Intralesional Cytotoxic Drugs

The charts below show the chances of developing various side effects from treatment with intralesional cytotoxic drugs.2,4-15 For some side effects, we currently do not have enough data to provide a percentage.

5-FU:1,4-9,13,15

Certain/Likely Side Effects (% = Incidence)

SHORT TERM Pain at injection siteup to 100%
SHORT TERM or LONG TERM Skin
darkening (hyperpigmentation)
up to 100%
SHORT TERM Shallow open sore
(superficial ulceration) at injection site
up to 65%
SHORT TERM Purple/red discolored spots
on the skin (purpura)
up to 20%

Possible/Rare Side Effects

SHORT TERM or LONG TERM Thinning of
the skin (atrophy)*
up to 8%
SHORT TERM Burning sensationup to 7.1%
SHORT TERM or LONG TERM Increased
itching (pruritus) of keloid scar**
up to 7.4%
SHORT TERM or LONG TERM Skin lightening (hypopigmentation)up to 4%
SHORT TERM or LONG TERM Whole-body (systemic) side effects†incidence not known

*Thinning of the skin (atrophy): Thinning of the skin after treatment with 5-FU can cause the skin to appear “sunken in.”

**Increased itching (pruritus) of keloid scar: Some keloid scars are accompanied by itching. In one study, one patient experienced an increase in keloid scar itching after intralesional treatment with 5-FU.9

†Whole-body (systemic) side effects: Whole-body side effects after intralesional 5-FU treatment are very rare. They may include changes in the composition of the blood, such as anemia (too few red blood cells), leucopenia (too few white blood cells), or thrombocytopenia (too few platelets).

Bleomycin:2,10-12,14

Certain/Likely Side Effects (% = Incidence)

SHORT TERM Shallow open sore (superficial ulceration) at injection siteup to 100%
SHORT TERM or LONG TERM Skin
darkening (hyperpigmentation)
up to 75%
SHORT TERM Pain at injection siteup to 50%
SHORT TERM Thinning of the skin (atrophy)*up to 21.4%

*Thinning of the skin (atrophy): Thinning of the skin after treatment with bleomycin can cause the skin to appear “sunken in.”

Possible/Rare Side Effects

SHORT TERM or LONG TERM Whole-body (systemic) side effects*incidence not known

*Whole-body (systemic) side effects: Whole-body side effects after intralesional bleomycin treatment are very rare. They may include changes in the composition of the blood, such as anemia (too few red blood cells), leucopenia (too few white blood cells), or thrombocytopenia (too few platelets).

Studies:   

5-FU:

Seven studies have looked at the side effects of intralesional treatment with 5-FU.

  • Study 1:

    • Authors: Kontochristopoulos et al.4
    • Total # of patients: 20
    • # of female patients: 9
    • # of male patients: 11
    • Age of patient: Average: 30
    • Dose: up to 100 mg/session
    • Duration of treatment and follow-up: 4-13 treatments (average: 7), follow-up for 12 months
    • Side effects:

      • Pain: 100%
      • Superficial ulcerations (shallow open sores) at injection sites: 30%
      • Transient hyperpigmentation (skin darkening): 100%
  • Study 2:

    • Authors: Manuskiatti and Fitzpatrick5
    • Total # of patients: 10
    • # of female patients: 6
    • # of male patients: 4
    • Age of patient: 25-74
    • Dose: (not reported)
    • Duration of treatment and follow-up: 10 treatments, follow-up very 8 weeks for 32 weeks
    • Side effects:

      • Mild to moderate pain: 100%
      • Purpura (purple/red discolored spots on the skin): 20%
  • Study 3:

    • Authors: Gupta and Kalra13
    • Total # of patients: 24
    • # of female patients: 12
    • # of male patients: 12
    • Age of patient: (not reported)
    • Dose: 50-150 mg/session
    • Duration of treatment and follow-up: Up to 16 treatments, (duration of follow-up not reported)
    • Side effects:

      • Mild to moderate hyperpigmentation (skin darkening): 100%
      • Ulceration (open sore) at injection site: 4.2%
  • Study 4:

    • Authors: Nanda and Reddy6
    • Total # of patients: 28
    • # of female patients: 16
    • # of male patients: 12
    • Age of patient: 11-55
    • Dose: 25-100 mg/session
    • Duration of treatment and follow-up: Up to 12 treatments, follow-up at 24 weeks
    • Side effects:

      • Pain: 100%
      • Ulceration (open sores): 21.4%
      • Burning sensation: 7.1%
  • Study 5:

    • Authors: Saha and Mukhopadhyay7
    • Total # of patients: 20
    • # of female patients: (not reported)
    • # of male patients: (not reported)
    • Age of patient: 16-66 Average: 34.7
    • Dose: Up to 100 mg/session
    • Duration of treatment and follow-up: 6 treatments, follow-up for up to 1 year
    • Side effects:

      • Hyperpigmentation (skin darkening): 90%
      • Pain: 95% Superficial ulceration (shallow open sores): 65%
  • Study 6:

    • Authors: Sharma et al.8
    • Total # of patients: 25 keloids (number of patients not reported)
    • # of female patients: (not reported)
    • # of male patients: (not reported)
    • Age of patient: 20-60
    • Dose: (not reported)
    • Duration of treatment and follow-up: Up to 11 treatments, follow-up for up to 1 year
    • Side effects:

      • Skin atrophy (thinning of the skin): 8%
      • Hyperpigmentation (skin darkening): 4%
      • Hypopigmentation (skin lightening): 4%
  • Study 7:

    • Authors: Prabhu et al.9
    • Total # of patients: 15
    • # of female patients: (not reported)
    • # of male patients: (not reported)
    • Age of patient: Up to 55
    • Dose: Up to 100 mg/session
    • Duration of treatment and follow-up: 4 treatments, follow-up monthly for 6 months
    • Side effects:

      • Ulceration (open sores): 7%
      • Increased pain: 7%
      • Increased pruritus (itching): 7%

Study 1: In a study published in 2005 in the Journal of the American Academy of Dermatology, Kontochristopoulos and colleagues treated 20 patients with keloids with intralesional injections of 5-FU. The patients received injections once a week for an average of 7 treatment sessions and were followed up for 12 months. All patients reported pain after injections, which was sometimes severe and persisted for 2 hours after injection. Six patients experienced superficial ulcerations (shallow open sores) at the injection sites soon after the first few treatment sessions. The ulcerations were accompanied by mild discomfort and discharge but were treated with an antibiotic cream and healed within 10 days. Additionally, all patients developed hyperpigmentation (skin darkening), which was transient and not cosmetically disturbing.4

Study 2: In a study published in 2002 in the journal Archives of Dermatology, Manuskiatti and Fitzpatrick treated 10 patients with keloids and hypertrophic scars with intralesional injections of 5-FU. The patients received injections every 2 weeks for the first 8 treatments and every 4 weeks for the last 2 treatments, for a total of 10 treatments. The researchers followed up with the patients every 8 weeks for 32 weeks. All patients reported experiencing pain. Purpura (purple/red discolored spots) occurred at the injection site in 20% of the patients.5

Study 3: In a study published in 2002 in the journal Dermatology, Gupta and Kalra treated 24 patients with small keloids (measuring less than 7 cm) with intralesional injections of 5-FU. The patients received 50-150 mg of 5-FU per week for a maximum of 16 sessions, but treatment was stopped before 16 sessions if desired results were achieved. Almost all patients experienced moderate to severe pain at the injection site, which lasted up to 15 minutes. All patients developed hyperpigmentation (skin darkening), but this disappeared gradually when treatment was stopped.13

Study 4: In a study published in 2004 in the journal Dermatologic Surgery, Nanda and Reddy treated 28 patients with keloids with intralesional injections of 5-FU. The patients received injections every week for up to 12 weeks and were followed up at 24 weeks. All patients experienced pain at the injection site. Some patients (21.4%) developed ulceration (open sores) at the injection site, which healed in 2-3 weeks with the application of topical antibiotics.6

Study 5: In a study published in 2012 in the Indian Journal of Surgery, Saha and Mukhopadhyay treated 20 patients with keloids with intralesional injections of 5-FU. The patients received the treatment at 1-week intervals for 6 sessions and were followed up for up to 1 year. Almost all patients experienced pain at the injection site and developed hyperpigmentation (skin darkening) as a result of the treatment.7

Study 6: In a study published in 2012 in the Journal of Pakistan Association of Dermatologists, Sharma and colleagues treated patients with a total of 25 keloids with intralesional injections of 5-FU. The patients received injections at weekly intervals for 4 weeks, then every 2 weeks for 2 months, and finally once a month for up to 3 months, depending on results. The total duration of treatment was limited to 6 months, and the researchers followed up with the patients for up to 1 year. A small minority of patients experienced side effects, which included skin atrophy (thinning of the skin), hyperpigmentation (skin darkening), and hypopigmentation (skin lightening).8

Study 7: In a study published in 2012 in the Journal of the Scientific Society, Prabhu and colleagues treated 15 patients with keloids with intralesional injections of 5-FU. The patients received injections at 1-week intervals for 4 weeks and were followed up every month for 6 months. One patient experienced increased pruritus (itching) of the keloid after treatment.9

Bleomycin:

Four studies have looked at the side effects of intralesional treatment with bleomycin.

  • Study 1:

    • Authors: España et al.10
    • Total # of patients: 13
    • # of female patients: 10
    • # of male patients: 3
    • Age of patient: 14-36
    • Dose: Up to 6 cm3/session at a concentration of 1.5 IU/ml
    • Duration of treatment and follow-up: 1-5 treatments, follow-up for up to 3 years
    • Side effects: Residual hyperpigmentation (skin darkening): 15.4%
  • Study 2:

    • Authors: Saray and Güleç14
    • Total # of patients: 14
    • # of female patients: 10
    • # of male patients: 4
    • Age of patient: 16-73 Average: 32.5
    • Dose: Up to 3.5 ml/session at a concentration of 1.5 IU/ml
    • Duration of treatment and follow-up: 2-6 treatments (average: 4 treatments), follow-up for 16-24 months (average: 19 months)
    • Side effects:

      • Mild to moderate pain after injection: 50%
      • Superficial ulceration (shallow open sore) at injection site: 100%
      • Hyperpigmentation (skin darkening): 28.6%
      • Skin atrophy (thinning of the skin): 21.4%
  • Study 3:

    • Authors: Naeini et al.11
    • Total # of patients: 23
    • # of female patients: 17
    • # of male patients: 6
    • Age of patient: Average: 28
    • Dose: Up to 10 IU/session at a concentration of 1.5 IU/ml
    • Duration of treatment and follow-up: 4 treatments, (duration of follow-up not reported)
    • Side effects: Hyperpigmentation (skin darkening): 75%
  • Study 4:

    • Authors: Aggarwal et al.12
    • Total # of patients: 50
    • # of female patients: 29
    • # of male patients: 21
    • Age of patient: 12-50
    • Dose: (not reported)
    • Duration of treatment and follow-up: 4 treatments, follow-up for 18 months
    • Side effects:

      • Ulceration (open sores) after injection: 16%
      • Pain: 30%
      • Hyperpigmentation (skin darkening): 14%

Study 1: In a study published in 2001 in the journal Dermatologic Surgery, España and colleagues treated 13 patients with keloids and hypertrophic scars with intralesional bleomycin. The patients were treated for 1 to 5 sessions at intervals of 1-4 months. Two patients, both with darker skin, experienced residual hyperpigmentation (skin darkening).10

Study 2: In a study published in 2005 in the International Journal of Dermatology, Saray and Güleç treated 14 patients with keloids and hypertrophic scars with intralesional bleomycin. The patients received 2-6 treatments at 4-week intervals and were followed up for at least 16 months. Half of the patients reported pain after injection lasting up to 7 days. Most patients who developed hyperpigmentation (skin darkening) had darker skin, and the hyperpigmentation resolved within 2 months. However, the patients who experienced skin atrophy (thinning of the skin) did not show improvement during the follow-up period.14

Study 3: In a study published in 2006 in Dermatologic Surgery, Naeini and colleagues treated 23 patients with keloids and hypertrophic scars with intralesional bleomycin. The patients received 4 treatment sessions at 1-month intervals. The only side effect was hyperpigmentation (skin darkening), which occurred in 75% of patients.11

Study 4: In a study published in 2008 in the Journal of Cosmetic Dermatology, Aggarwal and colleagues treated 50 patients with keloids and hypertrophic scars with intralesional bleomycin. Patients received 3 treatment sessions at 15-day intervals and then waited 2 months for the fourth and final session. Patients were followed up for 18 months. Most side effects were minor. Fifteen patients complained of pain after the first treatment. Eight patients developed ulceration (open sores) after the second treatment, but this healed within 10 days. Seven patients experienced hyperpigmentation (skin darkening), which disappeared after 1 year.12

References
  1. Bijlard E, Steltenpool S, and Niessen FB. Intralesional 5-fluorouracil in keloid treatment: a systematic review. Acta dermato-venereologica. 95(7), 778-82 (2015).
  2. Levy LL, and Zeichner JA. Management of acne scarring, part II. A comparative review of non-laser-based, minimally invasive approaches. Am J Clin Dermatol. 13(5), 331-340 (2012).
  3. Ledon JA, Savas J, Franca K, Chacon A, and Nouri K. Intralesional treatment for keloids and hypertrophic scars: a review. Dermatologic Surgery. 39(12), 1745-57 (2013).
  4. Kontochristopoulos G, et al. Intralesional 5-fluorouracil in the treatment of keloids: an open clinical and histopathologic study. J Am Acad Dermatol. 52(3 Pt 1):474-9 (2005).
  5. Manuskiatti W, and Fitzpatrick RE. Treatment response of keloidal and hypertrophic sternotomy scars: comparison among intralesional corticosteroid, 5-fluorouracil, and 585-nm flashlamp-pumped pulsed-dye laser treatments. Arch Dermatol. 138(9), 1149-55 (2002).
  6. Nanda S, and Reddy BS. Intralesional 5-fluorouracil as a treatment modality of keloids. Dermatol Surg. 30(1), 54-6; discussion 56-7 (2004).
  7. Saha AK, and Mukhopadhyay M. A comparative clinical study on role of 5-flurouracil versus triamcinolone in the treatment of keloids. Indian Journal of Surgery. 74(4), 326-9 (2012).
  8. Sharma S, Bassi R, and Gupta A. Treatment of small keloids with intralesional 5-fluorouracil alone vs. intralesional triamcinolone acetonide with 5-fluorouracil. Journal of Pakistan Association of Dermatology. 22(1), 35-40 (2017).
  9. Prabhu A, Sreekar H, Powar R, and Uppin VM. A randomized controlled trial comparing the efficacy of intralesional 5-fluorouracil versus triamcinolone acetonide in the treatment of keloids. Journal of the Scientific Society. 39(1), 19 (2012).
  10. España A, Solano T, and Quintanilla E. Bleomycin in the treatment of keloids and hypertrophic scars by multiple needle punctures. Dermatol Surg. 27(1), 23-7 (2001).
  11. Naeini FF, Najafian J, and Ahmadpour K. Bleomycin tattooing as a promising therapeutic modality in large keloids and hypertrophic scars. Dermatol Surg. 32(8), 1023-9; discussion 1029-30 (2006).
  12. Aggarwal H, Saxena A, Lubana PS, Mathur RK, and Jain DK. Treatment of keloids and hypertrophic scars using bleom. J Cosmet Dermatol. 7(1), 43-9 (2008).
  13. Gupta S, and Kalra A. Efficacy and safety of intralesional 5-fluorouracil in the treatment of keloids. Dermatology. 204(2), 130-2 (2002).
  14. Saray Y, and Güleç AT. Treatment of keloids and hypertrophic scars with dermojet injections of bleomycin: a preliminary study. Int J Dermatol. 44(9), 777-84 (2005).
  15. Uptodate.com. Keloids and hypertrophic scars. Available from: https://www-uptodate-com.eresources.mssm.edu/contents/keloids-and-hypertrophic-scars?source=see_link&sectionName=MANAGEMENT&anchor=H151854186#H151854186. Last retrieved on 7 November 2017.