Medical Policy


Subject: Corneal Collagen Cross-Linking
Document #: MED.00109 Publish Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017


This document addresses corneal collagen cross-linking (CXL, also known as 3-CR or C3R), a minimally invasive photochemical treatment of progressive keratoconus and other corneal thinning processes, such as ectasia after laser in-situ keratomileusis (LASIK).

Note: Please see the following related documents for additional information:

Position Statement

Investigational and Not Medically Necessary:

Corneal collagen cross-linking (CXL) is considered investigational and not medically necessary for all indications.


Corneal CXL is a procedure performed in the outpatient setting using topical anesthesia with the photosensitizer riboflavin (vitamin B2) and ultraviolet-A (UVA) irradiation. The procedure removes approximately 8 mm of the central corneal epithelium under topical anesthesia to allow better diffusion of the photosensitizer into the stroma. Following de-epithelialization, a solution with riboflavin is applied to the cornea until the stroma is completely penetrated. The cornea is then irradiated for 30 minutes with 370 nm UVA. The interaction of riboflavin and UVA causes the formation of covalent bonds between collagen molecules. Preclinical studies have demonstrated increased corneal rigidity and stability following CXL.

Raiskup-Wolf (2008) reported on a long-term retrospective study that involved 241 eyes of 130 subjects with progressive keratoconus who underwent CXL with riboflavin and ultraviolet-A light. Improvements in best-corrected visual acuity (BCVA), astigmatism, and maximum keratometry (K) values were statistically significant after the first year postoperatively (p<0.01 for all measures for all time points), and remained stable for the remainder of the follow-up. The author reported follow-up results out to 6 years, but significant loss to follow-up after the first year makes interpretation of results after 1 year unreliable.

In 2009, Grewal and colleagues described the results of a case series study of 102 subjects who were followed for 1 year following CXL treatment for keratoconus. They reported that there were no significant differences (p>0.05) between preoperative and 1 year postoperative measurements of BCVA, spherical equivalent, cylinder vector, central corneal thickness, anterior corneal curvature, or posterior corneal curvature. Additionally, no statistically significant differences were reported for apex anterior (p=0.9), posterior corneal elevation (p=0.7), lens density (p=0.33), or foveal thickness (p=0.1). The authors concluded that keratoconus did not progress and that unchanged lens density and foveal thickness suggest that the lens and macula were not affected after UVA exposure during CXL.

Caporossi and colleagues (2010) reported the long-term results of an open case series of 44 keratoconic eyes treated with CXL. Mean follow-up was 52.4 months (48-60 months). Keratoconus was stabilized in 44 treated eyes after 48 months, while 65% of the untreated fellow eyes showed a progression of 1.5 diopters at 24 months, prior to CXL treatment. In the treatment group, mean best corrected visual acuity improved by 1.9 Snellen lines, and uncorrected visual acuity improved by 2.7 Snellen lines.

A randomized sham and fellow-eye controlled prospective trial by Greenstein and colleagues (2011) involving 82 eyes, demonstrated that after CXL the cornea thins but then recovers toward baseline thickness by 6 months. The cause and clinical implications of corneal thickness changes with CXL require further study.

Asri and colleagues (2011) reported on the results of a retrospective case series involving 142 subjects with progressive keratoconus who underwent CXL and were followed for a mean of 10 months. Only 104 subjects (73.2%) were included in the 6 month follow-up. At 6 months, the authors reported that corrected distance visual acuity (CDVA) had stabilized in 53 eyes (48.1%), improved in 36 eyes (32.7%), and decreased in 18 eyes (16.3%). Also, keratoconus progression had stopped in 51 eyes (49%) and the maximum keratometry (K) value had decreased by more than 1.0 diopter in 37 eyes (35.5%); it continued to progress in 16 eyes (15.3%). At 12 months, only 64 subjects (45.1%) completed follow-up. The data from this set of subjects indicated that CDVA had stabilized in 31 eyes (47.6%), improved in 26 eyes (40.0%), and decreased in 8 eyes (12%). At 12 months, keratoconus progression had stopped in 42 eyes (68.8%) and the maximum K value had decreased by more than 2.0 diopters in 13 eyes (21.3%). The complication rate with loss of vision was 3.5%. The authors conclude that ultraviolet-A light associated with riboflavin CXL is an efficient procedure to stabilize and improve progressive keratoconus. The results reinforce previous studies highlighting the efficacy and safety of the procedure. However, they note that "A large prospective randomized clinical trial is needed."

A nonrandomized, comparative study enrolled 152 pediatric subjects, 10-18 years of age, treated with CXL for keratoconus (Caporossi, 2012). At 36 months, 77 eyes were evaluable for follow-up. Subjects were divided into two groups according to corneal thickness. The first group included subjects with corneal thickness > 450μm (n=56) and the second < 450μm (n=21). Data at 36 months showed an increase of +0.18 and +0.16 Snellen lines for uncorrected visual acuity and BSCV acuity, respectively, in the > 450μm group and +0.14 and +0.15 Snellen lines, respectively in the < 450μm group. Subjects in the < 450μm group showed a better and faster functional recovery than the thicker group at 3-month follow-up. Topographic results showed statistically significant improvement in K readings and asymmetry index values at 12, 24, and 36 months in both groups. Aberrometric surface indices, a measurement of imperfections in the surface of the eye as reflected by coma values, showed a statistically significant reduction in both groups at 36 months (p=0.0048 for the > 450μm group; p=0.0071 for the < 450μm group) compared with the baseline measurement at 3 months following the procedure. The authors concluded that their study demonstrated significant and rapid functional improvement in pediatric subjects.

Wittig-Silva and colleagues (2014) reported results from a randomized controlled clinical trial (RCT) investigating the efficacy and safety of CXL using 0.1% riboflavin and UVA in the management of progressive keratoconus. A total of 94 eyes were randomized to either a control group (n=48) or a treatment group (n=46). The primary outcome of maximum simulated keratometry value (Kmax) increased by a mean of 1.20 ± 0.28 diopters, 1.70 ± 0.36 diopters, and 1.75 ± 0.38 diopters at 12, 24, and 36 months, respectively (all p<0.001) in the control group. Whereas, in treated eyes, Kmax decreased by -0.72 ± 0.15 diopters, -0.96 ± 0.16 diopters, and -1.03 ± 0.19 diopters at 12, 24, and 36 months, respectively (all p<0.001). The mean change in uncorrected visual acuity (UCVA) showed deterioration in the control group (+0.10 ± 0.04 logMAR; p=0.034) at 36 months, whereas in the treatment group, both UCVA (-0.15 ± 0.06 logMAR; p=0.009) and best spectacle-corrected visual acuity (BSCVA) (-0.09 ± 0.03 logMAR; p=0.006) improved at 36 months. A total of 2 eyes had minor complications that did not affect the final visual acuity. This study's results are promising given the sustained improvement in clinically meaningful outcomes at 3 years post-operation, whereas keratoconus in the control group progressed. However, larger trials are needed to determine safety and efficacy of this procedure.

In 2015, Sykakis and colleagues published a Cochrane Review on the safety and efficacy of CXL for treating keratoconus. Only RCTs where UVA light and riboflavin were used for treatment and compared to no treatment were chosen for inclusion. In total, three RCTs were included which analyzed 219 eyes; 100 served as controls. The overall quality of the RCTs was deemed poor by the authors; all three were hampered by a high risk for performance bias, detection bias and attrition bias. Outcome measures reported across the studies differed to the extent that pooling of data was not possible and no data was reported on quality of life outcomes. The authors concluded that, "The evidence for the use of CXL in the management of keratoconus is limited due to the lack of properly conducted RCTs."

Additional systematic reviews and meta-analyses evaluating the safety and efficacy of CXL on keratoconus have been conducted with conflicting results. A review by Meiri and colleagues (2016) purports CXL is safe and efficacious; however, the rigorousness and comparability of procedural approaches of the studies (N=75) chosen for inclusion are lacking. A meta-analysis conducted by Li and colleagues (2016) in the same year chose only randomized controlled clinical trials for inclusion (N=6) and concluded that although CXL may be effective for stabilizing keratoconus, further long-term studies are warranted to assess the persistence of the effectiveness of CXL over time.

Additionally, several small case series and clinical trials have been published on the use of CXL (Bamdad, 2015; Chatzis, 2012; Coskunseven, 2009; De Bernardo, 2014; Derakhshan, 2011; Kymionis, 2009, 2011; Seyedian, 2015; Stojanovic, 2010; Vinciguerra, 2012). These have all demonstrated promising results, but their small number of subjects and limited methodology do not provide sufficiently rigorous data to allow proper evaluation of the safety and efficacy of this procedure.

In April 2016, the US Food and Drug Administration (FDA) granted approval for Photrexa® (riboflavin 5'-phosphate ophthalmic solution) 0.146% and Photrexa Viscous® (riboflavin 5'-phosphate in 20% dextran ophthalmic solution)  0.146% to be used along with the KXL® collagen cross-linking system for treatment of progressive keratoconus (Avedro Inc.; Waltham, MA). The approval marks a first-in-class treatment for this condition. According to the Product Information (PI) Label (2016), approval of Avedros' CXL system was based on three open-label Phase III clinical trials conducted in the United States (n=364). Kmax was the primary outcome; no data on visual acuity were described. Study participants were followed for just 12 months, thus the long-term safety and efficacy of the KXL system has not been established. Although three studies are mentioned, only two studies are described within the FDA PI Label.

At this time, there is insufficient published literature to establish the safety and durable effectiveness of CXL in the treatment of progressive keratoconus and other forms of corneal ectasia. Three trials were underway investigating the VEGA UV-A light system (Topocon Medical Systems, Oakland, NJ) in conjunction with 0.1% riboflavin, but they have each been terminated with no published results.


According to the National Eye Institute, keratoconus is the most common corneal dystrophy in the United States and reportedly affects approximately 1 in every 2000 Americans (2011). This progressive bilateral eye dystrophy is more prevalent in teens and young adults and is characterized by central steepening and stromal thinning of the cornea that impair visual acuity. Initial treatment often consists of hard contact lenses. A penetrating keratoplasty (i.e., corneal graft) is the next line of treatment for those individuals who develop intolerance to contact lenses. While visual acuity is typically improved with a keratoplasty, there is an associated risk of perioperative complications, long-term topical steroid use is required and endothelial cell loss occurs over time, which is a particular concern in younger individuals. As an alternative, a variety of keratorefractive procedures have been attempted, broadly divided into subtractive and additive techniques. Subtractive techniques include LASIK, but in general, results of this technique have been poor. Implantation of intrastromal corneal ring segments represents an additive technique where the implants are intended to reinforce the cornea, prevent further deterioration and potentially obviate the need for a penetrating keratoplasty. In contrast, CXL is felt to have the potential to slow the progression of the disease.

Ectasia also known as iatrogenic keratoconus or secondary keratoconus is a serious long-term complication of LASIK surgery. Reported treatments for the management of post-LASIK ectasia include hard contact lenses, intraocular pressure-lowering drugs, and intracorneal ring segments. Frequently, a penetrating keratoplasty is required. Corneal CXL is under study as a potential treatment for post-LASIK ectasia.


Cornea: The outermost layer of the eye; dome shaped and covers the front of the eye.

Ectasia: A buldging of the cornea which is surgically induced.

Keratoconus: Cone-shaped cornea with the apex of the cone being forward; also called conical cornea.


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary. 

0402T Collagen cross-linking of cornea (including removal of the corneal epithelium and intraoperative pachymetry when performed)
ICD-10 Diagnosis  
  All diagnoses

Peer Reviewed Publications:

  1. Asri D, Touboul D, Fournié P, et al. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg. 2011; 37(12):2137-2143.
  2. Bamdad S, Malekhosseini H, Khosravi A. Ultraviolet A/riboflavin collagen cross-linking for treatment of moderate bacterial corneal ulcers. Cornea. 2015; 34(4):402-406.
  3. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. 2010; 149(4):585-593.
  4. Caporossi A. Mazzotta C. Baiocchi S, et al. Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea. 2012; 31(3):227-231.
  5. Chatzis N. Hafezi F. Progression of keratoconus and efficacy of pediatric corneal collagen cross-linking in children and adolescents. J Refract Surg. 2012; 28(11):753-758.
  6. Chunyu T, Xiujun P, Zhengjun F, et al. Corneal collagen cross-linking in keratoconus: a systematic review and meta-analysis. Sci Rep. 2014; 4:5652.
  7. Coskunseven E, Jankov MR, Hafezi F. Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg. 2009; 25(4):371-376.
  8. De Bernardo M, Capasso L, Tortori A, et al. Trans epithelial corneal collagen crosslinking for progressive keratoconus: 6 months follow up. Cont Lens Anterior Eye. 2014; 37(6):438-441.
  9. Derakhshan A, Shandiz JH, Ahadi M, et al. Short-term outcomes of collagen crosslinking for early keratoconus. J Ophthalmic Vis Res. 2011; 6(3):155-159.
  10. Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011; 37(4):691-700.
  11. Grewal DS, Brar GS, Jain R, et al. Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: one-year analysis using Scheimpflug imaging. J Cataract Refract Surg. 2009; 35(3):425-432.
  12. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011; 37(1):149-160.
  13. Kymionis GD, Kontadakis GA, Kounis GA, et al. Simultaneous topography-guided PRK followed by corneal collagen cross-linking for keratoconus. J Refract Surg. 2009; 25(9):S807-811.
  14. Kymionis GD, Portaliou DM, Kounis GA, et al. Simultaneous topography-guided photorefractive keratectomy followed by corneal collagen cross-linking for keratoconus. Am J Ophthalmol. 2011; 152(5):748-755.
  15. Li J, Ji P, Lin X. Efficacy of corneal collagen cross-linking for treatment of keratoconus: a meta-analysis of randomized controlled trials. PLoS One. 2015; 10(5):e0127079.
  16. McAnena L, Doyle F, O'Keefe M. Cross-linking in children with keratoconus: a systematic review and meta-analysis. Acta Ophthalmol. 2017; 95(3):229-239.
  17. Meiri Z, Keren S, Rosenblatt A, et al. Efficacy of corneal collagen cross-linking for the treatment of keratoconus: a systematic review and meta-analysis. Cornea. 2016; 35(3):417-428.
  18. Raiskup F, Theuring A, Pillunat LE, Spoerl E. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg. 2015; 41(1):41-46.
  19. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008; 34(5):796-801.
  20. Seyedian MA, Aliakbari S, Miraftab M, et al. Corneal collagen cross-linking in the treatment of progressive keratoconus: a randomized controlled contralateral eye study. Middle East Afr J Ophthalmol. 2015; 22(3):340-345.
  21. Stojanovic A, Zhang J, Chen X, et al. Topography-guided transepithelial surface ablation followed by corneal collagen cross-linking performed in a single combined procedure for the treatment of keratoconus and pellucid marginal degeneration. J Refract Surg. 2010; 26(2):145-152.
  22. Vinciguerra P, Albe E, Frueh BE, et al. Two-year corneal cross-linking results in patients younger than 18 years with documented progressive keratoconus. Am J Ophthalmol. 2012; 154(3):520-526.
  23. Wittig-Silva C, Chan E, Islam FM, et al. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology. 2014; 121(4):812-821.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Academy of Ophthalmology (AAO). Corneal Ectasia PPP – 2013. For additional information visit the AAO website: Accessed on July 03, 20176.
  2. Avedro, Inc. Safety and Efficacy of the corneal collagen cross-linking in eyes with keratoconus. NLM Identifier: NCT01344187. Last updated on June 20, 2017. Available at: Accessed on July 03, 2017.
  3. Photrexa Viscous and Photrexa [Product Information], Waltham, MA. Avedro Inc. April 2016. Available at: Accessed on July 03, 2017.
  4. Sykakis E, Karim R, Evans JR, et al. Corneal collagen cross-linking for treating keratoconus. Cochrane Database Syst Rev. 2015;(3):CD010621.
  5. Topcon Medical Systems, Inc. Safety study of the VEGA UV-A system to treat keratoconus. Last updated January 28, 2013. Available at: Accessed on July 03, 2017.
Websites for Additional Information
  1. National Eye Institute (NEI). Facts about the cornea and corneal disease. Available at: Accessed on July 03, 2017.

Corneal cross-linking (CXL)
KXL System

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History




Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale and Reference sections.
Reviewed 08/04/2016 MPTAC review. Updated Rationale and Reference sections.
Reviewed 02/04/2016 MPTAC review. Updated Rationale and Reference sections.
  01/01/2016 Updated Coding section with 01/01/2016 CPT changes; removed ICD-9 codes.
Reviewed 02/05/2015 MPTAC review. Updated Rationale and Reference sections.
Reviewed 02/13/2014 MPTAC review. Updated Rationale and Reference sections.
Reviewed 02/14/2013 MPTAC review. Websites updated.
New 02/16/2012 MPTAC review. Initial document development.