Background
Method
Search strategy
Screening search results
Eligibility Criteria | |
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Inclusion | Exclusion |
•Studies of malignant disease •Studies of patients aged ≥18 years •Studies of oral SACT with non-conventional dosing •Studies examining the prescribing practices using unlicensed (non-standard) doses or schedules of oral SACT •Meta-analysis •Late phase clinical trials •Cohort studies •Cross-sectional studies •Retrospective studies •Observational studies •Case-control studies •Case-reports •MHRA: reports, legislative documents | •Studies of parenteral SACT (e.g. IM, IV, SC, IT) •Studies of oral SACT where non-conventional dosing has been used, but cannot be extracted independently of other reported data •Studies comparing different licensed doses of oral SACT for the same antineoplastic indication •New standard dose-finding studies •Animal studies •Early phase clinical trials •Pharmacokinetic studies •Narrative reviews •Opinion papers •Education papers •Commentaries •Editorials •Conference abstracts |
Quality appraisal and data extraction
Data to be extracted | Item |
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Publication ID | • Author • Publication date |
Study aim | • Title/Purpose/Aim |
Study design | • Study type: meta-analysis, late phase clinical trial, cohort study, cross-sectional study, retrospective study, observational study, Case-control study, case-report • Measurement tools, instruments, measures, outcome criteria |
Non-conventional dosing characteristics | • Oral SACT name • Dose • Duration of therapy |
Sample characteristics | • Number of participants • Country • Age • Gender • Cancer type |
Findings | • Reported efficacy outcomes • Reported side effects/toxicity outcomes • Reported health-related quality of life • Any other findings |
Strengths and limitations | • Findings of critical appraisal |
Data extraction
Data analysis
Results
Search results
Publication and country | Aims | Design | Schedule | Reported outcomes | ||
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Efficacy | Toxicity | QoL | ||||
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 |
Publication and country | Aims | Design | Schedule | Reported outcomes | ||
---|---|---|---|---|---|---|
Efficacy | Toxicity | QoL | ||||
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 |
Publication and country | Aims | Design | Schedule | Reported outcomes | ||
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Efficacy | Toxicity | QoL | ||||
Tanvetyanon et al (2003) US [44] | To describe use of once-weekly imatinib due to cutaneous reactions | Case report, sample = 1, indication: ALL | Dose ranged from 300 mg od to 400 mg once a week, includes dose interruptions
Licensed monotherapy starting dose:600 mg od
| Nil | Rash, fever, and facial swelling, syncope (with daily dosing, resolved with weekly dosing) | Nil |
Faber et al (2006) US [41] | To investigate safety and efficacy of intermittent dose imatinib following toxicities | Retrospective case series, sample = 12, indication: CML | Standard daily dose on initiation, changed to intermittent dose: range (300-600 mg 1-5 times a week)
Licensed monotherapy starting dose:400 mg od
| 7 favourable cytogenetic responses (2 complete and 5 major). Improved cytogenetic response in 5 patients, and 1 haematological progression. | Malaise, fatigue, diarrhoea, fluid retention and muscle cramps. | Nil |
Defina et al (2009) Italy [40] | To report tolerability and efficacy of alternate day dosing of lenalidomide | Prospective cohort study, sample = 6, indication: MDS | Lenalidomide 10 mg e.o.d (21/7 plus 7/7 break)
Licensed starting dose:10 mg od 21/7 plus 7/7 break
| Transfusion independence in all patients within 3-4 months. Cytogenetic response: CR (2) within 6-7 months, PR (3) within 7-9 months. | G3 thrombocytopenia (1), G3 neutropenia (2). | Nil |
Satoh et al (2011) Japan [39] | To compare the efficacy of low-dose gefitinib vs. standard dose | Retrospective cohort sample = 114, indication: EGFR NSCLC | Standard dose group (S1) n = 61: 250 mg od. Reduced dose group (S2), n = 53: 250 mg e.o.d
Licensed monotherapy starting dose:250 mg od
| Non-inferiority (response and disease control) between groups. Response and disease control rates (83%, 98%) in S2 and (66%, 82%) in S1. Median PFS and 1-year PFS rate: S2 (11.8 months, 50%), S1 (9.9 months, 36%). | Nil | Nil |
Hata et al (2012) Japan [42] | To describe efficacy and toxicity of intermittent erlotinib dosing in 4 cases | Case report, sample = 4, indication: EGFR NSCLC | Various doses used: 150 mg od, 150 mg e.o.d, 200 mg e.o.d, and 100 mg od. Different treatment durations and interruptions
Licensed monotherapy starting dose:150 mg od
| Responses ranged from partial response to progression. | (1) (2) and (3): G2–3 rash and paronychia resolved with 150 mg e.o.d in cases 1-3. G3 rash resolved with 100 mg od in case 4 | Nil |
Bojic et al (2012) Austria [43] | To report efficacy and toxicity of varying dosages of sunitinib used in 1 case | Case report, sample = 1, indication: metastatic RCC | Schedules used: 4/52 on 2/52 weeks off, continuous therapy, and 2/52 on 1/52 off
Licensed monotherapy starting dose:50 mg od 28/7 plus 2/52 break
| Different responses from different doses including CR, PR and relapse. | Fatigue and hypertension improved at 37.5 mg od. Improved toxicities and QoL at 2/52 on 1/52 off dosing | QoL improved |
Popat et al (2014) UK [11] | To evaluate efficacy and cost-saving of alternate day dosing of lenalidomide | Prospective cohort study, sample = 39, indication: multiple myeloma | Starting dose 25 mg od for 21/28 followed by 1/52 break. Dose reduced to e.o.d at 25 mg, 15 mg, or 10 mg per dose. Median duration 12 cycles
Licensed starting dose:25 mg od 21/7 plus 7/7 break
| ORR 85%, CR 3%, VGPR 23%, PR 59%, MR 13%, SD 0%, PD < 1%. Median PFS 11.5 months, Median OS 36.5 months. Cost-savings: £19,408.43/patient | Nil | Nil |
Abdel-Wahab et al (2014) US [45] | To report efficacy and toxicity of intermittent vemurafenib used in 1 case | Case report, sample = 1, indication: BRAF-mutant melanoma | Vemurafenib dose: range 480-960 mg bd, with interruptions due to toxicity. Cobimetinib added at 9 months: dose range 40-60mg od
Licensed monotherapy dose:960 mg bd
| Marked disease improvement at week 2. Near CR on intermittent schedule. | High WCC, fatigue, anaemia | Nil |
Fukuizumi et al (2015) Japan [46] | To describe management of crizotinib with dose reductions in 1 case | Case report, sample = 1, indication: ALK positive NSCLC | Dose variation: 250 mg bd, 250 mg od, 250 mg every 3 days, and 250 mg bd every 3 days, with dose interruptions.
Licensed monotherapy starting dose:250 mg bd
| Significant tumor response on escalating to 250 mg bd. Significant response maintained for 13 months with 250 mg bd every 3 days. | Dyspnoea, chest discomfort. | Nil |
Tsukita et al (2015) Japan [47] | To report a case of oesophagitis resolved with alternate day crizotinib | Case report, sample = 1, indication: ALK positive NSCLC | Dose variation: 250 mg bd, 200 mg bd, 200 mg e.o.d, 250 mg bd e.o.d, with interruptions due to toxicity
Licensed monotherapy starting dose:250 mg bd
| Shrinkage of the spinal metastases then re-growth. | Dysphasia and retrosternal pain, severe oesophagitis, Grade 3 ALT elevation. | Nil |
Saponara et al (2016) Italy [48] | To report four cases treated with low dose imatinib | Case report, sample = 4, indication: GIST | Dose ranges: 800 mg od to 300 mg od, with interruptions
Licensed monotherapy starting dose:400 mg od
| Responses variable from good to stable disease. | Fatigue, periorbital and leg oedema, and skin toxicities. | Nil |
Quality appraisal
Non-standard dosing strategies
Dose interruptions
Dose reductions
Other dosing strategies
Discussion
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Drug interruption strategy
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Dose reduction strategy
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Other dosing strategies