{"id":10551,"date":"2025-12-30T19:46:39","date_gmt":"2025-12-30T15:46:39","guid":{"rendered":"https:\/\/medscriptum.org\/?p=10551"},"modified":"2025-12-30T19:47:12","modified_gmt":"2025-12-30T15:47:12","slug":"mastering-locally-advanced-melanoma-resectable-vs-unresectable-rechallenge-strategies-and-emerging-adjuvant-frontiers","status":"publish","type":"post","link":"https:\/\/medscriptum.org\/en\/mastering-locally-advanced-melanoma-resectable-vs-unresectable-rechallenge-strategies-and-emerging-adjuvant-frontiers\/","title":{"rendered":"Mastering Locally Advanced Melanoma – Resectable vs Unresectable, Rechallenge Strategies, and Emerging Adjuvant Frontiers"},"content":{"rendered":"

Oncology’s precision era hinges on mastering subtle disease staging distinctions that determine life-altering treatment paths, from neoadjuvant immunotherapy combinations that deliver major pathological responses to metastatic protocols that navigate resistance landscapes. These critical resectability decisions significantly impact patient trajectories, balancing surgical feasibility, and long-term disease control, while exposing gaps in primary resistance mechanisms and rechallenge strategies that necessitate multidisciplinary innovation.<\/p>\n

Dr. Alice Indini, medical oncologist from Fondazione IRCCS Istituto Nazionale dei Tumori<\/a> Milan – Italian Melanoma Intergroup member, brings frontline trial insights to this challenge.<\/p>\n

In this interview, Dr. Indini clarifies surgical decision-making, neoadjuvant immunotherapy efficacy, resistance gaps in primary progressors, radiotherapy synergies, and rechallenge strategies post-adjuvant relapse.<\/p>\n

Locally advanced cutaneous melanoma can present in very different ways. How do you explain to non-specialists the key differences between potentially resectable and unresectable disease, and how these differences guide treatment strategies?<\/em><\/p>\n

There is an important distinction between locally advanced potentially resectable melanoma and locally advanced unresectable melanoma.<\/p>\n

For the unresectable form, which is somewhat more straightforward, we generally treat the patient similarly to those with metastatic disease. The same principles apply – immunotherapy remains the first-line approach, even in BRAF-mutant cases. These patients often have a somewhat better prognosis compared to metastatic disease, because there is no visceral or distant organ involvement. But, overall, the therapeutic considerations mirror those in metastatic melanoma.<\/p>\n

Locally advanced potentially resectable melanoma is different because these patients may benefit from a neoadjuvant treatment strategy. We now have access to robust data supporting neoadjuvant treatment with anti-PD-1-based therapy, especially with combination therapy using anti-PD-1 plus anti\u2013CTLA-4 as induction before surgery. This approach is highly valuable because it yields excellent pathologic response rates, including a high proportion of major pathological responses.<\/p>\n

Importantly, if the patient achieves a major pathological response after surgery, they can often transition to simple follow-up rather than requiring additional adjuvant therapy. These are essentially the two main treatment settings for locally advanced cutaneous melanoma.<\/p>\n

Building on that distinction between resectable and unresectable disease, could you explain how you determine which category a patient falls into?<\/em><\/p>\n

Determining whether a melanoma is resectable or unresectable is largely a surgical decision. These cases should always be discussed within a multidisciplinary team, where the surgeon can advise the oncologist on how feasible and how radical the surgery would need to be, as well as the potential impact on the patient.<\/p>\n

In many situations, if combined immunotherapy is available, we start with systemic treatment because we know it provides a high response rate. Once a response is achieved, we can then proceed to surgery.<\/p>\n

There are specific scenarios – for example, a distant-site relapse or oligoprogression (limited (usually 1-2) metastatic areas progressing while on\/off systemic therapy in the background of polymetastatic disease<\/i>) after a prior treatment – where surgery may be a good option, particularly if the treatment-free interval has been long. However, whenever possible, our approach is to initiate systemic therapy first and then proceed with surgery.<\/p>\n

Immunotherapy has undoubtedly revolutionized melanoma care, yet treatment resistance remains a major challenge. From your experience, what are the less-studied biological or tumor-microenvironment factors that contribute to resistance?<\/i><\/p>\n

There are several mechanisms of resistance. Some are responsible for primary resistance, where patients fail to respond from the beginning, while others contribute to secondary resistance that develops over time. We do know how to target a few of these mechanisms – for example, by adding other therapies – but overall, treatment options in this setting remain very limited.<\/p>\n

A major issue is that clinical trials often exclude patients with primary resistance during adjuvant or first-line antiPD1 treatment. This makes sense from a study-design perspective because these patients typically have rapidly progressing disease. However, it leaves us with a subset of patients for whom we have very few effective options.<\/p>\n

So while there are likely many biological and microenvironmental factors involved in treatment resistance, we currently understand only a small fraction of them – and our therapeutic tools in this area remain quite limited.<\/p>\n

Based on your clinical experience, what have you learned about optimal timing or combinations – such as integrating radiotherapy – to enhance responses without adding excessive toxicity?<\/i><\/p>\n

In the locally advanced setting, our usual approach is to begin with systemic therapy followed by surgery. However, in cases where surgery is challenging, we often integrate radiosurgery or radiotherapy, depending on the site of disease. The outcomes are very good, particularly when radiotherapy is combined with immunotherapy, but also with targeted therapies. The main practical consideration is that systemic therapy needs to be paused during radiation, but overall, the results are very encouraging.<\/p>\n

This combination strategy is also something we apply in the metastatic setting, because combining modalities can significantly enhance the effect of systemic treatments.<\/p>\n

\u200b\u200bIn your talk, you highlighted the anti-PD-1 rechallenge, which means <\/i>giving <\/i>PD-1 checkpoint inhibitors<\/i><\/a> again after a break, often after initial response or progression<\/i>. Could you elaborate on the role of rechallenging? And when might it be effective?<\/i><\/p>\n

Anti-PD-1 rechallenge can be considered, particularly in patients who relapse after adjuvant treatment – especially if the relapse occurs long after the completion of adjuvant therapy.<\/p>\n

In my experience, rechallenge is generally more effective when immunotherapy is combined rather than using anti-PD-1 monotherapy alone. Patients who relapse after adjuvant therapy – whether early or late – tend to have a lower probability of responding to anti-PD-1 alone. By contrast, combining anti-PD-1 with anti-CTLA-4 appears to increase the chances of response and disease control.<\/p>\n

It\u2019s also important to differentiate patients who electively stop anti-PD-1 after two years of confirmed disease control. If these patients relapse months or years later, they often respond to anti-PD-1 monotherapy, without needing to escalate therapy. The challenge is primarily with patients who relapse very soon after completing adjuvant treatment, as they are less likely to respond to antiPD1 monotherapy.<\/p>\n

Looking ahead, which breakthroughs – whether in adjuvant therapy, combination strategies, or multidisciplinary innovations – make you most optimistic for the near future?<\/i><\/p>\n

I am very optimistic about neoadjuvant therapy, as the results we are seeing are highly promising. However, we must keep in mind that currently these therapies are only applicable to a minority of patients, those with clinically detectable lymph-node disease, which represents about 20% of stage III melanoma cases.<\/p>\n

At the same time, I am cautious about adjuvant treatments because we do not have positive results on overall survival from major randomized clinical trials and real-world studies. This scenario is likely to evolve in the near future, particularly with the advent of neoadjuvant immunotherapies.<\/p>\n

Beyond that, I am very confident in novel therapeutic strategies, such as vaccines, and especially TILs therapy. For example, Jonathan Lim\u2019s work has shown truly impressive results. The timeline for broader implementation remains uncertain due to regulatory hurdles, translational challenges, and high costs. Nevertheless, I believe these represent the most promising approaches in the near future.<\/p>\n



<\/p>\n","protected":false},"excerpt":{"rendered":"

Oncology’s precision era hinges on mastering subtle disease staging distinctions that determine life-altering treatment paths, from neoadjuvant immunotherapy combinations that deliver major pathological responses to metastatic protocols that navigate resistance landscapes. These critical resectability decisions significantly impact patient trajectories, balancing surgical feasibility, and long-term disease control, while exposing gaps in primary resistance mechanisms and rechallenge […]<\/p>\n","protected":false},"author":5,"featured_media":10720,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[1653],"tags":[3524,3523,1811],"class_list":["post-10551","post","type-post","status-publish","format-standard","has-post-thumbnail","category-interview","tag-immunotherapy","tag-locally-advanced-melanoma","tag-treatment"],"acf":[],"_links":{"self":[{"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/posts\/10551","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/users\/5"}],"replies":[{"embeddable":true,"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/comments?post=10551"}],"version-history":[{"count":2,"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/posts\/10551\/revisions"}],"predecessor-version":[{"id":10729,"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/posts\/10551\/revisions\/10729"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/media\/10720"}],"wp:attachment":[{"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/media?parent=10551"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/categories?post=10551"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medscriptum.org\/en\/wp-json\/wp\/v2\/tags?post=10551"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}