Hyperthermie plus voedingsprogramma (kytogeen dieet) plus hyperbare zuurstoftherapie aanvullend op chemo geeft uitstekende resultaten op mediane overall overleving (42 maanden) bij patienten met gevorderde niet-kleincellige longkanker

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5 april 2019: lees ook dit artikel:

https://kanker-actueel.nl/vrouw-van-29-jaar-met-triple-negatieve-borstkanker-stadium-iv-komt-in-complete-remissie-door-aanvullend-op-chemo-persoonlijke-voedingsadviezen-kytogeen-dieet-hyperthermie-en-hyperbare-zuurstoftherapie.html

3 april 2019: Bron: International Journal of Hyperthermie

Patiënten met gevorderde niet-kleincellige longkanker (stadium IV) blijken veel baat te kunnen hebben bij aanvullend op chemo (carboplatin / paclitaxel ) een combinatie van hyperthermie, een persoonlijk voedingsprogramma op basis van het kytogene dieet en hyperbare zuurstoftherapie. Maar liefst 61,4 procent van de 44 deelnemende patienten reageerde met een complete remissie of een gedeeltelijke remissie (50 procent of meer). Slechts 22 procent had progressieve ziekte dus bij die patiënten had de aanpak geen succes. 15 patienten overleden voordat de 5-jarige studie eindigde maar 29 patienten waren nog in leven waarvan een aantal met progressievrije ziekte.

Meadiane overall overleving (OS) was 42.9 maanden (95% CI: 34.0–51.8) en progressievrije overleving (PFS) 41.0 maanden (95% CI: 31.1–50.9) wat extreem lang is voor deze groep van longkankerpatienten. De studie duurde van maart 2010 tot juni 2015. Het studierapport werd 1 april 2019 gepubliceerd.

Bijwerkingenprofielen per individuele patiënt waren goed te controleren aldus de onderzoekers.

Ik moet wel zeggen dat alle patienten heel intensief werden behandeld want om naast chemo ook hyperthermie te geven is heel gemakkelijk te doen. Maar voor elke patient werd ook een voedingsadvies samengesteld gegeven op basis van haar / zijn persoonlijke lichamelijke gestelheid op basis van het kytogeen dieet. En daarnaast kregen alle patienten ook nog eens sessies met hyperbare zuurstoftherapie. Maar het blijkt dus zeer de moeite waard te zijn gezien de mediane overall overleving van voor een aantal patienten langer dan 5 jaar. Zelfs uitzaaiingen in de hersenen waren geen contra indicatie, in tegendeel sommige patienten leven al langer dan 5 jaar daarmee. Wel was het zo hoe slechter de lichamelijke gestgeldhied hoe minder de resultaten. Zie Figure 3

Deze opmerkelijke studieresultaten (mediane overall overleving was zelfs beter dan voor immuuntherapie met atezolizumab bv.) werden afgelopen week gepresenteerd in het International Journal of Hyperthermie.

Hier de resultaten zoals gepresenteerd in het volledige studierapport:

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 dat gratis is in te zien inclusief grafieken van de karakteristieken van de patienten.

Survival estimates

At the end of 8 cycles of treatment, 42 out of 44 patients (95.4%) were alive and had completed 8 cycles of treatment. Two patients died after receiving 3 cycles of treatment. At the termination of follow-up (15 January 2016), 29 patients were alive (65.9%). Mean overall survival (OS) was 42.9 months (95% CI: 34.0–51.8). Corresponding figure for progression-free survival (PFS) was 41.0 months (95% CI: 31.1–50.9).

Table 3 shows mean survival rates (OS and PFS) by patient characteristics. A higher ECOG status (ECOG ≥2) was associated with worse OS (33.0 vs. 63.9 months, p = .009) and PFS (29.4 vs. 63.4 months, p = .009). On the other hand, age, histology, presence of brain metastasis and smoking had no effect on survival outcome. Figure 3 shows Kaplan–Meier curves for OS. In addition, a subgroup analysis of patients with available ALK fusion data (n = 29) showed numerically better overall survival (61.2 vs. 34.9 months) and progression-free survival rates (61.1 vs. 30.1 months) for patients with fusion (n = 5) than patients without fusion (n = 24); however, the difference did not reach statistical significance (p = .103 and .085, respectively).

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).

Hier het abstract van deze studie:

Received 10 Sep 2018, Accepted 27 Feb 2019, Published online: 01 Apr 2019

Abstract

Background: Previous evidence suggests that metabolically supported chemotherapy (MSCT), ketogenic diet, hyperthermia and hyperbaric oxygen therapy (HBOT) could all target vulnerabilities of cancer cells. This study aimed to evaluate the efficacy and the tolerability of this combination therapy in the treatment of stage IV non-small cell lung cancer (NSCLC).

Methods: Forty-four NSCLC patients with distant metastasis that received MSCT (administration of chemotherapy regimen following induced hypoglycemia) plus ketogenic diet, hyperthermia and HBOT combination were included in this retrospective study. Survival and treatment response rates as well as toxicities were evaluated.

Results: Overall response rate (ORR, complete response plus partial response) was 61.4%; whereas, 15.9% and 22.7% of patients had stable disease (SD) and progressive disease (PD), respectively. Mean overall survival (OS) and progression-free survival (PFS) was 42.9 months (95% CI: 34.0–51.8) and 41.0 months (95% CI: 31.1–50.9), respectively. A higher Eastern Cooperative Oncology Group (ECOG) performance status (ECOG ≥2) was associated with worse OS and PFS. Patients received chemotherapy cycles with acceptable toxicity and adverse events. No problems were encountered due to fasting, hypoglycemia, ketogenic diet, hyperthermia or hyperbaric oxygen therapy.

Conclusions: Findings of this study suggest that MSCT combined with other modalities targeting multiple pathways and cellular vulnerabilities may bring about remarkable improvements in survival outcomes and treatment response rates in metastatic NSCLC, without additional safety concerns. Large comparative studies are warranted to draw robust conclusions.

Referentielijst:

Disclosure statement

No potential conflict of interest was reported by the authors.

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.

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. [19Volk V, Cathomas R, Mark M, et al. Weekly carboplatin in combination with weekly paclitaxel in the treatment of metastatic non-small cell lung cancer: a single center 10-year experience. Support Care Cancer. 2016;24:2119–2128., , [Web of Science ®], , [Google Scholar]]	Belani et al. [57Belani CP, Barstis J, Perry MC, et al. Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. JCO. 2003;21:2933–2939., , [Web of Science ®], , [Google Scholar]]	Belani et al. [58Belani CP, Ramalingam S, Perry MC, et al. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. JCO. 2008;26:468–473., , [Web of Science ®], , [Google Scholar]]	Schuette et al. [59Schuette W, Blankenburg T, Guschall W, et al. Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer. 2006;7:338–343., , [Web of Science ®], , [Google Scholar]]	Kelly et al. [9Kelly K, Crowley J, Bunn PA, Jr, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non–small-cell lung cancer: a Southwest Oncology Group trial. JCO. 2001;19:3210–3218., , [Web of Science ®], , [Google Scholar]]	Schiller et al. [15Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–98., , [Web of Science ®], , [Google Scholar]]
Regimen	Weekly regimens					3-weekly regimens
	P 75 mg/m² days 1, 8, q3w	P 75 mg/m² days 1, 8, 15 q4w	P 100 mg/m² days 1, 8, 15 q4w	P 100 mg/m² days 1, 8, 15 q4w	P 100 mg/m² days 1, 8, 15, 22, 29, 36	P 225 mg/m² day 1, q3w	P 225 mg/m² 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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