Does an Alternative Sunitinib Dosing Schedule Really Improve Survival Outcomes Over a Conventional Dosing Schedule in Patients with Metastatic Renal Cell Carcinoma? An Updated Systematic Review and Meta-Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Inclusion Criteria and Study Eligibility
2.3. Data Extraction
2.4. Study Quality Assessments
2.5. Statistical Analysis
3. Results
3.1. Systematic Review Process
3.2. Quality Assessment
3.3. Oncological Outcomes; Progression-Free Survival and Overall Survival
3.4. Incidence of Adverse Events
4. Discussion
5. Conclusions
Funding
Conflicts of Interest
References
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Author(s) (Year) | Country | Study Design | Study Summary |
| Schedule | No. of Patients | Follow up (Months) | PFS (Months, IQR) | OS (Months, IQR) |
---|---|---|---|---|---|---|---|---|---|
Atkinson et al. (2014) | USA | Retrospective | Comparisons of oncological outcomes and incidence of adverse events between two groups: 2/1 and 4/2, 4/2 to 2/1 switch |
| 2/1 dosing | 24 | NR | Median 11.6 (5.8–18.3) | Median 27.7 (21.2–NE) |
4/2 dosing | 98 | Median 4.3 (3.4–6.4) | Median 17.7 (10.8–22.2) | ||||||
Kondo et al. (2014) | Japan | Retrospective | Comparisons of oncological outcomes and incidence of adverse events between two groups: 2/1 and 4/2 |
| 2/1 dosing | 26 | Mean 11.9 ± 8.1 (range 2.6–31.6) | Median 18.4 (NR) | NR |
4/2 dosing | 22 | Mean 13.3 ± 10.1 (range 1.5–39.1) | Median 9.1 (NR) | ||||||
Najjar et al. (2014) | Japan | Retrospective | Comparisons of incidence of adverse events between two groups: 2/1 and 4/2 |
| 2/1 dosing | 30 | Median 11.9 (range 0.9–73.3) | NR | NR |
4/2 dosing | 30 | Median 12.6 (range 1.2–62) | |||||||
Bracarda et al. (2015) | Europe | Retrospective | Comparisons of oncological outcomes and incidence of adverse events among three groups: 2/1, 4/2, and 4/2 to 2/1 switch |
| 2/1 dosing | 41 | Median 7.8 (IQR 5.8–22.4) | NR | NR |
4/2 dosing | 208 | Median 4.3 (IQR 2.0–12.0) | |||||||
Lee et al. (2015) | South Korea | Randomized controlled | Comparisons of oncological outcomes and incidence of adverse events between two groups: 2/1 and 4/2 |
| 2/1 dosing | 38 | Median 30.0 (IQR 19.5–53.6) | Median 12.1 (4.0–25.3) | Median 30.5 (18.9–42.0) |
4/2 dosing | 36 | Median 10.1 (7.5–12.7) | Median 28.4 (11.3–45.4) | ||||||
Miyake et al. (2015) | Japan | Retrospective | Comparisons of incidence of adverse events between two groups: 2/1 and 4/2 |
| 2/1 dosing | 45 | Median 3.4 (range 1.3–19.7) | NR | NR |
4/2 dosing | 45 | Median 8.9 (range 2.3–21.4) | |||||||
Pan et al. (2015) | China | Retrospective | Comparisons of oncological outcomes and incidence of adverse events among three groups: 2/1, 4/2, and 4/2 to 2/1 switch |
| 2/1 dosing | 32 | Median 1.5 years (range 1.0–2.2) | Median 11.2 (NR) | NR |
4/2 dosing | 50 | Median 1.9 years (range 1.3–2.7) | Median 9.5 (NR) | NR | |||||
El Din (2017) | Egypt | Retrospective | Comparisons of oncological outcomes and incidence of adverse events between two groups: 2/1 and 4/2 |
| 2/1 dosing | 26 | Median 23 (range 3–43) | Median 17 (2–43) | Median 24 (2–42) |
4/2 dosing | 30 | Median 24 (range 2–42) | Median 15 (1–42) | Median 23 (3–43) | |||||
Suo et al. (2017) | Canada | Retrospective | Comparisons of oncological outcomes and incidence of adverse events among three groups: 2/1, 4/2, 2/1 modified dosing (37.5 mg, 25 mg, or 12.5 mg) and continuous dosing (37.5 mg, 25 mg, or 12.5 mg) |
| 2/1 dosing | 9 | NR | Median 6.0 (NR) | Median 23.1 (NR) |
4/2 dosing | 59 | Median 3.0 (NR) | Median 11.2 (NR) | ||||||
Miyake et al. (2018) | Japan | Retrospective | Comparisons of oncological outcomes and incidence of adverse events among three groups: 2/1, 4/2, and 4/2 to 2/1 switch |
| 2/1 dosing | 47 | NR | Median 13.8 (NR) | Median 39.2 (NR) |
4/2 dosing | 62 | Median 6.3 (NR) | Median 30.8 (NR) | ||||||
Zhang et al. (2018) | China | Retrospective | Comparisons of oncological outcomes and incidence of adverse events among three groups: 2/1, 4/2, and 4/2 to 2/1 switch |
| 2/1 dosing | 24 | Median 37 | Median 11 (NR) | Median 28 (NR) |
4/2 dosing | 30 | Median 12.5 (NR) | Median 21 (NR) |
A. Quality assessment of a randomized controlled trial | |||||||||||
Author(s) (Year) | Random Sequence Generation (Selection Bias) | Allocation Concealment (Selection Bias) | Blinding of Participants and Personnel (Performance Bias) | Blinding of Outcome Assessment (Detection Bias) | Incomplete Outcome Data Addressed (Attrition Bias) | Selective Reporting (Reporting Bias) | Other Bias | ||||
Lee et al. (2015) | Low risk | Low risk | High risk | High risk | Low risk | Low risk | Unclear | ||||
B. Quality assessment of nonrandomized studies | |||||||||||
Author(s) (Year) | Selection (4) | Comparability (2) | Exposure (3) | Total score | |||||||
Adequate Definition of Cases | Representativeness of Cases | Selection of Controls | Definition of Controls | Control for Important Factor or Additional Factor | Ascertainment of Exposure | Same Method of Ascertainment for Cases and Controls | Non-Response Rate | ||||
Atkinson et al. (2014) | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 6 | ||
Kondo et al. (2014) | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 6 | ||
Najjar et al. (2014) | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 6 | ||
Bracarda et al. (2015) | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 6 | ||
Miyake et al. (2015) | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 6 | ||
Pan et al. (2015) | 1 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 5 | ||
El Din (2017) | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 6 | ||
Suo et al. (2017) | 1 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 5 | ||
Miyake et al. (2018) | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 6 | ||
Zhang et al. (2018) | 1 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 5 |
No. of Studies | Study Design | Risk of Bios | Inconsistency | Indirectness | Imprecision | Other Consideration | No. of Patients | Effect | Overall Quality of Evidence | |
---|---|---|---|---|---|---|---|---|---|---|
2/1 Schedule | 4/2 Schedule | |||||||||
1. Progression-free survival | ||||||||||
7 Unadjusted | observational studies | not serious | not serious | not serious | Serious * | none | 188 | 351 | HR 0.66 (0.54–0.82) | Very low |
4 Adjusted | observational studies | not serious | not serious | not serious | Serious ** | none | 83 | 209 | HR 0.58 (0.39–0.84) | Very low |
2. Overall survival | ||||||||||
5 Unadjusted | observational studies | not serious | not serious | not serious | Serious * | none | 130 | 279 | HR 0.75 (0.57–0.99) | Very low |
3 Adjusted | observational studies | not serious | not serious | not serious | Serious ** | none | 57 | 187 | HR 0.66 (0.42–1.04) | Very low |
Study (year) | Schedule | No. of Patients | Complication (No.) | |||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Hypo-Thyroidism | Leukopenia | Anemia | Thrombo-cytopenia | Liver Dysfunction | Anorexia | Nausea | Vomiting | Diarrhea | Dysgeusia | HFS | HTN | Fatigue | Stomatitis | Skin Color Change | ||||||||||||||||||
Al * | HG | Al * | HG * | All | HG | All | HG * | All | HG | All | HG | All | HG | All | HG | All * | HG | All * | HG | All * | HG | All * | HG * | All * | HG * | All * | HG * | All * | HG | |||
Kondo et al. (2014) | 2/1 | 26 | 10 | 0 | 22 | 5 | 20 | 3 | 24 | 5 | 18 | 0 | 11 | 1 | NR | NR | NR | NR | 9 | 0 | 6 | 0 | 15 | 0 | 16 | 0 | 19 | 1 | 10 | 0 | NR | NR |
4/2 | 22 | 13 | 0 | 18 | 1 | 19 | 1 | 19 | 6 | 16 | 0 | 14 | 1 | NR | NR | NR | NR | 16 | 1 | 10 | 0 | 19 | 2 | 17 | 0 | 19 | 1 | 13 | 0 | NR | NR | |
Najjar et al. (2014) | 2/1 | 30 | 13 | 0 | 1 | 1 | NR | NR | 2 | 0 | NR | NR | 2 | 1 | 2 | 1 | NR | NR | 11 | 1 | NR | NR | 5 | 0 | 8 | 2 | 16 | 2 | 3 | 0 | NR | NR |
4/2 | 30 | 11 | 2 | 6 | 3 | NR | NR | 6 | 3 | NR | NR | 7 | 2 | 6 | 2 | NR | NR | 12 | 6 | NR | NR | 15 | 8 | 8 | 6 | 21 | 11 | 6 | 2 | NR | NR | |
Bracarda et al. (2015) | 2/1 | 41 | 11 | 1 | NR | NR | NR | NR | 10 | 0 | NR | NR | 6 | 2 | 8 | 1 | 1 | 0 | 2 | 5 | 7 | 0 | 15 | 2 | 8 | 1 | 26 | 2 | 14 | 1 | NR | NR |
4/2 | 208 | 77 | 3 | NR | NR | NR | NR | 69 | 16 | NR | NR | 54 | 5 | 63 | 6 | 18 | 1 | 87 | 8 | 68 | 1 | 116 | 21 | 95 | 19 | 155 | 21 | 127 | 14 | NR | NR | |
Lee et al. (2015) | 2/1 | 38 | 17 | 0 | 14 | 4 | 27 | 5 | 27 | 9 | 9 | 0 | 21 | 0 | 12 | 0 | 5 | 0 | 14 | 0 | NR | NR | 26 | 7 | 21 | 9 | 22 | 1 | 27 | 1 | 13 | 0 |
4/2 | 36 | 13 | 0 | 22 | 10 | 26 | 3 | 28 | 8 | 11 | 0 | 18 | 0 | 9 | 0 | 6 | 0 | 5 | 1 | NR | NR | 27 | 13 | 26 | 12 | 30 | 2 | 31 | 4 | 20 | 0 | |
Miyake et al. (2015) | 2/1 | 45 | 20 | 0 | 33 | 3 | 26 | 3 | 41 | 13 | NR | NR | NR | NR | NR | NR | NR | NR | 16 | 0 | 10 | 0 | 15 | 1 | 16 | 1 | 13 | 4 | 11 | 0 | 19 | 0 |
4/2 | 45 | 28 | 1 | 36 | 8 | 28 | 4 | 44 | 23 | NR | NR | NR | NR | NR | NR | NR | NR | 27 | 1 | 13 | 0 | 25 | 5 | 25 | 5 | 23 | 8 | 13 | 0 | 26 | 0 | |
Pan et al. (2015) | 2/1 | 32 | 19 | 1 | 8 | 3 | 3 | 1 | 8 | 2 | NR | NR | NR | NR | NR | NR | NR | NR | 10 | 2 | NR | NR | 15 | 2 | 16 | 1 | 16 | 1 | 9 | 1 | NR | NR |
4/2 | 50 | 28 | 2 | 33 | 8 | 15 | 2 | 18 | 7 | NR | NR | NR | NR | NR | NR | NR | NR | 32 | 7 | NR | NR | 42 | 5 | 25 | 4 | 43 | 5 | 23 | 1 | NR | NR | |
El Din (2017) | 2/1 | 26 | 9 | 1 | 10 | 1 | 11 | 1 | 4 | 0 | 2 | 0 | NR | NR | Nausea and vomiting combine number | 3 | NR | NR | NR | 9 | 0 | 6 | 1 | 10 | 1 | 2 | 1 | 3 | NR | |||
4/2 | 30 | 12 | 4 | 15 | 1 | 11 | 3 | 13 | 3 | 3 | 2 | NR | NR | NR | NR | NR | NR | 11 | NR | NR | NR | 21 | 6 | 15 | 4 | 21 | 8 | 11 | 6 | 4 | NR | |
Miyake et al. (2018) | 2/1 | 47 | 23 | 0 | 34 | 4 | 25 | 5 | 43 | 4 | 20 | 0 | NR | NR | NR | NR | NR | NR | 20 | 0 | NR | NR | 21 | 5 | 17 | 2 | 14 | 5 | NR | NR | 20 | 0 |
4/2 | 62 | 40 | 2 | 50 | 7 | 42 | 6 | 61 | 17 | 34 | 0 | NR | NR | NR | NR | NR | NR | 40 | 2 | NR | NR | 34 | 6 | 37 | 5 | 42 | 11 | NR | NR | 38 | 0 | |
Zhang et al. (2018) | 2/1 | 24 | 9 | 0 | 11 | 2 | 6 | 1 | 8 | 2 | 8 | 2 | 5 | 0 | NR | NR | NR | NR | 7 | 1 | NR | NR | 10 | 5 | 4 | 2 | 10 | 3 | 7 | 1 | 4 | 0 |
4/2 | 30 | 17 | 2 | 17 | 9 | 16 | 2 | 16 | 2 | 8 | 1 | 12 | 1 | NR | NR | NR | NR | 11 | 4 | NR | NR | 15 | 3 | 12 | 4 | 17 | 7 | 11 | 4 | 6 | 1 |
Adverse Events | No. Studies | Dosing Schedule | No. of Patients | RR | p-Value | I2 (%) | pH-Value |
---|---|---|---|---|---|---|---|
(95% CI) | |||||||
Laboratory abnormalities | |||||||
Hypothyroidism * | 9 | 2/1 | 309 | 0.84 (0.72–0.99) | 0.04 | 0 | 0.53 |
4/2 | 513 | ||||||
Leukopenia * | 8 | 2/1 | 268 | 0.79 (0.63–0.99) | 0.04 | 60 | 0.01 |
4/2 | 205 | ||||||
Anemia | 7 | 2/1 | 238 | 0.86 (0.72–1.03) | 0.10 | 27 | 0.22 |
4/2 | 275 | ||||||
Thrombocytopenia | 9 | 2/1 | 309 | 0.89 (0.77–1.03) | 0.11 | 62 | 0.007 |
4/2 | 513 | ||||||
Liver dysfunction | 5 | 2/1 | 161 | 0.88 (0.70–1.12) | 0.31 | 0 | 0.84 |
4/2 | 180 | ||||||
Gastrointestinal adverse events | |||||||
Anorexia | 5 | 2/1 | 159 | 0.70 (0.47–1.04) | 0.08 | 38 | 0.17 |
4/2 | 326 | ||||||
Nausea | 3 | 2/1 | 109 | 0.77 (0.42–1.45) | 0.41 | 38 | 0.2 |
4/2 | 274 | ||||||
Vomiting | 2 | 2/1 | 79 | 0.62 (0.24–1.62) | 0.33 | 0 | 0 |
4/2 | 244 | ||||||
Diarrhea * | 8 | 2/1 | 309 | 0.62 (0.44–0.89) | 0.010 | 62 | 0.007 |
4/2 | 513 | ||||||
Dysgeusia * | 3 | 2/1 | 112 | 0.6 (0.39–0.92) | 0.02 | 0 | 0.68 |
4/2 | 275 | ||||||
Other adverse events | |||||||
Hand–foot syndrome * | 9 | 2/1 | 309 | 0.68 (0.58–0.81) | <0.00001 | 25 | 0.22 |
4/2 | 513 | ||||||
Hypertension * | 9 | 2/1 | 309 | 0.70 (0.58–0.84) | 0.0002 | 16 | 0.30 |
4/2 | 513 | ||||||
Fatigue * | 9 | 2/1 | 309 | 0.69 (0.60–0.81) | <0.00001 | 29 | 0.19 |
4/2 | 513 | ||||||
Stomatitis * | 8 | 2/1 | 262 | 0.70 (0.57–0.86) | 0.0006 | 10 | 0.35 |
4/2 | 451 | ||||||
Skin color change * | 4 | 2/1 | 180 | 0.70 (0.55–0.89) | 0.004 | 0 | 0.98 |
4/2 | 203 |
Adverse Events | No. Studies | Dosing Schedule | No. of Patients | RR | p-Value | I2 (%) | pH-Value |
---|---|---|---|---|---|---|---|
(95% CI) | |||||||
Laboratory abnormalities | |||||||
Hypothyroidism | 9 | 2/1 | 309 | 0.46 (0.17–1.23) | 0.12 | 0 | 0.88 |
4/2 | 513 | ||||||
Leukopenia * | 8 | 2/1 | 268 | 0.53 (0.32–0.87) | 0.01 | 0 | 0.52 |
4/2 | 305 | ||||||
Anemia | 7 | 2/1 | 238 | 1.02 (0.55–1.90) | 0.95 | 0 | 0.90 |
4/2 | 275 | ||||||
Thrombocytopenia * | 9 | 2/1 | 309 | 0.58 (0.40–0.83) | 0.003 | 0 | 0.52 |
4/2 | 513 | ||||||
Liver dysfunction | 5 | 2/1 | 161 | 0.91 (0.09–9.42) | 0.94 | 35 | 0.21 |
4/2 | 180 | ||||||
Gastrointestinal adverse events | |||||||
Anorexia | 5 | 2/1 | 159 | 1.05 (0.34–3.19) | 0.93 | 0 | 0.7 |
4/2 | 326 | ||||||
Nausea | 3 | 2/1 | 109 | 0.67 (0.14–1.45) | 0.41 | 38 | 0.2 |
4/2 | 274 | ||||||
Vomiting | 2 | 2/1 | 79 | 1.66 (0.07–40.02) | 0.76 | N.A | |
4/2 | 244 | ||||||
Diarrhea | 8 | 2/1 | 283 | 0.52 (0.19–1.41) | 0.20 | 42 | 0.10 |
4/2 | 483 | ||||||
Dysgeusia | 3 | 2/1 | 112 | 1.66 (0.07.40.02) | 0.76 | N.A | |
4/2 | 275 | ||||||
Other adverse events | |||||||
Hand–foot syndrome | 9 | 2/1 | 309 | 0.55 (0.29–1.02) | 0.06 | 30 | 0.18 |
4/2 | 513 | ||||||
Hypertension * | 9 | 2/1 | 309 | 0.51 (0.31–0.83) | 0.008 | 0 | 0.90 |
4/2 | 513 | ||||||
Fatigue * | 9 | 2/1 | 309 | 0.43 (0.26–0.70) | 0.0007 | 0 | 0.89 |
4/2 | 513 | ||||||
Stomatitis * | 8 | 2/1 | 262 | 0.32 (0.13–0.81) | 0.02 | 0 | 0.89 |
4/2 | 451 | ||||||
Skin color change | 4 | 2/1 | 154 | 0.41 (0.02–9.71) | 0.58 | N.A | |
4/2 | 173 |
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Chung, D.Y.; Kang, D.H.; Kim, J.W.; Kim, D.K.; Lee, J.Y.; Hong, C.H.; Cho, K.S. Does an Alternative Sunitinib Dosing Schedule Really Improve Survival Outcomes Over a Conventional Dosing Schedule in Patients with Metastatic Renal Cell Carcinoma? An Updated Systematic Review and Meta-Analysis. Cancers 2019, 11, 1830. https://doi.org/10.3390/cancers11121830
Chung DY, Kang DH, Kim JW, Kim DK, Lee JY, Hong CH, Cho KS. Does an Alternative Sunitinib Dosing Schedule Really Improve Survival Outcomes Over a Conventional Dosing Schedule in Patients with Metastatic Renal Cell Carcinoma? An Updated Systematic Review and Meta-Analysis. Cancers. 2019; 11(12):1830. https://doi.org/10.3390/cancers11121830
Chicago/Turabian StyleChung, Doo Yong, Dong Hyuk Kang, Jong Won Kim, Do Kyung Kim, Joo Yong Lee, Chang Hee Hong, and Kang Su Cho. 2019. "Does an Alternative Sunitinib Dosing Schedule Really Improve Survival Outcomes Over a Conventional Dosing Schedule in Patients with Metastatic Renal Cell Carcinoma? An Updated Systematic Review and Meta-Analysis" Cancers 11, no. 12: 1830. https://doi.org/10.3390/cancers11121830
APA StyleChung, D. Y., Kang, D. H., Kim, J. W., Kim, D. K., Lee, J. Y., Hong, C. H., & Cho, K. S. (2019). Does an Alternative Sunitinib Dosing Schedule Really Improve Survival Outcomes Over a Conventional Dosing Schedule in Patients with Metastatic Renal Cell Carcinoma? An Updated Systematic Review and Meta-Analysis. Cancers, 11(12), 1830. https://doi.org/10.3390/cancers11121830