| Cycle length: 21 days × 4 cycles |
| Drug | Dose and route | Administration | Given on days |
| Gemcitabine* | 1000 mg/m2 IV | Dilute in 250 mL normal saline (concentration no greater than 40 mg/mL) and administer over 30 minutes. | Days 1 and 8 |
| Capecitabine¶ | 750 mg/m2 per dose by mouth | Twice daily (total dose 1500 mg/m2 per day). Swallow whole with water within 30 minutes after a meal, with each dose as close to 12 hours apart as possible. Do not cut or crush tablets.Δ | Days 1 through 14 |
| Cycle length: Five to six weeks (chemoradiotherapy◊) |
| Capecitabine¶ | 665 mg/m2 per dose by mouth | Twice daily (total dose 1330 mg/m2 per day). Swallow whole with water within 30 minutes after a meal, with each dose as close to 12 hours apart as possible. Do not cut or crush tablets.Δ | Concurrently (seven days per week) with radiation beginning day 1 |
| Radiotherapy | 45 Gy to regional lymph nodes§ and 54 to 59.4 Gy to preoperative tumor bed | Three dimensional: 30 fractions (54 Gy) or 33 fractions for R1 resection (59.4 Gy). IMRT: 25 fractions (52.5 Gy [or 55 Gy for R1 resection]). | Five days per week beginning week 1 and continuing through week 6 |
| Pretreatment considerations: |
| Emesis risk | - LOW for both chemotherapy and chemoradiotherapy.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not indicated.[1]
- Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
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| Dose adjustment for baseline liver or renal dysfunction | - A lower starting dose of gemcitabine may be needed for patients with liver impairment.[2] A lower starting dose of capecitabine may be needed for patients with moderate renal impairment.[3]
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
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| Monitoring parameters: |
- CBC with differential and platelet count weekly during treatment.
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- Assess basic metabolic panel (including serum creatinine) and liver function tests every three weeks prior to each new chemotherapy cycle and weekly during chemoradiotherapy or otherwise as indicated during treatment.
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- Monitor for diarrhea, stomatitis, and cutaneous toxicity (palmar-plantar erythrodysesthesias) during treatment.
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- More frequent anticoagulant response (INR or prothrombin time) monitoring is necessary for patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy.
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- Cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
- Refer to UpToDate topics on cardiotoxicity of nonanthracycline cancer chemotherapy agents.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - This regimen should not be initiated unless neutrophils are ≥1500/microL and platelets are ≥100,000/microL.[1]
- Reduce the day 8 gemcitabine dose by 25% for an absolute neutrophil count of 500 to 1000/microL or a platelet count of 50,000 to 100,000/microL.[4,5]
- Decrease gemcitabine by 25% for subsequent cycles for febrile neutropenia, grade 4 hematologic toxicity lasting for more than seven days, or bleeding-associated thrombocytopenia.[5]
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| Pulmonary toxicity | - A variety of manifestations of pulmonary toxicity have been reported in patients treated with gemcitabine. Discontinue gemcitabine immediately and permanently.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents.
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| Thrombotic microangiopathy | - Thrombotic microangiopathy (TMA, also sometimes called thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) has been associated with gemcitabine in individuals who have received a large or small cumulative dose. Consider the possibility of TMA if the patient develops Coombs-negative hemolysis, thrombocytopenia, renal failure, and/or neurologic findings. Management consists of drug discontinuation and supportive care, without plasma exchange, as long as there is high confidence in a drug-induced etiology rather than TTP.
- Refer to UpToDate topics on drug-induced thrombotic microangiopathy.
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| Other toxicity (including hepatotoxicity) | - Hold gemcitabine for ≥grade 3 nonhematologic toxicity that is likely related to gemcitabine until it decreases ≤grade 1.[5] Restart gemcitabine with a 25% dose reduction.
- Gemcitabine is commonly associated with a transient rise in serum transaminases, but these are seldom of clinical significance. There is insufficient information from clinical studies to allow clear dose recommendations in these patients.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents.
- For capecitabine:
- Grade 2: For the first, second, and third occurrence, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment (first occurrence, no dosage adjustment; second occurrence, 75% of the starting dose; third occurrence, 50% of the starting dose).[3] For the fourth occurrence of a grade 2 toxicity, discontinue capecitabine therapy.
- Grade 3: For the first and second occurrence, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment at a reduced dose (first occurrence, 75% of the starting dose; second occurrence, 50% of the starting dose). For the third occurrence of a grade 3 toxicity, discontinue capecitabine therapy.
- Grade 4: Discontinue capecitabine therapy. Alternatively, hold capecitabine therapy, and begin next treatment at 50% of the starting dose when toxicity resolves to grade 1 or less; discontinue treatment for first recurrence of grade 4 toxicity.
- Patients with grade 3 or 4 hyperbilirubinemia may resume capecitabine once toxicity has reduced to grade ≤2, but at a reduced dose.[3]
- NOTE: Severe diarrhea, mucositis, and myelosuppression after capecitabine should prompt evaluation for dihydropyrimidine dehydrogenase deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Omitted capecitabine doses for toxicity are not replaced or restored. Resume treatment with the planned next cycle. |
| If there is a change in body weight of at least 10%, doses should be recalculated. |
