Introduction
Methods
Patient selection
Organ | Impending visceral crisis (IVC) | Visceral crisis (VC) |
---|---|---|
Liver | Extensive liver metastases (both right and left lobes) + AST/ALT or bilirubin ≥ 1.2 × upper limit of normal (ULN), in the absence of biliary obstruction or non-malignant liver disease | Extensive liver metastases (both right and left lobes) + AST/ALT ≥ 3 × ULN and/or bilirubin ≥ 1.5 × ULN, in the absence of biliary obstruction or non-malignant liver disease |
Lung/mediastinum | Bilateral lung metastases with significant dyspnoea on mild exertion, or impending superior vena cava obstruction (SVCO), in absence of known chronic lung disease | Lymphangitis or bilateral lung metastases with significant dyspnoea at rest or oxygen saturations < 95% on air, or SVCO, in absence of known chronic lung disease |
Gastrointestinal | Intra-abdominal/peritoneal metastases with clinical symptoms of bowel obstruction, without radiological evidence of bowel obstruction | Intra-abdominal/peritoneal metastases with radiological evidence of bowel obstruction |
Bone marrow | – | Extensive bone metastases and two or more of the following below the lower limit of normal: haemoglobin, neutrophil count and/or platelet count, in the absence of a non-breast cancer associated haematological disorder |
Data collection
Data analysis
Results
Baseline patient characteristics
CDK4/6i n = 27 (%) | Paclitaxel n = 32 (%) | p value | |
---|---|---|---|
Age (years) | |||
Median | 59 | 57 | 0.589 |
Range | 27–86 | 39–85 | |
Menopausal status | |||
Pre-menopause | 6 (22.2) | 6 (18.8) | 0.485 |
Peri-menopause/unknown | 4 (14.8) | 2 (6.3) | |
Post-menopause | 17 (63.0) | 24 (75.0) | |
Performance status | |||
0 | 6 (22.2) | 7 (21.9) | 0.037* |
1 | 18 (66.7) | 10 (31.3) | |
2 | 2 (7.4) | 11 (34.4) | |
3 | 1 (3.7) | 3 (9.4) | |
4 | 0 (0) | 1 (3.1) | |
De novo/recurrence | |||
De novo | 11 (40.7) | 2 (6.3) | 0.003* |
Recurrence | 16 (59.3) | 30 (93.8) | |
Metastatic sites | |||
Lung/pleura | 19 (70.4) | 17 (53.1) | 0.523 |
Liver | 17 (63.0) | 27 (84.4) | |
Bone | 19 (70.4) | 25 (78.1) | |
Abdominal/peritoneal | 6 (22.2) | 6 (18.8) | |
Adrenal | 0 (0) | 2 (6.3) | |
Brain | 0 (0) | 1 (3.1) | |
Number of metastatic sites | |||
1 | 1 (3.7) | 2 (6.3) | 0.696 |
2 | 7 (25.9) | 12 (37.5) | |
3 | 12 (44.4) | 11 (34.4) | |
4 | 6 (22.2) | 4 (12.5) | |
5 | 1 (3.7) | 2 (6.3) | |
6 | 0 | 1 (3.1) | |
ET sensitivity/resistance | |||
Sensitive or naive | 13 (48.1) | 6 (18.8) | 0.035* |
Primary resistance | 4 (14.8) | 4 (12.5) | |
Secondary resistance | 10 (37.0) | 22 (68.8) | |
Previous ET for ABC | |||
Yes | 0 (0) | 9 (28.1) | 0.003* |
No | 27 (100) | 23 (71.9) | |
Organ in IVC/VC | |||
Liver | 16 (59.3) | 20 (62.5) | 0.284 |
Lung/mediastinum | 7 (25.9) | 4 (12.5) | |
Gastrointestinal | 2 (7.4) | 2 (6.3) | |
Bone | 1 (3.7) | 2 (6.3) | |
Multiple | 1 (3.7) | 4 (12.5) | |
Liver + bone marrow | 1 | 1 | |
Liver + lung | 0 | 2 | |
Liver + lung + bone marrow | 0 | 1 | |
IVC or VC | |||
IVC | 16 (59.3) | 8 (25.0) | 0.009* |
VC | 11 (40.7) | 24 (75.0) |
CDK4/6i | Paclitaxel | p value | |
---|---|---|---|
Full blood count (non-bone marrow IVC/VC) | |||
Haemoglobin (g/L) | |||
Median | 133 | 123 | 0.100 |
Range | 94–162 | 87–149 | |
Platelets (× 109/L) | |||
Median | 287 | 250 | 0.341 |
Range | 114–610 | 39–737 | |
White cell count (× 109/L) | |||
Median | 9.3 | 8.0 | 0.209 |
Range | 2.7–27.1 | 4–17.6 | |
Neutrophils (× 109/L) | |||
Median | 7 | 6.1 | 0.408 |
Range | 0.8–21.2 | 2.2–19.7 | |
Other (all patients) | |||
Adjusted calcium (mmol/L) | |||
Median | 2.44 | 2.36 | 0.190 |
Range | 2.19–2.76 | 1.96–3.22 | |
LDH (IU/L) | |||
Median | 407.5 | 656.0 | 0.010* |
Range | 214–1141 | 198–2504 | |
Hepatic profile (liver IVC/VC only) | |||
Albumin (µmol/L) | |||
Median | 40 | 35 | 0.006* |
Range | 30–48 | 27–44 | |
Bilirubin (µmol/L) | |||
Median | 10 | 17 | 0.151 |
Range | 5–90 | 5–165 | |
AST/ALT (IU/L) | |||
Median | 71 | 132 | 0.012* |
Range | 45–218 | 49–1640 | |
ALP (IU/L) | |||
Median | 252 | 419 | 0.121 |
Range | 63–814 | 95–1710 |
Treatment characteristics of patients with IVC/VC receiving CDK4/6i or paclitaxel
CDK4/6i n = 27 (%) | Paclitaxel n = 32 (%) | |
---|---|---|
Name of systemic therapy | ||
Palbociclib | 25 (92.6) | – |
Abemaciclib | 2 (7.4) | – |
Paclitaxel | – | 30 (93.8) |
Nab-paclitaxel | – | 2 (6.2) |
ET combined with CDK4/6i | ||
Letrozole | 23 (85.2) | – |
Fulvestrant | 4 (14.8) | – |
Ovarian suppression | ||
Yes | 5 (18.5) | – |
No | 22 (81.5) | – |
Dose reduction at baseline | ||
Yes | 4 (14.8) | 13 (40.6) |
No | 23 (85.2) | 19 (59.4) |
Reason for dose reduction at baseline | ||
Abnormal hepatic profile | 2 | 9 |
Cytopenia | 1 | 2 |
Performance status | 1 | 1 |
Unknown | 0 | 1 |
Dose reduction after cycle 1 | ||
Yes | 6 (22.2) | 9 (28.1) |
No | 21 (77.8) | 23 (71.9) |
Reason for dose reduction after cycle 1 | ||
Toxicity | 5 (83.3) | 9 (100) |
Neutropenia | 4 | 3 |
Cytopenia | 1 | 2 |
Rash | 0 | 1 |
Mucositis | 0 | 1 |
Fatigue | 0 | 1 |
Not recorded | 0 | 1 |
Abnormal hepatic profile | 1 (16.7) | 0 (0) |
Treatment efficacy and outcomes of patients with IVC/VC receiving CDK4/6i vs. paclitaxel
CDK4/6i (n = 27) (%) | Paclitaxel (n = 32) (%) | p value | |
---|---|---|---|
Disease control at 4 months | |||
Response/stable disease | 21 (77.8) | 19 (59.4) | 0.168 |
Progression | 6 (22.2) | 13 (40.6) | |
Time to first objective improvement in IVC/VC (weeks) (in patients with disease control at 4 months) | |||
Median | 3.9 | 3.6 | 0.773 |
Range | 0.9–16 | 0.9–9.1 | |
≤ 4 weeks | 14 (66.7) | 11 (57.9) | 0.353 |
4–8 weeks | 4 (19.0) | 7 (36.8) | |
> 8 weeks | 3 (14.3) | 1 (5.3) | |
Time to first objective worsening in IVC/VC (weeks) (in patients with disease progression by 4 months) | |||
Median | 5.1 | 7.6 | 0.356 |
Range | 1.7–10 | 0.3–16 | |
≤ 4 weeks | 3 (50.0) | 2 (15.4) | 0.308 |
4–8 weeks | 2 (33.3) | 5 (38.5) | |
> 8 weeks | 1 (16.7) | 6 (46.2) | |
Reason for stopping treatment | |||
Disease progression | 13 (48.1) | 15 (46.9) | 0.216 |
Death | 3 (11.1) | 3 (9.4) | |
Toxicity | 1 (3.7) | 3 (9.4) | |
Other | 0 (0) | 5 (15.6) | |
Completed treatment | – | 6 (18.8) | |
N/A—Still on treatment | 8 (29.6) | 0 (0) | |
Maintenance therapy on completion or stopping of paclitaxel | |||
Yes | – | 11 (34.4) | |
Aromatase inhibitor | – | 4 | |
CDK4/6i + ET | – | 3 | |
Fulvestrant | – | 2 | |
Capecitabine | – | 2 | |
No—persistent chemotherapy toxicity | – | 1 (3.1) | |
N/A—progression and/or death | – | 20 (62.5) | |
Second line treatment after progression (at any timepoint) | |||
Yes | 14 (73.7) | 12 (40.0) | 0.039* |
Chemotherapy | 9 | 8 | |
CDK4/6i + ET | – | 3 | |
Fulvestrant | 3 | 1 | |
Aromatase inhibitor | 1 | – | |
Exemestane + everolimus | 1 | – | |
No—clinical deterioration and/or death | 5 (26.3) | 18 (60.0) | |
N/A—not progressed on first line treatment | 8 | 2 |
Survival outcomes of patients with IVC/VC who received CDK4/6i
Factor | n | Hazard ratio—PFS (95% CI) | p value | Hazard ratio—OS (95% CI) | p value |
---|---|---|---|---|---|
Age | |||||
< 65 | 17 | 1.00 | 0.643 | 1.00 | 0.553 |
≥ 65 | 10 | 0.87 (0.48–1.56) | 0.72 (0.25–2.08) | ||
Performance status | |||||
0 | 6 | 1.00 | 1.00 | ||
1 | 18 | 1.22 (0.37–4.03) | 0.095 | 0.80 (0.20–3.26) | 0.745 |
≥ 2 | 3 | 2.24 (0.40–12.66) | 0.307 | 3.86 (0.53–27.89) | 0.065 |
De novo/recurrence | |||||
De novo | 11 | 1.00 | 0.359 | 1.00 | 0.267 |
Recurrence | 16 | 0.66 (0.25–1.75) | 0.58 (0.21–1.61) | ||
Number of metastatic sites | |||||
1–2 | 8 | 1.00 | 1.00 | ||
3 | 12 | 2.17 (0.71–6.60) | 0.226 | 1.65 (0.47–5.81) | 0.462 |
≥ 4 | 7 | 3.06 (0.72–13.03) | 0.091 | 2.46 (0.52–11.63) | 0.194 |
Baseline LDH (IU/L) | |||||
< 500 | 15 | 1.00 | 0.901 | 1.00 | 0.774 |
≥ 500 | 7 | 0.93 (0.32–2.70) | 1.19 (0.34–4.10) | ||
ET-sensitivity/resistance | |||||
Sensitive or naive | 13 | 1.00 | 0.019* | 1.00 | 0.001* |
Primary/secondary resistance | 14 | 2.85 (1.09–7.48) | 6.11 (2.07–18.06) | ||
Organ with IVC/VC | |||||
Liver | 16 | 1.00 | 1.00 | ||
Lung | 7 | 0.58 (0.21–1.56) | 0.332 | 0.17 (0.05–0.53) | 0.048* |
Other or multiple | 4 | 0.23 (0.07–0.78) | 0.121 | 0.36 (0.09–1.46) | 0.301 |
Dose reduction at baseline | |||||
Yes | 4 | 1.00 | 0.579 | 1.00 | 0.818 |
No | 23 | 1.50 (0.42–5.33) | 0.84 (0.17–4.14) | ||
IVC/VC | |||||
IVC | 16 | 1.00 | 0.291 | 1.00 | 0.257 |
VC | 11 | 0.60 (0.23–1.55) | 0.49 (0.16–1.46) | ||
Baseline AST/ALT level—liver IVC/VC | |||||
1.2–2 × ULN | 7 | 1.00 | 1.00 | ||
2.1–3 × ULN | 6 | 0.52 (0.16–1.71) | 0.262 | 0.76 (0.22–2.63) | 0.645 |
> 3 × ULN | 4 | 0.73 (0.17–3.12) | 0.674 | 1.10 (0.21–5.69) | 0.899 |
Survival outcomes of patients with IVC/VC who received paclitaxel
Factor | n | Hazard ratio—PFS (95% CI) | p value | Hazard ratio—OS (95% CI) | p value |
---|---|---|---|---|---|
Age | |||||
< 65 | 10 | 1.00 | 0.834 | 1.00 | 0.592 |
≥ 65 | 22 | 1.08 (0.50–2.34) | 1.23 (0.55–2.74) | ||
Performance status | |||||
0–1 | 17 | 1.00 | 0.455 | 1.00 | 0.808 |
≥ 2 | 15 | 0.75 (0.33–1.66) | 0.89 (0.36–2.20) | ||
De novo/recurrence | |||||
De novo | 2 | 1.00 | 0.232 | 1.00 | 0.150 |
Recurrence | 30 | 0.43 (0.05–3.53) | 0.37 (0.04–3.54) | ||
Number of metastatic sites | |||||
1–2 | 14 | 1.00 | 1.00 | ||
3 | 11 | 1.36 (0.60–3.11) | 0.415 | 1.96 (0.79–4.88) | 0.098 |
≥ 4 | 7 | 1.03 (0.39–2.73) | 0.950 | 1.06 (0.39–2.86) | 0.905 |
Baseline LDH (IU/L) | |||||
< 500 | 6 | 1.00 | 0.364 | 1.00 | 0.384 |
≥ 500 | 12 | 1.58 (0.60–4.17) | 1.57 (0.58–4.23) | ||
ET-sensitivity/resistance | |||||
Sensitive or naive | 6 | 1.00 | 0.261 | 1.00 | 0.294 |
Primary or secondary resistance | 26 | 0.61 (0.21–1.75) | 0.62 (0.22–1.78) | ||
Organ with IVC/VC | |||||
Liver | 20 | 1.00 | 1.00 | ||
Lung | 4 | 1.72 (0.46–6.34) | 0.306 | 2.07 (0.54–7.98) | 0.291 |
Other or multiple | 8 | 0.72 (0.31–1.66) | 0.460 | 0.79 (0.33–1.91) | 0.620 |
Dose reduction at baseline | |||||
Yes | 13 | 1.00 | 0.283 | 1.00 | 0.231 |
No | 19 | 0.68 (0.32–1.44) | 0.64 (0.29–1.41) | ||
IVC/VC | |||||
IVC | 8 | 1.00 | 0.773 | 1.00 | 0.751 |
VC | 24 | 0.87 (0.33–2.27) | 0.87 (0.36–2.12) | ||
Baseline AST/ALT level—liver IVC/VC | |||||
1.2–2 × ULN | 4 | 1.00 | 0.330 | 1.00 | 0.755 |
2.1–3 × ULN | 6 | 0.57 (0.14–2.29) | 0.93 (0.25–3.47) | ||
3–6 × ULN | 7 | 0.58 (0.15–2.28) | 0.329 | 0.83 (0.23–2.92) | 0.823 |
≥ 6 × ULN | 7 | 0.81 (0.23- 2.89) | 0.852 | 0.58 (0.15–2.32) | 0.365 |
Previous ET for ABC | |||||
No | 23 | 1.00 | 0.984 | 1.00 | 0.269 |
Yes | 9 | 1.28 (0.56–2.93) | 1.55 (0.65–3.71) | ||
CDK4/6i as maintenance therapy or second line after paclitaxel | |||||
No | 26 | 1.00 | 0.0005* | 1.00 | 0.0003* |
Yes | 6 | 0.23 (0.11–0.47) | 0.23 (0.06–0.26) |
Comparison of survival outcomes in patients with IVC/VC treated with CDK4/6i vs. paclitaxel
Factor | n | Hazard ratio—PFS (95% CI) | p value | Hazard ratio—OS (95% CI) | p value |
---|---|---|---|---|---|
VC | |||||
CDK4/6i | 11 | 1.00 | 0.019* | 1.00 | 0.014* |
Paclitaxel | 24 | 2.73 (1.29–5.77) | 3.48 (1.56–7.75) | ||
IVC | |||||
CDK4/6i | 16 | 1.00 | 0.007* | 1.00 | 0.027* |
Paclitaxel | 8 | 3.03 (0.97–9.46) | 2.38 (0.77–7.40) | ||
ET-sensitive/naive | |||||
CDK4/6i | 13 | 1.00 | < 0.0001* | 1.00 | < 0.0001* |
Paclitaxel | 6 | 6.51 (1.20–35.45) | 11.72 (1.84–74.64) | ||
Primary/secondary ET-resistance | |||||
CDK4/6i | 14 | 1.00 | 0.199 | 1.00 | 0.653 |
Paclitaxel | 26 | 1.56 (0.80–3.05) | 1.18 (0.58–2.39) | ||
All patients—excluding previous ET for ABC | |||||
CDK4/6i | 27 | 1.00 | 0.003* | 1.00 | 0.011* |
Paclitaxel | 23 | 2.45 (1.25–4.79) | 2.36 (1.16–4.80) | ||
Liver only IVC/VC | |||||
CDK4/6i | 16 | 1.00 | 0.015* | 1.00 | 0.096 |
Paclitaxel | 20 | 2.21 (1.11–4.43) | 1.84 (0.88–3.83) | ||
Lung only IVC/VC | |||||
CDK4/6i | 7 | 1.00 | 0.012* | 1.00 | 0.009* |
Paclitaxel | 4 | 4.37 (0.74–25.91) | 10.15 (1.45–71.07) |