Economic burden of toxicities associated with metastatic colorectal cancer treatment regimens containing monoclonal antibodies

Figures & data

Table 1.  Summary of clinical studies of bevacizumab, cetuximab, or panitumumab for the treatment of mCRC in which associated grade 3–4 toxicities were reported.

Regimen	Reference	Study setting	Phase	Sample size	Treatment history
Cetuximab	Pessino et al.18	1st line	2	39	NA
	Cunningham et al.19	2nd line/3rd line	3	111	Irinotecan-based regimen
	Jonker et al.20	2nd line/3rd line	3	288	Fluoropyrimidine, irinotecan and oxaliplatin
Panitumumab	Van Cutsem et al.21	3rd line	3	231	Fluoropyrimidine, irinotecan and oxaliplatin
5-FU/LV + bevacizumab	Hurwitz et al.22	1st line	3	110	NA
	Kabbinavar et al.5	1st line	2/3	249	NA
IFL + bevacizumab	Hurwitz et al.2	1st line	3	402	NA
Irinotecan-based chemotherapy + bevacizumab	Hecht et al.23	1st line	3	113	NA
Irinotecan + cetuximab	Sobrero et al.24	2nd line	3	648	Fluoropyrimidine and oxaliplatin
	Cunningham et al.19	2nd line/3rd line	3	218	Oxaliplatin and irinotecan
FOLFIRI + cetuximab	Van Cutsem et al.6	1st line	3	599	NA
	Koo et al.25	3rd line	2	31	Fluoropyrimidine, irinotecan and oxaliplatin
FOLFIRI + panitumumab	Karthaus M et al. (Presented at Gastrointestinal Cancers Symposium 2009. Abstract 388)	1st line	2	154	NA
	Peeters M et al.26	2nd line	3	541	Oxaliplatin and bevacizumab
Oxaliplatin-based chemotherapy + bevacizumab	Hecht et al.23	1st line	3	397	NA
CapeOx + bevacizumab	Hochster et al.27	1st line	3	72	NA
	Saltz et al.28	1st line	3	349	NA
	Tol et al.29	1st line	3	368	NA
CapeOx + cetuximab	Adams et al.30	1st line	3	166	NA
FOLFOX4 + bevacizumab	Saltz et al.28	1st line	3	349	NA
	Giantonio et al.31	2nd line	3	287	Fluoropyrimidine and irinotecan
FOLFOX4 + cetuximab	Bokemeyer et al.4	1st line	3	170	NA
FOLFOX4 + panitumumab	Douillard et al.8	1st line	3	593	NA
mFOLFOX6 + bevacizumab	Hochster et al.27	1st line	3	71	NA

NA, not available.

Table 2.  Grouping of severe toxicities identified in association with bevacizumab, cetuximab, and panitumumab.

Representative event^a	Other adverse events within the group^b
Anemia	Thrombocytopenia
Arterial thromboembolic event	Cardiac ischemia, cerebrovascular ischemia, left ventricular dysfunction, thromboembolism
Hemorrhage
Deep vein thrombosis	Deep vein thrombophlebitis, venous thrombotic event, thrombotic event
Dyspnea
Failure to thrive	Anorexia, fatigue, weight loss
Febrile neutropenia	Infection (NOS), leukopenia, neutropenia
Fistula	Intestinal obstruction, fistula/intra-abdominal abscess, intra-abdominal thrombosis
Gastrointestinal perforation
Hypertension
Hypomagnesemia
Infusion reaction	Hypersensitivity reaction
Interstitial lung disease
Peripheral edema	Edema, hypocalcaemia, hypokalemia
Peripheral neuropathy	Asthenia, neuropathy, neurologic toxicity paresthesia, sensory neuropathy
Proteinuria
Pulmonary embolism
Renal failure
Reversible posterior leukoencephalopathy syndrome
Skin rash	Mucositis, stomatitis, skin toxicity, skin exfoliation, hand–foot syndrome, paronychia, skin and subcutaneous (all)
Urinary tract infection
Vomiting	Abdominal pain, constipation, diarrhea, dehydration
Wound-healing complication

^aThe representative toxicity was the most clinically significant event within that grouping (as determined by clinical opinion) on which the costs of the toxicities in the group were based.

^bToxicities were grouped based on anticipated similarities in treatment approach, as determined by clinical opinion.

NOS, not otherwise specified.

Table 3.  Inpatient costs of treating severe toxicities associated with the use of the monoclonal antibodies bevacizumab, cetuximab, and panitumumab in metastatic colorectal cancer.

Toxicity	ICD-9 code	Inpatient costs (2010 USD)
Anemia	285.22	6219
Arterial thromboembolic event	444.22	20,346
Deep vein thrombosis	451.41	8748
Dyspnea	786.05	5582
Failure to thrive	783.7	8104
Febrile neutropenia	288.03	12,606
Fistula	537.4	29,062
Gastrointestinal perforation	569.83	32,443
Hemorrhage	459	12,956
Hypertension	405.99	8453
Hypomagnesemia	275.2	6174
Infusion reaction	N/A	10,877*
Interstitial lung disease	515	13,001
Peripheral edema	782.3	5695
Peripheral neuropathy	357.6	13,113
Proteinuria	791.0	4618
Pulmonary embolism	415.19	11,411
Renal failure	584.9	10,688
Reversible posterior leukoencephalopathy syndrome	348.5	10,116
Skin rash	782.1	4424
Urinary tract infection	599.0	6890
Vomiting	787.01	5559
Wound-healing complication	998.32	13,240

*Costs based on Foley et al.32 as no ICD-9 code was available for this event.

Table 4.  Unit costs for resources used to determine the costs of toxicities in the outpatient setting.

Resource	CPT code	Unit cost (2010 USD)	Fee type
Basic metabolic panel	80047	12.12	Lab fee
Complete blood count	85025	11.14	Lab fee
Chest X-ray	71030	46.17	Professional fee
Computed	70450	193.05	Professional fee
tomography scan	72125	253.31	Professional fee
	70488	370.59	Professional fee
Electrocardiogram	93000	30.92	Professional fee
	93010	9.02	Professional fee
Electrolytes	80051	10.05	Lab fee
Medical stocking	A6531	45.43	Durable medical equipment fee
Physician visit, moderate complexity	99212	38.97	Professional fee
	99214	92.33	Professional fee
	99215	132.79	Professional fee
Platelets	85025	11.14	Lab fee
Protime	85610	5.62	Lab fee
Renal function test	78596	342.63	Professional fee
Spirometry	94010	32.84	Professional fee
Thyroid function test	78006	240.78	Professional fee
	78007	124.49	Professional fee
	84479	9.27	Lab fee
Tissue culture	88233	201.57	Lab fee
Ultrasound	37250	111.45	Professional fee
	37251	85.52	Professional fee
Urinalysis	81001	4.54	Lab fee
Vacuum closure system	97606	40.05	Professional fee
	A7043	36.02	Durable medical equipment fee

Table 5.  Outpatient costs of treating severe toxicities associated with the use of the monoclonal antibodies bevacizumab, cetuximab, and panitumumab in metastatic colorectal cancer.

Toxicity	Resource use assumptions*	Outpatient cost (2010 USD)
Anemia	2× physician visit; 2× complete blood count	207
Dyspnea	3× physician visit; 2× spirometry	343
Failure to thrive	2× physician visit; 1× complete blood count; 1× electrolytes; 1× thyroid function test	447
Febrile neutropenia	2× physician visit; 2× complete blood count; 1× electrolytes	217
Hypertension	2× physician visit	185
Hypomagnesemia	2× physician visit; 2× electrolytes	205
Infusion reaction	2× physician visit; 1× complete blood count; 1× electrocardiogram; 1× urinalysis; 1× renal function test	327
Peripheral edema	2× physician visit; 1× electrolytes; 1× medical stocking; 1× thyroid function test	481
Peripheral neuropathy	2× physician visit	185
Proteinuria	2× physician visit; 1× urinalysis; 1× basic metabolic panel	201
Skin rash	2× physician visit	185
Urinary tract infection	1× physician visit; 1× complete blood count	103
Vomiting	2× physician visit; 1× electrolytes	195
Wound-healing complication	2× physician visits; 1× tissue culture; 1× complete blood count; 1× ultrasound; 1× vacuum closure system	585

Based on clinical expert opinion, arterial thromboembolic event, hemorrhage, deep vein thrombosis, fistula, gastrointestinal perforation, interstitial lung disease, pulmonary embolism, renal failure, and reversible posterior leukoencephalopathy syndrome were all assumed to be treated on an inpatient basis only.

*Based on in-depth clinical interview.

Pessino A, Artale S, Sciallero S, et al. First-line single-agent cetuximab in patients with advanced colorectal cancer. Ann Oncol 2008;19:711-6

 PubMedGoogle Scholar

Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45

 PubMed Web of Science ®Google Scholar

Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040-8

 PubMed Web of Science ®Google Scholar

Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658-64

 PubMed Web of Science ®Google Scholar

Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 2005;23:3502-8

 PubMed Web of Science ®Google Scholar

Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005;23:3706-12

 PubMed Web of Science ®Google Scholar

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42

 PubMed Web of Science ®Google Scholar

Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009;27:672-80

 PubMed Web of Science ®Google Scholar

Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2311-9

 PubMed Web of Science ®Google Scholar

Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408-17

 PubMed Web of Science ®Google Scholar

Koo DH, Lee JL, Kim TW, et al. A Phase II study of cetuximab (Erbitux) plus FOLFIRI for irinotecan and oxaliplatin-refractory metastatic colorectal cancer. J Korean Med Sci 2007;22(Suppl):S98-S103

 PubMedGoogle Scholar

Peeters M, Price T, Cervantes A, et al. Randomised phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706-13

 PubMed Web of Science ®Google Scholar

Hochster HS, Hart LL, Ramanathan RK, et al. 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 2008;26:3523-9

 PubMed Web of Science ®Google Scholar

Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013-9

 PubMed Web of Science ®Google Scholar

Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563-72

 PubMed Web of Science ®Google Scholar

Adams RA, Meade AM, Madi A, et al. Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience. Br J Cancer 2009;100:251-8

 PubMed Web of Science ®Google Scholar

Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539-44

 PubMed Web of Science ®Google Scholar

Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27:663-71

 PubMed Web of Science ®Google Scholar

Douillard JY, Siena S, Caissdy J, et al. Randomised, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as a first-line treatment in patients with previously untreated metastatic colorectal cancer: the prime study. J Clin Oncol 2010;28:4697-705

 PubMed Web of Science ®Google Scholar

Foley KA, Wang PF, Barber BL, et al. Clinical and economic impact of infusion reactions in patients with colorectal cancer treated with cetuximab. Ann Oncol 2010;21:1455-6

 PubMed Web of Science ®Google Scholar