Cachexia and Sarcopenia in Oligometastatic Non-Small Cell Lung Cancer: Making a Potential Curable Disease Incurable?
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patient Inclusion and Study Design
2.2. Statistical Analysis
3. Results
3.1. Baseline Characteristics of Patients
3.2. Survival Analysis
3.3. Safety Profile
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Authors | Setting | Study Design | No. of Patients | Cachexia or Sarcopenia | Definition of Cachexia/Sarcopenia | Treatment | Outcome (Cachexia/Sarcopenia vs. Non-Cachexia/Sarcopenia) |
---|---|---|---|---|---|---|---|
Madeddu et al. [19] | Advanced NSCLC | Prospective, monocenter | 74 | Cachexia and sarcopenia | Cachexia: 1. Weight loss ≥ 5% during the past 6 months or weight loss of more than 2% and BMI < 20 2. MiniCASCO questionnaire [22] sarcopenia: SMI at L3, women < 39 cm2/m2; men < 55 cm2/m2 | ICI treatment | Cachexia was an independent predictor of negative survival in patients treated with ICI. Sarcopenia was not predictive of the PFS and OS in patients treated with ICI. |
Matsuo et al. [23] | Advanced or recurrent NSCLC | Retrospective, monocenter | 183 | Cachexia | Weight loss ≥ 5% during the past 6 months or weight loss of more than 2% and BMI < 20 | PD-1/PD-L1 inhibitors | Significantly shorter median PFS (2.1 vs. 5.1 months, p < 0.001) and OS (5.6 vs. 15.0 months, p < 0.001). Multivariate analysis: cachexia in combination with poor PS is associated with worse survival. |
Morimoto et al. [24] | All stages of NSCLC (81% stage III–IV), and recurrent | Retrospective, multicenter | 196 | Cachexia | Weight loss ≥ 5% during the past 6 months or weight loss of more than 2% and BMI < 20 | Chemoimmunotherapy | Overall population: significantly shorter median PFS (6.7 vs. 9.3 months, p = 0.04), and no significant difference in OS. In PD-L1 ≥ 50% expression: no significant difference in PFS and OS. |
Burtin et al. [25] | Stage I–III NSCLC | Prospective, monocenter | 936 | Sarcopenia | Low FFMI (women < 15 kg/m2; men < 17 kg/m2) [26] and handgrip weakness [27] | Primary RT, sequential CRT or concurrent CRT | Patients with PS 0–1: handgrip weakness and low FFMI were significant prognostic factors for OS. Patients with PS ≥ 2: handgrip weakness and low FFMI were not related to OS. |
Bolte et al. [28] | Advanced NSCLC | Retrospective, monocenter | 92 | Sarcopenia | Sex-specific 25th percentile of the PMI (at L3) in the cohort | Chemoimmunotherapy | Significantly shorter median OS (9.1 vs. 22.3 months, p = 0.003). |
Hasenauer et al. [29] | Stage I–III NSCLC | Retrospective, monocenter | 401 | Sarcopenia | SMI at L3. Sarcopenia: women < 38.5 cm2/m2; men < 52.4 cm2/m2 | VATS pulmonary resection | Sarcopenia is associated with a higher rate of postoperative complications and longer hospital stay. |
Karaman et al. [30] | Stage III NSCLC | Retrospective, monocenter | 56 | Sarcopenia | SMI at L3. Sarcopenia: women < 38.5 cm2/m2; men < 52.4 cm2/m2 | Concurrent CRT or RT only | Significantly shorter median OS (19.0 vs. 38.0 months, p < 0.04). |
Katsui et al. [31] | Stage III NSCLC | Retrospective, monocenter | 60 | Sarcopenia | SMI and PMI at L3, cut-off values based on time-dependent ROC curve | Concurrent CRT | Shorter 1,3,5-year OS rates in patient with low SMI (63.6%, 53.8% and 17.9%) vs. high SMI (92.1%, 59.6% and 51.0%). |
Lyu et al. [20] | Advanced NSCLC | Retrospective, monocenter | 131 | Sarcopenia | SMI at L3. Sarcopenia: women < 31.6 cm2/m2; men < 40.2 cm2/m2 | EGFR-TKI or ICI | Shorter median PFS (6.4 vs. 15.1 months, p < 0.001) and OS (13.0 vs. 26.0 months, p < 0.001). Sarcopenia was an independent predictor of poor OS and PFS. |
Yuan et al. [32] | Stage III–IV NSCLC | Retrospective, monocenter | 202 | Sarcopenia | SMI at L3. Sarcopenia: women < 32.5 cm2/m2; men 44.7 cm2/m2 | Treatment according NCCN guidelines | Significantly shorter median PFS (8.0 vs. 13.1 months, p = 0.02) and OS 13.3 months vs. 25.8 months, p = 0.003). |
Characteristic | All Patients (n = 234) | A: No Cachexia and No Sarcopenia (n = 133) | B: Cachexia, No Sarcopenia (n = 46) | C: Sarcopenia, No Cachexia (n = 34) | D: Cachexia and Sarcopenia (n = 21) | p Value |
---|---|---|---|---|---|---|
Median age at diagnosis (range), years | 67 (39–89) | 68 (39–89) | 67 (49–85) | 65 (48–88) | 66 (50–85) | 0.69 |
Sex (%) | 0.82 | |||||
Male | 123 (52.6) | 68 (51.1) | 25 (54.3) | 20 (58.8) | 10 (52.4) | |
Female | 111 (47.4) | 65 (48.9) | 21 (45.7) | 14 (41.2) | 11 (47.6) | |
WHO-PS (%) | 0.001 | |||||
0 | 102 (43.6) | 72 (54.1) | 12 (26.1) | 16 (47.1) | 2 (9.5) | |
1 | 108 (46.2) | 51 (38.3) | 26 (56.5) | 15 (44.1) | 16 (76.2) | |
2 | 21 (9.0) | 10 (7.5) | 6 (13.0) | 2 (5.9) | 3 (14.3) | |
3 * | 3 (1.3) | 0 (0) | 2 (4.3) | 1 (2.9) | 0 (0) | |
Median BMI (range), kg/m2 | 25.0 (15.8–42.1) | 26.4 (18.4–42.1) | 23.0 (16.6–35.9) | 24.5 (16.5–41.4) | 21.1 (15.8–31.2) | <0.001 |
Median weight loss in last 6 months before diagnosis (range), kg | 0 (0–25) | 0 (0–5) | 7.3 (2–25) | 0 (0–9) | 9 (1–25) | <0.001 |
Median PMI (range), mm2/m2 | 6.32 (1.50–14.58) | 7.05 (3.90–12.49) | 6.67 (3.78–14.58) | 4.21 (1.50–5.94) | 3.95 (2.13–5.89) | <0.001 |
Median LDH | 208 (120–699) | 208 (120–699) | 196 (132–499) | 211 (122–406) | 201 (151–415) | 0.82 |
Median CRP mg/L | 13 (1–268) | 12 (1–174) | 14 (1–268) | 13 (1–164) | 22 (1–217) | 0.14 |
Median serum albumin (range), g/dL | 39.0 (21.0–53.0) | 39.7 (21.2–53.0) | 37.8 (22.1–47.0) | 39.0 (29.5–49.0) | 36.0 (21.0–45.4) | 0.005 |
Median serum total protein g/dL | 70.4 (57.0–81.0) | 69.1 (57.0–76.0) | 73.7 (67.0–81.0) | 67.0 (57.0–71.0) | 76.1 (76.1–76.1) | 0.26 |
Smoking status | 0.02 | |||||
Current | 101 (43.2) | 44 (33.1) | 28 (60.9) | 17 (50.0) | 12 (57.1) | |
Former | 118 (50.4) | 79 (59.4) | 15 (32.6) | 16 (47.1) | 8 (38.1) | |
Never | 12 (5.1) | 9 (6.7) | 1 (2.2) | 1 (2.9) | 1 (4.8) | |
Unknown | 3 (1.3) | 1 (0.8) | 2 (4.3) | 0 (0) | 0 (0) | |
NSCLC subtype (%) | 0.83 | |||||
Non-squamous | 183 (78.2) | 102 (76.6) | 36 (78.3) | 27 (79.4) | 18 (85.7) | |
Squamous | 51 (21.8) | 31 (23.3) | 10 (21.7) | 7 (20.6) | 3 (14.3) | |
PD-L1 status (%) | 0.57 | |||||
Positive (≥50%) | 68 (29.1) | 34 (25.6) | 12 (26.1) | 14 (41.2) | 8 (38.1) | |
Positive (1–49%) | 45 (19.2) | 28 (21.1) | 6 (13.0) | 7 (20.6) | 4 (19.0) | |
Negative (<1%) | 39 (16.7) | 24 (18.0) | 8 (17.4) | 3 (8.8) | 4 (19.0) | |
Unknown | 82 (35.0) | 47 (35.3) | 20 (43.5) | 10 (29.4) | 5 (23.9) | |
Driver mutation (%) | ||||||
ALK+ | 1 (0.4) | 0 (0) | 0 (0) | 1 (2.9) | 0 (0) | 0.12 |
BRAF+ | 5 (2.1) | 3 (2.3) | 1 (2.2) | 0 (0) | 1 (4.8) | 0.70 |
EGFR + | 11 (4.7) | 8 (6.0) | 0 (0) | 2 (5.9) | 1 (4.8) | 0.41 |
KRAS+ | 62 (26.5) | 34 (25.6) | 13 (28.3) | 9 (26.5) | 6 (28.6) | 0.98 |
RET+ | 2 (0.9) | 1 (0.8) | 0 (0) | 0 (0) | 1 (4.8) | 0.21 |
ROS1+ | 3 (1.3) | 0 (0) | 2 (4.3) | 1 (2.9) | 0 (0) | 0.10 |
T stage ** (%) | 0.24 | |||||
x | 10 (4.3) | 9 (6.8) | 0 (0) | 1 (2.9) | 0 (0) | |
1a | 5 (2.1) | 2 (1.5) | 1 (2.2) | 2 (5.9) | 0 (0) | |
1b | 14 (6.0) | 8 (6.0) | 4 (8.7) | 1 (2.9) | 1 (4.8) | |
1c | 21 (9.0) | 13 (9.8) | 3 (6.5) | 5 (14.7) | 0 (0) | |
2a | 28 (12.0) | 17 (12.8) | 3 (6.5) | 7 (20.6) | 1 (4.8) | |
2b | 17 (7.3) | 10 (7.5) | 3 (6.5) | 1 (2.9) | 3 (14.3) | |
3 | 47 (20.1) | 29 (21.8) | 7 (15.2) | 6 (17.6) | 5 (23.8) | |
4 | 92 (39.3) | 45 (33.8) | 25 (54.3) | 11 (32.4) | 11 (52.4) | |
N stage (%) | 0.35 | |||||
0 | 70 (29.9) | 44 (33.1) | 9 (19.6) | 13 (38.2) | 4 (19.0) | |
1 | 16 (6.8) | 6 (4.5) | 4 (8.7) | 4 (11.8) | 2 (9.5) | |
2 | 85 (36.3) | 51 (38.3) | 16 (34.8) | 10 (29.4) | 8 (38.1) | |
3 | 63 (26.9) | 32 (24.1) | 17 (37.0) | 7 (20.6) | 7 (33.3) | |
Median number of metastases | 1 | 1 | 1 | 1 | 2 | 0.32 |
Number of metastases (%) | ||||||
1 | 127 (54.3) | 76 (57.1) | 24 (52.2) | 18 (52.9) | 9 (42.9) | 0.65 |
2 | 69 (29.5) | 42 (31.6) | 10 (21.7) | 9 (26.5) | 8 (38.1) | 0.47 |
3 | 20 (8.5) | 7 (5.3) | 7 (5.3) | 3 (8.8) | 3 (14.3) | 0.15 |
4 | 12 (5.1) | 4 (3.0) | 3 (6.5) | 4 (11.8) | 1 (4.8) | 0.21 |
5 | 6 (2.6) | 4 (3.0) | 2 (4.3) | 0 (0) | 0 (0) | 0.54 |
Metastatic sites (%) | ||||||
Brain | 95 (40.6) | 49 (36.8) | 17 (37.0) | 17 (50.0) | 12 (57.1) | 0.20 |
Bone | 45 (19.2) | 32 (24.1) | 8 (17.4) | 3 (8.8) | 2 (9.5) | 0.13 |
Adrenal | 30 (12.8) | 15 (11.3) | 7 (15.2) | 5 (14.7) | 3 (14.3) | 0.89 |
Lung | 64 (27.4) | 37 (27.8) | 13 (28.3) | 8 (23.5) | 6 (28.6) | 0.96 |
Nodal (extrathoracic) | 32 (13.7) | 18 (13.5) | 9 (19.6) | 3 (8.8) | 2 (9.5) | 0.51 |
Pleural | 12 (5.1) | 3 (2.3) | 3 (6.5) | 4 (11.8) | 2 (9.5) | |
Liver | 8 (3.4) | 4 (3.0) | 3 (6.5) | 1 (2.9) | 0 (0) | 0.54 |
Soft tissue | 6 (2.6) | 4 (3.0) | 0 (0) | 1 (2.9) | 1 (4.8) | 0.63 |
Renal | 2 (0.9) | 0 (0) | 1 (2.2) | 1 (2.9) | 0 (0) | 0.26 |
Subcutis | 1 (0.4) | 0 (0) | 1 (0.6) | 0.53 | 0 (0) | 0.86 |
Peritoneal | 1 (0.4) | 0 (0) | 1 (2.2) | 0 (0) | 0 (0) | 0.25 |
Type of systemic treatment | ||||||
Chemotherapy | 155 (79.5) | 91 (81.2) | 30 (83.3) | 23 (79.3) | 11 (61.1) | 0.67 |
Chemotherapy + ICI | 18 (9.2) | 12 (10.7) | 3 (8.3) | 1 (3.5) | 2 (11.1) | 0.23 |
ICI monotherapy | 12 (6.2) | 4 (3.6) | 1 (2.8) | 3 (10.3) | 4 (22.2) | 0.01 |
TKI | 10 (5.1) | 5 (4.5) | 2 (5.6) | 2 (5.9) | 1 (5.6) | 0.96 |
Best response after induction systemic treatment according to RECIST 1.1 (%) | 0.93 | |||||
CR | 3 (1.3) | 2 (1.5) | 1 (2.2) | 0 (0) | 0 (0) | |
PR | 103 (44.0) | 65 (48.9) | 16 (34.8) | 12 (35.3) | 10 (47.6) | |
SD | 57 (24.2) | 29 (21.8) | 12 (26.1) | 12 (35.3) | 4 (19.0) | |
PD | 46 (19.7) | 23 (17.3) | 12 (26.1) | 6 (17.6) | 5 (23.8) | |
Unknown | 25 (10.7) | 14 (10.5) | 5 (10.9) | 4 (11.8) | 6 (10.9) | |
Actual radical treatment (%) | 142 (60.7) | 86 (64.7) | 26 (56.5) | 19 (55.9) | 11 (52.4) | 0.54 |
Characteristics | Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|---|
Hazard Ratio (95% CI) | p-Value | Hazard Ratio (95% CI) | p-Value | ||
Age (ref: <75 years) | ≥75 years | 2.5 (1.3–4.9) | 0.005 | 2.1 (1.1–4.3) | 0.03 |
Gender (ref: male) | female | 0.5 (0.3–0.9) | 0.02 | 0.6 (0.3–1.0) | 0.07 |
WHO-PS (ref: 0–1) | 2–3 | 2.0 (0.8–4.6) | 0.12 | 1.7 (0.7–4.2) | 0.24 |
Smoking (ref: never) | Former | 1.5 (0.5–5.0) | 0.50 | ||
Current | 1.7 (0.5–5.7) | 0.37 | |||
Histology (ref: non-squamous) | Squamous | 0.4 (0.2–0.8) | 0.01 | 0.6 (0.3–1.1) | 0.09 |
BMI (ref: <25 kg/m2) | ≥25 kg/m2 | 1.2 (0.7–2.0) | 0.49 | ||
Cachexia | 0.7 (0.4–1.2) | 0.17 | 0.6 (0.4–1.2) | 0.15 | |
Sarcopenia | ≥6.05 mm2/m2 for men and ≥4.20 mm2/m2 for women | 1.0 (0.5–1.8) | 0.91 | 1.0 (0.5–1.8) | 0.92 |
Serum albumin (ref: <40 g/L) | ≥40 g/L | 0.8 (0.5–1.5) | 0.55 | ||
Serum CRP (ref: ≤5 mg/L) | >5 mg/L | 1.8 (0.9–3.5) | 0.09 | ||
Serum LDH (ref: <248) | ≥248 | 1.2 (0.7–2.1) | 0.59 | ||
Actionable driver mutation * (ref: yes) | 0.8 (0.3–2.1) | 0.64 |
Characteristics | Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|---|
Hazard Ratio (95% CI) | p-Value | Hazard Ratio (95% CI) | p-Value | ||
Age (ref: <75 years) | ≥75 years | 1.7 (0.8–3.6) | 0.16 | 1.9 (0.8–5.1) | 0.17 |
Gender (ref: male) | female | 0.6 (0.3–0.9) | 0.04 | 0.6 (0.3–1.2) | 0.13 |
WHO-PS (ref: 0–1) | 2–3 | 2.6 (0.8–7.8) | 0.10 | 2.5 (0.5–12.0) | 0.25 |
Smoking (ref: never) | Former | 2.4 (0.5–11.4) | 0.28 | ||
Current | 2.6 (0.6–12.2) | 0.25 | |||
Histology (ref: non-squamous) | Squamous | 1.0 (0.5–1.9) | 0.91 | ||
BMI (ref: <25 kg/m2) | ≥25 kg/m2 | 1.3 (0.7–2.2) | 0.43 | ||
Cachexia | 0.5 (0.2–1.0) | 0.05 | 0.4 (0.2–1.0) | 0.05 | |
Sarcopenia | ≥6.05 mm2/m2 for men and ≥4.20 mm2/m2 for women | 0.9 (0.5–1.8) | 0.84 | 1.3 (0.6–2.8) | 0.58 |
Serum albumin (ref: <40 g/L) | ≥40 g/L | 0.83 (0.5–1.6) | 0.56 | ||
Serum CRP (ref: ≤5 mg/L) | >5 mg/L | 2.8 (1.4–5.4) | 0.003 | 3.6 (1.3–5.2) | 0.008 |
Serum LDH (ref: <248) | ≥248 | 1.0 (0.5–1.8) | 0.94 | ||
Actionable driver mutation (ref: yes) * | 0.6 (0.2–1.9) | 0.36 |
Characteristics | Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|---|
Hazard Ratio (95% CI) | p-Value | Hazard Ratio (95% CI) | p-Value | ||
Age (ref: <75 years) | ≥75 years | 1.5 (0.5–4.2) | 0.45 | 0.8 (0.2–3.4) | 0.87 |
Gender (ref: male) | female | 0.5 (0.3–1.2) | 0.09 | 1.7 (0.6–4.5) | 0.29 |
WHO-PS (ref: 0–1) | 2 | 1.1 (0.2–5.4) | 0.93 | 0.8 (0.1–5.0) | 0.82 |
Smoking (ref: never) | Former | 0.8 (0.1–7.9) | 0.86 | ||
Current | 1.0 (0.1–10.0) | 0.98 | |||
Histology (ref: non-squamous) | Squamous | 0.3 (0.1–0.8) | 0.02 | 2.4 (0.8–7.0) | 0.11 |
BMI (ref: <25 kg/m2) | ≥25 kg/m2 | 2.1 (0.9–4.7) | 0.09 | ||
Cachexia | 1.0 (0.4–2.4) | 0.93 | 1.3 (0.4–3.7) | 0.67 | |
Sarcopenia | ≥6.05 mm2/m2 for men and ≥4.20 mm2/m2 for women | 1.1 (0.4–2.9) | 0.87 | 0.7 (0.2–2.5) | 0.55 |
Serum albumin (ref: <40 g/L) | ≥40 g/L | 1.7 (0.7–4.1) | 0.29 | ||
Serum CRP (ref: ≤5 mg/L) | >5 mg/L | 1.9 (0.6–5.6) | 0.25 | 0.6 (0.2–1.9) | 0.40 |
Serum LDH (ref: <248) | ≥248 | 1.3 (0.5–3.1) | 0.58 | ||
TRAE (ref: toxicity ≤ 2) | Toxicity grade ≥ 3 | 1.5 (0.7–3.4) | 0.32 | ||
Best response to induction systemic therapy (ref: CR and PR) | SD and PD | 2.2 (0.9–5.1) | 0.06 | ||
Actionable driver mutation (ref: yes) * | 0.89 (0.3–3.5) | 0.87 |
Characteristics | Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|---|
Hazard Ratio (95% CI) | p-Value | Hazard Ratio (95% CI) | p-Value | ||
Age (ref: <75 years) | ≥75 years | 0.9 (0.4–2.2) | 0.77 | 1.1 (0.3–3.9) | 0.84 |
Gender (ref: male) | female | 0.7 (0.4–1.4) | 0.35 | 1.2 (0.5–2.7) | 0.75 |
WHO-PS (ref: 0–1) | 2 | 3.4 (0.7–16.7) | 0.14 | 0.6 (0.1–3.0) | 0.50 |
Smoking (ref: never) | Former | 1.4 (0.2–9.0) | 0.71 | ||
Current | 1.2 (0.2–7.9) | 0.82 | |||
Histology (ref: non-squamous) | Squamous | 1.1 (0.5–2.4) | 0.90 | ||
BMI (ref: <25 kg/m2) | ≥25 kg/m2 | 1.0 (0.9–1.1) | 0.82 | ||
Cachexia | 0.5 (0.2–1.1) | 0.09 | 2.7 (1.0–6.9) | 0.05 | |
Sarcopenia | ≥6.05 mm2/m2 for men and ≥4.20 mm2/m2 for women | 1.2 (0.5–2.6) | 0.73 | 0.4 (0.2–1.3) | 0.13 |
Serum albumin (ref: <40 g/L) | ≥40 g/L | 1.2 (0.6–2.5) | 0.63 | ||
Serum CRP (ref: ≤5 mg/L) | >5 mg/L | 2.8 (1.2–6.7) | 0.02 | 0.4 (0.1–0.9) | 0.02 |
Serum LDH (ref: <248) | ≥248 | 1.2 (0.6–2.5) | 0.61 | ||
TRAE (ref: toxicity ≤ 2) | Toxicity grade ≥ 3 | 1.0 (0.5–2.0) | 0.99 | ||
Best response to induction systemic therapy (ref: CR and PR) | SD and PD | 1.5 (0.7–3.1) | 0.26 | ||
Actionable driver mutation (ref: yes) * | 2.2 (0.3–18.6) | 0.46 |
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Bartolomeo, V.; Jongbloed, M.; van de Worp, W.R.P.H.; Langen, R.; Degens, J.; Hendriks, L.E.L.; de Ruysscher, D.K.M. Cachexia and Sarcopenia in Oligometastatic Non-Small Cell Lung Cancer: Making a Potential Curable Disease Incurable? Cancers 2024, 16, 230. https://doi.org/10.3390/cancers16010230
Bartolomeo V, Jongbloed M, van de Worp WRPH, Langen R, Degens J, Hendriks LEL, de Ruysscher DKM. Cachexia and Sarcopenia in Oligometastatic Non-Small Cell Lung Cancer: Making a Potential Curable Disease Incurable? Cancers. 2024; 16(1):230. https://doi.org/10.3390/cancers16010230
Chicago/Turabian StyleBartolomeo, Valentina, Mandy Jongbloed, Wouter R. P. H. van de Worp, Ramon Langen, Juliette Degens, Lizza E. L. Hendriks, and Dirk K. M. de Ruysscher. 2024. "Cachexia and Sarcopenia in Oligometastatic Non-Small Cell Lung Cancer: Making a Potential Curable Disease Incurable?" Cancers 16, no. 1: 230. https://doi.org/10.3390/cancers16010230