11 May 2022

Managing regional patients with widespread non-melanoma skin cancer

Cancer

ByDr Bradley Wong

A multidisciplinary approach is critical to tackling the significant burden of non-melanoma skin cancer in regional and remote communities.

Australians have the greatest risk of non-melanoma skin cancer (NMSC) worldwide1-3, probably because of the country’s predominantly fair-skinned population and outdoor lifestyle.

High levels of ambient ultraviolet radiation in locations in close proximity to the equator is a primary factor in three-fold incidence gradient between northern and southern Australia, with Queenslanders experiencing the highest national incidence rates.1,4

Patients with multiple prior NMSC diagnoses are at significant risk of developing new lesions,5,6 with those patients with three or more prior NMSC diagnoses having a 90% chance of developing new lesions within three years.  

Likewise, patients over the age of 502,32 or those with multiple pre-cancerous actinic keratoses (AK) are also at an elevated risk of developing NMSC.7

While individual lesions are often very responsive to treatment, patients with a high tumour burden require constant intervention and are at further risk of severe consequences, including metastases and death. There is also an understanding that for patients with increasingly unmanageable disease, frequent individual lesion-specific treatments are burdensome and do not address the underlying cause or risk of new lesions.

Field cancerisation – challenges faced in contemporary clinical practice

Patients with an extensive history of cumulative sun exposure often exhibit several subclinical and visible changes in the skin.

In addition to photo-aging, they can possess large skin fields containing a mixture of AK, intraepithelial carcinoma, minimally invasive basal cell carcinomas, squamous cell carcinomas and grossly invasive disease. This concept is called “field cancerisation” and although first described 70 years ago,8 the term has been used with increasing frequency in recent years in the context of widespread NMSC.9-12 In this context, it refers to the expansion of UV-mutated cells across large areas of tissue that are predisposed to becoming cancerous.

This disease is generally seen in older patients (>65 years old) and reflects decades of cumulative sun exposure often associated with an outdoor lifestyle. The condition is being progressively characterised with deepening understanding of cancer pathways and the multiple interacting genetic mutations involved.

These patients have received multiple lesion-specific interventions to manage particularly problematic areas as they arise. However, an increasing understanding of field cancerisation has underscored the need to combine lesion-based therapies with those that target the surrounding pre-cancerous field at risk of developing new NMSC.

Field cancerisation of the skin has long posed a problem in medical practice, in particular the management of skin cancers on large, curved surfaces such as the scalp and limbs.

Treatments for severe presentations often include a combination of therapies over a long period. NMSC lesions may be excised while the surrounding pre-cancerous field is either treated with topical creams, cryotherapy, photodynamic therapy or simply monitored. Disease, and in some cases treatments, can be disfiguring and negatively affect quality of life.

Studies have shown that the efficacy of topical therapies is variable and may be less effective or durable for severe disease.13 In addition, treatments can be poorly tolerated because of toxicity, meaning that many patients do not complete the prescribed course.

This confluence of factors means that patients with extensive skin field cancerisation often have treatment fatigue due to increasingly frequent or invasive interventions.14-17

Growing trend towards multidisciplinary management of patients with widespread disease

Treatment of patients with widespread disease often presents additional complexities that necessitate multidisciplinary care from a range of specialists.

General practitioners, including skin specialists, are central to the care pathway, with dermatologists, plastic surgeons and radiation oncologists also playing a critical role in treatment decisions and delivery.

Metropolitan centres frequently have diverse networks of specialists conducive to the provision of multidisciplinary care. In the wider medical context, rural settings traditionally have fewer specialty resources. The nature of skin cancer aetiology, particularly in Australia, results in a high prevalence, and disproportionately high burden, of NMSC in rural areas. 1,18 This has led to the expansion of resources capable of providing excellent care for these communities; however, the rural setting can present logistical challenges. Increasing age and remoteness in such settings have also been identified as problematic factors in skin cancer management.19.

Patients with large NMSC burden often have multifocal disease across all sun-exposed skin, and so would benefit from long-term relationships with their specialist team, who know and understand their disease history.

Role of radiation therapy for patients who have exhausted other treatment options

One option available to patients with a wide variety of NMSC presentations is radiation therapy.

Radiation therapy has excellent cure rates for NMSC lesions,20-26 in addition to being non-invasive, thereby improving cosmetic and functional outcomes for some patients.  Radiation therapy may also be indicated in the adjuvant setting following surgical interventions for particularly high-risk disease. Advances in radiation therapy technology have allowed for the development of innovative strategies to treat patients with extensive skin field cancerisation.

Some cancer centres, such as GenesisCare, have developed comprehensive treatment protocols in consultation with dermatologists and radiation oncologists to provide a field-based treatment option to widespread cancerisation of the skin. This includes the use of volumetric modulated arc therapy (VMAT) to simultaneously target invasive and pre-cancerous lesions over large areas with different doses as required. VMAT utilises megavoltage linear accelerator (LINAC) radiation machines, which rotate around the patient during treatment. The machine continuously reshapes and changes the intensity of the radiation beam as it moves around the body.27

These plans are prepared rapidly and with precision, with reduced dosing to surrounding healthy tissue compared with other modalities.28-30 VMAT enables treatment to the skin of irregular curved surfaces that was previously difficult to treat evenly. This is ideal for treatment of large irregular curved surfaces such as the scalp, forehead, nose or the side of a face. For limbs, it can reduce the dose to the central tissues and provides a lymphoedema-prevention strategy to reduce risk of subcutaneous issues and future long-term swelling.

Other advances developed by oncology providers such as GenesisCare include the use of 3D-printed bolus, which is custom made for individual patients and fits perfectly to the patient’s skin. This ensures the maximal dose is delivered to the skin surface and provides consistent high-quality radiation therapy and reproducibility with quicker setup times.

The typical patient treated with wide-field radiation therapy is elderly and fair-skinned, with large areas of field change and multiple prior interventions for NMSC and pre-cancerous lesions.

They are typically emotionally fatigued from repeat visits and failed therapies. Often the patient is experiencing excision fatigue because of frequent, painful interventions with sometimes sub-optimal functional or cosmetic outcomes. 

Radiation therapy is an outpatient-based treatment made up of daily treatment lasting 15 minutes. The total treatment course for wide-field radiation therapy is commonly five weeks (25 treatments) sometimes with a mid-treatment break. This allows the patient to continue with their daily activities as normal, excluding travel and treatment time. Patients in regional and rural communities often have to travel for treatment, further adding to the emotional burden and treatment fatigue.

Investing in research and data registries to inform evidence-based practice

The most common side effect of modern radiation therapy is dermatitis, which is superficial and appears commonly occurring towards the end of treatment or in the period shortly after.

Twelve-month outcomes reported in a recent published peer-reviewed retrospective analysis of 41 fields from 32 patients with extensive skin field cancerisation +/- NMSC, treated at GenesisCare with widefield radiation therapy, are encouraging.31 Results show 80% of patients maintained complete clearance of the field at 12 months. Treatment was well tolerated, with the most common toxicities being Grade 1-2 alopecia, erythema, dryness and telangiectasia. Continuing follow-up of this cohort is important, with the National Dermatology and Radiation Oncology Registry (NDROR) aiming for 500 patients to be monitored out to five years post treatment.

Conclusion

Widefield radiation therapy, including VMAT, is a promising innovation for the management of certain heavily pre-treated patients with extensive skin field cancerisation with or without current NMSC.

Durable treatment outcomes for widespread skin cancerisation are required to reduce the number and frequency of future interventions. This is important not only from a disease burden and quality-of-life perspective, but also logistically, particularly for patients in regional settings.

In addition to widefield radiation therapy, lesion-directed radiation therapy continues to be an excellent option for certain isolated NMSCs possessing specific high-risk features in the adjuvant setting, or for patients who are ineligible for surgery. Many patients with multifocal disease at various stages across different anatomical sites will continue to require different therapeutic interventions. Multidisciplinary networks continue to be crucial for the management of such patients, with strong collaboration integral to achieving optimal outcomes for patients. This is also true in regional centres, where we work closely with a strong network of skin-specialised GP to drive patient care.

Dr Bradley Wong, MBBS, FRANZCR, is a radiation oncologist in Queensland, treating patients at GenesisCare’s centres on the Sunshine Coast, Buderim and Nambour, as well as GenesisCare’s centres in Bundaberg and on the Fraser Coast.

References

  1. Perera et al. Incidence and prevalence of non-melanoma skin cancer in Australia: A systematic review. Australasian Journal of Dermatology 2015 56:258–67.
  2. Staples MP, Elwood M, Burton RC, Williams JL, Marks R, Giles GG. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust 2006 Jan 2; 184(1):6-10
  3. Olsen CM, Pandeya N, Green AC et al. Keratinocyte cancer incidence in Australia: a review of population-based incidence trends and estimates of lifetime risk. Public Health Research and Practice. 2022; 32:1.
  4. Pollack A, McGrath M, Henderson J, Britt H. Skin cancer by state and territory. Aust Fam Physician. 2014 Aug; 43(8):507
  5. Wehner, Mackenzie R et al. “Timing of Subsequent New Tumors in Patients Who Present With Basal Cell Carcinoma or Cutaneous Squamous Cell Carcinoma.” JAMA dermatology (Chicago, Ill.) 151.4 (2015): 382–388. Web.
  6. Czarnecki D, Mar A, Staples M, Giles G, Meehan C. The development of non-melanocytic skin cancers in people with a history of skin cancer. Dermatology. 1994;189(4):364-7. doi: 10.1159/000246880. PMID: 7873821.
  7. Madani S, Marwaha S, Dusendang JR, et al. Ten-Year Follow-up of Persons With Sun-Damaged Skin Associated With Subsequent Development of Cutaneous Squamous Cell Carcinoma. JAMA Dermatol. 2021; 157(5):559–565.
  8. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953 Sep;6(5):963-8.
  9. Braakhuis, BJM., Tabor, MP, Kummer, JA., Leemans, C. R., & Brakenhoff, R. H. (2003). A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Research, 63(8), 1727–30.
  10. Vanharanta, Sakari et al.  Field Cancerization: Something New Under the Sun. Cell 2012;149(6):1179-81
  11. Lanoue J, Chen C, Goldenberg G. Actinic keratosis as a marker of field cancerization in excision specimens of cutaneous malignancies. Cutis. 2016 Jun;97(6):415-20.
  12. Willenbrink TJ, Ruiz ES, Cornejo CM, Schmults CD, Arron ST, Jambusaria-Pahlajani A. Field cancerization: Definition, epidemiology, risk factors, and outcomes. J Am Acad Dermatol. 2020 Sep;83(3):709-717.
  13. Sinclair R, Baker C, Spelman L, Supranowicz M, MacMahon B. A review of actinic keratosis, skin field cancerisation and the efficacy of topical therapies. Australas J Dermatol. 2021 May; 62(2):119-123.
  14. Fogarty GB, Christie D, Potter A. Volumetric modulated arc therapy (VMAT) for extended skin field cancerisation (ESFC): Radiobiological learnings from unique patient cases. Int J Radiol Radiat Ther. 2019; 6(5):156-162
  15. Staples MP, Elwood M, Burton RC, et al. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust. 2006; 184(1):6?10.
  16. Hofbauer G, Anliker M, Boehncke WH, et al. Swiss clinical practice guidelines on field cancerization of the skin. Swiss Med Wkly. 2014; 144:w14026.
  17. Willenbrink TJ, Ruiz ES, Cornejo CM, Schmults CD, Arron ST, Jambusaria-Pahlajani A. Field cancerization: Definition, epidemiology, risk factors, and outcomes. J Am Acad Dermatol. 2020 Sep; 83(3):709-717
  18. Sanofi. The burden of non-melanoma skin cancer in Australia. 2020 https://www.sanofi.com.au/-/media/Project/One-Sanofi-Web/Websites/Asia-Pacific/Sanofi-AU/en/Home/Healthcare-Solutions/Skin-Cancer-Unseen/NMSC-report_18-September-2020.pdf.
  19. Fennell KM, Martin K, Wilson CJ, Trenerry C, Sharplin G, Dollman J. Barriers to seeking help for skin cancer detection in rural Australia. J Clin Med 2017; 6(2):19.
  20. Wilder RB et al. Basal cell carcinoma treated with radiation therapy. Cancer. 1991; 68:2134-2137
  21. Wilder RB et al. Recurrent basal cell carcinoma treated with radiation therapy. Arch Dermatol. 1991; 127:1668-1672
  22. Childers BJ et al. Long-term results of irradiation for basal cell carcinoma of the skin of the nose. Plast Reconstr Surg 1994; 93:1169-1173
  23. Hernandex-Machin B et al. Office-based radiation therapy for cutaneous carcinoma: evaluation of 710 treatments. Int J Dermatol. 2007. 46:453-459
  24. Cognetta AB et al. Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. J A Acad Dermatol. 2012. 67:1235-1241
  25. Schulte KW et al Soft x-ray therapy for cutaneous basal cell and squamous cell carcinomas. J Am Acad Dermatol. 2005; 53:993-1001
  26. Grossi Marconi D et al. Head and Neck non-melanoma skin cancer treated by superficial x-ray therapy: An analysis of 1021 cases. PLoS One 2016; 11:e0156544
  27. Otto K. Volumetric modulated arc therapy: IMRT in a single gantry arc. Med Phys. 2008 Jan; 35(1):310-7.
  28. Wills, Rachel J et al. “Dosimetric Comparison of Volumetric Modulated Arc Therapy (VMAT) and High-Dose-Rate Brachytherapy (HDR-BT) for Superficial Skin Irradiation with Significant Curvature in One or More Planes.” Strahlentherapie und Onkologie (2021): n.
  29. Ostheimer, Christian et al. “Dosimetric Comparison of Intensity-Modulated Radiotherapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) in Total Scalp Irradiation: a Single Institutional Experience.” Radiation oncology journal 34.4 (2016): 313–321.
  30. Boman EL, Paterson DB, Pearson S, Naidoo N, Johnson C. Dosimetric comparison of surface mould HDR brachytherapy with VMAT. J Med Radiat Sci. 2018 Dec; 65(4):311-318
  31. Spelman L, Christie D, Kaminski A, Baker C, Supranowicz M, Sinclair R: Radiotherapy, Utilizing Volumetric Modulated Arc Therapy, for Extensive Skin Field Cancerization: A Retrospective Case Series Assessing Efficacy, Safety, and Cosmetic Outcomes at 12 Months After Treatment. Case Rep Dermatol 2022:31-38.
  32. Xiang F, Lucas R, Hales S, Neale R. Incidence of nonmelanoma skin cancer in relation to ambient UV radiation in white populations, 1978-2012: empirical relationships. JAMA Dermatol. 2014 Oct; 150(10):1063-71.