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==Overview==
==Overview==
Medical therapy in appendix cancer could be either supportive, [[Palliative care|palliative]], or curative. While [[Carcinoid Tumor|carcinoid]] tumors rarely need [[chemotherapy]], systemic [[chemotherapy]] as well as [[Intraperitoneal hyperthermic chemoperfusion|hyperthermic intraperitoneal]] [[chemotherapy]] plus/minus early postoperative intraperitoneal [[chemotherapy]] (EPIC) and/or [[Adjuvant therapy|concomitant intravenous chemotherapy]] are mainstream of medical treatment in [[adenocarcinoma]] of [[Vermiform appendix|appendix]]. Medical therapy is generally administered to control the [[Symptom|symptoms]] in patients with [[Carcinoid Tumor|carcinoid]] tumors and [[carcinoid syndrome]].




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. NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015</ref>
. NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015</ref>
:*[[Somatostatin]] analogs  
:*[[Somatostatin]] analogs  
::*Octreotide or lanreotide.
::*[[Octreotide]] or [[lanreotide]]
:*[[Loperamide]] or [[diphenoxylate]] for primary diarrhea
:*[[Loperamide]] or [[diphenoxylate]] for primary [[diarrhea]]
:* Somatostatin analogs for symptom control in patients with carcionid syndrome  
:* [[Somatostatin]] analogs for symptom control in patients with [[carcinoid syndrome]].
 


*'''Curative and palliative chemotherapy'''
*'''Curative and palliative chemotherapy'''
::*Systemic chemotherapy  
:*Systemic [[chemotherapy]]
::*Hyperthermic intraperitoneal chemotherapy<ref name="pmid21160924">González-Moreno S, González-Bayón LA, Ortega-Pérez G (2010) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21160924 Hyperthermic intraperitoneal chemotherapy: Rationale and technique.] ''World J Gastrointest Oncol'' 2 (2):68-75. [http://dx.doi.org/10.4251/wjgo.v2.i2.68 DOI:10.4251/wjgo.v2.i2.68] PMID: [https://pubmed.gov/21160924 21160924]</ref>
:*[[Intraperitoneal hyperthermic chemoperfusion|Hyperthermic intraperitoneal]] [[chemotherapy]]<ref name="pmid21160924">González-Moreno S, González-Bayón LA, Ortega-Pérez G (2010) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21160924 Hyperthermic intraperitoneal chemotherapy: Rationale and technique.] ''World J Gastrointest Oncol'' 2 (2):68-75. [http://dx.doi.org/10.4251/wjgo.v2.i2.68 DOI:10.4251/wjgo.v2.i2.68] PMID: [https://pubmed.gov/21160924 21160924]</ref>


*'''Systemic chemotherapy'''
*'''Systemic chemotherapy'''
*Systemic chemotherapy has not been generally recommended for carcionid tumors, but patients with noncacinoid tumors are usually receive chemotherapy.
*Systemic [[chemotherapy]] has not been generally recommended for carcionid tumors, but patients with non-cacinoid tumors are usually receive [[chemotherapy]].
:*Nevertheless systemic chemotherapy for metastatic appendiceal adenocarcinoma has not been studied appropriately
:*Nevertheless systemic [[chemotherapy]] for metastatic appendiceal [[adenocarcinoma]] has not been studied appropriately.
:*Many experts refer to current colorectal cancer chemotherapy approaches for adenocarcinoma of appendix
:*Many experts refer to current [[colorectal cancer]] [[chemotherapy]] approaches for [[adenocarcinoma]] of appendix.
:*'''Current colon cancer chemotherapy agents'''
:*'''Current colon cancer chemotherapy agents are as follows:'''  
 
::*5-fluorouracil (5-FU) : Traditional active agent
::*Irinotecan
::*Oxaliplatin
::*Vascular endothelial growth factor receptor inhibitors  (bevacizumab)
::*Epidermal growth factor receptor inhibitors (cetuximab and  panitumumab),
::*Aflibercept 
::*Regorafenib: inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1,2, and 3),
::*Capecitabine or 5-FU with or without a platinum drug
 
*'''FOLFOX6 has been widely recommended in patients with appendix adenocarcinoma.'''


:*Oxaliplatin, 5-FU and leucovorin or Capecitabine are active agents of the FOLFOX regime. Please see below for the details of FOlFOX6 <math>\blacktriangledown</math>
::*5-fluorouracil ([[Fluorouracil|5-FU]]) : Traditional active agent
::*[[Irinotecan]]
::*[[Oxaliplatin]]
::*[[Vascular endothelial growth factor]] receptor inhibitors ([[bevacizumab]])
::*[[Epidermal growth factor]] receptor [[Enzyme inhibitor|inhibitor]]<nowiki/>s ([[cetuximab]] and  [[panitumumab]]),
::*[[Aflibercept]] 
::*[[Regorafenib]]: inhibitor of [[Tyrosine kinase|angiogenic tyrosine kinase]]<nowiki/>s (including the [[Vascular endothelial growth factor|VEGF]] receptors 1,2, and 3),
::*[[Capecitabine]] or [[Fluorouracil|5-FU]] with or without a platinum drug


*'''[[FOLFOX regimen|FOLFOX]]-6 has been widely recommended in patients with [[Vermiform appendix|appendix]] [[adenocarcinoma]].''' 


==='''Modified FOLFOX6'''<ref name="pmid12177775">Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ et al. (2002) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12177775 A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer.] ''Br J Cancer'' 87 (4):393-9. [http://dx.doi.org/10.1038/sj.bjc.6600467 DOI:10.1038/sj.bjc.6600467] PMID: [https://pubmed.gov/12177775 12177775]</ref><ref name="pmid18640933">Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL et al. (2008) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18640933 Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study.] ''J Clin Oncol'' 26 (21):3523-9. [http://dx.doi.org/10.1200/JCO.2007.15.4138 DOI:10.1200/JCO.2007.15.4138] PMID: [https://pubmed.gov/18640933 18640933]</ref> ===
:*[[Oxaliplatin]], [[Fluorouracil|5-FU]] and [[leucovorin]] or [[capecitabine]] are active agents of the FOLFOX regime. <math>\blacktriangledown</math>




Cycle length 14 days
*


*'''Oxaliplatin''' 85 mg/m <sup>2</sup> IV  
{| class="wikitable"
|+
!'''Modified FOLFOX-6'''<ref name="pmid12177775">Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ et al. (2002) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12177775 A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer.] ''Br J Cancer'' 87 (4):393-9. [http://dx.doi.org/10.1038/sj.bjc.6600467 DOI:10.1038/sj.bjc.6600467] PMID: [https://pubmed.gov/12177775 12177775]</ref><ref name="pmid18640933">Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL et al. (2008) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18640933 Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study.] ''J Clin Oncol'' 26 (21):3523-9. [http://dx.doi.org/10.1200/JCO.2007.15.4138 DOI:10.1200/JCO.2007.15.4138] PMID: [https://pubmed.gov/18640933 18640933]</ref>
|-
|
*'''[[Oxaliplatin]]''' 85 mg/m <sup>2</sup> IV  
:*Dilute with 250 mL 5 percent dextrose in water (D5W)
:*Dilute with 250 mL 5 percent dextrose in water (D5W)
:*Administer over 2 hrs  
:*Administer over 2 hrs  
:*''Avoid extravasation: May cause significant tissue damage''
:*''Avoid extravasation: May cause significant tissue damage''
*'''Leucovorin''' 400  mg/m <sup>2</sup> IV  (d,l-racemic mixture)  / 200 mg/m <sup>2</sup> IV  (l-leucovorin)
|-
|
*'''[[Leucovorin]]''' 400  mg/m <sup>2</sup> IV  (d,l-racemic mixture)  / 200 mg/m <sup>2</sup> IV  (l-[[leucovorin]])
:*Dilute with 250 mL D5W
:*Dilute with 250 mL D5W
:*Administer over 2 hrs concurrent with oxaliplatin.
:*Administer over 2 hrs concurrent with [[oxaliplatin]].
*'''Fluorouracil (FU)''' 400 mg/m <sup>2</sup> IV bolus<ref name="pmid14657227">Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D et al. (2004) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14657227 FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.] ''J Clin Oncol'' 22 (2):229-37. [http://dx.doi.org/10.1200/JCO.2004.05.113 DOI:10.1200/JCO.2004.05.113] PMID: [https://pubmed.gov/14657227 14657227]</ref>
|-
:*Slow IV push over 5 mins (administer immediately after leucovorin)
|
:*'''Fluorouracil (FU)''' 2400 mg/m <sup>2</sup> IV
*'''[[Fluorouracil]] (FU)''' 400 mg/m <sup>2</sup> IV bolus<ref name="pmid14657227">Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D et al. (2004) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14657227 FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.] ''J Clin Oncol'' 22 (2):229-37. [http://dx.doi.org/10.1200/JCO.2004.05.113 DOI:10.1200/JCO.2004.05.113] PMID: [https://pubmed.gov/14657227 14657227]</ref>
:*Slow IV push over 5 mins (administer immediately after [[leucovorin]])
|-
|
*'''[[Fluorouracil]] (FU)''' 2400 mg/m <sup>2</sup> IV
:*Administer immediately after FU IV bolus
:*Administer immediately after FU IV bolus
:*Dilute with 500 to 1000 mL D5W  
:*Dilute with 500 to 1000 mL D5W  
:*Administer over 46 hours
:*Administer over 46 hours
*'''Doses should be recalculated if there is a 10 percent or more change in body weight.'''
|}
 
:*'''''Cycle length is 14 days'''''
 
:*'''Doses should be recalculated if there is a 10 percent or more change in body weight.'''
* '''Prior to each treatment<math>\blacktriangledown</math>'''
:* Assess changes in neurologic function
:* Assess electrolytes and liver and renal function
:* CBC with differential and platelet count


'''Common complications and approaches to complications'''
*'''Prior to each treatment<math>\blacktriangledown</math>'''
* '''Diarrhea:''' 
::* Assess changes in [[Neurology|neurologic]] function.
:* Grade 2 or worse diarrhea <math>\blacktriangledown</math>  
::* Assess [[Electrolyte disturbance|electrolyte]]<nowiki/>s and [[liver]] and [[renal function]].
:** Withhold treatment
::* [[Complete blood count|CBC]] with differential and [[platelet]] count.
:** Restart at a lower dose of FU after complete resolution
:* '''Severe diarrhea, mucositis, and myelosuppression after FU''' <math>\blacktriangledown</math>
:** Evaluate for dihydropyrimidine dehydrogenase deficiency


*'''Neurologic toxicity'''
*'''Common complications and approaches to complications'''
:*In order to decrease chance of developing Oxaliplatin induced neuropathy recommend patients to avoid exposure to cold up to 48 hours after each infusion.
:* '''Diarrhea:''' 
:*Transient grade 3 paresthesias/dysesthesias / grade 2 symptoms lasting longer than 1 week<math>\blacktriangledown</math>
::* Grade 2 or worse diarrhea: <math>\blacktriangledown</math>  
:**Decrease oxaliplatin dose by 25 percent.
::** Withhold treatment.
:*Grade 4 or persistent grade 3 paresthesia/dysesthesia<math>\blacktriangledown</math>
::** Restart at a lower dose of FU after complete resolution.
:**Discontinue oxaliplatin
::* '''[[Diarrhea|Severe diarrhea]], [[mucositis]], and [[Bone marrow suppression|myelosuppression]] after FU''':<math>\blacktriangledown</math>
::** Evaluate for [[dihydropyrimidine dehydrogenase]] deficiency.


*'''Myelotoxicity'''
:*'''Neurologic [[toxicity]]'''
:*Total white blood cell count <3000 cells/mm <sup>3</sup> , absolute neutrophil count <1500 cells/mm <sup>3</sup> , or platelets <100,000 /mm <sup>3</sup> on the day of treatment<math>\blacktriangledown</math>
::*In order to decrease chance of developing [[oxaliplatin]] induced [[neuropathy]] recommend patients to avoid exposure to cold up to 48 hours after each infusion.
:**Delay treatment cycle by one week
::*Transient grade 3 [[paresthesia]]/[[dysesthesia]] / grade 2 symptoms lasting longer than 1 week:<math>\blacktriangledown</math>
:*''If treatment is delayed for '''two weeks''' or delayed '''for one week on two separate occasions,''' eliminate FU bolus''
::**Decrease [[oxaliplatin]] dose by 25 percent.
:*If occurred again<math>\blacktriangledown</math>
::*Grade 4 or persistent grade 3 [[paresthesia]]/[[dysesthesia]]:<math>\blacktriangledown</math>
:**Reduce infusional FU by 20 percent and
::**Discontinue [[oxaliplatin]].
:**Reduce oxaliplatin dose from 65 mg/m <sup>2</sup>


:*'''Hyperthermic intraperitoneal chemotherapy'''<ref name="pmid21160924">González-Moreno S, González-Bayón LA, Ortega-Pérez G (2010) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21160924 Hyperthermic intraperitoneal chemotherapy: Rationale and technique.] ''World J Gastrointest Oncol'' 2 (2):68-75. [http://dx.doi.org/10.4251/wjgo.v2.i2.68 DOI:10.4251/wjgo.v2.i2.68] PMID: [https://pubmed.gov/21160924 21160924]</ref>
:*'''[[Bone marrow suppression|Myelotoxicity]]'''
:* '''Common HIPEC current regimens'''
::*Total white [[Complete blood count|blood cell count]] <3000 cells/mm <sup>3</sup> , absolute [[neutrophil]] count <1500 cells/mm <sup>3</sup> , or [[Platelet|platelets]] <100,000 /mm <sup>3</sup> on the day of treatment:<math>\blacktriangledown</math>
:*Oxaliplatin, 130 mg/m <sup>2</sup> for 60 minutes
::**Delay treatment cycle by one week.  
:*Concomitant intravenous chemotherapy 5-FU, 400 mg/m <sup>2</sup>
::*''If treatment is delayed for '''two weeks''' or delayed '''for one week on two separate occasions,''' eliminate FU bolus.''
:* Early postoperative intraperitoneal chemotherapy (EPIC) with 5-FU
::*''If occurred again:''<math>\blacktriangledown</math>
:*Mitomycin C, 35 mg/m <sup>2</sup> or  3.3mg/m2/L for 90 minutes
:::*Reduce infusional [[Fluorouracil|5-FU]] by 20 percent ''and''
:*Infuse the fluid at 43-45°Ci n order to maintain the intraperitoneal fluid temperature at 41-43°C
:::*Reduce [[oxaliplatin]] dose from 65 mg/m <sup>2</sup>  
:*To avoid renal toxicity maintain urine output higher than 100 cc (desirable 150 cc) every 15 min during HIPEC   


*[[Intraperitoneal hyperthermic chemoperfusion|'''Hyperthermic intraperitoneal''']] '''[[chemotherapy]] (HIPEC)'''<ref name="pmid21160924">González-Moreno S, González-Bayón LA, Ortega-Pérez G (2010) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21160924 Hyperthermic intraperitoneal chemotherapy: Rationale and technique.] ''World J Gastrointest Oncol'' 2 (2):68-75. [http://dx.doi.org/10.4251/wjgo.v2.i2.68 DOI:10.4251/wjgo.v2.i2.68] PMID: [https://pubmed.gov/21160924 21160924]</ref>
:*Delivered in the operating room after cytoreductive surgery.
:*In selected cases is accompanied by early postoperative intraperitoneal chemotherapy (EPIC) as well as concomitant intravenous chemotherapy (CIVC).
{| class="wikitable"
|+
!'''Common HIPEC current regimens'''
|-
|
*[[Oxaliplatin]], 130 mg/m <sup>2</sup> for 60 minutes
*Concomitant intravenous [[chemotherapy]] (CIVC) 5-FU, 400 mg/m <sup>2</sup>
* Early postoperative intraperitoneal [[chemotherapy]] (EPIC) with 5-FU
|-
|
* [[Mitomycin]] C, 35 mg/m <sup>2</sup> for 90 minutes
*Concomitant intravenous [[chemotherapy]] 5-FU, 400 mg/m <sup>2</sup>
* Early postoperative intraperitoneal chemotherapy (EPIC) with 5-FU
|-
|
*[[Mitomycin]] C, 35 mg/m <sup>2</sup>  for 90 minutes without EPIC or CIVC
|-
|
*[[Mitomycin]] C, 3.3 mg//m <sup>2</sup>/L for 90 minutes without EPIC or CIVC
|}
*'''''Infuse the fluid at 43-45°Ci n order to maintain the intraperitoneal fluid temperature at 41-43°C.'''''
*'''''To avoid renal toxicity maintain urine output higher than 100 cc (desirable 150 cc) every 15 min during HIPEC.'''''




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{{WH}}
{{WH}}
{{WS}}
{{WS}}
[[Category: (name of the system)]]
[[Category:Surgery]]
[[Category:Medicine]]
[[Category:Emergency medicine]]
[[Category:Oncology]]
[[Category:Up-To-Date]]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Overview

Medical therapy in appendix cancer could be either supportive, palliative, or curative. While carcinoid tumors rarely need chemotherapy, systemic chemotherapy as well as hyperthermic intraperitoneal chemotherapy plus/minus early postoperative intraperitoneal chemotherapy (EPIC) and/or concomitant intravenous chemotherapy are mainstream of medical treatment in adenocarcinoma of appendix. Medical therapy is generally administered to control the symptoms in patients with carcinoid tumors and carcinoid syndrome.


Medical Therapy

  • Supportive medical therapy for appendix cancer, may include:[1][2]
  • Curative and palliative chemotherapy
  • Systemic chemotherapy
  • Systemic chemotherapy has not been generally recommended for carcionid tumors, but patients with non-cacinoid tumors are usually receive chemotherapy.


Modified FOLFOX-6[4][5]
  • Dilute with 250 mL 5 percent dextrose in water (D5W)
  • Administer over 2 hrs
  • Avoid extravasation: May cause significant tissue damage
  • Dilute with 250 mL D5W
  • Administer over 2 hrs concurrent with oxaliplatin.
  • Slow IV push over 5 mins (administer immediately after leucovorin)
  • Administer immediately after FU IV bolus
  • Dilute with 500 to 1000 mL D5W
  • Administer over 46 hours
  • Cycle length is 14 days
  • Doses should be recalculated if there is a 10 percent or more change in body weight.
  • Prior to each treatment<math>\blacktriangledown</math>
  • Common complications and approaches to complications
  • Diarrhea:
  • Total white blood cell count <3000 cells/mm 3 , absolute neutrophil count <1500 cells/mm 3 , or platelets <100,000 /mm 3 on the day of treatment:<math>\blacktriangledown</math>
    • Delay treatment cycle by one week.
  • If treatment is delayed for two weeks or delayed for one week on two separate occasions, eliminate FU bolus.
  • If occurred again:<math>\blacktriangledown</math>
  • Reduce infusional 5-FU by 20 percent and
  • Reduce oxaliplatin dose from 65 mg/m 2
  • Delivered in the operating room after cytoreductive surgery.
  • In selected cases is accompanied by early postoperative intraperitoneal chemotherapy (EPIC) as well as concomitant intravenous chemotherapy (CIVC).
Common HIPEC current regimens
  • Mitomycin C, 35 mg/m 2 for 90 minutes
  • Concomitant intravenous chemotherapy 5-FU, 400 mg/m 2
  • Early postoperative intraperitoneal chemotherapy (EPIC) with 5-FU
  • Mitomycin C, 35 mg/m 2 for 90 minutes without EPIC or CIVC
  • Mitomycin C, 3.3 mg//m 2/L for 90 minutes without EPIC or CIVC
  • Infuse the fluid at 43-45°Ci n order to maintain the intraperitoneal fluid temperature at 41-43°C.
  • To avoid renal toxicity maintain urine output higher than 100 cc (desirable 150 cc) every 15 min during HIPEC.


References

  1. ↑ Moertel CG, Weiland LH, Nagorney DM, Dockerty MB (1987). "Carcinoid tumor of the appendix: treatment and prognosis". N. Engl. J. Med. 317 (27): 1699–701. doi:10.1056/NEJM198712313172704. PMID 3696178.
  2. ↑ Treatment Option Overview for GI Carcinoid Tumors . NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015
  3. ↑ 3.0 3.1 González-Moreno S, González-Bayón LA, Ortega-Pérez G (2010) Hyperthermic intraperitoneal chemotherapy: Rationale and technique. World J Gastrointest Oncol 2 (2):68-75. DOI:10.4251/wjgo.v2.i2.68 PMID: 21160924
  4. ↑ Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ et al. (2002) A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer 87 (4):393-9. DOI:10.1038/sj.bjc.6600467 PMID: 12177775
  5. ↑ Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL et al. (2008) Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 26 (21):3523-9. DOI:10.1200/JCO.2007.15.4138 PMID: 18640933
  6. ↑ Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D et al. (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22 (2):229-37. DOI:10.1200/JCO.2004.05.113 PMID: 14657227

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