Systemic therapy regimens for rectal cancer in both the adjuvant* and neoadjuvant^¶ setting: Concomitant chemoradiotherapy with infusional fluorouracil^[1]

Cycle length: 5 to 6 weeks (chemoradiotherapy).
Drug	Dose and route	Administration	Given on days
Fluorouracil (FU)	225 mg/m² per day IV	Infuse through a central line as a continuous infusion via a portable infusion device. To accommodate an ambulatory pump for outpatient treatment, can be administered undiluted (50 mg/mL) or the total dose can be diluted in 100 to 150 mL NS.^Δ	Daily by continuous infusion five days per week (Monday through Friday) during the entire five- to six-week course of radiation beginning on week 1
Radiotherapy (50.4 Gy)	1.8 Gy for five days a week	Begin within 24 hours of beginning chemotherapy.	Beginning week 1 and continuing to week 6
Pretreatment considerations:
Emesis risk	LOW. Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Infection prophylaxis	Primary prophylaxis with G-CSF is not indicated. Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
Dose adjustment for baseline liver or kidney dysfunction	A lower starting dose of FU may be needed for patients with liver impairment. Refer to UpToDate topics on chemotherapy hepatoxicity and dose modification in patients with liver disease.
Monitoring parameters:
CBC with differential and platelet count weekly during chemoradiotherapy.
Assess electrolytes and liver function weekly during chemoradiotherapy.
Monitor for diarrhea, stomatitis, and cutaneous toxicity (palmar-plantar erythrodysesthesias) during therapy.
More frequent anticoagulant response (INR or prothrombin time) monitoring is necessary for patients receiving concomitant FU and oral coumarin-derivative anticoagulant therapy.
Suggested dose modifications for toxicity:
Myelotoxicity	For neutrophils <1200/microL during therapy, hold FU until ≥1200/microL, then reduce FU to 175 mg/m² per day; if recurs, hold FU until neutrophils ≥1200/microL, then reduce FU to 125 mg/m² per day.^[2] For platelet count <75,000/microL during therapy, hold FU until ≥75,000/microL, and reduce FU to 175 mg/m² per day; if recurs, hold FU until platelet count ≥75,000/microL, and reduce FU to 125 mg/m² per day. If recovery takes >2 weeks, discontinue chemotherapy. For febrile neutropenia or infection with grade 3 or 4 neutropenia, hold chemotherapy until clinical resolution then resume at reduced dose of FU (175 mg/m² daily).
Gastrointestinal toxicity	Hold FU for grade 2 vomiting or grade 2 or 3 diarrhea or mucositis, and delay reinitiation of treatment until ≤grade 1; for first occurrence, reduce FU to 175 mg/m² per day; for second occurrence, reduce FU to 125 mg/m² per day; for third occurrence or any grade 4 diarrhea, or grade 3 or 4 vomiting, or if recovery takes >2 weeks, discontinue FU.^[2] NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for dihydropyrimidine dehydrogenase deficiency. Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
Hepatotoxicity	For grade 2 hepatotoxicity during therapy, hold FU until bilirubin, alkaline phosphatase, and AST are ≤grade 1; resume FU at 175 mg/m².^[2] Discontinue chemotherapy for grade 3 or 4 hepatotoxicity or if recovery takes >2 weeks.
Neurologic toxicity	There is no recommended dose for resumption of FU administration following development of hyperammonemic encephalopathy, acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances; the drug should be permanently discontinued.^[3]
Cardiotoxicity	Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. There is no recommended dose for resumption of FU administration following development of cardiac toxicity, and the drug should be discontinued.^[3]
Other clinically significant adverse events	For other grade 3 adverse events, hold FU until ≤grade 1, then resume at a lower dose (175 mg/m² per day); discontinue chemotherapy for grade 4.^[2]
If there is a change in body weight of at least 10%, doses should be recalculated.

This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

AST: aspartate aminotransferase; CBC: complete blood count; G-CSF: granulocyte-colony stimulating factors; INR: international normalized ratio; IV: intravenous.

* In the adjuvant setting, concomitant FU-based chemoradiotherapy is generally combined with four to six months of FU-based adjuvant chemotherapy. Chemotherapy options include short-term infusional FU plus leucovorin with or without oxaliplatin, capecitabine alone, or weekly FU plus leucovorin, as used for adjuvant treatment of colon cancer. The optimal sequencing has not been established, but the authors generally gave all the radiotherapy first or last, but not in between courses of chemotherapy. Refer to UpToDate content on adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy.

¶ In the neoadjuvant setting, concomitant chemoradiotherapy is generally given upfront prior to surgical resection. Following surgery, adjuvant chemotherapy for four to six months may be recommended. Chemotherapy options include short-term infusional FU plus leucovorin with or without oxaliplatin, capecitabine alone, or weekly FU plus leucovorin, as used for adjuvant treatment of colon cancer. Refer to UpToDate content on neoadjuvant chemoradiotherapy, radiotherapy, and chemotherapy for rectal adenocarcinoma.

Δ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).

References:

O'Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: Surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol 2014; 20:1927.
NSABP R-04 protocol. (Available online at http://www.nsabp.pitt.edu/R-04.asp, accessed August 8, 2019).
Fluorouracil injection. United States Prescribing Information. US National Library of Medicine. (Available online at https://dailymed.nlm.nih.gov, accessed June 12, 2012).

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Systemic therapy regimens for rectal cancer in both the adjuvant* and neoadjuvant¶ setting: Concomitant chemoradiotherapy with infusional fluorouracil[1]

Systemic therapy regimens for rectal cancer in both the adjuvant* and neoadjuvant^¶ setting: Concomitant chemoradiotherapy with infusional fluorouracil^[1]