. Median PFS 13.7 months. Median OS not reached.

G3≥  fatigue, diarrhoea or HFS in 25% of patients. Two discontinuations due to unresolved G3 fatigue and 4 due to CHF, proteinuria, concomitant G2 toxicities or osteonecrosis.

Nil