Neoadjuvant treatment for stage III and IV cutaneous melanoma
Cutaneous melanoma is amongst the most aggressive of all skin cancers. Neoadjuvant treatment is a form of induction therapy, given to shrink a cancerous tumour prior to the main treatment (usually surgery). The purpose is to improve survival and surgical outcomes. This review systematically appraises the literature investigating the use of neoadjuvant treatment for stage III and IV cutaneous melanoma.
To assess the effects of neoadjuvant treatment in adults with stage III or stage IV melanoma according to the seventh edition American Joint Committee on Cancer (AJCC) staging system.
We searched the following databases up to 10 August 2021 inclusive: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and four trials registers, together with reference checking and contact with study authors to identify additional studies. We also handsearched proceedings from specific conferences from 2016 to 2020 inclusive.
Randomised controlled trials (RCTs) of people with stage III and IV melanoma, comparing neoadjuvant treatment strategies (using targeted treatments, immunotherapies, radiotherapy, topical treatments or chemotherapy) with any of these agents or current standard of care (SOC), were eligible for inclusion.
Data collection and analysis
We used standard Cochrane methods. Primary outcomes were overall survival (OS) and adverse effects (AEs). Secondary outcomes included time to recurrence (TTR), quality of life (QOL), and overall response rate (ORR). We used GRADE to evaluate the certainty of the evidence.
We included eight RCTs involving 402 participants. Studies enrolled adults, mostly with stage III melanoma, investigated immunotherapies, chemotherapy, or targeted treatments, and compared these with surgical excision with or without adjuvant treatment. Duration of follow‐up and therapeutic regimens varied, which, combined with heterogeneity in the population and definitions of the endpoints, precluded meta‐analysis of all identified studies. We performed a meta‐analysis including three studies.
We are very uncertain if neoadjuvant treatment increases OS when compared to no neoadjuvant treatment (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.15 to 1.21; 2 studies, 171 participants; very low‐certainty evidence). Neoadjuvant treatment may increase the rate of AEs, but the evidence is very uncertain (26% versus 16%, risk ratio (RR) 1.58, 95% CI 0.97 to 2.55; 2 studies, 162 participants; very low‐certainty evidence). We are very uncertain if neoadjuvant treatment increases TTR (HR 0.51, 95% CI 0.22 to 1.17; 2 studies, 171 participants; very low‐certainty evidence). Studies did not report ORR as a comparative outcome or measure QOL data.
We are very uncertain whether neoadjuvant targeted treatment with dabrafenib and trametinib increases OS (HR 0.28, 95% CI 0.03 to 2.25; 1 study, 21 participants; very low‐certainty evidence) or TTR (HR 0.02, 95% CI 0.00 to 0.22; 1 study, 21 participants; very low‐certainty evidence) when compared to surgery. The study did not report comparative rates of AEs and overall response, and did not measure QOL.
We are very uncertain if neoadjuvant immunotherapy with talimogene laherparepvec increases OS when compared to no neoadjuvant treatment (HR 0.49, 95% CI 0.15 to 1.64; 1 study, 150 participants, very low‐certainty evidence). It may have a higher rate of AEs, but the evidence is very uncertain (16.5% versus 5.8%, RR 2.84, 95% CI 0.96 to 8.37; 1 study, 142 participants; very low‐certainty evidence). We are very uncertain if it increases TTR (HR 0.75, 95% CI 0.31 to 1.79; 1 study, 150 participants; very low‐certainty evidence). The study did not report comparative ORRs or measure QOL.
OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to the combination of ipilimumab and nivolumab as adjuvant treatment. There may be little or no difference in the rate of AEs between these treatments (9%, RR 1.0, 95% CI 0.75 to 1.34; 1 study, 20 participants; low‐certainty evidence). The study did not report comparative ORRs or measure TTR and QOL.
Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) likely results in little to no difference in OS when compared to neoadjuvant nivolumab monotherapy (P = 0.18; 1 study, 23 participants; moderate‐certainty evidence). It may increase the rate of AEs, but the certainty of this evidence is very low (72.8% versus 8.3%, RR 8.73, 95% CI 1.29 to 59; 1 study, 23 participants); this trial was halted early due to observation of disease progression preventing surgical resection in the monotherapy arm and the high rate of treatment‐related AEs in the combination arm. Neoadjuvant combination treatment may lead to higher ORR, but the evidence is very uncertain (72.8% versus 25%, RR 2.91, 95% CI 1.02 to 8.27; 1 study, 23 participants; very low‐certainty evidence). It likely results in little to no difference in TTR (P = 0.19; 1 study, 23 participants; low‐certainty evidence). The study did not measure QOL.
OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to neoadjuvant sequential immunotherapy (ipilimumab then nivolumab). Only Grade 3 to 4 immune‐related AEs were reported; fewer were reported with combination treatment, and the sequential treatment arm closed early due to a high incidence of severe AEs. The neoadjuvant combination likely results in a higher ORR compared to sequential neoadjuvant treatment (60.1% versus 42.3%, RR 1.42, 95% CI 0.87 to 2.32; 1 study, 86 participants; low‐certainty evidence). The study did not measure TTR and QOL.
No data were reported on OS, AEs, TTR, or QOL for the comparison of neoadjuvant interferon (HDI) plus chemotherapy versus neoadjuvant chemotherapy. Neoadjuvant HDI plus chemotherapy may have little to no effect on ORR, but the evidence is very uncertain (33% versus 22%, RR 1.75, 95% CI 0.62 to 4.95; 1 study, 36 participants; very low‐certainty evidence).
We are uncertain if neoadjuvant treatment increases OS or TTR compared with no neoadjuvant treatment, and it may be associated with a slightly higher rate of AEs. There is insufficient evidence to support the use of neoadjuvant treatment in clinical practice. Priorities for research include the development of a core outcome set for neoadjuvant trials that are adequately powered, with validation of pathological and radiological responses as intermediate endpoints, to investigate the relative benefits of neoadjuvant treatment compared with adjuvant treatment with immunotherapies or targeted therapies.
Claire Gorry, Laura McCullagh, Helen O'Donnell, Sarah Barrett, Susanne Schmitz, Michael Barry, Kay Curtin, Eamon Beausang, Rupert Barry, Imelda Coyne
Plain language summary
What are the benefits and risks of neoadjuvant treatment (drug treatment prior to surgery to remove a tumour) for melanoma, a type of skin cancer?
What did we want to find out?
Cutaneous melanoma is a very aggressive form of skin cancer. It is generally fatal if detected at an advanced stage. Earlier treatment may allow for surgical removal of the tumour and an improved chance of long‐term survival. Neoadjuvant treatment is drug treatment administered before surgery, to reduce the tumour size so that it is easier to remove, to reduce complications of surgery, and to reduce the risk of spread of the disease. New drug types, immunotherapies and targeted treatments, have been developed which may be effective for neoadjuvant use.
We wanted to find out if neoadjuvant treatment of stage III or IV melanoma helps people live longer, and to compare adverse (unwanted) effects with neoadjuvant treatment and routine care.
What did we do?
We searched the medical literature for randomised controlled trials that compared certain types of treatments for melanoma skin cancer. The types of treatment included are:
‐ targeted treatments ‐ such as dabrafenib and trametinib;
‐ immunotherapies ‐ such as ipilimumab and nivolumab;
‐ chemotherapy ‐ such as dacarbazine and temozolomide;
‐ topical treatments ‐ such as imiquimod;
We considered both single‐drug and combination‐drug treatments. We described and compared the results from these studies, taking into account the differences between the studies.
What did we find?
We identified eight randomised controlled trials that included 402 adults. The majority of people had stage III melanoma and were treated in hospital. Most studies used immunotherapies or targeted treatments, and compared these with surgery, with or without adjuvant treatment (treatment given after surgery to remove the tumour, to reduce the risk of the tumour coming back). No studies considered the impact of treatment on quality of life, and most studies did not compare tumour response rates after different treatments.
We are uncertain whether neoadjuvant treatment helps people live longer when compared with no neoadjuvant treatment. It may lead to more adverse events, and we are uncertain if it increases the time until the tumour comes back.
We are uncertain whether neoadjuvant targeted treatment with dabrafenib and trametinib helps people live longer, compared with no neoadjuvant treatment, or if it can increase the time until the tumour comes back. The study did not compare safety outcomes with each treatment.
We are uncertain if neoadjuvant immunotherapy with talimogene laherparepvec (T‐VEC) helps people live longer when compared with no neoadjuvant treatment. It may lead to more adverse events. We are uncertain if it increases the time until the tumour comes back.
No data were reported on whether neoadjuvant immunotherapy with combined ipilimumab and nivolumab helps people live longer, when compared with adjuvant (treatment given only after surgery) combined ipilimumab and nivolumab. There may be little or no difference in the rate of adverse events. No data were reported on whether neoadjuvant immunotherapy with combined ipilimumab and nivolumab increases the time until the tumour comes back.
Neoadjuvant combination of ipilimumab and nivolumab likely results in little or no difference in how long people live, when compared with neoadjuvant nivolumab. It may increase the rate of adverse events, but our confidence in the evidence is very low. It is worth noting that this trial was stopped early as patients in the neoadjuvant nivolumab arm may not be able to receive surgery due to disease progression and also because of a high rate of treatment‐related adverse events in the combination treatment arm. Combination treatment may lead to higher tumour response rates, but our confidence in the evidence is very low. The time until the tumour comes back may not be different.
No data were available on whether neoadjuvant immunotherapy with combined ipilimumab and nivolumab helps people live longer, when compared with neoadjuvant sequential treatment with ipilimumab and nivolumab. It likely results in fewer adverse events compared to sequential treatment, and may result in higher tumour response rates. The sequential treatment arm of the trial stopped recruiting patients due to a high incidence of severe AEs. Data on the time taken for the tumour to return were not collected.
No data were reported on whether neoadjuvant high‐dose interferon plus chemotherapy, when compared to neoadjuvant chemotherapy, can help people live longer, increase the time taken for the tumour to reoccur, reduce adverse events, or impact quality of life. It may have little to no effect on tumour response rates.
What does this mean?
We are uncertain if neoadjuvant treatment of stage III or IV melanoma will help people to live longer, or to have more time before the disease recurs. We are also uncertain if the benefits of neoadjuvant treatment outweigh the risks of adverse events.
How up to date is this evidence?
The evidence is up to date to August 2021.
Claire Gorry, Laura McCullagh, Helen O'Donnell, Sarah Barrett, Susanne Schmitz, Michael Barry, Kay Curtin, Eamon Beausang, Rupert Barry, Imelda Coyne
Implications for practice
We are uncertain if neoadjuvant treatment can improve overall survival (OS), compared with the standard of care (SOC) in people with stage III or IV melanoma. We are uncertain whether neoadjuvant treatment improves time to recurrence (TTR). Overall response rate (ORR) is highest with targeted treatment, and with combination regimens compared with single‐treatment regimens. There remains the possibility that neoadjuvant immunotherapy may reduce the likelihood of successful surgical resection due to rapid disease progression (Amaria 2018b), or that treatment‐related adverse events (AEs) may delay surgery. Neoadjuvant treatment may be associated with a slightly higher rate of AEs compared with SOC, and we are uncertain if the benefits outweigh the risks of harm. The identified trials were early‐phase clinical trials with poor external validity, inadequately powered to detect differences in outcomes between treatment arms, and confidence intervals often overlapped no effect. The majority of trials were using immunotherapy agents as neoadjuvant treatment, but in most trials the control arm did not reflect the current SOC, which is adjuvant immunotherapy or targeted treatment. Immunotherapies and targeted therapies do not currently have regulatory authorisation in the USA or Europe for neoadjuvant treatment of melanoma. Use of immunotherapy in the neoadjuvant setting could have significant cost issues for health services, due to the potential for cost‐offsets of immunotherapy treatment in the recurrent disease setting. This may be offset by the additional healthcare resource use in administering treatment in the neoadjuvant setting, where potentially many people would be considered eligible for treatment.
Implications for research
Phase III randomised controlled trials (RCTs) of sufficient size, duration of follow‐up and with adequate power to detect differences in time‐to event outcomes such as relapse‐free survival (RFS), are required to reduce the imprecision consistently highlighted as a quality issue in this review. The use of control arms which provide current standard of care adjuvant treatment with immunotherapy or targeted treatments, will be essential to recruit participants to these trials, and to elicit the benefits of neoadjuvant treatment versus adjuvant treatment. Blinding would be appropriate to address some of the concerns regarding performance and detection bias. The ongoing studies identified in this review are larger trials, including some phase III trials with appropriate adjuvant treatment as part of the control arm, will go some way to addressing the deficiencies in the certainty of evidence as highlighted in this review.
The use of optional or non‐standard of care adjuvant therapy was highlighted as a potential source of bias in this review. Since the inception of this review protocol, adjuvant treatment with immunotherapy or targeted therapy has become the accepted standard of care for stage III melanoma following surgical resection. Thus, future trials evaluating neoadjuvant treatment strategies should include adjuvant treatment with immunotherapies or targeted therapies in the control arm, to identify if there is meaningful clinical benefit to patients beyond that offered by adjuvant treatment. Future neoadjuvant trials identified in the review include an adjuvant treatment component in the investigational arm also, and will improve the quality of the available evidence. There are exceptions to this, for example where the objective of the trial is to risk‐stratify participants to avoid adjuvant treatment.
A challenge highlighted in the identified trials is the heterogeneity in trial design, including the use of varied definitions of trial endpoints. A defined core outcome set for neoadjuvant treatment trials is necessary. INMC 2019 goes some way towards this, suggesting that recurrence‐free survival, event‐free survival and distant metastatic‐free survival are the important survival outcomes to include in these trials, but unfortunately does not provide clear definitions of these endpoints. INMC 2019 similarly highlights the importance of consistent application of pathological scoring measures in order to validate its use as a surrogate outcome, and to enable cross‐trial comparisons; Tetzlaff 2018 is a welcome start. Further investigation of the relationship between radiographic response, pathological response and survival outcomes is required, as has been initiated by Menzies 2021, and if it potentially differs depending on treatment type, e.g. immunotherapies versus targeted treatments.
The included studies did not collect or report data on quality of life (QOL) outcomes, and rarely on surgical outcomes. The absence of data on QOL outcomes and on surgical outcomes makes a holistic assessment of the benefits and risks of neoadjuvant treatment challenging. These endpoints should be considered for inclusion in future neoadjuvant trial designs as a priority. The potential impact of neoadjuvant treatment on surgical outcomes, such as delays or cancellation of surgery due to AEs or disease progression, or differences in the R0 resection rate, or time to subsequent healing postsurgery, are relevant outcomes to patients and health systems alike, and should be considered in subsequent trials of neoadjuvant treatment. Reaching consensus on the most important surgical outcomes to record will be important. Similarly, information on QOL with neoadjuvant treatment will be important for informed decision‐making by patients, if electing to undergo neoadjuvant treatment or indeed, if considering entering a clinical trial of neoadjuvant treatment. Information on QOL is also important for economic evaluation of treatments, and prospective collection of data within RCTs can provide the information necessary to provide evidence of additional benefit to Health Technology Assessment agencies as well as regulatory authorities, thus facilitating patient access to treatment. The potential for neoadjuvant treatment to reduce drug costs should also be examined when designing future trials of neoadjuvant treatment, particularly if short courses of neoadjuvant treatment could reduce the risk of recurrence and therefore the high costs incurred in the metastatic setting. This is especially important given that the high costs associated with these drugs prohibits access in the metastatic setting in many countries (Kandolf Sekulovic 2018).
Treatments are associated with high costs in every jurisdiction, and consideration of the opportunity cost of funding these drugs as neoadjuvant treatment will be required. Data relevant to Health Technology Assessment agencies, as well as regulatory bodies, should be collected in trials, to ensure neoadjuvant treatment regimens are ultimately available to those who may benefit from them. Such endpoints include preference‐based measures of QOL, quantifying resource use, and cost offsets in the recurrent disease setting. It will also be essential to establish the nature of the relationship between pathological complete response (pCR), TTR and OS.
Histological or cytological staging was required prior to enrolment in the identified studies included in this review. In clinical practice, patient selection will be an important component of the provision of neoadjuvant treatment, requiring careful assessment of the likelihood of successful resection of the tumour, and balancing the potential risks of delaying surgery with the potential benefits of providing upfront systemic treatment. A recent publication from the INMC provides suggestions for harmonising the approach to issues of surgical relevance in neoadjuvant trials for melanoma, such as the definition of resectability, and the extent and scope of routine surgery (Van Akkooi 2022). The adoption of the eighth edition of the American Joint Committee on Cancer (AJCC) melanoma staging criteria, and the use of these criteria for staging melanoma in participants enrolled in future clinical trials, will impact on the comparability of future trials and trial outcomes with the trials included in this review, where all included trials used the seventh edition criteria.
Finally, we currently have little information about the consequences of neoadjuvant treatment for the available treatment options in the recurrent or metastatic disease setting, for example retreatment with immunotherapy, the potential for resistance emerging to targeted therapy etc. Neoadjuvant trials provide an opportunity to engage in translational research, to obtain extensive personalised information on immune response to treatment, genomic markers, and long‐term clinical outcomes, and to potentially inform personalised treatment choices for patients in future. Research in this area will be important to adequately inform choices on whether to opt for neoadjuvant treatment, and to identify those patients who are most likely to benefit.