CASE REPORT

A Case Report—Treatment of Metastatic Colorectal Cancerin a Patient on Hemodialysis

Ryan M. Bolonesi & Jane E. Rogers & Imad Shureiqi

# Springer Science+Business Media New York 2014

Introduction

End-stage renal disease (ESRD) represents a prevalent issuethroughout the USA. In 2011, there were 615,899 ESRDpatients with 430,273 patients on dialysis [1]. ESRD patientsare often accompanied by multiple comorbidities such asdiabetes, cardiovascular disease, hypertension, risk for hospi-talization, and risk of infection. In addition, ESRD may beassociated with an increased cancer risk dependent on the typeof cancer and age [2, 3]. Data regarding cancer management inESRD patients is limited. This lack of experience and associ-ated comorbidities presents a complex challenge in adminis-tering antineoplastic therapy.

Multiple considerations need to be evaluated prior to che-motherapy and targeted therapy administration in ESRD dial-ysis patients. These include the type of dialysis, pharmacody-namics and pharmacokinetic aspects of the agent selected, drugclearance by dialysis, dosing adjustments needed, literatureavailable, when to administer these agents in regard to dialysistreatment, and goal of providing cancer treatment [3, 4]. Wereport experience in a 55-year-old male with ESRD on hemo-dialysis that tolerated multiple lines of dose-reduced metastaticcolorectal (mCRC) treatment. These regimens includedFOLFIRI (fluorouracil, leucovorin, irinotecan) with intermit-tent bevacizumab, panitumumab plus irinotecan, FOLFOX(fluorouracil, leucovorin, oxaliplatin), and regorafenib.

Case Report

A 55-year-old mCRC male with a history of non-insulin-dependent diabetes mellitus since age 35, hypertension, anemiaof chronic disease, and ESRD on hemodialysis three timesweekly presented to our institution for a second opinion.

Prior to presenting to our institution, a diagnostic colonos-copy at an outside facility revealed colonic tumor at the hepaticflexure occupying 75–99%of the lumen. Right hemicolectomywas then performed. Surgical pathology revealed a moderatelydifferentiated adenocarcinoma with perforation to the visceralperitoneum, metastasis in 6/41 resected lymph nodes, andextramural tumor deposits. Intra-operatively, there was evi-dence of metastatic nodules in the liver which was then visual-ized on a post-operative PET/CT scan. The patient was thentreated with weekly regimen of 5-fluorouracil, leucovorin,and irinotecan for approximately 5 months before a breakin chemotherapy, at which point, he came to our institutionfor a second opinion.

Upon presentation at our institution, the patient had base-line CT scans performed. Chest CT scan was negative formetastatic disease, and CTof the abdomen revealed numerousunresectable hepatic metastasis including a lesion in the rightlobe measuring 2.6×2.3 cm as well as a lesion in the left lobemeasuring 3.7×3.7 cm. Baseline laboratory findings were asfollows: carcinoembryonic antigen (CEA) 54.5 ng/ml, he-moglobin 12.1 g/dL, platelet count 146,000, absolute neu-trophil count (ANC) 3.41×103, aspartate aminotransferase(AST) 22 IU/L, alanine aminotransferase (ALT)<12 IU/L,T-Bili 0.5 mg/dl, blood urea nitrogen 60 mg/dl, serumcreatinine 7.81 mg/dL, and albumin 4.7 g/dl. The patientwas initiated on irinotecan 100 mg/m2 IV over 90 min andcontinuous infusion of 5-fluorouracil 2,400 mg/m2 IV over46 h (FOLFIRI) every 2 weeks with standard pre-medicationsfor nausea on day 1. The patient received hemodialysis at anoutside facility Monday, Wednesday, and Friday, with chemo-therapy given onWednesday after dialysis.When bevacizumabwas added to FOLFIRI, hypertension became difficult to

R. M. Bolonesi (*) : J. E. RogersClinical Pharmacy Programs, Gastrointestinal Medical Oncology,University of Texas-M.D. Anderson Cancer Center, Anderson East(B5.4439), 1515 Holcombe Blvd, Unit 0455, Houston, TX 77030,USAe-mail: rmbolonesi@mdanderson.org

I. ShureiqiThe University of Texas MD Anderson Cancer Center, GI MedicalOncology, 1515 Holcombe blvd, unit 0426, Houston, TX 77030,USA

J Gastrointest CancDOI 10.1007/s12029-014-9611-1

control, and the patient developed transient volume overloadsymptoms that improved later on with controllinghypertension.

After the first cycle, the patient did experience some nauseaand a decrease in hemoglobin from 12.1 g/dL prior to the firstcycle to 10.9 g/dL prior to the second cycle; however, he wasasymptomatic without clinical evidence of any bleed. Hecontinued on the same doses ofmodified FOLFIRI for 5 cycleswith good tolerance, when the first set of restaging scans wereperformed revealing stable disease. He received an additional4 cycles, for a total of 10 cycles, when CT scans of the liverrevealed progression of the hepatic metastasis. Additionallythe patient received pegfilgrastim 6 mg subcutaneous on day 3of cycle 10 due to an ANC 1.27×103.

Subsequently, the patient went on to receive second-linepanitumumab and irinotecan given every 2 weeks. His dose ofirinotecan continued at 100 mg/m2 IV and panitumumab6 mg/kg IVon Wednesday after dialysis, along with standardanti-emetics and doxycycline for panitumumab rash prophy-laxis. He did not receive primary prophylaxis growth factorsupport. After cycle one, the patient presented to the emer-gency room with fevers up to 104 °F without neutropenia andwas treated for pneumonia before being discharged from thehospital. The patient continued on dose-modified irinotecan of100 mg/m2 IVand panitumumab of 6 mg/kg IVafter a 1-weekdelay, with the addition of pegfilgrastim 6 mg subcutaneouson day 2 with all subsequent cycles. Due to grade 3 EGFR-induced skin rash, his panitumumab dose was reduced to4 mg/kg with cycle four and all subsequent cycles. The rashwas managed with the dose reduction and with renally adjust-ed sulfamethoxazole/trimethoprim. He received a total of 20treatments when CT scans revealed progression of his livermetastasis, and he had an increasing CEA, at which point,treatment was stopped.

Third-line treatment was initiated with modified FOLFOX-6. The patient was given full-dose continuous infusion of 5-fluorouracil of 2,400 mg/m2 IV over 46 h and oxaliplatin65 mg/m2 IVon Wednesday before dialysis, to help facilitateclearance of oxaliplatin, with pegfilgrastim 6 mg subcutaneouson day 4 due to concern of neutropenia. Upon follow-up, thepatient reported missing pegfilgrastim dose which had beenscheduled, he reported no fevers within the previous 2 weeksafter treatment, and he was able to maintain his blood countswith an ANC of 4.06×103, platelets 138,000, and hemoglobin9.6 g/dl. The patient denied having diarrhea, nausea/vomiting,cold sensitivity, and neuropathy with cycle one. Therefore, withcycle number two, he continued on modified FOLFOX-6 withthe same doses without pegfilgrastim; however, the adminis-tration of chemotherapy was changed to after dialysis onWednesday. This change was made due to the fact that thepatient had no decline in platelets, hemoglobin, or ANC, andno reported adverse effects which are what would be expectedwith a significant exposure to oxaliplatin and 5-fluorouracil.

The change was designed to increase exposure of oxaliplatinand increase therapeutic benefit. After the second cycle, thepatient reported back prior to cycle three with increasing symp-toms from disease progression in the abdomen and peritonealdisease, as well as a CEA increase from 30.5 prior to modifiedFOLFOX-6 to 159.6 prior to cycle three. At this point, modi-fied FOLFOX-6 was discontinued.

The patient desired to continue to receive treatment in thefourth-line setting and unfortunately was not a clinical trialcandidate due to receiving hemodialysis. Regorafenib was theonly FDA-approved medication in this setting. At the time oftreatment, and currently, there are no recommendations avail-able for regorafenib use in patients with creatinine clearanceless than 60 ml/min or on hemodialysis [5]. Regorafenib isprimarily eliminated via the feces with less than 20 % elimi-nated in the urine. Given regorafenib’s pharmacology coupledwith the lack of data available in this setting, the decision wasmade to initiate regorafenib at a dose of 40 mg PO daily, thesmallest available dose, for 21 days on followed by 7 days off,with the goal of increasing his dose if treatment was tolerated.On day 2 of cycle one, the patient was seen in clinic withsignificant leukocytosis, without clinical evidence of infec-tion, and without regorafenib toxicities; therefore, he wascontinued on regorafenib as previously prescribed. On thestart of cycle two day 1, the patient presented to the emergencyroom with malaise, headaches, weakness, and dizziness.Workup revealed significant hypotension, electrocardiogramchanges, altered mental status, severe abdominal pain, andleukocytosis, at which point, the patient was admitted to theintensive care unit (ICU) for septic shock, severe abdominalpain, and leukocytosis, at which point, the patient was admit-ted to the ICU for hypotension and worsening cardiomyopa-thy. Echocardiogram showed mildly dilated left ventricle withejection fraction of 30–35 %. Coronary angiography revealed30–30 % blockage in the left anterior descending artery, non-obstructive plaque in heavy calcified circumflex artery, and50–70 % stenosis in the proximal and mid segments of theright coronary artery. Myocardial biopsy of the right ventricleshowed mild hypertrophy and focal interstitial fibrosis, but noevidence of myocarditis. Patient elected to limit his care tocomfort care and was transferred to a hospice service.

Discussion

Many antineoplastics were given to our patient during hismCRC treatment, among these were 5-fluorouracil (5-FU),irinotecan, panitumumab, oxaliplatin, and regorafenib. Priorto the administration of each regimen, an extensive literaturereview was performed along with the review of pharmacolog-ic considerations such as renal clearance and dialysis drugclearance of the parent compound and metabolites to establish

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Table 1 Case reports of FOLFIRI, FOLFOX, bevacizumab, and cetuximab given in the hemodialysis setting

Case Dose and dialysis Outcome/pharmacokinetic (PK) findings

71-year-old mCRC maleRegimen: FOLFIRI [9]

HemodialysisDosing:• Irinotecan 180 mg/m2

• 5-FU 400 mg/m2

• Leucovorin 400 mg/m2

• 5-FU 2,400 mg/m2 CI over 44 h• Cycle=2 weeks

-Cycles received: 1-Toxicity:• Grade III toxicity on cycle 1 day 9• Febrile neutropenia cycle 1 day 14• Died of septic shock cycle 1 day 18

57-year-old mCRC maleRegimen: FOLFIRI [9]

HemodialysisDosing:• Irinotecan 125 mg/m2

• 5-FU and leucovorin dosing: NR• Cycle=2 weeks

-Cycles received: 4• Chemotherapy given after hemodialysis sessions

-Toxicity:• No gastric or hematologic toxicity

-PK analysis:• Irinotecan partially dialyzable• SN-38 did not appear to be dialyzable

-Author conclusions:• Further studies are warranted

58-year-old mCRC maleRegimen: FOLFOX [11]

HemodialysisDosing:• Oxaliplatin 40 mg/m2

• 5-FU 200 mg/m2

• Leucovorin 200 mg/m2

• 5-FU 1,200 mg/m2 CI• Cycle=3 weeks• Oxaliplatin dose increased to50 mg/m2 and 5-FU to 80 %standard dose with the third cycle

-Cycles received: 11• 4-h hemodialysis session performed after end of oxaliplatin infusion,48 and 120 h after oxaliplatin infusion

-Toxicity:• Grade II leukopenia, neutropenia, and thrombocytopenia with fifth cycle• No dose adjustment required due to toxicity

-PK oxaliplatin analysis:• Free platinum level showed bimodal pattern (peaks 0 and 24 h afteroxaliplatin administration)• Greater AUC with lower Cmax compared to patients with normal renalfunction

-Author conclusions• FOLFOX given safely on a long-term basis with dose-reduced oxaliplatinevery 3 weeks

50-year-old mCRC maleRegimen: Bevacizumab plus

FOLFOX [12]

HemodialysisDosing:• Bevacizumab 5 mg/kg• Oxaliplatin 60 mg/m2 (increasedgradually to 70 and 85 mg/m2)• Leucovorin 200 mg/m2

• 5-FU 2,400 mg/m2 CI over 44 h• Cycle=3 weeks

-Cycles received: 8• 4-h hemodialysis session performed after end of oxaliplatin infusion

-Toxicity:• Grade I peripheral neuropathy

-PK oxaliplatin analysis:• Free platinum level showed bimodal pattern (peaks 2 and 26 h afteroxaliplatin administration)• Greater AUC with lower Cmax for free platinum compared to patientswith normal renal function

-Author conclusions:• Bevacizumab plus FOLFOX given safely to hemodialysis patients• No dosing adjustment for oxaliplatin required if hemodialysis performedsoon after administration• Extend FOLFOX interval to every 3 weeks

23-year-old mRCC maleRegimen: Bevacizumab [13]

HemodialysisDosing: 5 mg/kgCycle=2 weeks

-Cycles received: PK analysis after 6 months of treatment-Toxicity: NR-PK analysis:• Same as normal renal function

-Author conclusions:• Not dialyzable• No dosing adjustments needed• Administer regardless of hemodialysis session

48-year-old mCRC femaleRegimen: Cetuximab [14]+

Bevacizumab

HemodialysisDosing: 400 mg/m2 first dose;

250 mg/m2 weekly

-Cycles received: 2.5 months of therapy-Toxicity:• Fatigue and dry skin

-PK analysis:• Same as normal renal function

-Author conclusions:• Not dialyzable• No dosing adjustments needed

FOLFIRI 5-FU, leucovorin, irinotecan; CRC metastatic colorectal cancer; CI continuous infusion; PK pharmacokinetic; FOLFOX 5-FU, leucovorin,oxaliplatin; AUC area under the curve; mRCC metastatic renal cell carcinoma; NR not reported

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dose, timing of treatment, supportive care, and monitoringparameters.

5-FU (5-Fluorouracil), irinotecan, and irinotecan’s activemetabolite, SN-38, are primarily metabolized via the liverleaving minimal renal excretion (<10 % 5-FU, 11–20 %irinotecan, and <5 % SN-38) [4, 6]. Therefore, 5-FU andirinotecan require no dosing reductions for renal impairment.Renal elimination accounts for ~50% of oxaliplatin excretion.Although significant renal elimination, oxaliplatin has beengiven safely to patients with creatinine clearance >20 ml/minwith no dosing reductions required [6]. Bevacizumab andpanitumumab are eliminated via the reticuloendothelial sys-tem with renal elimination considered to be negligible, andtherefore, these agents require no renal impairment dosingadjustments ([7, 8] package inserts). Finally, regorafenib un-dergoes primarily hepatic metabolism with only 19 % ofactive drug excreted via the kidneys [5]. However, there arecurrently no recommendations on how to dose adjust thismedication in patients with a creatinine clearance of less than60 ml/min or if they are receiving dialysis.

Case reports of FOLFIRI, FOLFOX, bevacizumab,and cetuximab given in the hemodialysis setting aresummarized in Table 1. No reports were found usingpanitumumab or regorafenib. Irinotecan use in dialysispatients is complex. It appears that irinotecan may bepartly dialyzable with SN-38 having delayed clearance inESRD hemodialysis patients [9, 10]. Dosing adjustmentsappear to be necessary with myelosuppression and diarrhearepresenting the biggest concern. Based on the currentliterature and the experience with our patient, a dose re-duction of irinotecan (100–125 mg/m2) should be preferredif FOLFIRI is being considered in mCRC treatment alongwith antidiarrheals and consideration for granulocytecolony-stimulating factor (GCSF) prophylaxis. Althoughlimited data, it appears that bevacizumab modifications arenot necessary in hemodialysis patients, correlating with thepharmacological characteristics of this agent. Our patientreceived 10 cycles of dose reduced FOLFIRI with nofurther dosing adjustments required due to toxicity.Bevacizumab treatment was complicated with develop-ment of hypertension control difficulties that was likelyinfluenced by our patient’s other comorbidities. To ourknowledge, our case represents the first panitumumab casein a hemodialysis patient. Although pharmacokineticswere not performed, our patient tolerated 19 cyclesof panitumumab in combination with dose-reducedirinotecan. Our case report suggests that panitumumabadjustments are not required for hemodialysis.

Based on the current literature, many factors need to beconsidered when administering FOLFOX treatment in a he-modialysis patient. Pharmacokinetic analysis in two FOLFOXcase reports showed a similar bimodal-free platinum patternpeaking shortly after the infusion and approximately 24 h after

the infusion. In both reports, the patient was dialyzed imme-diately after the oxaliplatin infusion. Our patient toleratedthree cycles of dose-reduced FOLFOX.With this current data,clinicians should bear in mind when prescribing FOLFOXthat an upfront dose reduction in oxaliplatin is warranted withconsideration of extending the dosing interval for tolerability.Until more information is available, patients should receivedialysis immediately after the oxaliplatin infusion. Finally, toour knowledge this is the first report of regorafenib in a patienton hemodialysis. While no pharmacokinetic data was obtain-ed, the patient did tolerate regorafenib 40 mg PO daily for21 days with 1 week off without the common toxicitiesdescribed in the CORRECT trial [15]. However, he was onlyable to receive one cycle of treatment, and therefore, cautionin the dialysis setting is still warranted.

It is clear that more research is needed in the dialysis settingto establish a standard practice. Until more research is avail-able, a multidisciplinary discussion regarding antineoplasticpharmacological characteristics, type of dialysis, literatureavailable, patient comorbidities, goal of therapy, and perfor-mance status should be thoroughly reviewed prior to admin-istering chemotherapy or targeted therapy in the dialysissetting.

Conflict of Interest The authors declare that there are no conflicts ofinterest.

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