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;
- radiotherapy.
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.
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.
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.
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).