Primary mediastinal B-cell lymphoma

Section editor
	Tarsheen Sethi, MD, MSCI Yale University New Haven, CT tarsheen2

11 regimens on this page 11 variants on this page

Note: these regimens have been studied specifically in primary mediastinal B-cell lymphoma. Other large B-cell lymphoma regimens, such as those used in diffuse large B-cell lymphoma are also often used.

Guidelines

BSH

• 2019: Cwynarski et al. The management of primary mediastinal B-cell lymphoma: a British Society for Haematology Good Practice Paper

ESMO

• 2016: Vitolo et al. Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

Older

• 2013: ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) PubMed

NCCN

• NCCN Guidelines - B-cell Lymphomas

Untreated

DA-R-EPOCH

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DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin)

Regimen

Study	Evidence
Dunleavy et al. 2013 (NCI 93-C-0133)	Phase II
Purroy et al. 2014	Phase II, <20 pts in this subgroup

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV over 3 hours once on day 1

Chemotherapy

• Etoposide (Vepesid) 50 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 200 mg/m²)
• Prednisone (Sterapred) 60 mg/m² PO twice per day on days 1 to 5
• Vincristine (Oncovin) 0.4 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg/m²; dose was not capped)
• Cyclophosphamide (Cytoxan) 750 mg/m² IV over 2 hours once on day 5
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)

Supportive medications

• Filgrastim (Neupogen) 300 mcg SC once per day, starting on day 6 and continuing until ANC greater than 5,000/uL past nadir
• Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg (or equivalent if allergic) PO once per day on 3 days per week
  • Note: It's assumed this is what the supplement for Dunleavy et al. 2013 meant by "Baxtrim (sulphametoxazole and trimethoprim)"
• Omeprazole (Prilosec) 20 mg (or equivalent) PO once per day
• Docusate (Colace) (dose not specified) and Sennosides (Senna) 2 tablets PO twice per day as needed for constipation
• Lactulose 20 g PO every 6 hours as needed for constipation
• Hepatitis B surface antigen positive patients received daily antiviral therapy until 8 weeks after completion of chemotherapy

21-day cycle for 6 to 8 cycles

Dose adjustments

• Start cycle 1 as described above.
• Obtain CBCs twice per week for nadir measurements.
• If nadir ANC greater than 500, increase etoposide, doxorubicin, and cyclophosphamide by one level (20%) compared to previous cycle.
• If nadir ANC less than 500, use same doses as last cycle.
• If nadir platelet count less than 25,000, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to the previous cycle.

References

1. NCI 93-C-0133: Dunleavy K, Pittaluga S, Maeda LS, Advani R, Chen CC, Hessler J, Steinberg SM, Grant C, Wright G, Varma G, Staudt LM, Jaffe ES, Wilson WH. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013 Apr 11;368(15):1408-16. link to original article link to supplementary appendix contains verified protocol PubMed
2. Purroy N, Bergua J, Gallur L, Prieto J, Lopez LA, Sancho JM, García-Marco JA, Castellví J, Montes-Moreno S, Batlle A, de Villambrosia SG, Carnicero F, Ferrando-Lamana L, Piris MA, Lopez A. Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma: a phase II study conducted by the Spanish PETHEMA group. Br J Haematol. 2015 Apr;169(2):188-98. Epub 2014 Dec 18. link to original article PubMed

R-CHOP

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R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
R-CHOP-21
CHOP-R

Example orders

• Example orders for R-CHOP in lymphoma

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pfreundschuh et al. 2006 (NCIC CTG LY.9)	2000-2003	Phase III (E-esc)	1. CHOP 2. CHOEP 3. MACOP-B 4. PMitCEBO	Seems to have superior EFS

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive medications

• G-CSF with one of the following:
  • Filgrastim (Neupogen) used at physician discretion for neutropenia
  • Lenograstim (Granocyte) used at physician discretion for neutropenia

21-day cycle for 6 cycles

Subsequent treatment

• Radiation therapy

References

1. NCIC CTG LY.9: Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Rieger M, Osterborg A, Pettengell R, White D, Gill D, Walewski J, Kuhnt E, Loeffler M, Pfreundschuh M, Ho AD; MabThera International Trial (MInT) Group. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. Ann Oncol. 2011 Mar;22(3):664-70. Epub 2010 Aug 19. link to original article PubMed

R-CHOP (Prednisolone)

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R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone

Example orders

• Example orders for R-CHOP in lymphoma

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2013 (UK NCRI R-CHOP14v21)	2005-2008	Phase III (C)	R-CHOP-14	Might have inferior OS (*)

Note: the efficacy reported here is based on a post-hoc subgroup analysis.

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Prednisolone (Millipred) 40 mg/m² PO once per day on days 1 to 5

CNS prophylaxis

Per investigator discretion, but Cunningham et al. 2013 recommended that patients who had involvement of the "bone marrow, peripheral blood, nasal or paranasal sinuses, orbit, and testis" (they probably intended to say "or testis") receive:

• Methotrexate (MTX) 12.5 mg IT "for the first three cycles of treatment, administered as per local guidelines." No other details given.

Supportive medications

• Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12 at physician discretion
• Allopurinol (Zyloprim) 300 mg PO once per day during cycle 1
• Co-trimoxazole 80/400 mg PO twice per day on 3 days per week, taken throughout therapy, ending 2 weeks after chemotherapy is completed

21-day cycle for 8 cycles

References

1. UK NCRI R-CHOP14v21: Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26. Epub 2013 Apr 22. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Gleeson M, Hawkes EA, Cunningham D, Chadwick N, Counsell N, Lawrie A, Jack A, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford J, McMillan A, Davies J, Turner D, Kruger A, Johnson PW, Gambell J, Linch D. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) in the management of primary mediastinal B-cell lymphoma: a subgroup analysis of the UK NCRI R-CHOP 14 versus 21 trial. Br J Haematol. 2016 Nov;175(4):668-672. Epub 2016 Aug 1. link to original article PubMed

R-CHOP-14 (Prednisolone)

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R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone every 14 days

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2013 (UK NCRI R-CHOP14v21)	2005-2008	Phase III (E-esc)	R-CHOP-21	Might have superior OS (*)

Note: the efficacy reported here is based on a post-hoc subgroup analysis.

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

CNS prophylaxis

Per investigator discretion, but Cunningham et al. 2013 recommended that patients who had involvement of the "bone marrow, peripheral blood, nasal or paranasal sinuses, orbit, and testis" (they probably intended to say "or testis") receive:

• Methotrexate (MTX) 12.5 mg IT "for the first three cycles of treatment, administered as per local guidelines." No other details given.

Supportive medications

• Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12
• Allopurinol (Zyloprim) 300 mg PO once per day during cycle 1
• Co-trimoxazole 480 mg (route not specified) twice per day on 3 days per week, taken throughout therapy, ending 2 weeks after treatment is completed

14-day cycle for 6 cycles (8 cycles of rituximab)

References

1. UK NCRI R-CHOP14v21: Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26. Epub 2013 Apr 22. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Gleeson M, Hawkes EA, Cunningham D, Chadwick N, Counsell N, Lawrie A, Jack A, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford J, McMillan A, Davies J, Turner D, Kruger A, Johnson PW, Gambell J, Linch D. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) in the management of primary mediastinal B-cell lymphoma: a subgroup analysis of the UK NCRI R-CHOP 14 versus 21 trial. Br J Haematol. 2016 Nov;175(4):668-672. Epub 2016 Aug 1. link to original article PubMed

Consolidation after upfront therapy

Radiation therapy

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Regimen

Study	Evidence
Pfreundschuh et al. 2006 (NCIC CTG LY.9)	Non-randomized portion of RCT

Preceding treatment

• CHOP-like therapy x 6 versus R-CHOP-like therapy (including R-CHOP) x 6

Radiotherapy

• External beam radiotherapy: 30 to 40 Gy given to sites of primary bulky disease; 30 to 40 Gy to primary extranodal disease at physician discretion

References

1. NCIC CTG LY.9: Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Rieger M, Osterborg A, Pettengell R, White D, Gill D, Walewski J, Kuhnt E, Loeffler M, Pfreundschuh M, Ho AD; MabThera International Trial (MInT) Group. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. Ann Oncol. 2011 Mar;22(3):664-70. Epub 2010 Aug 19. link to original article PubMed

Relapsed or refractory, salvage therapy

R-DHAP

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R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study	Evidence	Comparator
Crump et al. 2014 (NCIC-CTG LY.12)	Phase III, <20 pts in subgroup (C)	R-GDP

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m²)
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1

21-day cycle for up to 3 cycles

References

1. NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains verified protocol PubMed NCT00078949

R-GDP

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R-GDP: Rituximab, Gemcitabine, Dexamethasone, Platinol (Cisplatin)

Regimen

Study	Evidence	Comparator
Crump et al. 2014 (NCIC-CTG LY.12)	Phase III, <20 pts in subgroup (E-switch-ic)	R-DHAP

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
• Cisplatin (Platinol) 75 mg/m² IV once on day 1

21-day cycle for up to 3 cycles

References

1. NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains verified protocol PubMed NCT00078949

Consolidation after salvage therapy

FluBuCy, then allo HSCT

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FluBuCy: Fludarabine, Busulfan, Cyclophosphamide

Regimen

Study	Evidence
Glass et al. 2014 (DSHNHL R3)	Phase II

Chemotherapy

• Fludarabine (Fludara) 25 mg/m²/day IV on days -8 to -4
• Busulfan (Myleran) 4 mg/kg/day PO on days -6 to -4
• Cyclophosphamide (Cytoxan) 60 mg/kg/day IV on days -3 and -2

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2 mg/kg IV from day -3 to -1 (unclear if this is a total dose or a daily dose)
  • Option also to use ATG-Fresenius S at a higher dose of 10 mg/kg
• Tacrolimus (Prograf) 8 to 12 mcg/L (route/frequency not specified) starting on day -1, tapered from day +100 in absence of GVHD
• Mycophenolate mofetil (CellCept) 1000 mg (route not specified) twice per day from day +1 to +28

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. DSHNHL R3: Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):757-66. Epub 2014 May 11. link to original article link to original protocol (in German) contains verified protocol PubMed

Relapsed or refractory, further lines of therapy

Axicabtagene ciloleucel monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Efficacy
Nellapu et al. 2017 (ZUMA-1)	2015-2016	Phase II, <20 pts in subgroup (RT)	ORR: 82%

Preceding treatment

• Lymphodepletion with FC

Immunotherapy

• Axicabtagene ciloleucel (Yescarta) target dose of 2 × 10⁶ CAR T cells/kg IV once on day 0

Supportive medications

• Acetaminophen (Tylenol) 650 mg PO once on day 0, approximately 60 minutes prior to Axicabtagene ciloleucel (Yescarta)
• Diphenhydramine (Benadryl) 12.5 mg IV or PO once on day 0, approximately 60 minutes prior to Axicabtagene ciloleucel (Yescarta)

One course; patients with initial response and disease progression at least 3 months later could be retreated

References

1. ZUMA-1: Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. Epub 2017 Dec 10. link to original article contains verified protocol link to PMC article PubMed

Lisocabtagene maraleucel monotherapy

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Regimen

Study	Years of enrollment	Evidence
Abramson et al. 2020 (TRANSCEND NHL-001)	2016-2019	Non-randomized (RT)

Immunotherapy

• Lisocabtagene maraleucel (Breyanzi)

References

1. TRANSCEND NHL-001: Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C, Sehgal A, Solomon SR, Ghosh N, Albertson TM, Garcia J, Kostic A, Mallaney M, Ogasawara K, Newhall K, Kim Y, Li D, Siddiqi T. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020 Sep 19;396(10254):839-852. Epub 2020 Sep 1. link to original article PubMed NCT02631044

Pembrolizumab monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Armand et al. 2016 (KEYNOTE-013)	2014-2016	Phase Ib
Armand et al. 2016 (KEYNOTE-170)	2016-2017	Phase II (RT)

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1

21-day cycle for up to 35 cycles (2 years)

References

1. KEYNOTE-013/KEYNOTE-170: Armand P, Rodig S, Melnichenko V, Thieblemont C, Bouabdallah K, Tumyan G, Özcan M, Portino S, Fogliatto L, Caballero MD, Walewski J, Gulbas Z, Ribrag V, Christian B, Perini GF, Salles G, Svoboda J, Zain J, Patel S, Chen PH, Ligon AH, Ouyang J, Neuberg D, Redd R, Chatterjee A, Balakumaran A, Orlowski R, Shipp M, Zinzani PL. Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma. J Clin Oncol. 2019 Dec 1;37(34):3291-3299. Epub 2019 Oct 14. link to original article contains verified protocol link to PMC article PubMed