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 IJCM  Vol.11 No.6 , June 2020
Parametrization of Survival Measures (Part III) Clinical Evidences in Single Arm Studies with Endpoint of Overall Survival
Abstract: Many clinical trials have prospective or retrospective data-sets without comparison to the control-group formed by the same cohort as the active one. The measured single arm naturally contains the relevant information, however, in most of the cases, it is impossible to obtain it from the complex survival curve without a reference. In our previous articles [1] [2], we had shown that the self-similar Weibull distribution fits the self-organized biological mechanisms well, and so it is the best option to study the single-arm survival curves, where self-organizing process is actively present. With the Weibull decomposition of the survival curve, we can fit at least two subgroups of patients. The weighted sum of the decomposed fractions could be optimized analytically and determining the best parameters of the components and the best composition ratio of the weighted sum is also possible. In this part of our series of articles, we will show how the method works in a real clinical environment through modulated electro-hyperthermia (mEHT) as a complementary method, applied curatively when no other conventional curative therapies are available. The decomposed function of the non-responding group provides an excellent agreement with the historical controls in pancreatic cancer and non-small-cell-lung-cancer studies. In the case of glioblastoma multiform, the historical missing control from the institute where the treatment was made does not allow a comparison. We used a modified Hardin-Jones-Pauling statistical estimation and had shown in single arm clinical trials for advanced pancreas, non-small cell lung cancer and glioblastoma multiforme, that this estimation is applicable, and it is corresponding with the historical arm and with the non-responding group where this comparison was available.
Cite this paper: Szasz, A. , Szigeti, G. and Szasz, M. (2020) Parametrization of Survival Measures (Part III) Clinical Evidences in Single Arm Studies with Endpoint of Overall Survival. International Journal of Clinical Medicine, 11, 389-419. doi: 10.4236/ijcm.2020.116034.
References

[1]   Szasz, O. and Szasz, A. (2018) Parameterization of Survival Measures (Part 1). International Journal of Clinical Medicine, 11, 316-347.

[2]   Szasz, A., Szigeti, G.P. and Szasz, A.M. (2018) Parameterization of Survival Measures (Part 2). International Journal of Clinical Medicine, 11, 348-373.

[3]   DeMets, D., Friedman, L. and Furberg, C. (2010) Fundamentals of Clinical Trials. 4th Edition, Springer, Berlin.
https://doi.org/10.1007/978-1-4419-1586-3

[4]   CDER (2006) “Exploratory IND Studies” Guidance for Industry, Investigators, and Reviewers. Food and Drug Administration, Silver Spring.
https://link.springer.com/article/10.1177/009286150704100303

[5]   Canadian Cancer Society (2017) Phases of Clinical Trials.

[6]   Vernon, C.C., Hand, J.W., Field, S.B., Machin, D., Whaley, J.B., van der Zee, J., van Putten, W.L.J., van Rhoon, G.C., van Dijk, J.D.P., Gonzalez Gonzalez, D., Liu, F.-F., Goodman, P. and Sherar, M. (1996) Radiotherapy with or without Hyperthermia in the Treatment of Superficial Localized Breast Cancer: Results from Five Randomized Controlled Trials. International Journal of Radiation Oncology, Biology, Physics, 35, 731-744.
https://doi.org/10.1016/0360-3016(96)00154-X

[7]   Sherar, M., Liu, F.-F., Pintilie, M., et al. (1997) Relationship between Thermal Dose and Outcome in Thermoradiotherapy Treatments for Superficial Recurrences of Breast Cancer: Data from a Phase III Trial. International Journal of Radiation Oncology, Biology, Physics, 39, 371-380.
https://doi.org/10.1016/S0360-3016(97)00333-7

[8]   Mitsumori, M., Zeng, Z.F., Oliynychenko, P., et al. (2007) Regional Hyperthermia Combined with Radiotherapy for Locally Advanced Non-Small Cell Lung Cancers. International Journal of Clinical Oncology, 12, 192-198.
https://doi.org/10.1007/s10147-006-0647-5

[9]   Shinn, K.S., Choi, I.B., Kay, C.S., et al. (1996) Thermoradiotherapy in the Treatment of Locally Advanced Nonsmall Cell Lung Cancer. The Journal of the Korean Society for Therapeutic Radiology and Oncology, 14, 115-122.
https://doi.org/10.1016/0169-5002(96)85955-1

[10]   Vasanthan, A., Mitsumori, M., Park, J.H., et al. (2005) Regional Hyperthermia Combined with Radiotherapy for Uterine Cervical Cancers: A Multi-Institutional Prospective Randomized Trial of the International Atomic Energy Agency. International Journal of Radiation Oncology, Biology, Physics, 61, 145-153.
https://doi.org/10.1016/j.ijrobp.2004.04.057

[11]   Zolciak-Siwinska, A., Piotrkowicz, N., Jonska-Gmyrek, J., et al. (2013) HDR Brachytherapy Combined with Interstitial Hyperthermia in Locally Advanced Cervical Cancer Patients Initially Treated with Concomitant Radiochemotherapy: A Phase III Study. Radiotherapy and Oncology, 109, 194-199.
https://doi.org/10.1016/j.radonc.2013.04.011

[12]   Jones, E.L., Oleson, J.R., Prosnitz, L.R., et al. (2005) Randomized Trial of Hyperthermia and Radiation for Superficial Tumors. Journal of Clinical Oncology, 23, 3079-3085.
https://doi.org/10.1200/JCO.2005.05.520

[13]   Evans, S.R. (2010) Clinical Trial Structures. Journal of Experimental Stroke & Translational Medicine, 3, 8-18.
https://doi.org/10.6030/1939-067X-3.1.8

[14]   Arun, B., Austin, T., Babiera, G.V., et al. (2017) A Comprehensive Lifestyle Randomized Clinical Trial: Design and Initial Patient Experience. Integrative Cancer Therapies, 16, 3-20.
https://doi.org/10.1177/1534735416679516

[15]   Snyders, K., Cho, D., Hong, J.H., et al. (2019) Benchmarking Single-Arm Studies against Historical Controls from Non-Small Cell Lung Cancer Trials: An Empirical Analysis of Bias. Acta Oncologica, 59, 90-95.
https://doi.org/10.1080/0284186X.2019.1674452

[16]   Rosenbaum, P.R. and Rubin, D.B. (1983) The Central Role of the Propensity Score in Observational Studies for Causal Effects. Biometrika, 70, 41-55.
https://doi.org/10.1093/biomet/70.1.41

[17]   Rosenbaum, P.R. and Rubin, D.B. (1984) Reducing Bias in Observational Studies Using Subclassification on the Propensity Score. Journal of the American Statistical Association, 79, 516-524.
https://doi.org/10.1080/01621459.1984.10478078

[18]   Rosenbaum, P.R. and Rubin, D.B. (1985) Constructing a Control Group Using Multivariate Matched Sampling Methods That Incorporate the Propensity Score. The American Statistician, 39, 33-38.
https://doi.org/10.1080/00031305.1985.10479383

[19]   Cochran, W.G. (1968) The Effectiveness of Adjustment by Sub-Classification in Removing Bias in Observational Studies. Biometrics, 24, 295-313.
https://doi.org/10.2307/2528036

[20]   Whitehead, J. (1999) A Unified Theory for Sequential Clinical Trials. Statistics in Medicine, 18, 2271-2286.
https://doi.org/10.1002/(SICI)1097-0258(19990915/30)18:17/18<2271::AID-SIM254>3.0.CO;2-Z

[21]   Evans, C.H. and Ildstad, S.T. (2001) Small Clinical Trials: Issues and Challenges. National Academy Press, Washington DC.
http://www.nap.edu/catalog/10078.html

[22]   Bellissant, E., Benichou, J. and Chastang, C. (1996) The Group Sequential Triangular Test for Phase II Cancer Clinical Trials. American Journal of Clinical Oncology, 19, 422-430.
https://doi.org/10.1097/00000421-199608000-00021

[23]   O’Fallon, J.R. (1985) Policies for Interim Analysis and Interim Reporting of Results. Cancer Treatment Reports, 69, 1101-1116.

[24]   Pocock, S.J. and Hughes, M.D. (1989) Practical Problems in Interim Analyses, with Particular Regard to Estimation. Controlled Clinical Trials, 10, 209S-221S.
https://doi.org/10.1016/0197-2456(89)90059-7

[25]   Emerson, S.S. and Fleming, T.R. (1990) Interim Analyses in Clinical Trials. Oncology, 4, 126-133.

[26]   Whitehead, J. and Sooriyarachchi, M.R. (1998) A Method for Sequential Analysis of Survival Data with Non-Proportional Hazards. Biometrics, 54, 1072-1084.
https://doi.org/10.2307/2533858

[27]   Williams, P.L. (1996) Sequential Monitoring of Clinical Trials with Multiple Survival, Endpoints. Statistics in Medicine, 15, 2341-2357.
https://doi.org/10.1002/(SICI)1097-0258(19961115)15:21<2341::AID-SIM453>3.0.CO;2-N

[28]   Konishi, T., Watanabe, T., Kishimoto, J., et al. (2007) Prognosis and Risk Factors of Metastasis in Colorectal Carcinoids: Results of a Nationwide Registry over 15 Years. Gut, 56, 863-868.
https://doi.org/10.1136/gut.2006.109157

[29]   Weinber, R.A. (2007) The Biology of Cancer. Garland Science, New York.
http://web.thu.edu.tw/cphu/www/cancer_biology/download/Ch_8_
pRb_and_Control_of_the_Cell_Cycle_Clock.pdf


[30]   Roussakow, S. (2013) Critical Analysis of Electromagnetic Hyperthermia Randomized Trials: Dubious Effect and Multiple Biases. Conference Papers in Medicine, 2013, Article ID: 412186.
https://doi.org/10.1155/2013/412186

[31]   Roussakow, S. (2013) The History of Hyperthermia Rise and Decline. Conference Papers in Medicine, 2013, Article ID: 428027.
https://doi.org/10.1155/2013/428027

[32]   Szasz, A., Szasz, N. and Szasz, O. (2010) Oncothermia—Principles and Practices. Springer Science, Heidelberg.
https://doi.org/10.1007/978-90-481-9498-8

[33]   Howie, L. and Peppercorn, J. (2013) Early Palliative Care in Cancer Treatment: Rationale, Evidence and Clinical Implications. Therapeutic Advances in Medical Oncology, 5, 318-323.
https://doi.org/10.1177/1758834013500375

[34]   Ferrell, B.R., Temel, J.S., Temin, S., Alesi, E.R., Balboni, T.A., Basch, E.M., Firn, J.I., Paice, J.A., Peppercorn, J.M., Phillips, T., Stovall, E.L., Zimmermann, C. and Smith, T.J. (2016) Integration of Palliative Care into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology, 35, 96-112.
https://doi.org/10.1200/JCO.2016.70.1474

[35]   Isenberg, S.R., Aslakson, R.A. and Smith, T.J. (2017) Implementing Evidence-Based Palliative Care Programs and Policy for Cancer Patients: Epidemiologic and Policy Implications of the 2016 American Society of Clinical Oncology Clinical Practice Guideline Update. Epidemiologic Reviews, 39, 123-131.
https://doi.org/10.1093/epirev/mxw002

[36]   Andocs, G., Renner, H., Balogh, L., Fonyad, L., Jakab, C. and Szasz, A. (2009) Strong Synergy of Heat and Modulated Electro-Magnetic Field in Tumor Cell Killing, Study of HT29 Xenograft Tumors in a Nude Mice Model. Strahlentherapie und Onkologie, 185, 120-126.
https://doi.org/10.1007/s00066-009-1903-1

[37]   Hegyi, G., Szigeti, G.P. and Szasz, A. (2013) Hyperthermia versus Oncothermia: Cellular Effects in Complementary Cancer Therapy. Evidence-Based Complementary and Alternative Medicine, 2013, Article ID: 672873.
https://doi.org/10.1155/2013/672873

[38]   Meggyeshazi, N., Andocs, G., Balogh, L., Balla, P., Kiszner, G., Teleki, I., Jeney, A. and Krenacs, T. (2014) DNA Fragmentation and Caspase-Independent Programmed Cell Death by Modulated Electrohyperthermia. Strahlentherapie und Onkologie, 190, 815-822.
https://doi.org/10.1007/s00066-014-0617-1

[39]   Tsang, Y.-W., Huang, C.-C., Yang, K.-L., Chi, M.-S., Chiang, H.-C., Wang, Y.-S., Andocs, G., Szasz, A., Li, W.-T. and Chi, K.-H. (2015) Improving Immunological Tumor Microenvironment Using Electro-Hyperthermia Followed by Dendritic Cell Immunotherapy. BMC Cancer, 15, Article No. 708.
https://doi.org/10.1186/s12885-015-1690-2

[40]   Qin, W., Akutsu, Y., Andocs, G., Sugnami, A., Hu, X., Yusup, G., Komatsu-Akimoto, A., Hoshino, I., Hanari, N., Mori, M., Isozaki, Y., Akanuma, N., Tamura, Y. and Matsubara, H. (2014) Modulated Electro-Hyperthermia Enhances Dendritic Cell Therapy through an Abscopal Effect in Mice. Oncology Reports, 32, 2373-2379.
https://doi.org/10.3892/or.2014.3500

[41]   Vancsik, T., Kovago, Cs., Kiss, E., Papp, E., Forika, G., Benyo, Z., Meggyeshazi, N. and Krenacs, T. (2018) Modulated Electro-Hyperthermia Induced Loco-Regional and Systemic Tumor Destruction in Colorectal Cancer Allografts. Journal of Cancer, 9, 41-53.
https://doi.org/10.7150/jca.21520

[42]   Andocs, G., Rehman, M.U., Zhao, Q.-L., Tabuchi, Y., Kanamori, M. and Kondo, T. (2016) Comparison of Biological Effects of Modulated Electro-Hyperthermia and Conventional Heat Treatment in Human Lymphoma U937 Cell. Cell Death Discovery (Nature Publishing Group), 2, 16039.
https://doi.org/10.1038/cddiscovery.2016.39

[43]   Yang, K.-L., Huang, C.-C., Chi, M.-S., Chiang, H.-C., Wang, Y.-S., Andocs, G., et al. (2016) In Vitro Comparison of Conventional Hyperthermia and Modulated Electro-Hyperthermia. Oncotarget, 7, 84082-84092.
https://doi.org/10.18632/oncotarget.11444

[44]   Szasz, A. (2013) Challenges and Solutions in Oncological Hyperthermia. Thermal Medicine, 29, 1-23.
https://doi.org/10.3191/thermalmed.29.1

[45]   Szasz, O. (2013) Renewing Oncological Hyperthermia-Oncothermia. Open Journal of Biophysics, 3, 245-252.
https://doi.org/10.4236/ojbiphy.2013.34030

[46]   Szasz, A. (2013) “Quo Vadis” Oncologic Hyperthermia? Conference Papers in Medicine, 2013, Article ID: 201671.
https://doi.org/10.1155/2013/201671

[47]   Szasz, A.M., Minnaar, C., Szentmartoni, Gy., Szigeti, G.P. and Dank, M. (2019) Review of the Clinical Evidences of Modulated Electro-Hyperthermia (mEHT) Method: An Update for the Practicing Oncologist. Frontiers in Oncology, 9, 1012.
https://doi.org/10.3389/fonc.2019.01012

[48]   Dani, A., Varkonyi, A., Magyar, T. and Szasz, A. (2008) Clinical Study for Advanced Pancreas Cancer Treated by Oncothermia. Forum Hyperthermie, 1, 13-20.

[49]   Volovat, C., Volovat, S.R., Scripcaru, V., et al. (2014) Second-Line Chemotherapy with Gemcitabine and Oxaliplatin in Combination with Loco-Regional Hyperthermia (EHY-2000) in Patients with Refractory Metastatic Pancreatic Cancer: Preliminary Results of a Prospective Trial. Romanian Reports in Physics, 66, 166-174.

[50]   Douwes, F.R. (2006) Thermochemotherapy of the Advanced Pancreas Carcinoma. Biologische Medizin, 35, 126-130.

[51]   Lee, D.Y., Haam, S.J., Kim, T.H., Lim, J.Y., Kim, E.J. and Kim, N.Y. (2013) Oncothermia with Chemotherapy in the Patients with Small Cell Lung Cancer. Conference Papers in Medicine, 2013, Article ID: 910363.
https://doi.org/10.1155/2013/910363

[52]   Dani, A., Varkonyi, A., Magyar, T. and Szasz, A. (2009) Clinical Study for Advanced Non-Small-Cell Lung-Cancer Treated by Oncothermia. Forum Hyperthermie, DGHT, Cologne, 26 September 2009.

[53]   Szasz, A. (2014) Current Status of Oncothermia Therapy for Lung Cancer. The Korean Journal of Thoracic and Cardiovascular Surgery, 47, 77-93.
https://doi.org/10.5090/kjtcs.2014.47.2.77

[54]   Ou, J., Zhu, X., Lu, Y., et al. (2017) The Safety and Pharmacokinetics of High Dose Intravenous Ascorbic Acid Synergy with Modulated Electrohyperthermia in Chinese Patients with Stage III-IV Non-Small Cell Lung Cancer. European Journal of Pharmaceutical Sciences, 109, 412-418.
https://doi.org/10.1016/j.ejps.2017.08.011

[55]   Sahinbas, H., Groenemeyer, D.H.W., Boecher, E. and Szasz, A. (2007) Retrospective Clinical Study of Adjuvant Electro-Hyperthermia Treatment for Advanced Brain-Gliomas. Deutsche Zeitschrift für Onkologie, 39, 154-160.
https://doi.org/10.1055/s-2007-986020

[56]   Wismeth, C., Dudel, C., Pascher, C., et al. (2010) Transcranial Electro-Hyperthermia Combined with Alkylating Chemotherapy in Patients with Relapsed High-Grade Gliomas—Phase I Clinical Results. Journal of Neuro-Oncology, 98, 395-405.
https://doi.org/10.1007/s11060-009-0093-0

[57]   Fiorentini, G., Giovanis, P., Rossi, S., et al. (2006) A Phase II Clinical Study on Relapsed Malignant Gliomas Treated with Electro-Hyperthermia. In Vivo, 20, 721-724.

[58]   Roussakow, S. (2017) Clinical and Economic Evaluation of Modulated Electrohyperthermia Concurrent to Dose-Dense Temozolomide 21/28 Days Regimen in the Treatment of Recurrent Glioblastoma: A Retrospective Analysis of a Two-Centre German Cohort Trial with Systematic Comparison and Effect-to-Treatment Analysis, BMJ Open, 7, e017387.
https://doi.org/10.1136/bmjopen-2017-017387

[59]   Van Gool, S.W., Makalowski, J., Feyen, O., Prix, L., Schirrmacher, V. and Stuecker, W. (2018) The Induction of Immunogenic Cell Death (ICD) during Maintenance Chemotherapy and Subsequent Multimodal Immunotherapy for Glioblastoma (GBM). Austin Oncology Case Reports, 3, 1-8.

[60]   Hager, E.D., Sahinbas, H., Groenemeyer, D.H., et al. (2008) Prospective Phase II Trial for Recurrent High-Grade Malignant Gliomas with Capacitive Coupled Low Radiofrequency (LRF) Deep Hyperthermia. Journal of Clinical Oncology, 26, 2047.
https://doi.org/10.1200/jco.2008.26.15_suppl.2047

[61]   Fiorentini, G., Sarti, D., Milandri, C., Dentioco, P., et al. (2018) Modulated Electrohyperthermia in Integrative Cancer Treatment for Relapsed Malignant Glioblastoma and Astrocytoma: Retrospective Multicenter Controlled Study. Integrative Cancer Therapies, 18, 1-11.
https://doi.org/10.1177/1534735418812691

[62]   Lee, S.-Y., Lee, N.-R., Cho, D.-H. and Kim, J.-S. (2017) Treatment Outcome Analysis of Chemotherapy Combined with Modulated Electro-Hyperthermia Compared with Chemotherapy Alone for Recurrent Cervical Cancer, Following Irradiation. Oncology Letters, 14, 73-78.
https://doi.org/10.3892/ol.2017.6117

[63]   Minnaar, C., Baeyens, A. and Kotzen, J. (2016) Update on Phase III Randomized Clinical Trial Investigating the Effects of the Addition of Electro-Hyperthermia to Chemoradiotherapy for Cervical Cancer Patients in South Africa. Physica Medica, 32, 151-152.
https://doi.org/10.1016/j.ejmp.2016.07.042

[64]   Ferrari, V.D., De Ponti, S., Valcamonico, F., et al. (2007) Deep Electro-Hyperthermia (EHY) with or without Thermo-Active Agents in Patients with Advanced Hepatic Cell Carcinoma: Phase II Study. Journal of Clinical Oncology, 25, 15168.
https://doi.org/10.1200/jco.2007.25.18_suppl.15168

[65]   Gadaleta-Caldarola, G., Infusino, S., Galise, I., et al. (2014) Sorafenib and Locoregional Deep Electro-Hyperthermia in Advanced Hepatocellular Carcinoma. A Phase II Study. Oncology Letters, 8, 1783-1787.
https://doi.org/10.3892/ol.2014.2376

[66]   Jeung, T.-S., Ma, S.-Y., Choi, J., et al. (2015) Results of Oncothermia Combined with Operation, Chemotherapy and Radiation Therapy for Primary, Recurrent and Metastatic Sarcoma. Case Reports in Clinical Medicine, 4, 157-168.
https://doi.org/10.4236/crcm.2015.45033

[67]   Volovat, C., Volovat, S.R., Scripcaru, V., et al. (2014) The Results of Combination of Ifosfamid and Locoregional Hyperthermia (EHY 2000) in Patients with Advanced Abdominal Soft-Tissue Sarcoma after Relapse of First Line Chemotherapy. Romanian Reports in Physics, 66, 175-181.

[68]   Mambrini, A., Del Freo, A., Pacetti, P., et al. (2007) Intra-Arterial and Systemic Chemotherapy plus External Hyperthermia in Unresectable Biliary Cancer. Clinical Oncology, 19, 806-808.
https://doi.org/10.1016/j.clon.2007.08.013

[69]   Pang, C.L.K., Zhang, X., Wang, Z., Ou, J., Lu, Y., Chen, P., Zhao, C., et al. (2017) Local Modulated Electro-Hyperthermia in Combination with Traditional Chinese Medicine vs. Intraperitoneal Chemoinfusion for Treatment of Peritoneal Carcinomatosis with Malignant Ascites: A Phase II Randomized Trial. Molecular and Clinical Oncology, 6, 723-732.
https://doi.org/10.3892/mco.2017.1221

[70]   Hager, E.D. (2004) Lebermetastasen bei kolorektalen Karzinomen. Deutsche Zeitschrift für Onkologie, 36, 132-134.

[71]   Hager, E.D., Dziambor, H., Höhmann, D., et al. (1999) Deep Hyperthermia with Radiofrequencies in Patients with Liver Metastases from Colorectal Cancer. Anticancer Research, 19, 3403-3408.

[72]   Cover, T.M. and Thomas, J.A. (2005) Elements of Information Theory. Wiley, Hoboken.
https://doi.org/10.1002/047174882X

[73]   Pauling, L. (1989) Biostatistical Analysis of Mortality Data for Cohorts of Cancer Patients. Proceedings of the National Academy of Sciences of the United States of America, 86, 3466-3468.
https://doi.org/10.1073/pnas.86.10.3466

[74]   Herman, Z.S. (1998) On Understanding the Hardin Jones-Pauling Biostatistical Theory of Survival Analysis for Cancer Patients. The Journal of Orthomolecular Medicine, 13, 1-12.

[75]   Herman, Z.S. (1998) The Application of the Hardin Jones-Pauling Biostatistical Theory of Survival Analysis for Cancer Patients to a Clinical Trial Purporting to Test the Efficacy of Vitamin C in Lengthening the Survival Times of Patients with Advanced Colorectal Cancer. The Journal of Orthomolecular Medicine, 13, 225-232.

[76]   Pauling, L. and Herman, Z.S. (1989) Criteria for the Validity of Clinical Trials of Treatments of Cohorts of Cancer Patients Based on the Hardin Jones Principle. Proceedings of the National Academy of Sciences of the United States of America, 86, 6835-6837.
https://doi.org/10.1073/pnas.86.18.6835

[77]   Rouaud, M. (2013) Probability, Statistics and Estimation; Creative Commons Attribution-Non-Commercial 4.0 International License (CC BY-NC 4.0).

[78]   Glasziou, P.P., Simes, R.J. and Gelber, R.D. (1990) Quality Adjusted Survival Analysis. Statistics in Medicine, 9, 1259-1276.
https://doi.org/10.1002/sim.4780091106

[79]   Martin, A.J. and Simes, R.J. (2013) Quality-Adjusted Survival as an End Point in Breast Cancer Trials. Journal of Clinical Investigation, 3, 545-555.
https://doi.org/10.4155/cli.13.37

[80]   Cole, B.F., Gelber, R.D., Gelber, S. and Mukhopadhyay, P. (2014) A Quality-Adjusted Survival (Q-TWiST) Model for Evaluating Treatments for Advanced Stage Cancer. Journal of Biopharmaceutical Statistics, 14, 111-124.
https://doi.org/10.1081/BIP-120028509

 
 
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