12.3 Metastatic disease and systemic therapies: health system implications and discussion
Health system implications
Clinical practice
The optimal use of targeted therapy and combination therapies may require greater collaboration and coordination between surgeons, radiation oncologists, dermatologists and medical oncologists and GPs, including more shared decision making.
Implementation of the recommendations will not otherwise result in changes to the way that care is currently organised.
Resourcing
Implementation of the recommendations for review and assessment by multidisciplinary teams with experience in managing advanced keratinocyte cancers (KCs) would require adequate funding to ensure equitable access for patients in rural and remote regions.
Increased use of hedgehog signalling pathway inhibitors (HPIs) would result in high per-patient costs to the Pharmaceutical Benefits Scheme (PBS) for a very small proportion of patients with KCs.
Barriers to implementation
Checkpoint inhibitor therapy is not currently funded in Australia by the PBS, although the agents are available for use if patients are able to self-fund or if alternative funding mechanisms can be provided.
Better access to multidisciplinary clinics and clinical trials is likely to improve patient outcomes.
Discussion
Unresolved issues
The roles of chemotherapy in the management of advanced KC have not been defined. More evidence is needed to determine its efficacy in combination with surgery or radiotherapy (RT), as definitive treatment, as adjuvant treatment in combination with RT, or alone after surgery in patients with cutaneous squamous cell carcinoma (cSCC) who are not eligible for further RT.
Research into novel therapies and strategies for managing immune suppressed patients should be a priority. Sentinel node biopsy is a new technique already used in the management of melanoma and breast cancer, which may be applicable also in high-risk cutaneous cSCC.
A proportion of patients experience potentially fatal relapse of cSCC after surgical resection and adjuvant RT for locoregional recurrence following initial treatment. Better strategies and protocols for identifying these patients are needed.
Current studies are exploring the addition of immunotherapy to adjuvant RT to improve outcomes for patients with high-risk cSCC or BCC.
Clinical experience of new therapies in patients with chronic lymphocytic leukaemia and other haematologic malignancies, outside the context of clinical trials, may inform the management of advanced cSCC.
Studies currently underway
The following relevant clinical trials are underway:
- Radiotherapy with avelumab in unresectable cSCC – a phase II study of immune stimulation with pembrolizumab and radiotherapy in patients with unresectable cutaneous squamous cell carcinoma.[1]
- PD-1 in Patients With Advanced Basal Cell Carcinoma Who Experienced Progression of Disease on patients with advanced basal cell carcinoma who experienced progression of disease on hedgehog pathway inhibitor therapy, or were intolerant of prior hedgehog pathway inhibitor therapy – a study of cemiplimab after tumour progression on, or intolerance to, hedgehog signalling pathway inhibitor therapy in patients with locally advanced or metastatic basal cell carcinoma.[2]
- Direct local injection of talimogene laherparepvec into refractory KCs combined with nivolumab immunotherapy.[3]
The following clinical trial has been proposed:
- checkpoint inhibitors in addition to radiotherapy, compared with RT alone, as adjuvant treatment for high-risk resected SCC (including in patients with lymph node involvement) – Trans Tasman Radiation Oncology Group (TROG).
Future research priorities
Research priorities for the management of BCC include:
- developing topical formulations of HPIs for the treatment of locally advanced KC, with the goal of minimising systemic exposure and therefore minimising systemic side effects
- evaluating the combination of HPIs with RT evaluating the cost effectiveness and patient experience of pre-operative HPI therapy
- evaluating the combination of HPIs with immunotherapy in patients with metastatic disease.
Research priorities for the management of cSCC include:
- the role of checkpoint inhibitor immunotherapy as an adjuvant treatment following surgery, either alone or in combination with RT
- combining other types of immunotherapy (such as interleukin-2) or chemotherapy with checkpoint inhibitors
- improving the ability to identify patients with resected cSCC who are at high or low risk of recurrence or local metastases.
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References
- ↑ U.S. National Library of Medicine. clinicaltrials.gov. [homepage on the internet] USA: NIH; 2018 Nov 9 [cited 2019 May 24; updated 2019 Apr 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT03737721.
- ↑ U.S. National Library of Medicine. clinicaltrials.gov. [homepage on the internet] USA: NIH; 2017 Apr 28 [cited 2019 May 24; updated 2019 Apr 3]. Available from: https://clinicaltrials.gov/ct2/show/NCT03132636.
- ↑ U.S. National Library of Medicine. clinicaltrials.gov. [homepage on the internet] USA: NIH; 2016 Dec 1 [cited 2019 May 24; updated 2019 May 21]. Available from: https://clinicaltrials.gov/ct2/show/NCT02978625.