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Costs of Oral Complications of Cancer Therapies: Estimates and a Blueprint for Future Study

Costs of Oral Complications of Cancer Therapies: Estimates and a Blueprint for Future Study Abstract Oral complications of cancer treatment are common; however, their clinical and economic importance is often underappreciated. We reviewed the literature on the economic implications of oral complications, updating a previous report in the predecessor to this issue. We searched the Medline and Scopus databases for papers published as of December 31, 2017 that described the economic consequences of preventing and managing oral complications and reviewed the literature reporting the costs of oral mucositis, xerostomia, and osteonecrosis. Cost estimates were inflated to 2017 US dollars. We identified 16 papers describing the cost of managing mucositis, eight describing the cost of osteoradionecrosis, one describing the cost of bisphosphonate-associate osteonecrosis of the jaw, and four describing the cost of xerostomia. The incremental cost of oral mucositis was approximately $5000–$30 000 among patients receiving radiation therapy and $3700 per cycle among patients receiving chemotherapy. The incremental cost of mucositis-related hospitalization among stem cell transplant recipients exceeded $70 000. Conservative management of osteoradionecrosis (antibiotics, debridement) costs $4000–$35 000, although estimates as high as $74 000 have been reported. Hyperbaric oxygen therapy may add $10 000–$50 000 to the cost of therapy. Sialogogues are required for years for the management of xerostomia at a cost of $40–$200 per month. Serious (hospitalization, hyperbaric oxygen therapy) or long-term (sialogogues) outcomes are the major drivers of cost. Future research should address patients’ out-of-pocket costs and the costs of oral complications of new treatments. Multisite studies, particularly those conducted by cooperative groups, should be prioritized. Oral complications of emerging cancer therapies can cause serious morbidity, including mucositis, xerostomia, oral infections, acute and chronic oral pain, oral graft-versus-host disease, osteoradionecrosis, and bisphosphonate-associated osteonecrosis of the jaw. The incidence and management of these complications are described in other chapters in this monograph. Considering the severity of their morbidity and the complexity of their management, these complications may result in increased resource utilization and cost (1). The economic implications of oral complications were examined in a predecessor to this monograph, which was published in 2001 (2). Since that publication, new therapies have emerged (ie, targeted therapies), existing therapies have been modified (ie, stem cell transplant or intensity modulated radiation therapy), and associations between commonly used therapies and toxicities have been identified (ie, bisphosphonates and osteonecrosis of the jaw). In this manuscript, we report the results of a review of the literature on the economic implications of four oral complications—oral mucositis, xerostomia, osteoradionecrosis, and bisphosphonate-associated osteonecrosis of the jaw—focusing on their relationships with emerging cancer therapies. Owing to the paucity of data in the literature, we also propose a conceptual framework for their future study. Conceptual Framework and Search Strategy The costs of oral complications result from interventions to manage oral complications and their outcomes (pain medications, nutritional support, pilocarpine, hyperbaric oxygen [HBO], antibiotics, and debridement) as well as from interventions to prevent them (palifermin, amifostine, intensity-modulated radiation therapy) (Figure 1). Prevention costs accrue to all patients, whereas management costs accrue only to those affected. Assuming a payer’s perspective, the costs of preventing and managing these complications accrue to both third-party payers (private insurance companies or public plans such as Medicare) and to patients. Figure 1. View largeDownload slide Conceptual model of the costs of oral complications. G-tube = gastrostomy tube; HBO = hyperbaric oxygen therapy; IMRT = intensity modulated radiation therapy; RT = radiation therapy. *Low-level laser and hyperbaric oxygen have been studied for both prevention and treatment of oral mucositis and osteoradionecrosis, respectively. Figure 1. View largeDownload slide Conceptual model of the costs of oral complications. G-tube = gastrostomy tube; HBO = hyperbaric oxygen therapy; IMRT = intensity modulated radiation therapy; RT = radiation therapy. *Low-level laser and hyperbaric oxygen have been studied for both prevention and treatment of oral mucositis and osteoradionecrosis, respectively. Patient’s costs include over-the-counter medications, copayments, deductibles, time costs, transportation costs, productivity costs, and wages lost. Third-party payer’s costs may include the costs of professionals’ time, outpatient visits, medications, hospitalizations, and laboratory and diagnostic tests. We searched the Medline and Scopus databases for papers published before December 31, 2017, describing the economic consequences of preventing and managing oral mucositis, radiation-induced xerostomia, osteoradionecrosis, osteonecrosis of the jaw, oral pain and infections, and oral graft-versus-host disease with the goal of including both patient and third-party payer costs. Search terms included “mucositis,” “stomatitis,” “xerostomia,” “osteoradionecrosis” or “osteonecrosis,” “oral pain,” or “oral graft-versus-host disease” in combination with “cost,” “economic analysis,” “cost-effectiveness,” or “cost-benefit.” We also searched the publications cited by papers identified in the original search to identify other related papers. Perhaps because oral mucositis is a common complication of cancer therapy, an occasional cause of serious morbidity, and a target for recent new drug development, information on the cost of preventing and managing oral mucositis was more readily available in the literature than information about other oral complications. Our search identified 16 papers with cost estimates that are summarized in Table 1. In contrast, osteoradionecrosis is quite uncommon, but more frequently causes serious morbidity and requires aggressive and costly management. Our search identified eight papers describing the cost of managing osteoradionecrosis; these are reported in Table 2. One paper reporting the cost of bisphosphonate-associated osteonecrosis of the jaw is described in the text. Four papers with estimates of the costs of xerostomia management were identified. These were augmented by estimates on the current cost of sialogogues and are reported in Table 3. In all tables, sponsorship of studies by pharmaceutical industry has been indicated to permit the reader to assess possible sources of bias. Table 1. Estimates of the cost of managing or preventing oral mucositis* First author, publication year (ref.) Treatment Cancer Cost component Cost estimate Original paper† 2017, US$ Peterman, 2001 (2) RT±CT Head and neck Incremental cost, low and high estimates 2949; 4037 5067; 6938 Elting, 2007 (3) RT Head and neck Incremental cost, mucositis vs none 5978 7965 Elting, 2007 (3) CT+RT Head and neck Incremental cost, mucositis vs none 6046 8056 Nonzee, 2008 (4) CT+RT Head and neck Incremental cost 17 244 22 597 Sartori, 1996 (5) – Head and neck Mean daily cost of PEG management and side effects 28 890 L 34 Sartori, 1996 (5) – Head and neck Mean daily cost of NG tube management and side effects 27 340 L 32 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, amifostine prophylaxis 4401 7605 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, no prophylaxis 5873 10 154 Antunes, 2016 CT+RT Head and neck Prevention and supportive care costs, low-level laser therapy 1940 (2013) 2049 Antunes, 2016 CT+RT Head and neck Standard preventive care and supportive care, NO low-level laser therapy 251 (2013) 265 OCCI 2004, 2005 (7) – Other ENT infections Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs 3013 CAD 2957 OCCI 2009, 2010 (7) – Oral cavity/salivary gland/jaw Average cost of oral mucositis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 5059 CAD 4966 OCCI 2009, 2010 (7) – Miscellaneous ENT disorder Average cost of candida stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4872 CAD 4783 OCCI 2009, 2010 (7) – Oral cavity, salivary gland, or jaw Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4662 CAD 4576 Corry, 2009 (8) CT/RT Head and neck Cost of each PEG tube, insertion (by surgeon), and median 14 nights stay in hospital 110; 626; 3556 AU 95; 540; 3065 Corry, 2009 (8) CT/RT Head and neck Cost of each NG tube, insertion (by nurse), & median 4-night stay in hospital 26;50; 1016 AU 22; 43; 1076 Nonzee, 2008 (4) CT+RT NSCLC Incremental cost 25 060 32 531 Banz, 2011(9) CT NSCLC Management cost per event grade III/IV in Germany; France; Italy; Spain 312€ 441€ 45€ 102€ 37452054121 Sonis, 2001 (10) HSCT – Incremental hospital charges, oral ulceration 42 749 73 461 Vera-Llonch, 2007 (11) HSCT – Incremental hospital charge grade V vs grade 0 over 28 days‡ 223 426 375 204 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, palifermin prophylaxis 73 938 107 895 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, no prophylaxis 77 535 113 145 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – autologous transplant 37 010; 47 568 40 359; 51 872 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – Allogeneic transplant 54 655; 70 953 59 599; 77 373 Elting, 2003 (14) CT Any myelo-suppressed Estimated incremental hospital cost per cycle 2384 3762 Weiner, 2007 (15) CT All Inpatient-specific daily cost; with and without supportive drugs 1058; 1091 1609; 1658 Elting, 2004 (16) All All Hospitalization cost 7985 12 088 First author, publication year (ref.) Treatment Cancer Cost component Cost estimate Original paper† 2017, US$ Peterman, 2001 (2) RT±CT Head and neck Incremental cost, low and high estimates 2949; 4037 5067; 6938 Elting, 2007 (3) RT Head and neck Incremental cost, mucositis vs none 5978 7965 Elting, 2007 (3) CT+RT Head and neck Incremental cost, mucositis vs none 6046 8056 Nonzee, 2008 (4) CT+RT Head and neck Incremental cost 17 244 22 597 Sartori, 1996 (5) – Head and neck Mean daily cost of PEG management and side effects 28 890 L 34 Sartori, 1996 (5) – Head and neck Mean daily cost of NG tube management and side effects 27 340 L 32 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, amifostine prophylaxis 4401 7605 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, no prophylaxis 5873 10 154 Antunes, 2016 CT+RT Head and neck Prevention and supportive care costs, low-level laser therapy 1940 (2013) 2049 Antunes, 2016 CT+RT Head and neck Standard preventive care and supportive care, NO low-level laser therapy 251 (2013) 265 OCCI 2004, 2005 (7) – Other ENT infections Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs 3013 CAD 2957 OCCI 2009, 2010 (7) – Oral cavity/salivary gland/jaw Average cost of oral mucositis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 5059 CAD 4966 OCCI 2009, 2010 (7) – Miscellaneous ENT disorder Average cost of candida stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4872 CAD 4783 OCCI 2009, 2010 (7) – Oral cavity, salivary gland, or jaw Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4662 CAD 4576 Corry, 2009 (8) CT/RT Head and neck Cost of each PEG tube, insertion (by surgeon), and median 14 nights stay in hospital 110; 626; 3556 AU 95; 540; 3065 Corry, 2009 (8) CT/RT Head and neck Cost of each NG tube, insertion (by nurse), & median 4-night stay in hospital 26;50; 1016 AU 22; 43; 1076 Nonzee, 2008 (4) CT+RT NSCLC Incremental cost 25 060 32 531 Banz, 2011(9) CT NSCLC Management cost per event grade III/IV in Germany; France; Italy; Spain 312€ 441€ 45€ 102€ 37452054121 Sonis, 2001 (10) HSCT – Incremental hospital charges, oral ulceration 42 749 73 461 Vera-Llonch, 2007 (11) HSCT – Incremental hospital charge grade V vs grade 0 over 28 days‡ 223 426 375 204 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, palifermin prophylaxis 73 938 107 895 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, no prophylaxis 77 535 113 145 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – autologous transplant 37 010; 47 568 40 359; 51 872 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – Allogeneic transplant 54 655; 70 953 59 599; 77 373 Elting, 2003 (14) CT Any myelo-suppressed Estimated incremental hospital cost per cycle 2384 3762 Weiner, 2007 (15) CT All Inpatient-specific daily cost; with and without supportive drugs 1058; 1091 1609; 1658 Elting, 2004 (16) All All Hospitalization cost 7985 12 088 * Italics indicate studies sponsored by pharmaceutical industry. AU = Australian dollar; CAD = Canadian dollar; CT = chemotherapy; CT+RT = chemoradiotherapy; ENT = ear, nose, and throat; HCST = hematopoietic stem cell transplant; L = Italian lire; NSCLC = non-small cell lung cancer; NG = nasogastric; OCCI = Ontario Case Costing Initiative; PEG = percutaneous endoscopic gastrostomy; RT = radiation therapy; TBI = total body irradiation. † Currency in US dollars, unless otherwise noted. ‡ Mean charge, US dollars: for grade 0 = $339 273; for grade 5 = $693 488. View Large Table 1. Estimates of the cost of managing or preventing oral mucositis* First author, publication year (ref.) Treatment Cancer Cost component Cost estimate Original paper† 2017, US$ Peterman, 2001 (2) RT±CT Head and neck Incremental cost, low and high estimates 2949; 4037 5067; 6938 Elting, 2007 (3) RT Head and neck Incremental cost, mucositis vs none 5978 7965 Elting, 2007 (3) CT+RT Head and neck Incremental cost, mucositis vs none 6046 8056 Nonzee, 2008 (4) CT+RT Head and neck Incremental cost 17 244 22 597 Sartori, 1996 (5) – Head and neck Mean daily cost of PEG management and side effects 28 890 L 34 Sartori, 1996 (5) – Head and neck Mean daily cost of NG tube management and side effects 27 340 L 32 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, amifostine prophylaxis 4401 7605 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, no prophylaxis 5873 10 154 Antunes, 2016 CT+RT Head and neck Prevention and supportive care costs, low-level laser therapy 1940 (2013) 2049 Antunes, 2016 CT+RT Head and neck Standard preventive care and supportive care, NO low-level laser therapy 251 (2013) 265 OCCI 2004, 2005 (7) – Other ENT infections Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs 3013 CAD 2957 OCCI 2009, 2010 (7) – Oral cavity/salivary gland/jaw Average cost of oral mucositis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 5059 CAD 4966 OCCI 2009, 2010 (7) – Miscellaneous ENT disorder Average cost of candida stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4872 CAD 4783 OCCI 2009, 2010 (7) – Oral cavity, salivary gland, or jaw Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4662 CAD 4576 Corry, 2009 (8) CT/RT Head and neck Cost of each PEG tube, insertion (by surgeon), and median 14 nights stay in hospital 110; 626; 3556 AU 95; 540; 3065 Corry, 2009 (8) CT/RT Head and neck Cost of each NG tube, insertion (by nurse), & median 4-night stay in hospital 26;50; 1016 AU 22; 43; 1076 Nonzee, 2008 (4) CT+RT NSCLC Incremental cost 25 060 32 531 Banz, 2011(9) CT NSCLC Management cost per event grade III/IV in Germany; France; Italy; Spain 312€ 441€ 45€ 102€ 37452054121 Sonis, 2001 (10) HSCT – Incremental hospital charges, oral ulceration 42 749 73 461 Vera-Llonch, 2007 (11) HSCT – Incremental hospital charge grade V vs grade 0 over 28 days‡ 223 426 375 204 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, palifermin prophylaxis 73 938 107 895 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, no prophylaxis 77 535 113 145 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – autologous transplant 37 010; 47 568 40 359; 51 872 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – Allogeneic transplant 54 655; 70 953 59 599; 77 373 Elting, 2003 (14) CT Any myelo-suppressed Estimated incremental hospital cost per cycle 2384 3762 Weiner, 2007 (15) CT All Inpatient-specific daily cost; with and without supportive drugs 1058; 1091 1609; 1658 Elting, 2004 (16) All All Hospitalization cost 7985 12 088 First author, publication year (ref.) Treatment Cancer Cost component Cost estimate Original paper† 2017, US$ Peterman, 2001 (2) RT±CT Head and neck Incremental cost, low and high estimates 2949; 4037 5067; 6938 Elting, 2007 (3) RT Head and neck Incremental cost, mucositis vs none 5978 7965 Elting, 2007 (3) CT+RT Head and neck Incremental cost, mucositis vs none 6046 8056 Nonzee, 2008 (4) CT+RT Head and neck Incremental cost 17 244 22 597 Sartori, 1996 (5) – Head and neck Mean daily cost of PEG management and side effects 28 890 L 34 Sartori, 1996 (5) – Head and neck Mean daily cost of NG tube management and side effects 27 340 L 32 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, amifostine prophylaxis 4401 7605 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, no prophylaxis 5873 10 154 Antunes, 2016 CT+RT Head and neck Prevention and supportive care costs, low-level laser therapy 1940 (2013) 2049 Antunes, 2016 CT+RT Head and neck Standard preventive care and supportive care, NO low-level laser therapy 251 (2013) 265 OCCI 2004, 2005 (7) – Other ENT infections Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs 3013 CAD 2957 OCCI 2009, 2010 (7) – Oral cavity/salivary gland/jaw Average cost of oral mucositis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 5059 CAD 4966 OCCI 2009, 2010 (7) – Miscellaneous ENT disorder Average cost of candida stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4872 CAD 4783 OCCI 2009, 2010 (7) – Oral cavity, salivary gland, or jaw Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4662 CAD 4576 Corry, 2009 (8) CT/RT Head and neck Cost of each PEG tube, insertion (by surgeon), and median 14 nights stay in hospital 110; 626; 3556 AU 95; 540; 3065 Corry, 2009 (8) CT/RT Head and neck Cost of each NG tube, insertion (by nurse), & median 4-night stay in hospital 26;50; 1016 AU 22; 43; 1076 Nonzee, 2008 (4) CT+RT NSCLC Incremental cost 25 060 32 531 Banz, 2011(9) CT NSCLC Management cost per event grade III/IV in Germany; France; Italy; Spain 312€ 441€ 45€ 102€ 37452054121 Sonis, 2001 (10) HSCT – Incremental hospital charges, oral ulceration 42 749 73 461 Vera-Llonch, 2007 (11) HSCT – Incremental hospital charge grade V vs grade 0 over 28 days‡ 223 426 375 204 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, palifermin prophylaxis 73 938 107 895 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, no prophylaxis 77 535 113 145 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – autologous transplant 37 010; 47 568 40 359; 51 872 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – Allogeneic transplant 54 655; 70 953 59 599; 77 373 Elting, 2003 (14) CT Any myelo-suppressed Estimated incremental hospital cost per cycle 2384 3762 Weiner, 2007 (15) CT All Inpatient-specific daily cost; with and without supportive drugs 1058; 1091 1609; 1658 Elting, 2004 (16) All All Hospitalization cost 7985 12 088 * Italics indicate studies sponsored by pharmaceutical industry. AU = Australian dollar; CAD = Canadian dollar; CT = chemotherapy; CT+RT = chemoradiotherapy; ENT = ear, nose, and throat; HCST = hematopoietic stem cell transplant; L = Italian lire; NSCLC = non-small cell lung cancer; NG = nasogastric; OCCI = Ontario Case Costing Initiative; PEG = percutaneous endoscopic gastrostomy; RT = radiation therapy; TBI = total body irradiation. † Currency in US dollars, unless otherwise noted. ‡ Mean charge, US dollars: for grade 0 = $339 273; for grade 5 = $693 488. View Large Table 2. Cost of managing osteoradionecrosis among patients with head and neck cancers* First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ Marx, 1985 HBO without surgery, average total cost $62 000 275 057 Marx, 1985 No HBO, average total cost $69 000 306 112 Marx, 1985 University of Miami HBO surgery protocol 30 000 133 092 Dempsey, 1997 (17) Conservative (medication, ± sequestrectomy; ± extractions ±reconstruction) 63 212 CAD 78 809 Dempsey, 1997 (17) HBO (medication, ± sequestrectomy; ± extractions ± reconstruction) 10 172 CAD 12 683 MSAC Au, 2000(18) HBO (30 dives) 6941 AUD 8521 NHS, 2007 (19) HBO (30- to 60-min dives), treatment only 900 GPB 1908 Kelishadi, 2009 (20) HBO (30- to 90-min dives), all costs 21 120 26 520 Kelishadi, 2009 (20) Debridement 3890 4884 Kelishadi, 2009 (20) Surgical resection plus microvascular free flap 30 030 37 707 Fonseca, 2011 (21) Hyperbaric chamber per session, per cycle (15 sessions) 329 R 4935 R 3825743 Park, 2017 Free-flap reconstruction (in- and out-patient costs, HBO, and surgery) 123 900 NZD 85 098 Patel, 2017 Surgical management (one or more surgical procedures, in- and out-patient stays, medication HBO) 28 785 GBP 41 754 First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ Marx, 1985 HBO without surgery, average total cost $62 000 275 057 Marx, 1985 No HBO, average total cost $69 000 306 112 Marx, 1985 University of Miami HBO surgery protocol 30 000 133 092 Dempsey, 1997 (17) Conservative (medication, ± sequestrectomy; ± extractions ±reconstruction) 63 212 CAD 78 809 Dempsey, 1997 (17) HBO (medication, ± sequestrectomy; ± extractions ± reconstruction) 10 172 CAD 12 683 MSAC Au, 2000(18) HBO (30 dives) 6941 AUD 8521 NHS, 2007 (19) HBO (30- to 60-min dives), treatment only 900 GPB 1908 Kelishadi, 2009 (20) HBO (30- to 90-min dives), all costs 21 120 26 520 Kelishadi, 2009 (20) Debridement 3890 4884 Kelishadi, 2009 (20) Surgical resection plus microvascular free flap 30 030 37 707 Fonseca, 2011 (21) Hyperbaric chamber per session, per cycle (15 sessions) 329 R 4935 R 3825743 Park, 2017 Free-flap reconstruction (in- and out-patient costs, HBO, and surgery) 123 900 NZD 85 098 Patel, 2017 Surgical management (one or more surgical procedures, in- and out-patient stays, medication HBO) 28 785 GBP 41 754 * Italics indicate studies sponsored by pharmaceutical industry. AUD = Australian dollar; CAD = Canadian dollar; GBP = British pound; HBO = hyperbaric oxygen; L = Italian lire; NHS = National Health Service; NZD = New Zealand dollar; R= Brazil reais. † Currency in US dollars, unless otherwise noted. View Large Table 2. Cost of managing osteoradionecrosis among patients with head and neck cancers* First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ Marx, 1985 HBO without surgery, average total cost $62 000 275 057 Marx, 1985 No HBO, average total cost $69 000 306 112 Marx, 1985 University of Miami HBO surgery protocol 30 000 133 092 Dempsey, 1997 (17) Conservative (medication, ± sequestrectomy; ± extractions ±reconstruction) 63 212 CAD 78 809 Dempsey, 1997 (17) HBO (medication, ± sequestrectomy; ± extractions ± reconstruction) 10 172 CAD 12 683 MSAC Au, 2000(18) HBO (30 dives) 6941 AUD 8521 NHS, 2007 (19) HBO (30- to 60-min dives), treatment only 900 GPB 1908 Kelishadi, 2009 (20) HBO (30- to 90-min dives), all costs 21 120 26 520 Kelishadi, 2009 (20) Debridement 3890 4884 Kelishadi, 2009 (20) Surgical resection plus microvascular free flap 30 030 37 707 Fonseca, 2011 (21) Hyperbaric chamber per session, per cycle (15 sessions) 329 R 4935 R 3825743 Park, 2017 Free-flap reconstruction (in- and out-patient costs, HBO, and surgery) 123 900 NZD 85 098 Patel, 2017 Surgical management (one or more surgical procedures, in- and out-patient stays, medication HBO) 28 785 GBP 41 754 First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ Marx, 1985 HBO without surgery, average total cost $62 000 275 057 Marx, 1985 No HBO, average total cost $69 000 306 112 Marx, 1985 University of Miami HBO surgery protocol 30 000 133 092 Dempsey, 1997 (17) Conservative (medication, ± sequestrectomy; ± extractions ±reconstruction) 63 212 CAD 78 809 Dempsey, 1997 (17) HBO (medication, ± sequestrectomy; ± extractions ± reconstruction) 10 172 CAD 12 683 MSAC Au, 2000(18) HBO (30 dives) 6941 AUD 8521 NHS, 2007 (19) HBO (30- to 60-min dives), treatment only 900 GPB 1908 Kelishadi, 2009 (20) HBO (30- to 90-min dives), all costs 21 120 26 520 Kelishadi, 2009 (20) Debridement 3890 4884 Kelishadi, 2009 (20) Surgical resection plus microvascular free flap 30 030 37 707 Fonseca, 2011 (21) Hyperbaric chamber per session, per cycle (15 sessions) 329 R 4935 R 3825743 Park, 2017 Free-flap reconstruction (in- and out-patient costs, HBO, and surgery) 123 900 NZD 85 098 Patel, 2017 Surgical management (one or more surgical procedures, in- and out-patient stays, medication HBO) 28 785 GBP 41 754 * Italics indicate studies sponsored by pharmaceutical industry. AUD = Australian dollar; CAD = Canadian dollar; GBP = British pound; HBO = hyperbaric oxygen; L = Italian lire; NHS = National Health Service; NZD = New Zealand dollar; R= Brazil reais. † Currency in US dollars, unless otherwise noted. View Large Table 3. Cost of managing xerostomia among patients with head and neck cancers* First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ www.GoodRX.com‡ Pilocarpine purchase price 1 mo prescription 5 mg tid N/A 46–190 www.GoodRX.com‡ Cevimeline purchase price 1 mo prescription 30 mg tid N/A 87–158 Taylor, 2003 (22) Composite fillings for dental caries 120–250 192–399 Taylor, 2003 (22) Implants for dental caries 3000 4789 Bonastre, 2007 (23) Total cost of IMRT, planning for IMRT, each IMRT session 10 916 EUR; 2773 EUR, 247 EUR 15 725; 3993; 377 Van de Werf, 2009 (24) Total cost of IMRT, increased cost for quality assurance for IMRT 10 878 EUR; 1463 EUR 15 695; 2110 Yong, 2012 (25) Total cost of IMRT; consultation; CT simulation; dosimetry; quality assurance; treatment preparation and delivery and review visits; overhead 16 085 CAD; 292 CAD; 574 CAD; 2221 CAD; 678 CAD; 10 338 CAD; 1982 CAD 13 159; 238; 469; 1817; 553; 8457; 1622 First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ www.GoodRX.com‡ Pilocarpine purchase price 1 mo prescription 5 mg tid N/A 46–190 www.GoodRX.com‡ Cevimeline purchase price 1 mo prescription 30 mg tid N/A 87–158 Taylor, 2003 (22) Composite fillings for dental caries 120–250 192–399 Taylor, 2003 (22) Implants for dental caries 3000 4789 Bonastre, 2007 (23) Total cost of IMRT, planning for IMRT, each IMRT session 10 916 EUR; 2773 EUR, 247 EUR 15 725; 3993; 377 Van de Werf, 2009 (24) Total cost of IMRT, increased cost for quality assurance for IMRT 10 878 EUR; 1463 EUR 15 695; 2110 Yong, 2012 (25) Total cost of IMRT; consultation; CT simulation; dosimetry; quality assurance; treatment preparation and delivery and review visits; overhead 16 085 CAD; 292 CAD; 574 CAD; 2221 CAD; 678 CAD; 10 338 CAD; 1982 CAD 13 159; 238; 469; 1817; 553; 8457; 1622 * Italics indicate studies sponsored by pharmaceutical industry. CAD = Canadian dollar; CT = chemotherapy; EUR = euro; IMRT = intensity modulated radiation therapy; N/A = not applicable. † Currency in US dollars, unless otherwise noted. ‡ Accessed July 26, 2018. View Large Table 3. Cost of managing xerostomia among patients with head and neck cancers* First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ www.GoodRX.com‡ Pilocarpine purchase price 1 mo prescription 5 mg tid N/A 46–190 www.GoodRX.com‡ Cevimeline purchase price 1 mo prescription 30 mg tid N/A 87–158 Taylor, 2003 (22) Composite fillings for dental caries 120–250 192–399 Taylor, 2003 (22) Implants for dental caries 3000 4789 Bonastre, 2007 (23) Total cost of IMRT, planning for IMRT, each IMRT session 10 916 EUR; 2773 EUR, 247 EUR 15 725; 3993; 377 Van de Werf, 2009 (24) Total cost of IMRT, increased cost for quality assurance for IMRT 10 878 EUR; 1463 EUR 15 695; 2110 Yong, 2012 (25) Total cost of IMRT; consultation; CT simulation; dosimetry; quality assurance; treatment preparation and delivery and review visits; overhead 16 085 CAD; 292 CAD; 574 CAD; 2221 CAD; 678 CAD; 10 338 CAD; 1982 CAD 13 159; 238; 469; 1817; 553; 8457; 1622 First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ www.GoodRX.com‡ Pilocarpine purchase price 1 mo prescription 5 mg tid N/A 46–190 www.GoodRX.com‡ Cevimeline purchase price 1 mo prescription 30 mg tid N/A 87–158 Taylor, 2003 (22) Composite fillings for dental caries 120–250 192–399 Taylor, 2003 (22) Implants for dental caries 3000 4789 Bonastre, 2007 (23) Total cost of IMRT, planning for IMRT, each IMRT session 10 916 EUR; 2773 EUR, 247 EUR 15 725; 3993; 377 Van de Werf, 2009 (24) Total cost of IMRT, increased cost for quality assurance for IMRT 10 878 EUR; 1463 EUR 15 695; 2110 Yong, 2012 (25) Total cost of IMRT; consultation; CT simulation; dosimetry; quality assurance; treatment preparation and delivery and review visits; overhead 16 085 CAD; 292 CAD; 574 CAD; 2221 CAD; 678 CAD; 10 338 CAD; 1982 CAD 13 159; 238; 469; 1817; 553; 8457; 1622 * Italics indicate studies sponsored by pharmaceutical industry. CAD = Canadian dollar; CT = chemotherapy; EUR = euro; IMRT = intensity modulated radiation therapy; N/A = not applicable. † Currency in US dollars, unless otherwise noted. ‡ Accessed July 26, 2018. View Large No articles describing the economic implications of oral pain or oral graft-versus-host disease were identified, and none was identified that addressed the economic implications of any of these oral complications when induced by emerging therapies. Thus, we summarize the literature on the cost of oral complications with conventional therapies as described below and hypothesize about expected differences in cost with emerging therapies. No articles provided estimates of patients’ out-of-pocket costs, and few provided cost estimates across the entire continuum of care from prevention to management of long-term outcomes. Therefore, we provide a blueprint for future cost analyses. No attempt was made to aggregate estimates through meta-analytic techniques owing to the small number of articles identified and heterogeneity of study populations and designs. To facilitate examination of costs across multiple studies, cost estimates from the original reports were inflated to 2017 US dollars using the Consumer Price Index for health care (www.bls.gov; accessed July 12, 2018). The results of several studies were reported in currencies other than US dollars. In those cases, the original estimate was inflated to 2017 in the original currency (using the country-specific Consumer Price Index for health care), and the 2017 estimate was converted into US dollars based on estimates of the Purchasing Power Parity for gross domestic product computed by the International Monetary Fund (www.imf.org; www.oecd.org; accessed July 12, 2018). Results Costs of Oral Mucositis Management and Prevention In the predecessor to this issue, Peterman and colleagues provided low ($2949) and high ($4037) estimates of the incremental cost of managing patients with head and neck cancers with radiation- or chemoradiation-induced oral mucositis (2). Inflating these estimates to 2017 US dollars provides a range of the incremental costs of oral mucositis between $5067 and $6938 in this population (Table 1). Among more recent estimates in the same population, some are quite similar ($7965 and $8056) (3) whereas others are substantially higher ($22 597) (4). Nonzee et al. reported incremental costs of mucositis exceeding $30 000 among patients with non-small cell lung cancer who were receiving chemo-radiation; however, it is notable that patients in this study experienced an additional 14 days of mucositis-related hospitalization, exceeding the mean duration of hospitalization in prior studies (4). The Ontario Case Costing Initiative provides total cost data for oral mucositis and stomatitis in clinically homogeneous groups, ranging from $2957 to $4966 (7). The excess costs associated with mucositis result from management of costly and serious outcomes, most notably, excess days with enteral or parenteral feedings, hospital days, and episodes of febrile neutropenia. For example, between 15% and 55% of patients undergoing radiation of head and neck cancer require enteral feedings (3,26–28). The mean daily cost of percutaneous endoscopic gastrostomy (PEG) or nasogastric (NG) tube management is approximately $30, often required for 4–6 months (5). The total cost for inserting a PEG tube is almost 10 times that of an NG tube because the PEG tubes are inserted by surgeons ($540 and $43, respectively). Furthermore, the inpatient cost for patients with PEG tubes is three times the cost of patients with NG tubes (8) (Table 1). Mucositis-associated hospitalizations also contribute substantially to the cost of care (Table 1). The incremental cost of oral mucositis-associated hospitalization among stem-cell recipients is high, exceeding $70 000 for patients who develop ulceration and $375 000 among those with grade V mucositis (ulceration at four or more oral sites) (10,11). Comparison of these costs with those in other clinical settings is difficult owing to the high cost of hospitalization (often in specialized hospital units) among stem-cell recipients. Furthermore, comparison with other studies is likely inappropriate because charges, rather than costs, were analyzed; charges may be double or triple the costs of delivering care and payments typically are far lower than charges. In patients who receive standard dose, myelosuppressive chemotherapy, hospitalization may add more than $3700 per cycle when mucositis is present (14). Although hospitalization in this setting is not common, it is expensive, approaching $10 000 per episode, when it occurs (29). When mucositis occurs in concert with other complications, the cost of hospitalization increases considerably (15). In one study, the hospitalization cost for feeding tube insertion exceeded $250 per night. The inpatient costs were $3065 and $1076 for patients with PEG and NG tubes with median stays of 14 and four nights, respectively. Combining the cost of tube insertion and hospital stay, the total cost for a patient with a PEG tube was three times that of a patient with an NG tube (8). Because of the high cost of managing mucositis-associated outcomes (enteral and parenteral feedings, hospitalizations, and febrile neutropenia), preventive strategies can be economically attractive, although the economic profile is affected by the tradeoff between the cost of the preventive strategy and the cost and prevalence of the serious outcomes of mucositis. Cryo-prevention, accomplished by exposure of the oral mucosa to ice during chemotherapy infusion, is an inexpensive and highly effective means of mucositis prevention in some clinical settings; it is recommended in current international guidelines when 5-fluorouracil and edatrexate are used (30). This is an excellent example of a cost-effective means for preventing costly outcomes. However, even in the case where the cost of prevention is large, it may be offset by savings achieved through preventing even more expensive outcomes. For example, the acquisition cost of palifermin (human keratinocyte growth factor) may be offset by fewer hospital days, fewer episodes of febrile neutropenia, and reduced requirements for total parenteral nutrition among stem cell transplant recipients whose conditioning regimens include total body irradiation (12) (Table 1). In this same population, the cost of low-level laser therapy, oral care, and dental consultations also appears to be offset by a reduced incidence and severity of oral mucositis and its attendant opioid and parenteral nutrition use (13) (Table 1). Whether palifermin’s favorable economic profile would be seen in other clinical settings with a lower incidence of severe mucositis and fewer serious outcomes remains unstudied. However, a recent study of low-level laser therapy among patients receiving chemo-radiation for head and neck cancers suggests that although this intervention does not save money in this population, it could be considered a cost-effective means for reducing morbidity from oral mucositis (31). Costs of Osteoradionecrosis Management and Prevention Osteoradionecrosis is uncommon and many patients respond to antibiotic therapy. Occasionally, it is refractory to conservative therapy, and debridement of necrotic bone is required at a cost approximating $4800 (Table 2) (20). Other surgical procedures including sequestration, resection or reconstruction increase costs from $37 000 to as much as $78 000 (17,20). The use of HBO therapy for treatment is controversial; when it is used, the cost is approximately $800 per treatment, often for a total of 15–30 treatments, although administration of as many as 60 treatments is not uncommon (32). Thus, the cost of such treatment may approach $40 000. Other analyses show the cost for hyperbaric chamber per session is $382, and the cost per cycle (15 sessions) is $5743 (21). One study shows a modified protocol for HBO treatment is more effective and less expensive than conservative treatment ($12 683 vs $78 809) (17). In the case where all of these treatment modalities are required, reported costs range between $40 000 and $85 000 (33,34). Marx and colleagues compared treatment costs of three strategies, no HBO therapy, HBO without surgery, and a specialized HBO surgery protocol and found lower costs ($306 112 vs $275 057 vs $133 092) and superior resolution rates (8% vs 17% vs 100%) with the specialized HBO surgery protocol (35). The incremental cost of using HBO treatments to prevent osteoradionecrosis is estimated to exceed $30 000 per case avoided (18). Similarly, other authors have estimated the cost of an HBO preventive strategy to be approximately $35 491 (35). Costs of Bisphosphonate-Associated Osteonecrosis of the Jaw Osteonecrosis of the jaw is a well-described complication of bisphosphonate therapy among patients with cancer. As in the case of osteoradionecrosis, multiple treatment modalities may be used from medication to extractions and more extensive surgical procedures. As would be expected from a wide range of treatment strategies, costs vary considerably. Najm and colleagues estimate the median cost of treatment to be $2032 with a maximum cost of $30 593 (36). Interestingly, the two most expensive components of total costs were medications (primarily antibiotics) and clinic visits, perhaps due to the prolonged course of these patients. Costs of Xerostomia Management and Prevention Xerostomia is common during and after radiation therapy for head and neck cancers and total body irradiation before transplantation, but it rarely results in severe morbidity or hospitalization. However, xerostomia persists long after radiation is concluded and can be associated with costly outcomes (Table 3). Pilocarpine or cevimeline often are used to ameliorate the symptoms, at a cost of $46–$190 and $87–$158 per month, respectively (purchase price from GoodRx, accessed July 12, 2018). Recent data from the Centers for Medicare and Medicaid Services show that 100% of Part D prescription plans cover pilocarpine therapy of xerostomia (37). Although the cost seems low when compared with the cost of mucositis management, it is an ongoing expense for an extended period of time. Moreover, patients with xerostomia are at increased risk for dental caries. Management of these events may cost from $192 to $399 for composite fillings and $4500 and higher for implants (22). Prevention of xerostomia may be achieved if salivary function is preserved by avoiding irradiation of salivary and submandibular glands. Intensity modulated radiation therapy (IMRT) and other conformal methods of radiation therapy may achieve this goal, but they are more costly to deliver than conventional radiation therapy owing to increased planning time (38) and quality assurance (24). The total cost for IMRT is estimated to be approximately $15 725 (23). The costs attributable to the additional IMRT planning and each treatment session were $3993 and $377, respectively (23). The cost for IMRT with daily quality assurance using an electronic portal imaging device was estimated to be $15 695, of which approximately 14% of the total cost, $2110, was for IMRT planning and quality assurance (24). Another study estimated total cost for IMRT at $13 159, including consultation, planning, quality assurance, preparation and delivery, and overhead. About 18% and 64% of total cost were for IMRT planning and quality assurance, and preparation and delivery. The cost could be as high as $14 213 with longer time for planning, quality assurance, and delivery (25). Discussion Although information about the economic implications of oral complications of cancer treatment is limited, based on the available literature, we conclude that serious outcomes (hospitalization and enteral feedings) or chronic use of interventions (sialogogues) are the most important drivers of cost. In this respect, these complications are similar to other complications of cancer treatment. For example, chemotherapy-induced diarrhea is typically controlled with loperamide or other relatively inexpensive agents. However, a study of patients with colorectal cancer who developed grade 3–4 diarrhea that required hospitalization showed that parenteral fluids were required in 87% and 14% died during the hospitalization; the average cost of these hospitalizations exceed CAD $8000 (39). Despite this observation, it is important to note that even mild oral mucositis is a major concern to patients and to their caregivers. Ethier and colleagues report that the parents of children receiving chemotherapy were willing to pay an average of CAD$1371 to prevent mild mucositis and CAD$ 5499 to prevent severe mucositis in their children (40). In most studies of the cost of complications of treatment, an attempt is made to identify the incremental cost of the complication, typically by comparing the average costs of patients with the complication to those without. It is, however, the rare patient who experiences a single complication in isolation. More typically, complications occur in clusters, and, thus, it is difficult to identify costs attributable to a single complication. This clinical reality has important implications for interpretation of all such studies. In particular, it cannot be assumed that the cost of preventing a single complication will be offset by savings of the magnitude described by such studies. Only in the case where all complications that are usually observed together are prevented can this assumption be valid. It is important to note that oral mucositis is not a prominent feature of emerging chemotherapies (ie, monoclonal antibodies) (41,42). However, because these therapies are often administered in combination with conventional chemotherapy regimens, it is unlikely that oral mucositis or its costs will be substantially reduced in the foreseeable future. Furthermore, as experience with these drugs accumulates, it is possible that increased risk will be demonstrated with some combinations. Similarly, many contemporary stem cell transplant conditioning regimens avoid total body irradiation, and thus the incidence of both oral mucositis and adverse outcomes are lower. It is reasonable to expect that oral mucositis will have a smaller impact on the cost of these regimens. In contrast to chemotherapy-induced oral mucositis, radiation-induced oral mucositis may increase in incidence and severity as chemotherapy increasingly accompanies radiation therapy in the treatment of head and neck cancers. Both the incidence and severity of oral mucositis reportedly increase in the case where chemotherapy is administered alongside radiation therapy (28), although this finding is not consistent across all studies (26). As this practice increases, an increase in the incidence of serious outcomes and their costs is possible. IMRT has rapidly replaced conventional radiation therapy and is becoming the standard of care for head and neck cancers. Although a reduced risk of oral mucositis with IMRT was hypothesized, no reduction in incidence or severity has been demonstrated in multiple studies of this treatment modality (3,26). However, the use of IMRT may be associated with a reduced incidence of xerostomia. An Agency for Healthcare Research and Quality report indicated that IMRT causes fewer cases of xerostomia than traditional radiation therapies (43). The risk of xerostomia is determined by radiation fields and doses to the saliva-producing glands. In the case where these glands can be protected through use of IMRT, it is reasonable to expect reductions in the incidence, severity, and economic costs of xerostomia. Whether the use of chemo-radiation will result in more cases or more severe osteoradionecrosis and whether IMRT will result in fewer or less severe cases of osteoradionecrosis is not known. Estimation of any change in the economic costs of osteoradionecrosis caused by these emerging therapies awaits future research. However, an increase in osteonecrosis of the jaw has mirrored the increasing use of bisphosphonates (44). Further study of the economic costs of this condition also await future research. Blueprint for Future Research Based on our review of the published literature, there are substantial gaps in our knowledge about the economic burden imposed by oral complications of cancer therapy (Table 4). Examination of the dates of data collection and publication for articles cited clearly demonstrates the lack of information about complications following newly developed therapies. Updates to these studies would fill this need. Our search failed to identify articles examining out-of-pocket costs, patient time cost, and lost wages and productivity from oral complications. Out-of-pocket costs may be substantial and could affect patient compliance with treatment regimens. Such costs may be most applicable to management of less severe oral complications (ie, use of liquid nutritional products in patients who do not require enteral nutrition). Thus, although their cost may be less than that incurred for severe complications, their use may be far more common. It is important to note that out-of-pocket costs may vary by insurance plan. Careful consideration of out-of-pocket costs, across multiple payers and plans, should be a priority. Accurate estimates of the incidence and duration of oral complications are critical to accurate estimates of cost. Previous research demonstrates inconsistencies between clinician- and patient-reported estimates of incidence of oral mucositis and its severity and duration (45–47). Unfortunately, many studies examine only clinician-reported incidence. There is a critical need for studies of patient-reported incidence and severity of oral mucositis. Table 4. Gaps in knowledge of the economic burden of oral complications Perspective Gaps in cost knowledge Patients Insurance co-pays and deductibles; over-the-counter medications, nutritional supplements, and noncovered medical therapies; transportation and dependent care during clinical and hospital visits; time costs; lost wages Clinical Incidence and cost of oral complications accounting for other simultaneous complications Providers Cost of resources used; opportunity costs of resources used Payers Population-based prevention and treatment costs and incidence of oral complications to support evidence-based coverage and reimbursement decisions Society Productivity lost Perspective Gaps in cost knowledge Patients Insurance co-pays and deductibles; over-the-counter medications, nutritional supplements, and noncovered medical therapies; transportation and dependent care during clinical and hospital visits; time costs; lost wages Clinical Incidence and cost of oral complications accounting for other simultaneous complications Providers Cost of resources used; opportunity costs of resources used Payers Population-based prevention and treatment costs and incidence of oral complications to support evidence-based coverage and reimbursement decisions Society Productivity lost View Large Table 4. Gaps in knowledge of the economic burden of oral complications Perspective Gaps in cost knowledge Patients Insurance co-pays and deductibles; over-the-counter medications, nutritional supplements, and noncovered medical therapies; transportation and dependent care during clinical and hospital visits; time costs; lost wages Clinical Incidence and cost of oral complications accounting for other simultaneous complications Providers Cost of resources used; opportunity costs of resources used Payers Population-based prevention and treatment costs and incidence of oral complications to support evidence-based coverage and reimbursement decisions Society Productivity lost Perspective Gaps in cost knowledge Patients Insurance co-pays and deductibles; over-the-counter medications, nutritional supplements, and noncovered medical therapies; transportation and dependent care during clinical and hospital visits; time costs; lost wages Clinical Incidence and cost of oral complications accounting for other simultaneous complications Providers Cost of resources used; opportunity costs of resources used Payers Population-based prevention and treatment costs and incidence of oral complications to support evidence-based coverage and reimbursement decisions Society Productivity lost View Large Collection of data from patients about out-of-pocket costs, incidence and severity of oral complications, and outcomes can be complex and expensive. Funding for such studies is particularly challenging. Thus, we strongly support the current trend to collect such data alongside clinical trials, particularly those sponsored by cooperative groups. In addition to their research infrastructure and large patient populations, cooperative group trials have the added advantage of being conducted at multiple sites. As previously mentioned, virtually all studies of the cost of oral complications compare the average costs of groups of patients with and without the complication. The difference between these costs is considered the incremental cost of the oral complication. However, such an analysis is based on the assumption that the oral complication occurs independently of other complications and that the costs of other complications are equally distributed between the groups with and without the oral complication. Clinical experience and prior research suggest that this is an incorrect assumption; complications often occur together in the same patient. Furthermore, costs increase exponentially (not linearly) as the number of complications increase (48). Future analyses of the costs of oral complications must account for the impact of other coexisting complications to provide accurate estimates of the cost directly attributable to oral complications. With a few notable exceptions (7,11,15), the studies identified in our search described single institution rather than population-based costs. Because of the impact of local practice patterns and varying case-mix and payer mix, this approach reduces the generalizability of results. Multisite and population-based studies of the incidence and costs of oral complications are sorely needed to support evidence-based coverage and reimbursement policies. Also, there are important limitations to examining the costs of oral complications of cancer therapies across nations and health-care systems. The literature shows that the cost of these complications is driven primarily by the cost of serious outcomes that may be treated in the hospital. In some countries and health-care systems, hospital occupancy rates and daily costs are both low, whereas in others they are expensive and occupancy rates are high. The direct costs of hospital days and the opportunity cost of their use for treating oral complications will vary considerably among health-care systems. Responsible evaluation of the economic implications of these complications and application of findings to policy decisions require careful attention to the health-care system environment. Oral complications of cancer therapy can result in important economic costs. Based on current knowledge about the incidence of oral complications with emerging therapies, costs may be unchanged with newer chemotherapy regimens, increase with chemoradiation, and remain unchanged or decrease with the use of IMRT. The impact of emerging therapies on the cost of osteoradionecrosis is unknown. The total cost of bisphosphonate-associated osteonecrosis of the jaw certainly will increase with increasing incidence, but few estimates of its cost are available. Future research focusing on oral complications of emerging therapies should include patient-reported incidence and severity and out-of-pocket costs. Multicenter and population-based studies with careful attention to the impact of variation in the health-care system environment should be a priority. Notes Affiliation of authors: Department of Health Services Research, University of Texas M. D. Anderson Cancer Center, Houston, TX (LSE, YCC). 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For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Costs of Oral Complications of Cancer Therapies: Estimates and a Blueprint for Future Study

JNCI Monographs , Volume 2019 (53) – Aug 1, 2019

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Abstract

Abstract Oral complications of cancer treatment are common; however, their clinical and economic importance is often underappreciated. We reviewed the literature on the economic implications of oral complications, updating a previous report in the predecessor to this issue. We searched the Medline and Scopus databases for papers published as of December 31, 2017 that described the economic consequences of preventing and managing oral complications and reviewed the literature reporting the costs of oral mucositis, xerostomia, and osteonecrosis. Cost estimates were inflated to 2017 US dollars. We identified 16 papers describing the cost of managing mucositis, eight describing the cost of osteoradionecrosis, one describing the cost of bisphosphonate-associate osteonecrosis of the jaw, and four describing the cost of xerostomia. The incremental cost of oral mucositis was approximately $5000–$30 000 among patients receiving radiation therapy and $3700 per cycle among patients receiving chemotherapy. The incremental cost of mucositis-related hospitalization among stem cell transplant recipients exceeded $70 000. Conservative management of osteoradionecrosis (antibiotics, debridement) costs $4000–$35 000, although estimates as high as $74 000 have been reported. Hyperbaric oxygen therapy may add $10 000–$50 000 to the cost of therapy. Sialogogues are required for years for the management of xerostomia at a cost of $40–$200 per month. Serious (hospitalization, hyperbaric oxygen therapy) or long-term (sialogogues) outcomes are the major drivers of cost. Future research should address patients’ out-of-pocket costs and the costs of oral complications of new treatments. Multisite studies, particularly those conducted by cooperative groups, should be prioritized. Oral complications of emerging cancer therapies can cause serious morbidity, including mucositis, xerostomia, oral infections, acute and chronic oral pain, oral graft-versus-host disease, osteoradionecrosis, and bisphosphonate-associated osteonecrosis of the jaw. The incidence and management of these complications are described in other chapters in this monograph. Considering the severity of their morbidity and the complexity of their management, these complications may result in increased resource utilization and cost (1). The economic implications of oral complications were examined in a predecessor to this monograph, which was published in 2001 (2). Since that publication, new therapies have emerged (ie, targeted therapies), existing therapies have been modified (ie, stem cell transplant or intensity modulated radiation therapy), and associations between commonly used therapies and toxicities have been identified (ie, bisphosphonates and osteonecrosis of the jaw). In this manuscript, we report the results of a review of the literature on the economic implications of four oral complications—oral mucositis, xerostomia, osteoradionecrosis, and bisphosphonate-associated osteonecrosis of the jaw—focusing on their relationships with emerging cancer therapies. Owing to the paucity of data in the literature, we also propose a conceptual framework for their future study. Conceptual Framework and Search Strategy The costs of oral complications result from interventions to manage oral complications and their outcomes (pain medications, nutritional support, pilocarpine, hyperbaric oxygen [HBO], antibiotics, and debridement) as well as from interventions to prevent them (palifermin, amifostine, intensity-modulated radiation therapy) (Figure 1). Prevention costs accrue to all patients, whereas management costs accrue only to those affected. Assuming a payer’s perspective, the costs of preventing and managing these complications accrue to both third-party payers (private insurance companies or public plans such as Medicare) and to patients. Figure 1. View largeDownload slide Conceptual model of the costs of oral complications. G-tube = gastrostomy tube; HBO = hyperbaric oxygen therapy; IMRT = intensity modulated radiation therapy; RT = radiation therapy. *Low-level laser and hyperbaric oxygen have been studied for both prevention and treatment of oral mucositis and osteoradionecrosis, respectively. Figure 1. View largeDownload slide Conceptual model of the costs of oral complications. G-tube = gastrostomy tube; HBO = hyperbaric oxygen therapy; IMRT = intensity modulated radiation therapy; RT = radiation therapy. *Low-level laser and hyperbaric oxygen have been studied for both prevention and treatment of oral mucositis and osteoradionecrosis, respectively. Patient’s costs include over-the-counter medications, copayments, deductibles, time costs, transportation costs, productivity costs, and wages lost. Third-party payer’s costs may include the costs of professionals’ time, outpatient visits, medications, hospitalizations, and laboratory and diagnostic tests. We searched the Medline and Scopus databases for papers published before December 31, 2017, describing the economic consequences of preventing and managing oral mucositis, radiation-induced xerostomia, osteoradionecrosis, osteonecrosis of the jaw, oral pain and infections, and oral graft-versus-host disease with the goal of including both patient and third-party payer costs. Search terms included “mucositis,” “stomatitis,” “xerostomia,” “osteoradionecrosis” or “osteonecrosis,” “oral pain,” or “oral graft-versus-host disease” in combination with “cost,” “economic analysis,” “cost-effectiveness,” or “cost-benefit.” We also searched the publications cited by papers identified in the original search to identify other related papers. Perhaps because oral mucositis is a common complication of cancer therapy, an occasional cause of serious morbidity, and a target for recent new drug development, information on the cost of preventing and managing oral mucositis was more readily available in the literature than information about other oral complications. Our search identified 16 papers with cost estimates that are summarized in Table 1. In contrast, osteoradionecrosis is quite uncommon, but more frequently causes serious morbidity and requires aggressive and costly management. Our search identified eight papers describing the cost of managing osteoradionecrosis; these are reported in Table 2. One paper reporting the cost of bisphosphonate-associated osteonecrosis of the jaw is described in the text. Four papers with estimates of the costs of xerostomia management were identified. These were augmented by estimates on the current cost of sialogogues and are reported in Table 3. In all tables, sponsorship of studies by pharmaceutical industry has been indicated to permit the reader to assess possible sources of bias. Table 1. Estimates of the cost of managing or preventing oral mucositis* First author, publication year (ref.) Treatment Cancer Cost component Cost estimate Original paper† 2017, US$ Peterman, 2001 (2) RT±CT Head and neck Incremental cost, low and high estimates 2949; 4037 5067; 6938 Elting, 2007 (3) RT Head and neck Incremental cost, mucositis vs none 5978 7965 Elting, 2007 (3) CT+RT Head and neck Incremental cost, mucositis vs none 6046 8056 Nonzee, 2008 (4) CT+RT Head and neck Incremental cost 17 244 22 597 Sartori, 1996 (5) – Head and neck Mean daily cost of PEG management and side effects 28 890 L 34 Sartori, 1996 (5) – Head and neck Mean daily cost of NG tube management and side effects 27 340 L 32 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, amifostine prophylaxis 4401 7605 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, no prophylaxis 5873 10 154 Antunes, 2016 CT+RT Head and neck Prevention and supportive care costs, low-level laser therapy 1940 (2013) 2049 Antunes, 2016 CT+RT Head and neck Standard preventive care and supportive care, NO low-level laser therapy 251 (2013) 265 OCCI 2004, 2005 (7) – Other ENT infections Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs 3013 CAD 2957 OCCI 2009, 2010 (7) – Oral cavity/salivary gland/jaw Average cost of oral mucositis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 5059 CAD 4966 OCCI 2009, 2010 (7) – Miscellaneous ENT disorder Average cost of candida stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4872 CAD 4783 OCCI 2009, 2010 (7) – Oral cavity, salivary gland, or jaw Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4662 CAD 4576 Corry, 2009 (8) CT/RT Head and neck Cost of each PEG tube, insertion (by surgeon), and median 14 nights stay in hospital 110; 626; 3556 AU 95; 540; 3065 Corry, 2009 (8) CT/RT Head and neck Cost of each NG tube, insertion (by nurse), & median 4-night stay in hospital 26;50; 1016 AU 22; 43; 1076 Nonzee, 2008 (4) CT+RT NSCLC Incremental cost 25 060 32 531 Banz, 2011(9) CT NSCLC Management cost per event grade III/IV in Germany; France; Italy; Spain 312€ 441€ 45€ 102€ 37452054121 Sonis, 2001 (10) HSCT – Incremental hospital charges, oral ulceration 42 749 73 461 Vera-Llonch, 2007 (11) HSCT – Incremental hospital charge grade V vs grade 0 over 28 days‡ 223 426 375 204 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, palifermin prophylaxis 73 938 107 895 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, no prophylaxis 77 535 113 145 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – autologous transplant 37 010; 47 568 40 359; 51 872 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – Allogeneic transplant 54 655; 70 953 59 599; 77 373 Elting, 2003 (14) CT Any myelo-suppressed Estimated incremental hospital cost per cycle 2384 3762 Weiner, 2007 (15) CT All Inpatient-specific daily cost; with and without supportive drugs 1058; 1091 1609; 1658 Elting, 2004 (16) All All Hospitalization cost 7985 12 088 First author, publication year (ref.) Treatment Cancer Cost component Cost estimate Original paper† 2017, US$ Peterman, 2001 (2) RT±CT Head and neck Incremental cost, low and high estimates 2949; 4037 5067; 6938 Elting, 2007 (3) RT Head and neck Incremental cost, mucositis vs none 5978 7965 Elting, 2007 (3) CT+RT Head and neck Incremental cost, mucositis vs none 6046 8056 Nonzee, 2008 (4) CT+RT Head and neck Incremental cost 17 244 22 597 Sartori, 1996 (5) – Head and neck Mean daily cost of PEG management and side effects 28 890 L 34 Sartori, 1996 (5) – Head and neck Mean daily cost of NG tube management and side effects 27 340 L 32 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, amifostine prophylaxis 4401 7605 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, no prophylaxis 5873 10 154 Antunes, 2016 CT+RT Head and neck Prevention and supportive care costs, low-level laser therapy 1940 (2013) 2049 Antunes, 2016 CT+RT Head and neck Standard preventive care and supportive care, NO low-level laser therapy 251 (2013) 265 OCCI 2004, 2005 (7) – Other ENT infections Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs 3013 CAD 2957 OCCI 2009, 2010 (7) – Oral cavity/salivary gland/jaw Average cost of oral mucositis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 5059 CAD 4966 OCCI 2009, 2010 (7) – Miscellaneous ENT disorder Average cost of candida stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4872 CAD 4783 OCCI 2009, 2010 (7) – Oral cavity, salivary gland, or jaw Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4662 CAD 4576 Corry, 2009 (8) CT/RT Head and neck Cost of each PEG tube, insertion (by surgeon), and median 14 nights stay in hospital 110; 626; 3556 AU 95; 540; 3065 Corry, 2009 (8) CT/RT Head and neck Cost of each NG tube, insertion (by nurse), & median 4-night stay in hospital 26;50; 1016 AU 22; 43; 1076 Nonzee, 2008 (4) CT+RT NSCLC Incremental cost 25 060 32 531 Banz, 2011(9) CT NSCLC Management cost per event grade III/IV in Germany; France; Italy; Spain 312€ 441€ 45€ 102€ 37452054121 Sonis, 2001 (10) HSCT – Incremental hospital charges, oral ulceration 42 749 73 461 Vera-Llonch, 2007 (11) HSCT – Incremental hospital charge grade V vs grade 0 over 28 days‡ 223 426 375 204 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, palifermin prophylaxis 73 938 107 895 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, no prophylaxis 77 535 113 145 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – autologous transplant 37 010; 47 568 40 359; 51 872 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – Allogeneic transplant 54 655; 70 953 59 599; 77 373 Elting, 2003 (14) CT Any myelo-suppressed Estimated incremental hospital cost per cycle 2384 3762 Weiner, 2007 (15) CT All Inpatient-specific daily cost; with and without supportive drugs 1058; 1091 1609; 1658 Elting, 2004 (16) All All Hospitalization cost 7985 12 088 * Italics indicate studies sponsored by pharmaceutical industry. AU = Australian dollar; CAD = Canadian dollar; CT = chemotherapy; CT+RT = chemoradiotherapy; ENT = ear, nose, and throat; HCST = hematopoietic stem cell transplant; L = Italian lire; NSCLC = non-small cell lung cancer; NG = nasogastric; OCCI = Ontario Case Costing Initiative; PEG = percutaneous endoscopic gastrostomy; RT = radiation therapy; TBI = total body irradiation. † Currency in US dollars, unless otherwise noted. ‡ Mean charge, US dollars: for grade 0 = $339 273; for grade 5 = $693 488. View Large Table 1. Estimates of the cost of managing or preventing oral mucositis* First author, publication year (ref.) Treatment Cancer Cost component Cost estimate Original paper† 2017, US$ Peterman, 2001 (2) RT±CT Head and neck Incremental cost, low and high estimates 2949; 4037 5067; 6938 Elting, 2007 (3) RT Head and neck Incremental cost, mucositis vs none 5978 7965 Elting, 2007 (3) CT+RT Head and neck Incremental cost, mucositis vs none 6046 8056 Nonzee, 2008 (4) CT+RT Head and neck Incremental cost 17 244 22 597 Sartori, 1996 (5) – Head and neck Mean daily cost of PEG management and side effects 28 890 L 34 Sartori, 1996 (5) – Head and neck Mean daily cost of NG tube management and side effects 27 340 L 32 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, amifostine prophylaxis 4401 7605 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, no prophylaxis 5873 10 154 Antunes, 2016 CT+RT Head and neck Prevention and supportive care costs, low-level laser therapy 1940 (2013) 2049 Antunes, 2016 CT+RT Head and neck Standard preventive care and supportive care, NO low-level laser therapy 251 (2013) 265 OCCI 2004, 2005 (7) – Other ENT infections Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs 3013 CAD 2957 OCCI 2009, 2010 (7) – Oral cavity/salivary gland/jaw Average cost of oral mucositis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 5059 CAD 4966 OCCI 2009, 2010 (7) – Miscellaneous ENT disorder Average cost of candida stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4872 CAD 4783 OCCI 2009, 2010 (7) – Oral cavity, salivary gland, or jaw Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4662 CAD 4576 Corry, 2009 (8) CT/RT Head and neck Cost of each PEG tube, insertion (by surgeon), and median 14 nights stay in hospital 110; 626; 3556 AU 95; 540; 3065 Corry, 2009 (8) CT/RT Head and neck Cost of each NG tube, insertion (by nurse), & median 4-night stay in hospital 26;50; 1016 AU 22; 43; 1076 Nonzee, 2008 (4) CT+RT NSCLC Incremental cost 25 060 32 531 Banz, 2011(9) CT NSCLC Management cost per event grade III/IV in Germany; France; Italy; Spain 312€ 441€ 45€ 102€ 37452054121 Sonis, 2001 (10) HSCT – Incremental hospital charges, oral ulceration 42 749 73 461 Vera-Llonch, 2007 (11) HSCT – Incremental hospital charge grade V vs grade 0 over 28 days‡ 223 426 375 204 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, palifermin prophylaxis 73 938 107 895 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, no prophylaxis 77 535 113 145 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – autologous transplant 37 010; 47 568 40 359; 51 872 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – Allogeneic transplant 54 655; 70 953 59 599; 77 373 Elting, 2003 (14) CT Any myelo-suppressed Estimated incremental hospital cost per cycle 2384 3762 Weiner, 2007 (15) CT All Inpatient-specific daily cost; with and without supportive drugs 1058; 1091 1609; 1658 Elting, 2004 (16) All All Hospitalization cost 7985 12 088 First author, publication year (ref.) Treatment Cancer Cost component Cost estimate Original paper† 2017, US$ Peterman, 2001 (2) RT±CT Head and neck Incremental cost, low and high estimates 2949; 4037 5067; 6938 Elting, 2007 (3) RT Head and neck Incremental cost, mucositis vs none 5978 7965 Elting, 2007 (3) CT+RT Head and neck Incremental cost, mucositis vs none 6046 8056 Nonzee, 2008 (4) CT+RT Head and neck Incremental cost 17 244 22 597 Sartori, 1996 (5) – Head and neck Mean daily cost of PEG management and side effects 28 890 L 34 Sartori, 1996 (5) – Head and neck Mean daily cost of NG tube management and side effects 27 340 L 32 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, amifostine prophylaxis 4401 7605 Bennett, 2001 (6) CT+RT Head and neck Supportive care costs, no prophylaxis 5873 10 154 Antunes, 2016 CT+RT Head and neck Prevention and supportive care costs, low-level laser therapy 1940 (2013) 2049 Antunes, 2016 CT+RT Head and neck Standard preventive care and supportive care, NO low-level laser therapy 251 (2013) 265 OCCI 2004, 2005 (7) – Other ENT infections Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs 3013 CAD 2957 OCCI 2009, 2010 (7) – Oral cavity/salivary gland/jaw Average cost of oral mucositis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 5059 CAD 4966 OCCI 2009, 2010 (7) – Miscellaneous ENT disorder Average cost of candida stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4872 CAD 4783 OCCI 2009, 2010 (7) – Oral cavity, salivary gland, or jaw Average cost of other forms of stomatitis related to care; also includes nursing, diagnostic imaging, pharmacy, and labs. 4662 CAD 4576 Corry, 2009 (8) CT/RT Head and neck Cost of each PEG tube, insertion (by surgeon), and median 14 nights stay in hospital 110; 626; 3556 AU 95; 540; 3065 Corry, 2009 (8) CT/RT Head and neck Cost of each NG tube, insertion (by nurse), & median 4-night stay in hospital 26;50; 1016 AU 22; 43; 1076 Nonzee, 2008 (4) CT+RT NSCLC Incremental cost 25 060 32 531 Banz, 2011(9) CT NSCLC Management cost per event grade III/IV in Germany; France; Italy; Spain 312€ 441€ 45€ 102€ 37452054121 Sonis, 2001 (10) HSCT – Incremental hospital charges, oral ulceration 42 749 73 461 Vera-Llonch, 2007 (11) HSCT – Incremental hospital charge grade V vs grade 0 over 28 days‡ 223 426 375 204 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, palifermin prophylaxis 73 938 107 895 Elting, 2007 (12) TBI+HSCT Hematologic Hospital costs, no prophylaxis 77 535 113 145 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – autologous transplant 37 010; 47 568 40 359; 51 872 Bezinelli, 2014 (13) HSCT±TBI – Mean cost of transplantation with and without low-level laser therapy and dental management – Allogeneic transplant 54 655; 70 953 59 599; 77 373 Elting, 2003 (14) CT Any myelo-suppressed Estimated incremental hospital cost per cycle 2384 3762 Weiner, 2007 (15) CT All Inpatient-specific daily cost; with and without supportive drugs 1058; 1091 1609; 1658 Elting, 2004 (16) All All Hospitalization cost 7985 12 088 * Italics indicate studies sponsored by pharmaceutical industry. AU = Australian dollar; CAD = Canadian dollar; CT = chemotherapy; CT+RT = chemoradiotherapy; ENT = ear, nose, and throat; HCST = hematopoietic stem cell transplant; L = Italian lire; NSCLC = non-small cell lung cancer; NG = nasogastric; OCCI = Ontario Case Costing Initiative; PEG = percutaneous endoscopic gastrostomy; RT = radiation therapy; TBI = total body irradiation. † Currency in US dollars, unless otherwise noted. ‡ Mean charge, US dollars: for grade 0 = $339 273; for grade 5 = $693 488. View Large Table 2. Cost of managing osteoradionecrosis among patients with head and neck cancers* First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ Marx, 1985 HBO without surgery, average total cost $62 000 275 057 Marx, 1985 No HBO, average total cost $69 000 306 112 Marx, 1985 University of Miami HBO surgery protocol 30 000 133 092 Dempsey, 1997 (17) Conservative (medication, ± sequestrectomy; ± extractions ±reconstruction) 63 212 CAD 78 809 Dempsey, 1997 (17) HBO (medication, ± sequestrectomy; ± extractions ± reconstruction) 10 172 CAD 12 683 MSAC Au, 2000(18) HBO (30 dives) 6941 AUD 8521 NHS, 2007 (19) HBO (30- to 60-min dives), treatment only 900 GPB 1908 Kelishadi, 2009 (20) HBO (30- to 90-min dives), all costs 21 120 26 520 Kelishadi, 2009 (20) Debridement 3890 4884 Kelishadi, 2009 (20) Surgical resection plus microvascular free flap 30 030 37 707 Fonseca, 2011 (21) Hyperbaric chamber per session, per cycle (15 sessions) 329 R 4935 R 3825743 Park, 2017 Free-flap reconstruction (in- and out-patient costs, HBO, and surgery) 123 900 NZD 85 098 Patel, 2017 Surgical management (one or more surgical procedures, in- and out-patient stays, medication HBO) 28 785 GBP 41 754 First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ Marx, 1985 HBO without surgery, average total cost $62 000 275 057 Marx, 1985 No HBO, average total cost $69 000 306 112 Marx, 1985 University of Miami HBO surgery protocol 30 000 133 092 Dempsey, 1997 (17) Conservative (medication, ± sequestrectomy; ± extractions ±reconstruction) 63 212 CAD 78 809 Dempsey, 1997 (17) HBO (medication, ± sequestrectomy; ± extractions ± reconstruction) 10 172 CAD 12 683 MSAC Au, 2000(18) HBO (30 dives) 6941 AUD 8521 NHS, 2007 (19) HBO (30- to 60-min dives), treatment only 900 GPB 1908 Kelishadi, 2009 (20) HBO (30- to 90-min dives), all costs 21 120 26 520 Kelishadi, 2009 (20) Debridement 3890 4884 Kelishadi, 2009 (20) Surgical resection plus microvascular free flap 30 030 37 707 Fonseca, 2011 (21) Hyperbaric chamber per session, per cycle (15 sessions) 329 R 4935 R 3825743 Park, 2017 Free-flap reconstruction (in- and out-patient costs, HBO, and surgery) 123 900 NZD 85 098 Patel, 2017 Surgical management (one or more surgical procedures, in- and out-patient stays, medication HBO) 28 785 GBP 41 754 * Italics indicate studies sponsored by pharmaceutical industry. AUD = Australian dollar; CAD = Canadian dollar; GBP = British pound; HBO = hyperbaric oxygen; L = Italian lire; NHS = National Health Service; NZD = New Zealand dollar; R= Brazil reais. † Currency in US dollars, unless otherwise noted. View Large Table 2. Cost of managing osteoradionecrosis among patients with head and neck cancers* First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ Marx, 1985 HBO without surgery, average total cost $62 000 275 057 Marx, 1985 No HBO, average total cost $69 000 306 112 Marx, 1985 University of Miami HBO surgery protocol 30 000 133 092 Dempsey, 1997 (17) Conservative (medication, ± sequestrectomy; ± extractions ±reconstruction) 63 212 CAD 78 809 Dempsey, 1997 (17) HBO (medication, ± sequestrectomy; ± extractions ± reconstruction) 10 172 CAD 12 683 MSAC Au, 2000(18) HBO (30 dives) 6941 AUD 8521 NHS, 2007 (19) HBO (30- to 60-min dives), treatment only 900 GPB 1908 Kelishadi, 2009 (20) HBO (30- to 90-min dives), all costs 21 120 26 520 Kelishadi, 2009 (20) Debridement 3890 4884 Kelishadi, 2009 (20) Surgical resection plus microvascular free flap 30 030 37 707 Fonseca, 2011 (21) Hyperbaric chamber per session, per cycle (15 sessions) 329 R 4935 R 3825743 Park, 2017 Free-flap reconstruction (in- and out-patient costs, HBO, and surgery) 123 900 NZD 85 098 Patel, 2017 Surgical management (one or more surgical procedures, in- and out-patient stays, medication HBO) 28 785 GBP 41 754 First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ Marx, 1985 HBO without surgery, average total cost $62 000 275 057 Marx, 1985 No HBO, average total cost $69 000 306 112 Marx, 1985 University of Miami HBO surgery protocol 30 000 133 092 Dempsey, 1997 (17) Conservative (medication, ± sequestrectomy; ± extractions ±reconstruction) 63 212 CAD 78 809 Dempsey, 1997 (17) HBO (medication, ± sequestrectomy; ± extractions ± reconstruction) 10 172 CAD 12 683 MSAC Au, 2000(18) HBO (30 dives) 6941 AUD 8521 NHS, 2007 (19) HBO (30- to 60-min dives), treatment only 900 GPB 1908 Kelishadi, 2009 (20) HBO (30- to 90-min dives), all costs 21 120 26 520 Kelishadi, 2009 (20) Debridement 3890 4884 Kelishadi, 2009 (20) Surgical resection plus microvascular free flap 30 030 37 707 Fonseca, 2011 (21) Hyperbaric chamber per session, per cycle (15 sessions) 329 R 4935 R 3825743 Park, 2017 Free-flap reconstruction (in- and out-patient costs, HBO, and surgery) 123 900 NZD 85 098 Patel, 2017 Surgical management (one or more surgical procedures, in- and out-patient stays, medication HBO) 28 785 GBP 41 754 * Italics indicate studies sponsored by pharmaceutical industry. AUD = Australian dollar; CAD = Canadian dollar; GBP = British pound; HBO = hyperbaric oxygen; L = Italian lire; NHS = National Health Service; NZD = New Zealand dollar; R= Brazil reais. † Currency in US dollars, unless otherwise noted. View Large Table 3. Cost of managing xerostomia among patients with head and neck cancers* First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ www.GoodRX.com‡ Pilocarpine purchase price 1 mo prescription 5 mg tid N/A 46–190 www.GoodRX.com‡ Cevimeline purchase price 1 mo prescription 30 mg tid N/A 87–158 Taylor, 2003 (22) Composite fillings for dental caries 120–250 192–399 Taylor, 2003 (22) Implants for dental caries 3000 4789 Bonastre, 2007 (23) Total cost of IMRT, planning for IMRT, each IMRT session 10 916 EUR; 2773 EUR, 247 EUR 15 725; 3993; 377 Van de Werf, 2009 (24) Total cost of IMRT, increased cost for quality assurance for IMRT 10 878 EUR; 1463 EUR 15 695; 2110 Yong, 2012 (25) Total cost of IMRT; consultation; CT simulation; dosimetry; quality assurance; treatment preparation and delivery and review visits; overhead 16 085 CAD; 292 CAD; 574 CAD; 2221 CAD; 678 CAD; 10 338 CAD; 1982 CAD 13 159; 238; 469; 1817; 553; 8457; 1622 First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ www.GoodRX.com‡ Pilocarpine purchase price 1 mo prescription 5 mg tid N/A 46–190 www.GoodRX.com‡ Cevimeline purchase price 1 mo prescription 30 mg tid N/A 87–158 Taylor, 2003 (22) Composite fillings for dental caries 120–250 192–399 Taylor, 2003 (22) Implants for dental caries 3000 4789 Bonastre, 2007 (23) Total cost of IMRT, planning for IMRT, each IMRT session 10 916 EUR; 2773 EUR, 247 EUR 15 725; 3993; 377 Van de Werf, 2009 (24) Total cost of IMRT, increased cost for quality assurance for IMRT 10 878 EUR; 1463 EUR 15 695; 2110 Yong, 2012 (25) Total cost of IMRT; consultation; CT simulation; dosimetry; quality assurance; treatment preparation and delivery and review visits; overhead 16 085 CAD; 292 CAD; 574 CAD; 2221 CAD; 678 CAD; 10 338 CAD; 1982 CAD 13 159; 238; 469; 1817; 553; 8457; 1622 * Italics indicate studies sponsored by pharmaceutical industry. CAD = Canadian dollar; CT = chemotherapy; EUR = euro; IMRT = intensity modulated radiation therapy; N/A = not applicable. † Currency in US dollars, unless otherwise noted. ‡ Accessed July 26, 2018. View Large Table 3. Cost of managing xerostomia among patients with head and neck cancers* First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ www.GoodRX.com‡ Pilocarpine purchase price 1 mo prescription 5 mg tid N/A 46–190 www.GoodRX.com‡ Cevimeline purchase price 1 mo prescription 30 mg tid N/A 87–158 Taylor, 2003 (22) Composite fillings for dental caries 120–250 192–399 Taylor, 2003 (22) Implants for dental caries 3000 4789 Bonastre, 2007 (23) Total cost of IMRT, planning for IMRT, each IMRT session 10 916 EUR; 2773 EUR, 247 EUR 15 725; 3993; 377 Van de Werf, 2009 (24) Total cost of IMRT, increased cost for quality assurance for IMRT 10 878 EUR; 1463 EUR 15 695; 2110 Yong, 2012 (25) Total cost of IMRT; consultation; CT simulation; dosimetry; quality assurance; treatment preparation and delivery and review visits; overhead 16 085 CAD; 292 CAD; 574 CAD; 2221 CAD; 678 CAD; 10 338 CAD; 1982 CAD 13 159; 238; 469; 1817; 553; 8457; 1622 First author, publication year (ref.) Cost component Cost estimate Original paper† 2017, US$ www.GoodRX.com‡ Pilocarpine purchase price 1 mo prescription 5 mg tid N/A 46–190 www.GoodRX.com‡ Cevimeline purchase price 1 mo prescription 30 mg tid N/A 87–158 Taylor, 2003 (22) Composite fillings for dental caries 120–250 192–399 Taylor, 2003 (22) Implants for dental caries 3000 4789 Bonastre, 2007 (23) Total cost of IMRT, planning for IMRT, each IMRT session 10 916 EUR; 2773 EUR, 247 EUR 15 725; 3993; 377 Van de Werf, 2009 (24) Total cost of IMRT, increased cost for quality assurance for IMRT 10 878 EUR; 1463 EUR 15 695; 2110 Yong, 2012 (25) Total cost of IMRT; consultation; CT simulation; dosimetry; quality assurance; treatment preparation and delivery and review visits; overhead 16 085 CAD; 292 CAD; 574 CAD; 2221 CAD; 678 CAD; 10 338 CAD; 1982 CAD 13 159; 238; 469; 1817; 553; 8457; 1622 * Italics indicate studies sponsored by pharmaceutical industry. CAD = Canadian dollar; CT = chemotherapy; EUR = euro; IMRT = intensity modulated radiation therapy; N/A = not applicable. † Currency in US dollars, unless otherwise noted. ‡ Accessed July 26, 2018. View Large No articles describing the economic implications of oral pain or oral graft-versus-host disease were identified, and none was identified that addressed the economic implications of any of these oral complications when induced by emerging therapies. Thus, we summarize the literature on the cost of oral complications with conventional therapies as described below and hypothesize about expected differences in cost with emerging therapies. No articles provided estimates of patients’ out-of-pocket costs, and few provided cost estimates across the entire continuum of care from prevention to management of long-term outcomes. Therefore, we provide a blueprint for future cost analyses. No attempt was made to aggregate estimates through meta-analytic techniques owing to the small number of articles identified and heterogeneity of study populations and designs. To facilitate examination of costs across multiple studies, cost estimates from the original reports were inflated to 2017 US dollars using the Consumer Price Index for health care (www.bls.gov; accessed July 12, 2018). The results of several studies were reported in currencies other than US dollars. In those cases, the original estimate was inflated to 2017 in the original currency (using the country-specific Consumer Price Index for health care), and the 2017 estimate was converted into US dollars based on estimates of the Purchasing Power Parity for gross domestic product computed by the International Monetary Fund (www.imf.org; www.oecd.org; accessed July 12, 2018). Results Costs of Oral Mucositis Management and Prevention In the predecessor to this issue, Peterman and colleagues provided low ($2949) and high ($4037) estimates of the incremental cost of managing patients with head and neck cancers with radiation- or chemoradiation-induced oral mucositis (2). Inflating these estimates to 2017 US dollars provides a range of the incremental costs of oral mucositis between $5067 and $6938 in this population (Table 1). Among more recent estimates in the same population, some are quite similar ($7965 and $8056) (3) whereas others are substantially higher ($22 597) (4). Nonzee et al. reported incremental costs of mucositis exceeding $30 000 among patients with non-small cell lung cancer who were receiving chemo-radiation; however, it is notable that patients in this study experienced an additional 14 days of mucositis-related hospitalization, exceeding the mean duration of hospitalization in prior studies (4). The Ontario Case Costing Initiative provides total cost data for oral mucositis and stomatitis in clinically homogeneous groups, ranging from $2957 to $4966 (7). The excess costs associated with mucositis result from management of costly and serious outcomes, most notably, excess days with enteral or parenteral feedings, hospital days, and episodes of febrile neutropenia. For example, between 15% and 55% of patients undergoing radiation of head and neck cancer require enteral feedings (3,26–28). The mean daily cost of percutaneous endoscopic gastrostomy (PEG) or nasogastric (NG) tube management is approximately $30, often required for 4–6 months (5). The total cost for inserting a PEG tube is almost 10 times that of an NG tube because the PEG tubes are inserted by surgeons ($540 and $43, respectively). Furthermore, the inpatient cost for patients with PEG tubes is three times the cost of patients with NG tubes (8) (Table 1). Mucositis-associated hospitalizations also contribute substantially to the cost of care (Table 1). The incremental cost of oral mucositis-associated hospitalization among stem-cell recipients is high, exceeding $70 000 for patients who develop ulceration and $375 000 among those with grade V mucositis (ulceration at four or more oral sites) (10,11). Comparison of these costs with those in other clinical settings is difficult owing to the high cost of hospitalization (often in specialized hospital units) among stem-cell recipients. Furthermore, comparison with other studies is likely inappropriate because charges, rather than costs, were analyzed; charges may be double or triple the costs of delivering care and payments typically are far lower than charges. In patients who receive standard dose, myelosuppressive chemotherapy, hospitalization may add more than $3700 per cycle when mucositis is present (14). Although hospitalization in this setting is not common, it is expensive, approaching $10 000 per episode, when it occurs (29). When mucositis occurs in concert with other complications, the cost of hospitalization increases considerably (15). In one study, the hospitalization cost for feeding tube insertion exceeded $250 per night. The inpatient costs were $3065 and $1076 for patients with PEG and NG tubes with median stays of 14 and four nights, respectively. Combining the cost of tube insertion and hospital stay, the total cost for a patient with a PEG tube was three times that of a patient with an NG tube (8). Because of the high cost of managing mucositis-associated outcomes (enteral and parenteral feedings, hospitalizations, and febrile neutropenia), preventive strategies can be economically attractive, although the economic profile is affected by the tradeoff between the cost of the preventive strategy and the cost and prevalence of the serious outcomes of mucositis. Cryo-prevention, accomplished by exposure of the oral mucosa to ice during chemotherapy infusion, is an inexpensive and highly effective means of mucositis prevention in some clinical settings; it is recommended in current international guidelines when 5-fluorouracil and edatrexate are used (30). This is an excellent example of a cost-effective means for preventing costly outcomes. However, even in the case where the cost of prevention is large, it may be offset by savings achieved through preventing even more expensive outcomes. For example, the acquisition cost of palifermin (human keratinocyte growth factor) may be offset by fewer hospital days, fewer episodes of febrile neutropenia, and reduced requirements for total parenteral nutrition among stem cell transplant recipients whose conditioning regimens include total body irradiation (12) (Table 1). In this same population, the cost of low-level laser therapy, oral care, and dental consultations also appears to be offset by a reduced incidence and severity of oral mucositis and its attendant opioid and parenteral nutrition use (13) (Table 1). Whether palifermin’s favorable economic profile would be seen in other clinical settings with a lower incidence of severe mucositis and fewer serious outcomes remains unstudied. However, a recent study of low-level laser therapy among patients receiving chemo-radiation for head and neck cancers suggests that although this intervention does not save money in this population, it could be considered a cost-effective means for reducing morbidity from oral mucositis (31). Costs of Osteoradionecrosis Management and Prevention Osteoradionecrosis is uncommon and many patients respond to antibiotic therapy. Occasionally, it is refractory to conservative therapy, and debridement of necrotic bone is required at a cost approximating $4800 (Table 2) (20). Other surgical procedures including sequestration, resection or reconstruction increase costs from $37 000 to as much as $78 000 (17,20). The use of HBO therapy for treatment is controversial; when it is used, the cost is approximately $800 per treatment, often for a total of 15–30 treatments, although administration of as many as 60 treatments is not uncommon (32). Thus, the cost of such treatment may approach $40 000. Other analyses show the cost for hyperbaric chamber per session is $382, and the cost per cycle (15 sessions) is $5743 (21). One study shows a modified protocol for HBO treatment is more effective and less expensive than conservative treatment ($12 683 vs $78 809) (17). In the case where all of these treatment modalities are required, reported costs range between $40 000 and $85 000 (33,34). Marx and colleagues compared treatment costs of three strategies, no HBO therapy, HBO without surgery, and a specialized HBO surgery protocol and found lower costs ($306 112 vs $275 057 vs $133 092) and superior resolution rates (8% vs 17% vs 100%) with the specialized HBO surgery protocol (35). The incremental cost of using HBO treatments to prevent osteoradionecrosis is estimated to exceed $30 000 per case avoided (18). Similarly, other authors have estimated the cost of an HBO preventive strategy to be approximately $35 491 (35). Costs of Bisphosphonate-Associated Osteonecrosis of the Jaw Osteonecrosis of the jaw is a well-described complication of bisphosphonate therapy among patients with cancer. As in the case of osteoradionecrosis, multiple treatment modalities may be used from medication to extractions and more extensive surgical procedures. As would be expected from a wide range of treatment strategies, costs vary considerably. Najm and colleagues estimate the median cost of treatment to be $2032 with a maximum cost of $30 593 (36). Interestingly, the two most expensive components of total costs were medications (primarily antibiotics) and clinic visits, perhaps due to the prolonged course of these patients. Costs of Xerostomia Management and Prevention Xerostomia is common during and after radiation therapy for head and neck cancers and total body irradiation before transplantation, but it rarely results in severe morbidity or hospitalization. However, xerostomia persists long after radiation is concluded and can be associated with costly outcomes (Table 3). Pilocarpine or cevimeline often are used to ameliorate the symptoms, at a cost of $46–$190 and $87–$158 per month, respectively (purchase price from GoodRx, accessed July 12, 2018). Recent data from the Centers for Medicare and Medicaid Services show that 100% of Part D prescription plans cover pilocarpine therapy of xerostomia (37). Although the cost seems low when compared with the cost of mucositis management, it is an ongoing expense for an extended period of time. Moreover, patients with xerostomia are at increased risk for dental caries. Management of these events may cost from $192 to $399 for composite fillings and $4500 and higher for implants (22). Prevention of xerostomia may be achieved if salivary function is preserved by avoiding irradiation of salivary and submandibular glands. Intensity modulated radiation therapy (IMRT) and other conformal methods of radiation therapy may achieve this goal, but they are more costly to deliver than conventional radiation therapy owing to increased planning time (38) and quality assurance (24). The total cost for IMRT is estimated to be approximately $15 725 (23). The costs attributable to the additional IMRT planning and each treatment session were $3993 and $377, respectively (23). The cost for IMRT with daily quality assurance using an electronic portal imaging device was estimated to be $15 695, of which approximately 14% of the total cost, $2110, was for IMRT planning and quality assurance (24). Another study estimated total cost for IMRT at $13 159, including consultation, planning, quality assurance, preparation and delivery, and overhead. About 18% and 64% of total cost were for IMRT planning and quality assurance, and preparation and delivery. The cost could be as high as $14 213 with longer time for planning, quality assurance, and delivery (25). Discussion Although information about the economic implications of oral complications of cancer treatment is limited, based on the available literature, we conclude that serious outcomes (hospitalization and enteral feedings) or chronic use of interventions (sialogogues) are the most important drivers of cost. In this respect, these complications are similar to other complications of cancer treatment. For example, chemotherapy-induced diarrhea is typically controlled with loperamide or other relatively inexpensive agents. However, a study of patients with colorectal cancer who developed grade 3–4 diarrhea that required hospitalization showed that parenteral fluids were required in 87% and 14% died during the hospitalization; the average cost of these hospitalizations exceed CAD $8000 (39). Despite this observation, it is important to note that even mild oral mucositis is a major concern to patients and to their caregivers. Ethier and colleagues report that the parents of children receiving chemotherapy were willing to pay an average of CAD$1371 to prevent mild mucositis and CAD$ 5499 to prevent severe mucositis in their children (40). In most studies of the cost of complications of treatment, an attempt is made to identify the incremental cost of the complication, typically by comparing the average costs of patients with the complication to those without. It is, however, the rare patient who experiences a single complication in isolation. More typically, complications occur in clusters, and, thus, it is difficult to identify costs attributable to a single complication. This clinical reality has important implications for interpretation of all such studies. In particular, it cannot be assumed that the cost of preventing a single complication will be offset by savings of the magnitude described by such studies. Only in the case where all complications that are usually observed together are prevented can this assumption be valid. It is important to note that oral mucositis is not a prominent feature of emerging chemotherapies (ie, monoclonal antibodies) (41,42). However, because these therapies are often administered in combination with conventional chemotherapy regimens, it is unlikely that oral mucositis or its costs will be substantially reduced in the foreseeable future. Furthermore, as experience with these drugs accumulates, it is possible that increased risk will be demonstrated with some combinations. Similarly, many contemporary stem cell transplant conditioning regimens avoid total body irradiation, and thus the incidence of both oral mucositis and adverse outcomes are lower. It is reasonable to expect that oral mucositis will have a smaller impact on the cost of these regimens. In contrast to chemotherapy-induced oral mucositis, radiation-induced oral mucositis may increase in incidence and severity as chemotherapy increasingly accompanies radiation therapy in the treatment of head and neck cancers. Both the incidence and severity of oral mucositis reportedly increase in the case where chemotherapy is administered alongside radiation therapy (28), although this finding is not consistent across all studies (26). As this practice increases, an increase in the incidence of serious outcomes and their costs is possible. IMRT has rapidly replaced conventional radiation therapy and is becoming the standard of care for head and neck cancers. Although a reduced risk of oral mucositis with IMRT was hypothesized, no reduction in incidence or severity has been demonstrated in multiple studies of this treatment modality (3,26). However, the use of IMRT may be associated with a reduced incidence of xerostomia. An Agency for Healthcare Research and Quality report indicated that IMRT causes fewer cases of xerostomia than traditional radiation therapies (43). The risk of xerostomia is determined by radiation fields and doses to the saliva-producing glands. In the case where these glands can be protected through use of IMRT, it is reasonable to expect reductions in the incidence, severity, and economic costs of xerostomia. Whether the use of chemo-radiation will result in more cases or more severe osteoradionecrosis and whether IMRT will result in fewer or less severe cases of osteoradionecrosis is not known. Estimation of any change in the economic costs of osteoradionecrosis caused by these emerging therapies awaits future research. However, an increase in osteonecrosis of the jaw has mirrored the increasing use of bisphosphonates (44). Further study of the economic costs of this condition also await future research. Blueprint for Future Research Based on our review of the published literature, there are substantial gaps in our knowledge about the economic burden imposed by oral complications of cancer therapy (Table 4). Examination of the dates of data collection and publication for articles cited clearly demonstrates the lack of information about complications following newly developed therapies. Updates to these studies would fill this need. Our search failed to identify articles examining out-of-pocket costs, patient time cost, and lost wages and productivity from oral complications. Out-of-pocket costs may be substantial and could affect patient compliance with treatment regimens. Such costs may be most applicable to management of less severe oral complications (ie, use of liquid nutritional products in patients who do not require enteral nutrition). Thus, although their cost may be less than that incurred for severe complications, their use may be far more common. It is important to note that out-of-pocket costs may vary by insurance plan. Careful consideration of out-of-pocket costs, across multiple payers and plans, should be a priority. Accurate estimates of the incidence and duration of oral complications are critical to accurate estimates of cost. Previous research demonstrates inconsistencies between clinician- and patient-reported estimates of incidence of oral mucositis and its severity and duration (45–47). Unfortunately, many studies examine only clinician-reported incidence. There is a critical need for studies of patient-reported incidence and severity of oral mucositis. Table 4. Gaps in knowledge of the economic burden of oral complications Perspective Gaps in cost knowledge Patients Insurance co-pays and deductibles; over-the-counter medications, nutritional supplements, and noncovered medical therapies; transportation and dependent care during clinical and hospital visits; time costs; lost wages Clinical Incidence and cost of oral complications accounting for other simultaneous complications Providers Cost of resources used; opportunity costs of resources used Payers Population-based prevention and treatment costs and incidence of oral complications to support evidence-based coverage and reimbursement decisions Society Productivity lost Perspective Gaps in cost knowledge Patients Insurance co-pays and deductibles; over-the-counter medications, nutritional supplements, and noncovered medical therapies; transportation and dependent care during clinical and hospital visits; time costs; lost wages Clinical Incidence and cost of oral complications accounting for other simultaneous complications Providers Cost of resources used; opportunity costs of resources used Payers Population-based prevention and treatment costs and incidence of oral complications to support evidence-based coverage and reimbursement decisions Society Productivity lost View Large Table 4. Gaps in knowledge of the economic burden of oral complications Perspective Gaps in cost knowledge Patients Insurance co-pays and deductibles; over-the-counter medications, nutritional supplements, and noncovered medical therapies; transportation and dependent care during clinical and hospital visits; time costs; lost wages Clinical Incidence and cost of oral complications accounting for other simultaneous complications Providers Cost of resources used; opportunity costs of resources used Payers Population-based prevention and treatment costs and incidence of oral complications to support evidence-based coverage and reimbursement decisions Society Productivity lost Perspective Gaps in cost knowledge Patients Insurance co-pays and deductibles; over-the-counter medications, nutritional supplements, and noncovered medical therapies; transportation and dependent care during clinical and hospital visits; time costs; lost wages Clinical Incidence and cost of oral complications accounting for other simultaneous complications Providers Cost of resources used; opportunity costs of resources used Payers Population-based prevention and treatment costs and incidence of oral complications to support evidence-based coverage and reimbursement decisions Society Productivity lost View Large Collection of data from patients about out-of-pocket costs, incidence and severity of oral complications, and outcomes can be complex and expensive. Funding for such studies is particularly challenging. Thus, we strongly support the current trend to collect such data alongside clinical trials, particularly those sponsored by cooperative groups. In addition to their research infrastructure and large patient populations, cooperative group trials have the added advantage of being conducted at multiple sites. As previously mentioned, virtually all studies of the cost of oral complications compare the average costs of groups of patients with and without the complication. The difference between these costs is considered the incremental cost of the oral complication. However, such an analysis is based on the assumption that the oral complication occurs independently of other complications and that the costs of other complications are equally distributed between the groups with and without the oral complication. Clinical experience and prior research suggest that this is an incorrect assumption; complications often occur together in the same patient. Furthermore, costs increase exponentially (not linearly) as the number of complications increase (48). Future analyses of the costs of oral complications must account for the impact of other coexisting complications to provide accurate estimates of the cost directly attributable to oral complications. With a few notable exceptions (7,11,15), the studies identified in our search described single institution rather than population-based costs. Because of the impact of local practice patterns and varying case-mix and payer mix, this approach reduces the generalizability of results. Multisite and population-based studies of the incidence and costs of oral complications are sorely needed to support evidence-based coverage and reimbursement policies. Also, there are important limitations to examining the costs of oral complications of cancer therapies across nations and health-care systems. The literature shows that the cost of these complications is driven primarily by the cost of serious outcomes that may be treated in the hospital. In some countries and health-care systems, hospital occupancy rates and daily costs are both low, whereas in others they are expensive and occupancy rates are high. The direct costs of hospital days and the opportunity cost of their use for treating oral complications will vary considerably among health-care systems. Responsible evaluation of the economic implications of these complications and application of findings to policy decisions require careful attention to the health-care system environment. Oral complications of cancer therapy can result in important economic costs. Based on current knowledge about the incidence of oral complications with emerging therapies, costs may be unchanged with newer chemotherapy regimens, increase with chemoradiation, and remain unchanged or decrease with the use of IMRT. The impact of emerging therapies on the cost of osteoradionecrosis is unknown. The total cost of bisphosphonate-associated osteonecrosis of the jaw certainly will increase with increasing incidence, but few estimates of its cost are available. Future research focusing on oral complications of emerging therapies should include patient-reported incidence and severity and out-of-pocket costs. Multicenter and population-based studies with careful attention to the impact of variation in the health-care system environment should be a priority. Notes Affiliation of authors: Department of Health Services Research, University of Texas M. D. Anderson Cancer Center, Houston, TX (LSE, YCC). 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Journal

JNCI MonographsOxford University Press

Published: Aug 1, 2019

References