Evre II-IV rektum kanserinde metabolik destekli kemoterapinin ketojenik diyet, hipertermi ve hiperbarik oksijen tedavisi ile kombinasyonunun ön sonuçları

Yıl 2020, Cilt: 5 Sayı: 1, 16 - 20, 20.03.2020

Mehmet Salih İyikesici

https://doi.org/10.25000/acem.650341

Cited By: 4

Öz

Amaç:
Evre II-IV rektum kanserinde sistemik kemoterapi
multimodalite tedavisinin bir parçasıdır. Özellikle, tanı sırasında küratif
rezeksiyona uygun olmayan hastaların sonuçlarını iyileştirmek için daha etkili
yaklaşımlara gerek vardır. Metabolik destekli kemoterapi (MDKT) tümör
hücresinin bozulmuş enerji metabolizmasını hedef alan yeni bir yaklaşımdır. Bu
çalışma, ketojenik diyet, hipertermi ve hiperbarik oksiyen tedavisi (HBOT) ile kombine
edilmiş MDKT’nin başlangıçta cerrahi için uygun olmayan evre II-IV rektum kanseri
hastalarındaki etkinliğini değerlendirmeyi amaçlamıştır.

Yöntemler:
Metabolik destekli kemoterapi (MDKT) tedavisi ile
ketojenik diyet, hipertermi ve HBOT kombinasyonu almış 21 evre II-IV rektum
kanseri hastası çalışmaya dahil edilmiştir. Birinci basamak kemoterapi
oksaliplatin bazlı, ikinci basamak kemoterapi ise irinotekan bazlıdır. Genel
sağkalım ve progresyonsuz sağkalım hesaplanmıştır.

Bulgular: Ortalama takip
süresi 33.3±22.0 aydır. Ortalama genel sağkalım 58.6 ay
(95% CI, 43.3 - 73.9), ortalama progresyonsuz sağkalım 45.1 ay (95% CI,
28.9-61.2) olarak bulunmuştur. Metastatik hastalığı olanlarda ortalama genel
sağkalım 35.7 ay olmuştur. Çok değişkenli analiz erkek cinsiyet ve evre IV
hastalığın kötü progresyonsuz sağkalım için bağımsız belirteçler olduğunu
göstermiştir. Başka hiçbir parametre sağkalım sonuçlarını etkilememiştir.

Sonuç: Bu çalışmanın bulguları, tümör hücresinin birçok
zayıf noktasını hedef alan bu yeni kombinasyon protokolünün ilerlemiş rektum
kanseri hastalarında, özellikle de metastatik hastalığı olanlarda, ek
güvenilirlik endişesi oluşturmadan kullanılabileceği yönünde ümit vermektedir.
Ancak, daha net çıkarımlara ulaşmak için uzun dönem sonuçlar gereklidir.

Anahtar Kelimeler

rektum kanseri, metabolik destekli kemoterapi, ketojenik diyet, hipertermi, hiperbarik oksijen tedavisi, sağkalım

Preliminary results of metabolically supported chemotherapy combined with ketogenic diet, hyperthermia and hyperbaric oxygen therapy in stage II-IV rectal cancer

Öz

Aim: Systemic chemotherapy is a part of multi-modality
treatment in patients with stage II-IV rectal cancer. In particular, patients
not eligible for curative resection at the time of diagnosis require more
efficient approaches to improve outcomes. Metabolically supported chemotherapy
(MSCT) is a novel approach targeting dysregulated energy mechanism of the tumor
cell. This study aimed to examine the efficacy of MSCT combined with ketogenic
diet, hyperthermia and hyperbaric oxygen therapy (HBOT) in patients with stage
II-IV rectal cancer not eligible for surgery at baseline.

Methods: Twenty-one patients diagnosed with stage II-IV rectal
carcinoma who received metabolically supported chemotherapy (MSCT) combined
with ketogenic diet, hyperthermia and HBOT were included. First-line
chemotherapy regimen was oxaliplatin-based, whereas second line regimen was
irinotecan-based. Overall survival and progression-free survival were estimated.

Results: Mean duration of follow-up was 33.3±22.0 months.
Mean overall survival was 58.6 months (95% CI, 43.3 - 73.9) and corresponding
figure for progression-free survival was 45.1 months (95% CI, 28.9-61.2). Mean
overall survival for patients with metastatic disease was 35.7 months. Multivariate
analysis identified male gender and stage IV disease as independent predictors
of worse progression free survival. No other parameter effected survival
outcomes.

Conclusion: Findings of this study are promising for potential use
of this novel combinatorial protocol targeting multiple vulnerabilities of
tumor cells in patients with advanced rectal cancer, particularly for patients
with metastatic disease, without additional safety concerns. However, long term
results are warranted to draw firm conclusion. 

Anahtar Kelimeler

rectal cancer, metabolically supported chemotherapy, ketogenic diet, hyperthermia, hyperbaric oxygen therapy, survival

Kaynakça

• 1 Benson AB, 3rd, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:874-901.
• 2 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7-30.
• 3 Cheng L, Eng C, Nieman LZ, Kapadia AS, Du XL. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J Clin Oncol. 2011;34:573-80.
• 4 Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212-36.
• 5 Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386-422.
• 6 Yoshino T, Arnold D, Taniguchi H, Pentheroudakis G, Yamazaki K, Xu RH, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol. 2018;29:44-70.
• 7 Iyikesici MS, Slocum A, Turkmen E, Akdemir O, Slocum AK, Berkarda FB. Complete response of locally advanced (stage III) rectal cancer to metabolically supported chemoradiotherapy with hyperthermia. International Journal of Cancer Research and Molecular Mechanisms. 2016;2.1:1-4.
• 8 Iyikesici MS, Slocum AK, Slocum A, Berkarda FB, Kalamian M, Seyfried TN. Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer. Cureus. 2017;9:e1445.
• 9 Iyikesici MS. Long-Term Survival Outcomes of Metabolically Supported Chemotherapy with Gemcitabine-Based or FOLFIRINOX Regimen Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy in Metastatic Pancreatic Cancer. Complement Med Res. 2019:1-9.
• 10 Iyikesici MS. 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. Int J Hyperthermia. 2019;36:446-55.
• 11 Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab (Lond). 2010;7:7.
• 12 Warburg OK. Uber den Stoffwechsel der Carcinomzelle. Biochem Z. 1924;152:309-44.
• 13 Warburg O. On the origin of cancer cells. Science. 1956;123:309-14.
• 14 Frezza C, Pollard PJ, Gottlieb E. Inborn and acquired metabolic defects in cancer. J Mol Med (Berl). 2011;89:213-20.
• 15 Bayley JP, Devilee P. The Warburg effect in 2012. Curr Opin Oncol. 2012;24:62-7.
• 16 Ayre SG, Garcia y Bellon DP, Garcia DP, Jr. Insulin, chemotherapy, and the mechanisms of malignancy: the design and the demise of cancer. Med Hypotheses. 2000;55:330-4.
• 17 Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond). 2007;4:5.
• 18 Poff AM, Ward N, Seyfried TN, Arnold P, D'Agostino DP. Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy. PLoS One. 2015;10:e0127407.
• 19 Ohguri T, Imada H, Narisada H, Yahara K, Morioka T, Nakano K, et al. Systemic chemotherapy using paclitaxel and carboplatin plus regional hyperthermia and hyperbaric oxygen treatment for non-small cell lung cancer with multiple pulmonary metastases: preliminary results. Int J Hyperthermia. 2009;25:160-7.
• 20 Ohguri T, Kunugita N, Yahara K, Imada H, Uemura H, Shinya N, et al. Efficacy of hyperbaric oxygen therapy combined with mild hyperthermia for improving the anti-tumour effects of carboplatin. Int J Hyperthermia. 2015;31:643-8.
• 21 Zoul Z, Filip S, Melichar B, Dvorak J, Odrazka K, Petera J. Weekly paclitaxel combined with local hyperthermia in the therapy of breast cancer locally recurrent after mastectomy--a pilot experience. Onkologie. 2004;27:385-8.
• 22 Moyer HR, Delman KA. The role of hyperthermia in optimizing tumor response to regional therapy. Int J Hyperthermia. 2008;24:251-61.
• 23 Wouters BG, van den Beucken T, Magagnin MG, Lambin P, Koumenis C. Targeting hypoxia tolerance in cancer. Drug Resist Updat. 2004;7:25-40.
• 24 Vaupel P, Mayer A, Hockel M. Tumor hypoxia and malignant progression. Methods Enzymol. 2004;381:335-54.
• 25 Vaupel P, Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist. 2004;9 Suppl 5:4-9.
• 26 Hoogsteen IJ, Marres HA, van der Kogel AJ, Kaanders JH. The hypoxic tumour microenvironment, patient selection and hypoxia-modifying treatments. Clin Oncol (R Coll Radiol). 2007;19:385-96.
• 27 Bennett M, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy: a systematic review of randomised controlled trials. Cancer Treat Rev. 2008;34:577-91.
• 28 Schwartz LH, Litiere S, de Vries E, Ford R, Gwyther S, Mandrekar S, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016;62:132-7.
• 29 Valentini V, Coco C, Rizzo G, Manno A, Crucitti A, Mattana C, et al. Outcomes of clinical T4M0 extra-peritoneal rectal cancer treated with preoperative radiochemotherapy and surgery: a prospective evaluation of a single institutional experience. Surgery. 2009;145:486-94.
• 30 Guillem JG, Chessin DB, Cohen AM, Shia J, Mazumdar M, Enker W, et al. Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg. 2005;241:829-38.
• 31 Mohiuddin M, Regine WF, John WJ, Hagihara PF, McGrath PC, Kenady DE, et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys. 2000;46:883-8.
• 32 Bird T, Michael M, Bressel M, Chu J, Chander S, Cooray P, et al. FOLFOX and intensified split-course chemoradiation as initial treatment for rectal cancer with synchronous metastases. Acta Oncol. 2017;56:646-52.
• 33 Kim SH, Kim JH, Jung SH. Comparison of oncologic outcomes of metastatic rectal cancer patients with or without neoadjuvant chemoradiotherapy. Int J Colorectal Dis. 2015;30:1193-9.
• 34 Demetrius LA, Coy JF, Tuszynski JA. Cancer proliferation and therapy: the Warburg effect and quantum metabolism. Theor Biol Med Model. 2010;7:2.
• 35 Schilsky RL, Bailey BD, Chabner BA. Characteristics of membrane transport of methotrexate by cultured human breast cancer cells. Biochem Pharmacol. 1981;30:1537-42.
• 36 Gasparro FP, Knobler RM, Yemul SS, Bisaccia E, Edelson RL. Receptor-mediated photo-cytotoxicity: synthesis of a photoactivatable psoralen derivative conjugated to insulin. Biochem Biophys Res Commun. 1986;141:502-9.
• 37 Poznansky MJ, Singh R, Singh B, Fantus G. Insulin: carrier potential for enzyme and drug therapy. Science. 1984;223:1304-6.
• 38 Papa V, Pezzino V, Costantino A, Belfiore A, Giuffrida D, Frittitta L, et al. Elevated insulin receptor content in human breast cancer. J Clin Invest. 1990;86:1503-10.
• 39 Yee D. The insulin-like growth factors and breast cancer--revisited. Breast Cancer Res Treat. 1998;47:197-9.
• 40 Gross GE, Boldt DH, Osborne CK. Perturbation by insulin of human breast cancer cell cycle kinetics. Cancer Res. 1984;44:3570-5.
• 41 Poff AM, Ari C, Seyfried TN, D'Agostino DP. The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS One. 2013;8:e65522.
• 42 Seyfried TN, Flores R, Poff AM, D'Agostino DP, Mukherjee P. Metabolic therapy: a new paradigm for managing malignant brain cancer. Cancer Lett. 2015;356:289-300.
• 43 Schmidt M, Pfetzer N, Schwab M, Strauss I, Kammerer U. Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. Nutr Metab (Lond). 2011;8:54.
• 44 Rieger J, Bahr O, Maurer GD, Hattingen E, Franz K, Brucker D, et al. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol. 2014;44:1843-52.
• 45 Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28:1028-35.
• 46 Seyfried TN, Yu G, Maroon JC, D'Agostino DP. Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutr Metab (Lond). 2017;14:19.
• 47 Al-Waili NS, Butler GJ, Beale J, Hamilton RW, Lee BY, Lucas P. Hyperbaric oxygen and malignancies: a potential role in radiotherapy, chemotherapy, tumor surgery and phototherapy. Med Sci Monit. 2005;11:RA279-89.
• 48 Petre PM, Baciewicz FA, Jr., Tigan S, Spears JR. Hyperbaric oxygen as a chemotherapy adjuvant in the treatment of metastatic lung tumors in a rat model. J Thorac Cardiovasc Surg. 2003;125:85-95.