Difference between revisions of "Staging page"

From HemOnc.org - A Hematology Oncology Wiki
Jump to navigation Jump to search
m
m
Line 3: Line 3:
 
[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
</div>
 
</div>
−
{{#lst:Section editor transclusions|giei}}
+
{{#lst:Section editor transclusions|leuk}}
−
''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Pancreatic NET - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
 
−
<big>Note: for more general neuroendocrine regimens, please visit the '''[[neuroendocrine tumors]]''' page.</big>
 
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
Line 12: Line 10:
 
|}
 
|}
 
{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
−
=Guidelines=
+
''Note: these regimens are primarily culled from literature that describes them as part of a comprehensive treatment regimen. If that is the case, the original regimens can be found on the following pages:''
−
==[http://www.esmo.org/ ESMO]==
+
*[[Acute promyelocytic leukemia]]
−
*'''2020:''' Pavel et al. [https://doi.org/10.1016/j.annonc.2020.03.304 Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
*[[Adult T-cell leukemia-lymphoma]]
−
===Older===
+
*[[B-cell acute lymphoblastic leukemia]]
−
*'''2012:''' Öberg et al. [https://www.esmo.org/Guidelines/Endocrine-and-Neuroendocrine-Cancers/Neuroendocrine-Gastroenteropancreatic-Tumours Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
*[[T-cell acute lymphoblastic leukemia]]
−
==NANETS==
+
=CNS prophylaxis, local therapy=
−
*'''2020:''' Halfdanarson et al. [https://doi.org/10.1097/mpa.0000000000001597 The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors]
+
==IT Cytarabine & Methotrexate {{#subobject:c47af4|Regimen=1}}==
−
*'''2020:''' Howe et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7029300/ The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors]
 
−
==[https://www.nccn.org/ NCCN]==
 
−
*[https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf NCCN Guidelines - Neuroendocrine Tumors]
 
−
=All lines of therapy=
 
−
==Capecitabine & Temozolomide {{#subobject:738284|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:fc2dd9|Variant=1}}===
+
===Regimen variant #1, 16 doses {{#subobject:8be879|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 25%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ Strosberg et al. 2011]
+
|[https://doi.org/10.1002/cncr.21776 Thomas et al. 2006]
−
| style="background-color:#ffffbe" |Retrospective
+
|style="background-color:#ffffbe"|Pilot, <20 pts
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====CNS therapy, prophylaxis====
−
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+
*[[Methotrexate (MTX)]] by the following route-based criteria:
−
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day at bedtime on days 10 to 14
+
**LP: 12 mg IT once on day 2
−
====Supportive therapy====
+
**Ommaya reservoir: 6 mg IT once on day 2
−
*[[Ondansetron (Zofran)]] 8 mg (route not specified) once per day on days 1 to 14, prior to [[Temozolomide (Temodar)]]
+
*[[Cytarabine (Ara-C)]] 100 mg IT once on day 7
−
'''28-day cycles'''
+
'''Given each cycle for a total of 16 intrathecal treatments'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 6 to 8 doses {{#subobject:f842e7|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1999.17.8.2461 Thomas et al. 1999]
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|[http://www.bloodjournal.org/content/103/12/4396.long Thomas et al. 2003]
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
''Total number of doses depends on risk for CNS relapse based on serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%.''
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] by the following route-based criteria:
 +
**LP: 12 mg IT once on day 2
 +
**Ommaya reservoir: 6 mg IT once on day 2
 +
*[[Cytarabine (Ara-C)]] 100 mg IT once on either day 7 or 8
 +
'''Given each cycle (approximately every 3 weeks) for a total of 6 or 8 intrathecal treatments'''
 +
</div></div>
 +
===References===
 +
# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [https://doi.org/10.1200/jco.1999.17.8.2461 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561310 PubMed]
 +
# Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. [http://www.bloodjournal.org/content/103/12/4396.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14551133 PubMed]
 +
## '''Update:''' Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. [http://www.haematologica.org/content/100/5/653 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420214/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25682595 PubMed]
 +
# Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. [https://doi.org/10.1002/cncr.21776 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16502413 PubMed]
 +
## '''Update:''' Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. [https://doi.org/10.3816/clm.2007.s.034 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18284717 PubMed]
 +
# '''MDACC 2006-0478:''' Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://www.bloodjournal.org/content/116/12/2070.long link to original article] '''contains dosing details in manuscript'''--parts of the protocol were not explicitly listed in this reference, which instead referred to [[#Hyper-CVAD_.26_Imatinib_.28Gleevec.29_.28induction_.26_maintenance.29|Thomas et al. 2004]] and [[#Hyper-CVAD_.28induction.29|Kantarjian et al. 2004]] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853 PubMed] NCT00390793
 +
## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://doi.org/10.1002/cncr.29646 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885 PubMed]
 +
==IT Cytarabine, Methotrexate, Methylprednisolone {{#subobject:eb3e09|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:daa284|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 +
|2003-2005
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
''Intrathecal treatments are given on days 1 & 8 of induction, day 29 of each series of consolidation blocks, and day 1 of late intensification -- 6 doses total.''
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] 40 mg IT mixed with methotrexate and methylprednisolone
 +
*[[Methotrexate (MTX)]] 15 mg IT mixed with cytarabine and methylprednisolone
 +
*[[Methylprednisolone (Solumedrol)]] 40 mg IT mixed with cytarabine and methotrexate
 +
'''6 doses'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Retrospective:''' Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. Epub 2010 Sep 7. [https://doi.org/10.1002/cncr.25425 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20824724 PubMed]
+
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
−
==Doxorubicin & Streptozocin {{#subobject:5c625d|Regimen=1}}==
+
==IT Cytarabine, Methotrexate, Prednisone {{#subobject:d81b63|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a9c7ed|Variant=1}}===
+
===Regimen {{#subobject:6f33ca|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 25%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
| rowspan="2" |[https://doi.org/10.1056/NEJM199202203260804 Moertel et al. 1992]
+
|[https://doi.org/10.1200/jco.2007.11.9958 Tsukasaki et al. 2007 (JCOG 9801)]
−
|rowspan=2|1978-1985
+
|style="background-color:#91cf61"|Non-randomized
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 
−
|1. [[#Chlorozotocin_monotherapy_88|Chlorozotocin]]
 
−
| style="background-color:#1a9850" |Superior OS
 
 
|-
 
|-
−
|2. [[#Fluorouracil_.26_Streptozocin|5-FU & Streptozocin]]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024033/ Ishida et al. 2015 (Kyowa 0761-003)]
−
| style="background-color:#1a9850" |Superior OS
+
|style="background-color:#91cf61"|Non-randomized
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Treatments were given after cycles 1, 3, and 5 after platelets greater than 70 × 10<sup>9</sup>/L and within 2 days before the next cycle.''
−
====Chemotherapy====
+
====CNS therapy, prophylaxis====
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 22
+
*[[Cytarabine (Ara-C)]] 40 mg IT mixed with methotrexate and prednisone
−
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5
+
*[[Methotrexate (MTX)]] 15 mg IT mixed with cytarabine and prednisone
−
'''42-day cycles'''
+
*[[Prednisone (Sterapred)]] 10 mg IT mixed with cytarabine and methotrexate
 +
'''3 doses'''  
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://doi.org/10.1056/NEJM199202203260804 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1310159 PubMed]
+
<!-- Presented in part at the 47th Annual Meeting of the American Society of Hematology, December 10-13, 2005, Atlanta, GA. -->
−
==Everolimus monotherapy {{#subobject:78dff1|Regimen=1}}==
+
# '''JCOG 9801:''' Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M; [[Study_Groups#JCOG|JCOG]]. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007 Dec 1;25(34):5458-64. Epub 2007 Oct 29. [https://doi.org/10.1200/jco.2007.11.9958 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17968021 PubMed] NCT00145002
 +
# '''Kyowa 0761-003:''' Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015 Jun;169(5):672-82. Epub 2015 Mar 2. [https://doi.org/10.1111/bjh.13338 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024033/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25733162 PubMed] NCT01173887
 +
==IT Cytarabine & WBRT {{#subobject:d62e53|Regimen=1}}==
 +
Cytarabine & WBRT: Cytarabine & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:5ea369|Variant=1}}===
+
===Regimen {{#subobject:b3f29d|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 25%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010 (RADIANT-1)]
 
−
|2006-2007
 
−
| style="background-color:#91cf61" |Phase 2
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)]
+
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
−
|2007-2009
+
|style="background-color:#91cf61"|Non-randomized portion of RCT
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
−
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 11 vs 4.6 mo<br>(HR 0.35, 95% CI 0.27-0.45)
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: while this is not chemoradiation in the traditional sense, the delivery of chemotherapy and radiation overlap so may have synergistic effects.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====CNS therapy, prophylaxis====
−
*[[Everolimus (Afinitor)]] 10 mg PO once per day
+
*[[Cytarabine (Ara-C)]] as follows:
−
'''Continued indefinitely'''
+
**Consolidation & Maintenance: 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses (8 doses, total)
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 2400 cGy, given during consolidation
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''RADIANT-1:''' Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [https://doi.org/10.1200/jco.2009.24.2669 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19933912 PubMed] NCT00363051
+
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
−
# '''RADIANT-3:''' Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. [https://doi.org/10.1056/NEJMoa1009290 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21306238 PubMed] NCT00510068
+
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]  
−
## '''Update:''' Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, He W, Chen D, Capdevila J, de Vries EGE, Tomassetti P, Hobday T, Pommier R, Öberg K. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J Clin Oncol. 2016 Nov 10;34(32):3906-3913. Epub 2016 Sep 30. [https://doi.org/10.1200/JCO.2016.68.0702 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791842/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27621394 PubMed]
+
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]  
−
# '''Review:''' Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. Epub 2013 Feb 22. [http://cancerres.aacrjournals.org/content/73/5/1449.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23436795 PubMed]
+
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
−
#'''COMPETE:''' NCT03049189
+
==IT Methotrexate monotherapy {{#subobject:98fb82|Regimen=1}}==
−
#'''COMPOSE:''' NCT04919226
 
−
==Everolimus & Octreotide {{#subobject:d6b3eb|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:b0f62f|Variant=1}}===
+
===Regimen {{#subobject:0f3d6e|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 33%"|Study
+
!style="width: 25%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]
+
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
−
|2005-2006
+
|style="background-color:#91cf61"|Non-randomized portion of RCT
−
| style="background-color:#91cf61" |Phase 2
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====CNS therapy, prophylaxis====
−
*[[Everolimus (Afinitor)]] 5 mg PO once per day
+
*[[Methotrexate (MTX)]] as follows:
−
====Endocrine therapy====
+
**Phase 1: 12 mg IT once on day 15
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
+
**Phase 2: 12 mg IT once per day on days 1, 8, 15, 22
−
'''28-day cycles'''
+
</div></div>
−
</div></div><br>
+
===References===
 +
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
 +
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]  
 +
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 +
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 +
==IT Methotrexate & Hydrocortisone {{#subobject:d0d04e|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:f82bb5|Variant=1}}===
+
===Regimen {{#subobject:edc35f|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
!style="width: 20%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 20%"|Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]
+
|[http://www.bloodjournal.org/content/50/3/471.long Sullivan et al. 1977]
−
|2005-2006
+
|1971-1973
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9851" |Phase 3 (C)
 +
|IT MTX, Ara-C, HC
 +
| style="background-color:#ffffbf" |Seems not superior
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010 (RADIANT-1)]
+
|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015 (AMC-UUCM-2008-0310)]
−
|2006-2007
+
|2009-2012
−
| style="background-color:#91cf61" |Phase 2
+
|style="background-color:#91cf61"|Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
 
|}
 
|}
−
''Note: In Yao et al. 2008, everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory." Patients in RADIANT-1 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study; they were continued on their prestudy dose up to 30 mg.''
+
''Treatment can be started during or after induction.''
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====CNS therapy, prophylaxis====
−
====Targeted therapy====
+
*[[Methotrexate (MTX)]] 15 mg IT (schedule not specified), admixed with hydrocortisone
−
*[[Everolimus (Afinitor)]] 10 mg PO once per day
+
*[[Hydrocortisone (Cortef)]] 50 mg IT (schedule not specified), admixed with methotrexate
−
====Endocrine therapy====
+
'''Up to 10 doses'''
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
 
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [https://doi.org/10.1200/jco.2008.16.7858 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18779618 PubMed]
+
# Sullivan MP, Moon TE, Trueworthy R, Vietti TJ, Humphrey GB, Komp D. Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Blood. 1977 Sep;50(3):471-9. [http://www.bloodjournal.org/content/50/3/471.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/577889 PubMed]
−
# '''RADIANT-1:''' Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [https://doi.org/10.1200/jco.2009.24.2669 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19933912 PubMed] NCT00363051
+
# '''AMC-UUCM-2008-0310:''' Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26065651 PubMed] NCT00844298
−
==FAS {{#subobject:66b05e|Regimen=1}}==
+
==IT Methotrexate & Methylprednisolone {{#subobject:6a4bad|Regimen=1}}==
−
FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:de76a2|Variant=1}}===
+
===Regimen {{#subobject:358389|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 25%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2004.04.024 Kouvaraki et al. 2004]
+
|[http://www.bloodjournal.org/content/116/17/3171.long Lo-Coco et al. 2010 (GIMEMA AIDA-2000)]
−
| style="background-color:#ffffbe" |Retrospective
+
|style="background-color:#91cf61"|Non-randomized
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''It is not explicitly stated but presumably these are admixed and given together.''
−
====Chemotherapy====
+
====CNS therapy, prophylaxis====
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+
*[[Methotrexate (MTX)]] 12 mg IT once prior to each consolidation cycle
−
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV bolus once on day 1
+
*[[Methylprednisolone (Solumedrol)]] 40 mg IT once prior to each consolidation cycle
−
*[[Streptozocin (Zanosar)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+
'''Total of 3 doses'''
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Retrospective:''' Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. [https://doi.org/10.1200/jco.2004.04.024 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15570077 PubMed]
+
# '''GIMEMA AIDA-2000:''' Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. [http://www.bloodjournal.org/content/116/17/3171.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20644121 PubMed] NCT001064570
−
==Fluorouracil & Streptozocin {{#subobject:6f7b84|Regimen=1}}==
+
==IT Methotrexate & WBRT {{#subobject:4b9a67|Regimen=1}}==
 +
IT Methotrexate & WBRT: '''<u>I</u>'''ntra'''<u>T</u>'''hecal Methotrexate & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:e45011|Variant=1}}===
+
===Regimen {{#subobject:b1f086|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 185: Line 223:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198011203032101 Moertel et al. 1980]
+
|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
−
|1972-1978
+
|1980-1986
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
+
|style="background-color:#91cf61"|Phase 2
−
|[[#Fluorouracil_monotherapy_88|Fluorouracil]]
+
| style="background-color:#d3d3d3" |
−
| style="background-color:#d9ef8b" |Might have superior OS
+
| style="background-color:#d3d3d3" |
−
|-
 
−
| rowspan="2" |[https://doi.org/10.1056/NEJM199202203260804 Moertel et al. 1992]
 
−
|rowspan=2|1978-1985
 
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
−
|1. [[#Chlorozotocin_monotherapy_88|Chlorozotocin]]
 
−
| style="background-color:#ffffbf" |Did not meet endpoint of OS
 
 
|-
 
|-
−
|2. [[#Doxorubicin_.26_Streptozocin|Doxorubicin & Streptozocin]]
+
|[https://doi.org/10.1200/JCO.1998.16.3.920 Nachman et al. 1998 (CCG 1882)]
−
| style="background-color:#d73027" |Inferior OS
+
|1989-1995
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#IT_Methotrexate_monotherapy|IT MTX]]; intensified
 +
| style="background-color:#ffffbf" |Seems not superior
 
|-
 
|-
 
|}
 
|}
−
''Note: treatment details are from Moertel et al. 1992.''
+
''Treatment is started within 1 week of achieving complete remission. Details are from Linker et al. 1987''
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====CNS therapy, prophylaxis====
−
====Chemotherapy====
+
*[[Methotrexate (MTX)]] 12 mg IT once per week x 6 doses concurrent with radiation
−
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5
+
====Radiotherapy====
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+
*[[External_beam_radiotherapy|Whole-brain irradiation]], 18 Gy total given in 10 fractions over 12 to 14 days
−
'''42-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20;303(21):1189-94. [https://doi.org/10.1056/NEJM198011203032101 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6252466 PubMed]
+
# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed]
−
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://doi.org/10.1056/NEJM199202203260804 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1310159 PubMed]
+
## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
−
==Lanreotide Depot/Autogel monotherapy {{#subobject:8bca3a|Regimen=1}}==
+
# '''CCG 1882:''' Nachman J, Sather HN, Cherlow JM, Sensel MG, Gaynon PS, Lukens JN, Wolff L, Trigg ME. Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. J Clin Oncol. 1998 Mar;16(3):920-30. [https://doi.org/10.1200/JCO.1998.16.3.920 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9508174 PubMed]
 +
==WBRT {{#subobject:4c3d39|Regimen=1}}==
 +
WBRT: '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a9ee08|Variant=1}}===
+
===Regimen {{#subobject:bcb463|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
 
!style="width: 20%"|Years of enrollment
 
!style="width: 20%"|Years of enrollment
Line 221: Line 257:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa1316158 Caplin et al. 2014 (CLARINET)]
+
|[https://doi.org/10.1016/s0140-6736(81)91849-3 Nesbit et al. 1981]
−
|2006-2013
+
|1972-1975
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
+
|[[#WBRT|WBRT]]; lower-dose
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: NYR vs 18 mo<br>(HR 0.47, 95% CI 0.30-0.73)
+
| style="background-color:#ffffbf" |Seems not superior
 +
|-
 +
|[https://doi.org/10.1056/NEJM198303033080902 Freeman et al. 1983 (CALGB 7611)]
 +
|1976-1979
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Intermediate-dose MTX
 +
| style="background-color:#ffffbf" |Mixed results
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ Caplin et al. 2016 (CLARINET OLE)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754320/ Pui et al. 2009 (Total Therapy XV)]
−
|2009-NR
+
|2000-2007
−
| style="background-color:#91cf61" |Non-randomized
+
| style="background-color:#1a9851" |Phase 3 (C)
−
| style="background-color:#d3d3d3" |
+
|Observation
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#ffffbf" |Seems not superior
 
|-
 
|-
 
|}
 
|}
 +
''Note: in Total Therapy XV, this is the control arm of a de-escalation study.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Radiotherapy====
−
*[[Lanreotide (Somatuline) | Lanreotide (Somatuline) Depot/Autogel]] 120 mg SC once on day 1
+
*[[External_beam_radiotherapy|Whole-brain irradiation]]
−
'''28-day cycle for 96 weeks (CLARINET) or up to 8 years (CLARINET OLE)'''
+
'''One course'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''CLARINET:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. [https://doi.org/10.1056/NEJMoa1316158 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25014687 PubMed] NCT00353496
+
# Nesbit ME Jr, Sather HN, Robison LL, Ortega J, Littman PS, D'Angio GJ, Hammond GD; Children's Cancer Group. Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukaemia: comparison of 1800 rad and 2400 rad: a report for Children's Cancer Study Group. Lancet. 1981 Feb 28;1(8218):461-6. [https://doi.org/10.1016/s0140-6736(81)91849-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6110090 PubMed]
−
# '''CLARINET OLE:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Gomez-Panzani E, Ruszniewski P; CLARINET Investigators. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. 2016 Mar;23(3):191-9. Epub 2016 Jan 7. [https://doi.org/10.1530/erc-15-0490 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26743120 PubMed] NCT00842348
+
# '''CALGB 7611:''' Freeman AI, Weinberg V, Brecher ML, Jones B, Glicksman AS, Sinks LF, Weil M, Pleuss H, Hananian J, Burgert EO Jr, Gilchrist GS, Necheles T, Harris M, Kung F, Patterson RB, Maurer H, Leventhal B, Chevalier L, Forman E, Holland JF. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med. 1983 Mar 3;308(9):477-84. [https://doi.org/10.1056/NEJM198303033080902 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6571946 PubMed]
−
==Lanreotide & Interferon alfa-2b {{#subobject:9c5a59|Regimen=1}}==
+
## '''Update:''' Freeman AI, Boyett JM, Glicksman AS, Brecher ML, Leventhal BG, Sinks LF, Holland JF. Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: a ten-year follow-up. Med Pediatr Oncol. 1997 Feb;28(2):98-107. [https://doi.org/10.1002/(SICI)1096-911X(199702)28:2%3C98::AID-MPO3%3E3.0.CO;2-N link to original article] [https://pubmed.ncbi.nlm.nih.gov/8986145 PubMed]
 +
# '''Total Therapy XV:''' Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009 Jun 25;360(26):2730-41. [https://doi.org/10.1056/NEJMoa0900386 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754320/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19553647 PubMed] NCT00137111
 +
=CNS prophylaxis, systemic therapy=
 +
==Mercaptopurine & WBRT {{#subobject:fab960|Regimen=1}}==
 +
Mercaptopurine & WBRT: Mercaptopurine & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:652f4d|Variant=1}}===
+
===Regimen {{#subobject:846b99|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 33%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]
+
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
−
| style="background-color:#ffffbe" |Pilot, <20 pts
+
|2003-2005
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
 
|}
 
|}
−
''Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''
+
''Chemoradiation is given before maintenance therapy.''
−
====Endocrine therapy====
+
====Chemotherapy====
−
*[[Lanreotide (Somatuline)]] 3 mg SC twice per day
+
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/day PO during irradiation
−
====Immunotherapy====
+
====Radiotherapy====
−
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)
+
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 18 Gy (details not provided)
 +
'''One course'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12025889 PubMed]
+
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
−
==Octreotide monotherapy {{#subobject:665a8b|Regimen=1}}==
+
=CNS treatment, local therapy=
 +
==IT Cytarabine & Methotrexate {{#subobject:7536ce|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:cd8cf6|Variant=1}}===
+
===Regimen variant #1, LP {{#subobject:c0aa53|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 25%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1093/annonc/mdh216 Oberg et al. 2004]
+
|[https://doi.org/10.1200/jco.1999.17.8.2461 Thomas et al. 1999]
−
| style="background-color:#ffffbe" |Consensus guideline
+
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
 
|}
 
|}
 +
''Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====CNS therapy, treatment====
−
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given two to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
+
*[[Methotrexate (MTX)]] by the following criteria:
−
**"A reasonable starting dose is" 0.15 mg SC three times per day
+
**Measurable CNS disease: 12 mg IT once per week
−
'''Continued indefinitely'''
+
**First 4 weeks after cell count & cytology are negative: 12 mg IT once per week on weeks 1 & 3
−
</div></div>
+
**Remainder of induction: 12 mg IT once on day 2
−
===References===
+
*[[Cytarabine (Ara-C)]] by the following criteria:
−
# '''Review:''' Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. [https://doi.org/10.1016/s0039-6109(05)70141-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11459269 PubMed]
+
**Measurable CNS disease: 100 mg IT once per week
−
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956 PubMed]
+
**First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
−
==Octreotide LAR monotherapy {{#subobject:e356ea|Regimen=1}}==
+
**Remainder of induction: 100 mg IT once on day 7 or 8
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:f0bc1b|Variant=1}}===
+
===Regimen variant #2, Ommaya reservoir {{#subobject:c0aa53|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 25%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2009.22.8510 Rinke et al. 2009 (PROMID)]
+
|[https://doi.org/10.1200/jco.1999.17.8.2461 Thomas et al. 1999]
−
|2001-2008
+
|style="background-color:#91cf61"|Phase 2
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
 
−
| style="background-color:#1a9850" |Superior TTP<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59)
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====CNS therapy, treatment====
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
+
*[[Methotrexate (MTX)]] by the following criteria:
−
'''28-day cycles'''
+
**Measurable CNS disease: 6 mg IT once per week
 +
**First 4 weeks after cell count & cytology are negative: 6 mg IT once per week on weeks 1 & 3
 +
**Remainder of induction: 6 mg IT once on day 2
 +
*[[Cytarabine (Ara-C)]] by the following criteria:
 +
**Measurable CNS disease: 100 mg IT once per week
 +
**First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
 +
**Remainder of induction: 100 mg IT once on day 7 or 8
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956 PubMed]
+
# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [https://doi.org/10.1200/jco.1999.17.8.2461 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561310 PubMed]
−
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057 PubMed] NCT00171873
+
==IT Cytarabine, Methotrexate, Methylprednisolone {{#subobject:833d98|Regimen=1}}==
−
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709 PubMed] NCT01578239
 
−
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
 
−
#'''NETTER-2:''' NCT03972488
 
−
==Octreotide & Interferon alfa {{#subobject:1cf4c5|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:cbf5c4|Variant=1}}===
+
===Regimen {{#subobject:0ded48|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 33%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]
+
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
−
| style="background-color:#ffffbe" |Pilot, <20 pts
+
|2003-2005
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
 
|}
 
|}
−
''Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''
+
''Intrathecal treatments are given as follows: eight between days -7 and 21 of induction, four during the first two consolidation blocks, and one at day 29 of consolidation blocks 3 and 6 -- 14 total doses.''
−
====Endocrine therapy====
+
====CNS therapy, treatment====
−
*[[Octreotide (Sandostatin)]] 0.05 to 0.5 mg SC given two to three times per day
+
*[[Cytarabine (Ara-C)]] 40 mg IT mixed with methotrexate and methylprednisolone
−
====Immunotherapy====
+
*[[Methotrexate (MTX)]] 15 mg IT mixed with cytarabine and methylprednisolone
−
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)
+
*[[Methylprednisolone (Solumedrol)]] 40 mg IT mixed with cytarabine and methotrexate
 +
'''14 doses'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7686765 PubMed]
+
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
−
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12025889 PubMed]
+
==IT Cytarabine, Methotrexate, WBRT {{#subobject:2457a6|Regimen=1}}==
−
==Lutetium Lu 177 dotatate & Octreotide LAR {{#subobject:ee13c4|Regimen=1}} ==
+
Cytarabine, Methotrexate, WBRT: Cytarabine, Methotrexate, '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:33d0ef|Variant=1}}===
+
===Regimen variant #1, LP {{#subobject:b3fdae|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 17%"|Study
+
!style="width: 25%"|Study
−
!style="width: 15%"|Years of enrollment
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
|-
−
!style="width: 17%"|Comparator
+
|[http://www.bloodjournal.org/content/103/12/4396.long Thomas et al. 2003]
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
|style="background-color:#91cf61"|Phase 2
−
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
−
|2012-2016
+
|style="background-color:#91cf61"|Phase 2
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 
−
| [[#Octreotide_LAR_monotherapy|Octreotide LAR]]; high-dose
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: NYR vs 8.4 mo<br>(HR 0.21, 95% CI 0.13-0.33)
 
−
| style="background-color:#d73027" |More cytopenias (neutropenia, thrombocytopenia and lymphopenia)
 
 
|-
 
|-
 
|}
 
|}
−
''Note: patients had well-differentiated (Ki67 less than 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions''
+
''Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====CNS therapy, treatment====
−
* [[Octreotide LAR (Sandostatin LAR)]] 30 mg SC once on day 1, '''given 2 hours after each lutetium Lu 177 dotatate infusion'''
+
*[[Methotrexate (MTX)]] by the following criteria:
−
'''4-week cycles'''
+
**Measurable CNS disease: 12 mg IT once per week
−
====Radioconjugate therapy====
+
**First 4 weeks after cell count & cytology are negative: 12 mg IT once per week on weeks 1 & 3
−
* [[Lutetium Lu 177 dotatate (Lutathera)]] 7.4 GBq (200 mCi) IV once on day 1
+
**Remainder of induction: 12 mg IT once on day 2
−
====Supportive therapy====
+
*[[Cytarabine (Ara-C)]] by the following criteria:
−
* For renal protection, an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes prior to drug infusion.
+
**Measurable CNS disease: 100 mg IT once per week
−
'''8-week cycle for 4 cycles'''
+
**First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
−
=== References ===
+
**Remainder of induction: 100 mg IT once on day 7 or 8
−
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709 PubMed] NCT01578239
+
====Radiotherapy====
−
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
+
*Therapeutic [[External_beam_radiotherapy|whole-brain irradiation]] is given to patients with CNS disease at presentation
−
==Sunitinib monotherapy {{#subobject:ee13d2|Regimen=1}}==
+
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:80d0ef|Variant=1}}===
+
===Regimen variant #2, Ommaya reservoir {{#subobject:b3fadu|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 17%"|Study
+
!style="width: 25%"|Study
−
!style="width: 15%"|Years of enrollment
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
|-
−
!style="width: 17%"|Comparator
+
|[http://www.bloodjournal.org/content/103/12/4396.long Thomas et al. 2003]
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
|style="background-color:#91cf61"|Phase 2
−
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa1003825 Raymond et al. 2011 (A6181111)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
−
|2007-2009
+
|style="background-color:#91cf61"|Phase 2
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
−
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
 
−
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br>Median PFS: 12.6 vs 5.8 mo<br>(HR 0.32, 95% CI 0.18-0.55)
 
−
| style="background-color:#d73027" |More diarrhea; seems to have worse insomnia
 
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br>
+
''Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).''
−
''Note: while the initial publication seemed to have a significant survival advantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====CNS therapy, treatment====
−
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day
+
*[[Methotrexate (MTX)]] by the following criteria:
−
'''Continued indefinitely'''
+
**Measurable CNS disease: 6 mg IT once per week
 +
**First 4 weeks after cell count & cytology are negative: 6 mg IT once per week on weeks 1 & 3
 +
**Remainder of induction: 6 mg IT once on day 2
 +
*[[Cytarabine (Ara-C)]] by the following criteria:
 +
**Measurable CNS disease: 100 mg IT once per week
 +
**First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
 +
**Remainder of induction: 100 mg IT once on day 7 or 8
 +
====Radiotherapy====
 +
*Therapeutic [[External_beam_radiotherapy|whole-brain irradiation]] is given to patients with CNS disease at presentation
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''A6181111:''' Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. [https://doi.org/10.1056/NEJMoa1003825 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21306237 PubMed] NCT00428597
+
# Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. [http://www.bloodjournal.org/content/103/12/4396.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14551133 PubMed]
−
## '''HRQoL analysis:''' Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. [https://doi.org/10.1007/s11523-016-0462-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27924459 PubMed]
+
## '''Update:''' Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. [http://www.haematologica.org/content/100/5/653 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420214/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25682595 PubMed]
−
## '''Update:''' Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. [https://doi.org/10.1093/annonc/mdw561 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27836885 PubMed]
+
# '''MDACC 2006-0478:''' Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://www.bloodjournal.org/content/116/12/2070.long link to original article] '''contains dosing details in manuscript'''--parts of the protocol were not explicitly listed in this reference, which instead referred to [[#Hyper-CVAD_.26_Imatinib_.28Gleevec.29_.28induction_.26_maintenance.29|Thomas et al. 2004]] and [[#Hyper-CVAD_.28induction.29|Kantarjian et al. 2004]] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853 PubMed] NCT00390793
−
==Temozolomide monotherapy {{#subobject:69ae1c|Regimen=1}}==
+
## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://doi.org/10.1002/cncr.29646 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885 PubMed]
 +
==IT Methotrexate monotherapy {{#subobject:d4a3c5|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:6aac4c|Variant=1}}===
+
===Regimen {{#subobject:183c87|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 33%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM196107272650404 Shanbrom et al. 1961]
 +
|1957-1960
 +
| style="background-color:#ffffbe" |Pilot
 
|-
 
|-
−
|[http://clincancerres.aacrjournals.org/content/13/10/2986.long Ekeblad et al. 2007]
+
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
−
| style="background-color:#ffffbe" |Retrospective
+
|2003-2005
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====CNS therapy, treatment====
−
*[[Temozolomide (Temodar)]] as follows:
+
*[[Methotrexate (MTX)]] as follows:
−
**Cycle 1: 100 or 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
+
**Prephase: 15 mg IT once at some point between days -7 and -4
−
**Cycle 2 onwards: increased as tolerated up to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic
 
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Retrospective:''' Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000 PubMed]
+
# Shanbrom E, Miller S, Fairbanks VF. Intrathecal administration of amethopterin in leukemic encephalopathy of young adults. N Engl J Med. 1961 Jul 27;265:169-71. [https://doi.org/10.1056/NEJM196107272650404 link to original article] [https://pubmed.ncbi.nlm.nih.gov/13750662 PubMed]
−
==Temozolomide & Bevacizumab {{#subobject:ce7fe6|Regimen=1}}==
+
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
 +
==IT Methotrexate & WBRT {{#subobject:d129ea|Regimen=1}}==
 +
IT Methotrexate & WBRT: '''<u>I</u>'''ntra'''<u>T</u>'''hecal Methotrexate & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:be3718|Variant=1}}===
+
===Regimen {{#subobject:f7b824|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 421: Line 476:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ Chan et al. 2012 (DFCI 04-272)]
+
|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
−
|2004-2005
+
|1980-1986
−
| style="background-color:#91cf61" |Phase 2
+
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Treatment starts while patient is receiving induction therapy.''
−
====Chemotherapy====
+
====CNS therapy, treatment====
−
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21
+
*[[Methotrexate (MTX)]] as follows:
−
====Targeted therapy====
+
**Induction: 12 mg IT once per week x 10 doses
−
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
+
**Remainder of first year of therapy: 12 mg IT once per month
−
====Supportive therapy====
+
====Radiotherapy====
−
*PCP prophylaxis: [[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO once every Monday, Wednesday, and Friday
+
*[[External_beam_radiotherapy|Whole-brain irradiation]], 28 Gy total given (no details provided)
−
**Allergic patients received alternate prophylaxis
 
−
*VZV prophylaxis: [[Acyclovir (Zovirax)]] 400 mg PO three times per day
 
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''DFCI 04-272:''' Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. Epub 2012 Jul 9. [https://doi.org/10.1200/jco.2011.40.3147 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22778320 PubMed] NCT00137774
+
# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed]
−
==Temozolomide & Thalidomide {{#subobject:16afb7|Regimen=1}}==
+
## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
 +
=CNS treatment, systemic therapy=
 +
==Mercaptopurine & WBRT {{#subobject:d6ba9e|Regimen=1}}==
 +
Mercaptopurine & WBRT: Mercaptopurine & '''<u>W</u>'''hole '''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:cd21c7|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 +
|2003-2005
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
''Treatment administered before HSCT or maintanence initiation.''
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/day PO during irradiation
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] 15 Gy before HCT (details not provided)
 +
'''One course'''
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:ceca5a|Variant=1}}===
+
===Regimen variant #2 {{#subobject:cd75g7|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 33%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2005.03.6046 Kulke et al. 2006]
+
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
−
| style="background-color:#91cf61" |Phase 2
+
|2003-2005
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Treatment administered before HSCT or maintanence initiation.''
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21
+
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/day PO during irradiation
−
====Targeted therapy====
+
====Radiotherapy====
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
+
*[[External_beam_radiotherapy|Whole-brain irradiation]] 24 Gy before maintenance therapy initiation (details not provided)
−
'''28-day cycles'''
+
'''One course'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. [https://doi.org/10.1200/jco.2005.03.6046 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16421420 PubMed]
+
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
−
[[Category:Pancreatic NET regimens]]
+
[[Category:CNS leukemia regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
−
[[Category:Endocrine cancers]]
+
[[Category:CNS cancers]]
−
[[Category:Gastrointestinal cancers]]
 

Revision as of 11:32, 16 October 2022

Back to Top

Section editor transclusions

0 regimens on this page
0 variants on this page


Note: these regimens are primarily culled from literature that describes them as part of a comprehensive treatment regimen. If that is the case, the original regimens can be found on the following pages:

CNS prophylaxis, local therapy

IT Cytarabine & Methotrexate

Regimen variant #1, 16 doses

Study Evidence
Thomas et al. 2006 Pilot, <20 pts

CNS therapy, prophylaxis

Given each cycle for a total of 16 intrathecal treatments


Regimen variant #2, 6 to 8 doses

Study Evidence
Thomas et al. 1999 Phase 2
Thomas et al. 2003 Phase 2
Ravandi et al. 2010 (MDACC 2006-0478) Phase 2

Total number of doses depends on risk for CNS relapse based on serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%.

CNS therapy, prophylaxis

Given each cycle (approximately every 3 weeks) for a total of 6 or 8 intrathecal treatments

References

  1. Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. link to original article contains dosing details in manuscript PubMed
  2. Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. link to original article contains dosing details in manuscript PubMed
    1. Update: Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. link to original article link to PMC article PubMed
  3. Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. link to original article contains dosing details in manuscript PubMed
    1. Update: Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. link to original article PubMed
  4. MDACC 2006-0478: Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains dosing details in manuscript--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 link to PMC article PubMed NCT00390793
    1. Update: Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. link to original article link to PMC article PubMed

IT Cytarabine, Methotrexate, Methylprednisolone

Regimen

Study Years of enrollment Evidence
Huguet et al. 2009 (GRAALL-2003) 2003-2005 Phase 2

Intrathecal treatments are given on days 1 & 8 of induction, day 29 of each series of consolidation blocks, and day 1 of late intensification -- 6 doses total.

CNS therapy, prophylaxis

6 doses

References

  1. GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

IT Cytarabine, Methotrexate, Prednisone

Regimen

Study Evidence
Tsukasaki et al. 2007 (JCOG 9801) Non-randomized
Ishida et al. 2015 (Kyowa 0761-003) Non-randomized

Treatments were given after cycles 1, 3, and 5 after platelets greater than 70 × 109/L and within 2 days before the next cycle.

CNS therapy, prophylaxis

3 doses

References

  1. JCOG 9801: Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M; JCOG. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007 Dec 1;25(34):5458-64. Epub 2007 Oct 29. link to original article contains dosing details in manuscript PubMed NCT00145002
  2. Kyowa 0761-003: Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015 Jun;169(5):672-82. Epub 2015 Mar 2. link to original article link to PMC article PubMed NCT01173887

IT Cytarabine & WBRT

Cytarabine & WBRT: Cytarabine & Whole Brain Radiation Therapy

Regimen

Study Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) Non-randomized portion of RCT

Note: while this is not chemoradiation in the traditional sense, the delivery of chemotherapy and radiation overlap so may have synergistic effects.

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) as follows:
    • Consolidation & Maintenance: 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses (8 doses, total)

Radiotherapy

References

  1. MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
    1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
    2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
    3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed

IT Methotrexate monotherapy

Regimen

Study Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) Non-randomized portion of RCT

CNS therapy, prophylaxis

  • Methotrexate (MTX) as follows:
    • Phase 1: 12 mg IT once on day 15
    • Phase 2: 12 mg IT once per day on days 1, 8, 15, 22

References

  1. MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
    1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
    2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
    3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed

IT Methotrexate & Hydrocortisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sullivan et al. 1977 1971-1973 Phase 3 (C) IT MTX, Ara-C, HC Seems not superior
Kim et al. 2015 (AMC-UUCM-2008-0310) 2009-2012 Phase 2

Treatment can be started during or after induction.

CNS therapy, prophylaxis

Up to 10 doses

References

  1. Sullivan MP, Moon TE, Trueworthy R, Vietti TJ, Humphrey GB, Komp D. Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Blood. 1977 Sep;50(3):471-9. link to original article PubMed
  2. AMC-UUCM-2008-0310: Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. link to original article contains dosing details in manuscript PubMed NCT00844298

IT Methotrexate & Methylprednisolone

Regimen

Study Evidence
Lo-Coco et al. 2010 (GIMEMA AIDA-2000) Non-randomized

It is not explicitly stated but presumably these are admixed and given together.

CNS therapy, prophylaxis

Total of 3 doses

References

  1. GIMEMA AIDA-2000: Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, Mandelli F; GIMEMA. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 8;116(17):3171-9. Epub 2010 Jul 19. link to original article contains dosing details in manuscript PubMed NCT001064570

IT Methotrexate & WBRT

IT Methotrexate & WBRT: IntraThecal Methotrexate & Whole Brain Radiation Therapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Linker et al. 1987 1980-1986 Phase 2
Nachman et al. 1998 (CCG 1882) 1989-1995 Phase 3 (C) IT MTX; intensified Seems not superior

Treatment is started within 1 week of achieving complete remission. Details are from Linker et al. 1987

CNS therapy, prophylaxis

Radiotherapy

References

  1. Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains dosing details in manuscript PubMed
  2. CCG 1882: Nachman J, Sather HN, Cherlow JM, Sensel MG, Gaynon PS, Lukens JN, Wolff L, Trigg ME. Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. J Clin Oncol. 1998 Mar;16(3):920-30. link to original article PubMed

WBRT

WBRT: Whole Brain Radiation Therapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Nesbit et al. 1981 1972-1975 Phase 3 (C) WBRT; lower-dose Seems not superior
Freeman et al. 1983 (CALGB 7611) 1976-1979 Phase 3 (C) Intermediate-dose MTX Mixed results
Pui et al. 2009 (Total Therapy XV) 2000-2007 Phase 3 (C) Observation Seems not superior

Note: in Total Therapy XV, this is the control arm of a de-escalation study.

Radiotherapy

One course

References

  1. Nesbit ME Jr, Sather HN, Robison LL, Ortega J, Littman PS, D'Angio GJ, Hammond GD; Children's Cancer Group. Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukaemia: comparison of 1800 rad and 2400 rad: a report for Children's Cancer Study Group. Lancet. 1981 Feb 28;1(8218):461-6. link to original article PubMed
  2. CALGB 7611: Freeman AI, Weinberg V, Brecher ML, Jones B, Glicksman AS, Sinks LF, Weil M, Pleuss H, Hananian J, Burgert EO Jr, Gilchrist GS, Necheles T, Harris M, Kung F, Patterson RB, Maurer H, Leventhal B, Chevalier L, Forman E, Holland JF. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med. 1983 Mar 3;308(9):477-84. link to original article PubMed
    1. Update: Freeman AI, Boyett JM, Glicksman AS, Brecher ML, Leventhal BG, Sinks LF, Holland JF. Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: a ten-year follow-up. Med Pediatr Oncol. 1997 Feb;28(2):98-107. link to original article PubMed
  3. Total Therapy XV: Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009 Jun 25;360(26):2730-41. link to original article link to PMC article PubMed NCT00137111

CNS prophylaxis, systemic therapy

Mercaptopurine & WBRT

Mercaptopurine & WBRT: Mercaptopurine & Whole Brain Radiation Therapy

Regimen

Study Years of enrollment Evidence
Huguet et al. 2009 (GRAALL-2003) 2003-2005 Phase 2

Chemoradiation is given before maintenance therapy.

Chemotherapy

Radiotherapy

One course

References

  1. GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

CNS treatment, local therapy

IT Cytarabine & Methotrexate

Regimen variant #1, LP

Study Evidence
Thomas et al. 1999 Phase 2

Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).

CNS therapy, treatment

  • Methotrexate (MTX) by the following criteria:
    • Measurable CNS disease: 12 mg IT once per week
    • First 4 weeks after cell count & cytology are negative: 12 mg IT once per week on weeks 1 & 3
    • Remainder of induction: 12 mg IT once on day 2
  • Cytarabine (Ara-C) by the following criteria:
    • Measurable CNS disease: 100 mg IT once per week
    • First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
    • Remainder of induction: 100 mg IT once on day 7 or 8


Regimen variant #2, Ommaya reservoir

Study Evidence
Thomas et al. 1999 Phase 2

Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).

CNS therapy, treatment

  • Methotrexate (MTX) by the following criteria:
    • Measurable CNS disease: 6 mg IT once per week
    • First 4 weeks after cell count & cytology are negative: 6 mg IT once per week on weeks 1 & 3
    • Remainder of induction: 6 mg IT once on day 2
  • Cytarabine (Ara-C) by the following criteria:
    • Measurable CNS disease: 100 mg IT once per week
    • First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
    • Remainder of induction: 100 mg IT once on day 7 or 8

References

  1. Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. link to original article contains dosing details in manuscript PubMed

IT Cytarabine, Methotrexate, Methylprednisolone

Regimen

Study Years of enrollment Evidence
Huguet et al. 2009 (GRAALL-2003) 2003-2005 Phase 2

Intrathecal treatments are given as follows: eight between days -7 and 21 of induction, four during the first two consolidation blocks, and one at day 29 of consolidation blocks 3 and 6 -- 14 total doses.

CNS therapy, treatment

14 doses

References

  1. GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

IT Cytarabine, Methotrexate, WBRT

Cytarabine, Methotrexate, WBRT: Cytarabine, Methotrexate, Whole Brain Radiation Therapy

Regimen variant #1, LP

Study Evidence
Thomas et al. 2003 Phase 2
Ravandi et al. 2010 (MDACC 2006-0478) Phase 2

Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).

CNS therapy, treatment

  • Methotrexate (MTX) by the following criteria:
    • Measurable CNS disease: 12 mg IT once per week
    • First 4 weeks after cell count & cytology are negative: 12 mg IT once per week on weeks 1 & 3
    • Remainder of induction: 12 mg IT once on day 2
  • Cytarabine (Ara-C) by the following criteria:
    • Measurable CNS disease: 100 mg IT once per week
    • First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
    • Remainder of induction: 100 mg IT once on day 7 or 8

Radiotherapy


Regimen variant #2, Ommaya reservoir

Study Evidence
Thomas et al. 2003 Phase 2
Ravandi et al. 2010 (MDACC 2006-0478) Phase 2

Note: while there is measurable CNS disease, both drugs are given every week, alternating, usually separated by at least 48 hours (e.g., on Mondays & Thursdays).

CNS therapy, treatment

  • Methotrexate (MTX) by the following criteria:
    • Measurable CNS disease: 6 mg IT once per week
    • First 4 weeks after cell count & cytology are negative: 6 mg IT once per week on weeks 1 & 3
    • Remainder of induction: 6 mg IT once on day 2
  • Cytarabine (Ara-C) by the following criteria:
    • Measurable CNS disease: 100 mg IT once per week
    • First 4 weeks after cell count & cytology are negative: 100 mg IT once per week on weeks 2 & 4
    • Remainder of induction: 100 mg IT once on day 7 or 8

Radiotherapy

References

  1. Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. link to original article contains dosing details in manuscript PubMed
    1. Update: Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. link to original article link to PMC article PubMed
  2. MDACC 2006-0478: Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains dosing details in manuscript--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 link to PMC article PubMed NCT00390793
    1. Update: Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. link to original article link to PMC article PubMed

IT Methotrexate monotherapy

Regimen

Study Years of enrollment Evidence
Shanbrom et al. 1961 1957-1960 Pilot
Huguet et al. 2009 (GRAALL-2003) 2003-2005 Phase 2

CNS therapy, treatment

  • Methotrexate (MTX) as follows:
    • Prephase: 15 mg IT once at some point between days -7 and -4

References

  1. Shanbrom E, Miller S, Fairbanks VF. Intrathecal administration of amethopterin in leukemic encephalopathy of young adults. N Engl J Med. 1961 Jul 27;265:169-71. link to original article PubMed
  2. GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

IT Methotrexate & WBRT

IT Methotrexate & WBRT: IntraThecal Methotrexate & Whole Brain Radiation Therapy

Regimen

Study Years of enrollment Evidence
Linker et al. 1987 1980-1986 Phase 2

Treatment starts while patient is receiving induction therapy.

CNS therapy, treatment

  • Methotrexate (MTX) as follows:
    • Induction: 12 mg IT once per week x 10 doses
    • Remainder of first year of therapy: 12 mg IT once per month

Radiotherapy

References

  1. Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains dosing details in manuscript PubMed

CNS treatment, systemic therapy

Mercaptopurine & WBRT

Mercaptopurine & WBRT: Mercaptopurine & Whole Brain Radiation Therapy

Regimen variant #1

Study Years of enrollment Evidence
Huguet et al. 2009 (GRAALL-2003) 2003-2005 Phase 2

Treatment administered before HSCT or maintanence initiation.

Chemotherapy

Radiotherapy

One course


Regimen variant #2

Study Years of enrollment Evidence
Huguet et al. 2009 (GRAALL-2003) 2003-2005 Phase 2

Treatment administered before HSCT or maintanence initiation.

Chemotherapy

Radiotherapy

One course

References

  1. GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027
Retrieved from "https://hemonc.org/w/index.php?title=Staging_page&oldid=63206"