• Systemic anti-cancer therapies may be classified as vesicants, irritants, or non-irritants, based on their potential to cause tissue damage if extravasation occurs.
• Reactions secondary to Kadcyla extravasation have occurred. Kadcyla has been classified as an irritant by the UK National Health Service (NHS) and the Cancer Institute of NSW's eviQ.
• No specific treatment for epidermal necrosis following Kadcyla extravasation is known or recommended. Resources for the management of extravasation with chemotherapeutic agents have been published.
• Case reports on reactions following Kadcyla extravasation are available.

Systemic anti-cancer therapies may be classified based on the potential to cause tissue damage if extravasation occurs, as described in Table 1.[1-3]

Table 1. Extravasation classification of systemic anti-cancer therapies [1-3]

It should be noted that any chemotherapeutic agent has the potential to cause significant symptoms and tissue damage if the volume or concentration of the drug that extravasated is high.[1]

Classification of Kadcyla

Kadcyla is an antibody-drug-conjugate (ADC) comprised of an anti-human epidermal growth factor receptor 2 monoclonal antibody (IgG1) covalently linked to the microtubule inhibitory drug DM1 via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate).[4]

Monoclonal antibodies are typically classified as non-irritants, however there is limited evidence to classify ADCs.[2,5] Roche does not provide an extravasation classification for Kadcyla.[4]

Reactions secondary to extravasation have been observed in Kadcyla clinical studies.[4] Kadcyla has been classified as an irritant by the UK NHS and the Cancer Institute of NSW's eviQ.[1,6]

Extravasation reactions in Kadcyla clinical studies

In Kadcyla clinical studies, reactions secondary to extravasation have been observed.[4] These reactions were observed most frequently within 24 hours of infusion, were usually mild and comprised of the following signs at the infusion site:

• erythema
• tenderness
• skin irritation
• pain, and
• swelling.

Extravasation reactions in the post-marketing setting

In the post-marketing setting, very rare cases of epidermal injury or necrosis following extravasation have been observed, including delayed reactions.[4,7]

Roche does not have specific recommendations for the treatment of Kadcyla extravasation.[4]

During Kadcyla administration, the infusion site should be closely monitored for possible subcutaneous infiltration.[4] If extravasation occurs, the infusion should be terminated immediately and the patient should be examined regularly as necrosis may occur within days to weeks after infusion.[7]

No specific treatment for epidermal necrosis following Kadcyla extravasation is known or recommended.[4] Case resolution has occurred in majority of cases with general clinical practice measures.[8]

Clinical guidelines

Resources for the management of extravasation with chemotherapeutic agents have been published.[1-3,5,6] Examples include but are not limited to clinical practice guidelines published by the European Society for Medical Oncology (ESMO), the NHS and eviQ. The interested clinician is directed to the full guidelines for further information.

• ESMO - Management of Chemotherapy Extravasation.[5] ESMO Clinical Practice Guidelines may be accessed at: https://www.esmo.org/guidelines/guidelines-by-topic/supportive-and-palliative-care/chemotherapy-extravasation
• NHS - West Midlands Expert Advisory Group for Systemic Anti-Cancer Therapy (SACT).[1] Network Guidelines for the Management of Extravasation of a SACT Including Cytotoxic Agents may be accessed at: https://www.england.nhs.uk/mids-east/cancer-expert-advisory-groups/systemic-anti-cancer-therapy/
• eviQ - Cancer Institute of NSW.[9] Algorithm - extravasation management of intravenous anti-cancer therapies may be accessed at: https://www.eviq.org.au/clinical-resources/extravasation/1078-extravasation-management-immediate-manageme

Sibaud et al. reported a patient with diffuse, painful erythema that occurred 1 day after infusion of Kadcyla.[10] The erythema progressed over 6 days, followed by spontaneous improvement of symptoms after 15 days and no permanent damage. The authors suggested that this was a tissue irritant reaction.

Shafaee et al. described a patient who developed swelling 9 hours after the completion of the Kadcyla infusion.[11] Blisters developed within 2 days, and the patient was treated with opioids for pain control. After 4 weeks, the site had healed with residual hyperpigmentation.

Sallevelt et al. reported a patient who was found to have erythematous painless swelling upon completion of the Kadcyla infusion.[12] Based on the extent of the swelling, it was likely that the entire infusion volume was administered subcutaneously. The patient was initially observed and treated with acetaminophen for pain control. Blistering of the skin occurred approximately 11 days after infusion. The blisters were surgically removed, followed by local treatment with silver sulphadiazine for infection prophylaxis. At 6 weeks after extravasation, the skin had healed, with residual hyperpigmentation of the skin still present.

1. Network Guidelines for the Management of Extravasation of a Systemic Anti-Cancer Therapy Including Cytotoxic Agents. July 19, 2019. Available at https://www.england.nhs.uk/mids-east/cancer-expert-advisory-groups/systemic-anti-cancer-therapy/. Accessed on July 20, 2023.
2. Kreidieh F, Moukadem H, El Saghir N. Overview, prevention and management of chemotherapy extravasation. World J Clin Oncol 2016;7:87-97. https://www.ncbi.nlm.nih.gov/pubmed/26862492
3. Extravasation management. July 14, 2022. Available at https://www.eviq.org.au/clinical-resources/extravasation/157-extravasation-management#background. Accessed on July 19, 2023.
4. Roche Internal Regulatory Report. Accessed 19 July 2023.
5. Pérez Fidalgo J, García Fabregat L, Cervantes A, et al. Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol 2012;23 Suppl 7:vii167-73. https://www.ncbi.nlm.nih.gov/pubmed/22997449
6. Quicklink summary table - treatments for extravasation of intravenous anti-cancer therapies. July 13, 2022. Available at https://www.eviq.org.au/clinical-resources/extravasation/1002-quicklink-summary-table-treatments-for-extr. Accessed on July 25, 2023.
7. Kadcyla Summary of Product Characteristics. March 22, 2023. Available at https://www.ema.europa.eu/en/documents/product-information/kadcyla-epar-product-information_en.pdf. Accessed on July 19, 2023.
8. Roche Internal Clinical Report. Accessed 19 July 2023.
9. Algorithm - extravasation management of intravenous anti-cancer therapies. July 13, 2022. Available at https://www.eviq.org.au/clinical-resources/extravasation/1078-extravasation-management-immediate-manageme. Accessed on July 19, 2023.
10. Sibaud V, Nougarolis S, Borjesson C, et al. T-DM1 extravasation: first description. J Eur Acad Dermatol Venereol 2016;30:1235-1236. https://www.ncbi.nlm.nih.gov/pubmed/25879278
11. Shafaee M, Salahudeen A, Valero V. Skin necrosis after ado-trastuzumab emtansine extravasation. J Oncol Pract 2017;13:555-556. https://www.ncbi.nlm.nih.gov/pubmed/28678590
12. Sallevelt B, Teunis T, Agterof M, et al. Extravasation of an antibody-drug conjugate: A case report of epidermal necrosis after trastuzumab-emtansine extravasation. J Clin Pharm Ther 2020;45:832-835. https://www.ncbi.nlm.nih.gov/pubmed/32412114