Feasibility study of metabolically supported chemotherapy with weekly carboplatin/paclitaxel combined with ketogenic diet, hyperthermia and hyperbaric oxygen therapy in metastatic non-small cell lung cancer

Figures & data

Figure 1. Study diagram. MSCT: metabolically supported chemotherapy; KD: ketogenic diet; HT: hyperthermia; HBOT: hyperbaric oxygen therapy. Patients were referred with stage IV disease to our clinic and all were eligible for our standard protocol upon admission.

Figure 2. Placement of hyperthermia electrode. View from left (A) and above (B).

Table 1. Demographical and clinical characteristics of the patients at baseline.

Characteristic	n = 44
Age, year, median (range)	65 (35–87)
Age >65 years	20 (44.5%)
Male gender	39 (88.6%)
Histology
Adenocarcinoma	34 (77.3%)
Squamous cell carcinoma	8 (18.2%)
Undifferentiated	2 (4.5%)^a
Metastatic sites
0–1	0 (0 %)
2	4 (9.1%)
≥3	40 (90.9%)
Brain metastases	18 (40.9%)
Mutation status
EGFR
Mutation present	0 (0%)
No mutation detected	29 (65.9%)
Not evaluated	15 (34.1%)
ALK fusion
Fusion	5 (11.4%)
No fusion detected	24 (54.5%)
Not evaluated	15 (34.1%)
Smoking status
Nonsmoker	6 (13.6%)
Smoker	38 (86.4%)
Diabetes	14 (31.8%)
Presence of any comorbidity	32 (72.7%)^b
Performance status
ECOG 0-1	8 (18.2%)
ECOG 2	21 (47.7%)
ECOG 3	15 (34.1%)
Second malignancy	1 (2.3%)^c

Notes: Unless otherwise stated, data presented as n (%). EGFR: epidermal growth factor receptor; ALK: anaplastic lymphoma kinase; ECOG: Eastern Cooperative Oncology Group. ^aOne large cell carcinoma and one bronchoalveolar carcinoma; ^bdiabetes, hypertension or chronic obstructive pulmonary disease; ^cthis patient had been diagnosed with bladder carcinoma before NSCLC.

Table 2. Treatment response by patient characteristics.

	ORR n (%)	SD n (%)	PD n (%)	p value
All patients (n = 44)	27 (61.4 %)	7 (15.9 %)	10 (22.7 %)
Age (years)
≤65 (n = 24)	15 (62.5 %)	4 (16.7 %)	5 (20.8 %)	.95
>65 (n = 20)	12 (60.0 %)	3 (15.0 %)	5 (25.0 %)
Histology
AC (n = 34)	21 (61.8 %)	6 (17.6 %)	7 (20.6 %)	.29
SCC (n = 8)	6 (75.0 %)	0 (0 %)	2 (25.0 %)
UC (n = 2)	0 (.0 %)	1 (50.0 %)	1 (50.0 %)
Performance status
ECOG 0–1 (n = 8)	5 (62.5 %)	2 (25.0 %)	1 (12.5 %)	.62
ECOG ≥2 (n = 36)	22 (61.1 %)	5 (13.9 %)	9 (25.0 %)
Metastatic sites
0–1 (n = 0)	0 (0 %)	0 (.0 %)	0 (.0 %)	.25
2 (n = 4)	4 (100.0 %)	0 (.0 %)	0 (.0 %)
≥3 (n = 40)	23 (57.5 %)	7 (17.5 %)	10 (25.0 %)
Brain Metastases
Yes (n = 18)	8 (44.4 %)	3 (16.7 %)	7 (38.9 %)	.09
No (n = 26)	19 (73.1 %)	4 (15.4 %)	3 (11.5 %)
Smoking status
Yes (n = 38)	25 (65.8 %)	4 (10.5 %)	9 (23.7 %)	.05*
No (n = 6)	2 (33.3 %)	3 (50.0 %)	1 (16.7 %)

Notes: ORR: Overall Response Rate (Complete Response (CR)+Partial Response (PR)); SD: Stable Disease; PD: Progressive Disease; AC: adenocarcinoma; SC: squamous cell carcinoma; UC: undifferentiated carcinoma (including large cell carcinoma and bronchoalveolar carcinoma); ECOG: Eastern Cooperative Oncology Group. *p = .048 before rounding to two decimals.

Figure 3. Kaplan–Meier curves for overall survival: (A) all patients; and patients stratified by ECOG performance status (B), age (C), and presence of brain metastasis (D). p values are calculated with Log-rank test. A higher ECOG status (ECOG ≥2) was associated with worse overall survival (Panel B, p = .009). However, older age (Panel C) and the presence of brain metastasis (Panel D) did not have an effect on overall survival outcome (p > .05 for both).

Table 3. Mean survival rates by patient characteristics.

	OS		PFS
	Months (95% CI)	p value^a	Months (95% CI)	p value^a
All patients (n = 44)	42.9 (34.0–51.8)		41.0 (31.1–50.9)
Age (years)
≤65 (n = 24)	47.1 (35.7–58.5)	.19	46.8 (34.7–58.9)	.10
>65 (n = 20)	32.9 (25.9–39.9)		26.6 (19.6–33.7)
Histology
AC (n = 34)	45.1 (34.9–55.4)	.47	43.6 (31.8–55.3)	.61
SCC (n = 8)	32.6 (18.5–46.7)		32.4 (18.2–46.6)
UC (n = 2)	37.3 (31.9–42.7)		35.8 (27.5–44.1)
Performance status
ECOG 0–1 (n = 8)	63.9 (52.9–74.9)	.009	63.4 (51.6–75.2)	.009
ECOG ≥2 (n = 36)	33.0 (27.2–38.7)		29.4 (22.6–36.1)
Brain metastases
Yes (n = 18)	34.6 (24.4–44.9)	.09	30.9 (19.1–42.8)	.07
No (n = 26)	42.6 (34.9–50.3)		40.6 (32.3–48.9)
Smoking status
Yes (n = 38)	36.8 (30.6–43.1)	.53	33.9 (26.6–41.2)	.36
No (n = 6)	49.8 (31.6–68.0)		49.7 (31.3–68.0)

Notes: OS: Overall Survival; PFS: Progression- free survival; AC: adenocarcinoma; SC: squamous cell carcinoma; UC: undifferentiated carcinoma (including large cell carcinoma and bronchoalveolar carcinoma); ECOG: Eastern Cooperative Oncology Group. ^aLog-rank test.

Table 4. Comparison with other studies evaluating carboplatin /paclitaxel combinations in NSCLC patients.

	Current study	Volk et al. [19]	Belani et al. [57]	Belani et al. [58]	Schuette et al. [59]	Kelly et al. [9]	Schiller et al. [15]
Regimen	Weekly regimens					3-weekly regimens
	P 75 mg/m^2 days 1, 8, q3w	P 75 mg/m^2 days 1, 8, 15 q4w	P 100 mg/m^2 days 1, 8, 15 q4w	P 100 mg/m^2 days 1, 8, 15 q4w	P 100 mg/m^2 days 1, 8, 15, 22, 29, 36	P 225 mg/m^2 day 1, q3w	P 225 mg/m^2 day 1, q3w
	C AUC 2 days 1, 8, q3w	C AUC 3 days 1, 8, 15 q4w	C AUC 6 day 1, q4w	C AUC 6 day 1, q4w	q8w C AUC 2 days 1, 8, q3w	C AUC 6 days 1, q3w	C AUC 6 days 1, q3w
n	44	190	132	223	457	206	290
Age (years)
median	65	66	65	65	32	62	63
range	35–87	39–88	42–87	28–84	n.a.	26–80	30–85
≥70 years of age (%)	25	39	28^a	n.a.	n.a.	n.a.	n.a.
Stage (%)
III	0	7	23.5	18	26	12	14
IV	100	93	76.5	82	69	88	86
ECOG PS (%)
0–1	18.2	81	85.6	84	91	100	95
≥2	81.8	19	14,4	12	6	0	5
Brain metastasis (%)	40.9	27	n.a.	n.a.	0	0	12
Efficacy
ORR (%)	61.4	34,4	32	27,6	38	25	17
PFS (months)	41.0	3,4	6,9	4,6	6.1	4	3.1
OS (months)	42.9	6.3	11.3	9.7	8.9	8	8.1
Toxicity
Neuropathy ≥ grade 3 (%)	2.3	6	5	12^b	4	13	10
Neutropenia ≥ grade 3 (%)	6.8	14	22	13	17	57	63

Notes: P: paclitaxel; C: carboplatin; n.a.: no data available; ECOG PS: Eastern Cooperative Oncology Group performance status; ORR: overall response rate (complete response (CR)+partial response (PR)); PFS: progression-free survival; OS: overall survival. ^aProportion of patients ≥70 years of age in the whole study population (111of 390 patients); ^bOnly grade 2–3 neuropathy observed.

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