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Health Line
20 hours ago
- Health
- Health Line
Understanding the Stages of Thyroid Cancer
Key takeaways Thyroid cancer staging helps doctors determine the best treatment and predict the likely outcome. It uses the American Joint Committee on Cancer (AJCC)'s TNM system, which assesses tumor size, lymph node involvement, and metastasis. Staging differs among the main types of thyroid cancer, including medullary, follicular, papillary, and anaplastic. Anaplastic thyroid cancer is aggressive and is always stage IV. Early stage cancers generally have better treatment outcomes and survival rates. The American Cancer Society estimates that about 43,800 people in the United States will be diagnosed with thyroid cancer by the end of 2022. Women are affected three times more often than men. Doctors stage thyroid cancer from stage I to stage IV depending on how far along your cancer has progressed. Different staging systems are used for different types of thyroid cancer. Keep reading to learn more about how the most common types of thyroid cancer are staged. How is the staging for thyroid cancer determined? Thyroid cancer is most often staged using the American Joint Committee on Cancer (AJCC) TNM staging system. This staging system considers: T: How big the tumor is and whether it has spread to nearby tissues. N: Whether the cancer has spread into nearby lymph nodes. M: Whether the cancer has metastasized, meaning spread to distant tissues. The AJCC staging system differs depending on which type of thyroid cancer you have. The four main types are: Medullary thyroid cancer: Develops in special cells called C cells that produce the hormone calcitonin. Follicular thyroid cancer: A usually slow-growing cancer that develops in follicular cells. These cells produce and secrete triiodothyronine (T3) and thyroxine (T4). Papillary thyroid cancer: Develops in follicular cells and makes up 80% to 85% of thyroid cancers. It generally has the best outlook. Anaplastic thyroid cancer: Makes up less than 2% of thyroid cancers but is the most aggressive type. It develops in follicular cells. Knowing which stage you're in helps doctors figure out what the best treatment option may be. It can also give you and your healthcare team the best idea of what to expect in terms of life expectancy and chances of being cured. Staging for medullary thyroid cancer The overall 5-year relative survival rate for medullary thyroid cancer is nearly 100% if it's limited to your thyroid and 89% for all stages combined. The 5-year relative survival rate is a measure of how many people with the cancer are alive 5 years later compared to people without the cancer. Here's a look at the AJCC's TNM system for medullary thyroid cancer: Stage TNM groups Description I T1 N0 M0 T1: The cancer is smaller than 0.8 inches across and only found in the thyroid. N0: It has not spread to nearby lymph nodes. M0: It has not spread to distant body parts. II T2 N0 M0 T2: The cancer is bigger than 0.8 inches but smaller than 1.6 inches across. It's only found in the thyroid. N0: It has not spread to nearby lymph nodes. M0: It has not spread to distant body parts. OR II T3 N0 M0 T3: The cancer is larger than 1.6 inches across and is limited to the thyroid or has grown outside the thyroid but hasn't spread to nearby tissues. N0: It has not spread to nearby lymph nodes. M0: It has not spread to distant body parts. III T1, T2, or T3 N1a M0 T1 to T3: The cancer can be any size but hasn't invaded tissues around your thyroid. N1a: The cancer has spread to lymph nodes in your neck. M0: The cancer hasn't spread to any distant body parts. IVA T4a Any N M0 T4a: The cancer is any size and has grown into nearby tissues such as your windpipe or voice box. Any N: It may or may not have spread to nearby lymph nodes. M0: It hasn't spread to distant body parts. OR IVA T1, T2, or T3 N1b M0 T1 to T3: The cancer is any size and may have grown outside the thyroid. It hasn't grown into any nearby structures. N1b: The cancer has spread to lymph nodes in your neck. M0: The cancer has not spread to distant body parts. IVB T4b Any N M0 T4b: The cancer is any size and has either grown toward your spine or into major blood vessels nearby. Any N: The cancer may or may not have spread to lymph nodes. M0: The cancer has not spread to distant body parts. IVC Any T Any N M1 Any T: The cancer is any size and may have grown into nearby structures. Any N: The cancer may or may not have spread into lymph nodes. M1: The cancer has spread into distant areas such as your liver, brain, or bone. Staging for differentiated (papillary and follicular) thyroid cancer Staging for papillary or follicular thyroid cancer depends on whether you're over or under the age of 55. The overall 5-year relative survival rate for people with papillary thyroid cancer is nearly 100% and about 98% for follicular cancer. Stage Age of diagnos is TNM groups Description I younger than 55 years Any T Any N M0 Any T: The cancer is any size. Any N: The cancer may or may not have spread to lymph nodes. MO: It hasn't spread to distant areas. OR I 55 years or older T1 N0 or NX M0 T1: The cancer is smaller than 0.8 inches across and is only found in your thyroid gland. N0 or NX: The cancer hasn't spread to nearby lymph nodes or there isn't enough information to assess if the cancer has spread to lymph nodes. M0: The cancer hasn't spread to distant areas. OR I 55 years or older T2 N0 or NX M0 T2: The cancer is larger than 0.8 inches across but smaller than 1.6 inches. It's limited to your thyroid. N0 or NX: The cancer hasn't spread to nearby lymph nodes or there isn't enough information to assess if the cancer has spread to lymph nodes. M0: The cancer hasn't spread to distant areas. II younger than 55 years Any T Any N M1 Any T: The cancer is any size. Any N: The cancer may or may not have spread to nearby lymph nodes. M1: The cancer has spread to distant body parts like your bone or internal organs. OR II 55 years or older T1 N1 M0 T1: The cancer is smaller than 0.8 inches across and limited to the thyroid. N1: The cancer has spread to nearby lymph nodes. M0: The cancer hasn't spread to distant areas. OR II 55 years or older T2 N1 M0 T2: The cancer is larger than 0.8 inches across but smaller than 1.6 inches. It's limited to your thyroid. N1: The cancer has spread to nearby lymph nodes. M0: The cancer hasn't spread to nearby areas. OR II 55 years or older T3a or T3b Any N M0 T3a or T3b: The cancer is larger than 1.6 inches across but limited to the thyroid or the muscles that support your thyroid. Any N: The cancer may or may not have spread into nearby lymph nodes. M0: The cancer hasn't spread to distant sites. III 55 years or older T4a Any N M0 T4a: The cancer is any size and has grown beyond your thyroid into surrounding tissues such as your voice box or windpipe. Any N: The cancer may or may not have spread into nearby lymph nodes. M0: The cancer hasn't spread to distant sites. IVA 55 years or older T4b Any N M0 T4b: The cancer has spread extensively beyond your thyroid toward your spine or into large blood vessels in the surrounding area. Any N: The cancer may or may not have spread into nearby lymph nodes. M0: The cancer has not spread to distant locations. IVB 55 years or older Any T Any N M1 Any T: The cancer is any size. Any N: The cancer may or may not have spread to nearby lymph nodes. M1: The cancer has spread to distant parts of your body. Staging for undifferentiated (anaplastic) thyroid cancer Anaplastic cancer has the poorest outlook of any thyroid cancer. Its 5-year relative survival rate is 7%. All anaplastic cancers are considered to be stage IV. It's divided into substages depending on its features. Stage Stage grouping Description IVA T1, T2 or T3a N0 or NX M0 T1, T2, or T3a: The cancer can be any size as long as it's contained to your thyroid. N0 or NX: The cancer hasn't spread to nearby lymph nodes or there's not enough information to know if it has. M0: The cancer has not spread to distant parts of your body. IVB T1, T2 or T3a N1 M0 T1, T2, or T3a: The cancer can be any size as long as it's contained to your thyroid. N1: The cancer has spread to nearby lymph nodes. M0: The cancer has not spread to distant parts of your body. OR IVB T3b Any N M0 T3b: The cancer is any size and has grown into the muscles that support your thyroid. Any N: The cancer may or may not have spread into nearby lymph nodes. M0: The cancer has not spread to distant parts of your body. OR T4 Any N M0 T4: The cancer has grown beyond the thyroid gland and into nearby tissue such as your voice box or windpipe. It also may have grown toward your spine or large blood vessels nearby. Any N: The cancer may or may not have spread to nearby lymph nodes. M0: The cancer has not spread to distant parts of your body. IVC Any T Any N M1 Any T: The cancer can be any size. Any N: The cancer may or may not have spread to nearby lymph nodes. M1: The cancer has spread into distant body parts such as your bones or internal organs. Takeaway Thyroid cancer is broken into stages depending on how far the cancer has progressed. The AJCC's TNM staging for papillary or follicular thyroid cancer also considers your age. Cancers in early stages are considered easier to treat and have a better outlook. Due to the aggressive nature of anaplastic thyroid cancer, it's always considered stage IV. Knowing what stage of cancer you're in helps doctors understand how to best manage your cancer. It can also give you an idea of your chances of survival. Survival statistics are often based on old data, so your chances of survival might be better than statistics suggest.
Medscape
09-05-2025
- Health
- Medscape
Pembrolizumab for Advanced Melanoma: Is It Worth It?
In the 11 years since it was approved for the treatment of melanoma, pembrolizumab (Keytruda) has become the go-to for adjuvant or neoadjuvant therapy for advanced melanoma, despite the potential for side effects, which can be severe and occur in more than half of all patients. Oncologists need to weigh the risk of those side effects against the strong evidence supporting the effectiveness of pembrolizumab to improve survival. More often than not, those scales tip toward using the drug to treat advanced melanoma, experts say. Evidence has accumulated about which types of patients may be more susceptible to drug-related toxicities, how oncologists and other providers in the multidisciplinary team can manage those toxicities, and which treatment protocols may be most effective. Today, pembrolizumab is indicated for the treatment of about 20 types of cancer, but the first indication for which the US Food and Drug Administration (FDA) approved it was advanced or unresectable melanoma in people who had already tried ipilimumab and a BRAF inhibitor if their tumors had a BRAF mutation. It was the first immune checkpoint inhibitor (ICI) targeting programmed cell death 1 (PD-1) approved by the FDA. While it has been shown to extend life expectancy in melanoma and other types of cancers compared with ipilimumab, an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4), and other older treatments, the side effects of pembrolizumab have been well-documented, particularly higher-grade toxicities (grades 3-5). Researchers who have studied the drug told Medscape Medical News that years of experience have demonstrated pembrolizumab is safe to use in just about any patient with advanced melanoma. The approval for pembrolizumab for advanced melanoma was based on the phase 3 KEYNOTE-006 trial, which found that the overall survival rate at 33 months was 50% vs 39% in patients on pembrolizumab vs ipilimumab. The rate of grade 3-5 adverse events (AEs) in the trial was 13%-16% for those on pembrolizumab and 20% for those on ipilimumab. A 10-year follow-up of the KEYNOTE-006 trial reported an overall survival rate of 34% for those on pembrolizumab and 23.6% for those on ipilimumab. Who Can Be on Pembrolizumab? 'I think you can consider trying it in any patient,' Omid Hamid, MD, chief of Research and IM/Oncology at Cedars-Sinai The Angeles Clinic and Research Institute, Los Angeles, and co-author of a safety evaluation published last year of almost 9000 patients in 31 clinical trials of pembrolizumab, said. Exceptions may be reinitiating pembrolizumab in a patient who had to halt treatment after a life-threatening AE or any patient with connective tissue disease or who has had a transplant, Hamid said. The 2024 safety evaluation included patients with advanced melanoma in the pivotal phase 3 KEYNOTE-006 trial. The study also identified other patient conditions that may give oncologists pause before using pembrolizumab: Anemia, pneumonia, hematologic malignancies, myocarditis, and gastric bleeding and myositis. 'The myocarditis, the myositis that comes with the myasthenia has a significant mortality associated with it, about 20%, so we need to understand that,' Hamid said. Sapna Patel, MD, a professor of oncology at the University of Colorado Anschutz Medical Campus in Aurora, Colorado, led a phase 2 trial, known as SWOG S1801, that randomly assigned patients with surgically resectable stage IIIB-IVC melanoma to two pembrolizumab regimens: One with three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) and the second with surgery followed by 200 mg pembrolizumab every 3 weeks for 18 doses for about 1 year or until disease recurrence or unacceptable toxic events developed (adjuvant-only group). Event-free survival at 2 years was 72% in the former group vs 49% in the latter. Neoadjuvant-adjuvant pembrolizumab is indicated for patients with melanoma involving lymph nodes, particularly when the lymph nodes are readily measured on cross-sectional imaging or palpable on clinical exam, Patel said. 'We're currently investigating whether this can be expanded to other stages of melanoma,' she said. 'It is also approved to be given entirely postoperatively in the adjuvant setting, as well as for metastatic melanoma that has spread to distant parts of the body.' Patel called SWOG S1801 'a practice-changing trial' that showed that using the standard regimen of 18 doses of pembrolizumab before and after the surgery instead of giving all the doses after surgery can yield superior results, Patel told Medscape Medical News . Who May Not Be Good Candidates for Adjuvant Pembrolizumab? Patients with concurrent autoimmune conditions and those of advanced age who may not derive a long-term benefit in reducing recurrence risk may not be good candidates for adjuvant pembrolizumab, said Jason Luke, MD, director of the Immunotherapy and Drug Development Center at the University of Pittsburgh, Pittsburgh. Luke led the long-term follow-up of the pivotal KEYNOTE-716 trial of patients on adjuvant pembrolizumab with resected stage IIB/IIC melanoma, which found that recurrence-free survival at 48 months was 71.3% for pembrolizumab and 58.3% for placebo. The trial did not reveal any new safety signals. 'Patients with active autoimmune disease requiring treatment or organ transplant recipients may not be optimal candidates for this type of treatment,' Patel added. Similarly, she said, patients on chronic immune suppression would not likely benefit from treatment with an ICI. Even when side effects occur, oncologists should consider whether to discontinue pembrolizumab treatment carefully, Hamid said. 'There are times where you might think to discontinue it, but in scenarios where this is a life-threatening disease or you have other options that limit their lifespan and there may be an imminent cause of mortality, pembrolizumab would be indicated despite the potential side effects,' he said. Safety Profile The safety evaluation Hamid co-authored found that more than half of all patients had an any-cause grade 3-5 AE, and about 1 in 8 discontinued treatment. However, 6% of toxicities were immune-mediated, which he described as 'very low.' This year a real-world study from Northern Ireland found that even low-grade immune-related AE (irAE) toxicities in patients on adjuvant pembrolizumab for stage III melanoma could have a significant impact. Up to one third of them had to stop treatment. In this study, 70% of patients had a treatment-related toxicity, with 51% of all patients having a grade 1-2 toxicity. Among patients with only low-grade toxicity, 15% required hospitalized and 33% required immunosuppression with oral corticosteroids treatment. But steroid treatment comes with its own challenges, the study authors noted. 'Steroid tapering should be gradual as premature discontinuation may lead to relapse,' they wrote. However, long-term steroid use carries a risk for bone loss, particularly in patients aged 50 years or older. 'The risk of bone loss may be observed even at low doses and within the first month of treatment,' they wrote. Some patients may not respond to steroids for irAEs as shown in a different study, where 6.2% of patients with melanoma treated with checkpoint inhibitors did not respond to steroids. In patients with grade 2 toxicities who discontinue therapy, the Northern Ireland researchers wrote, 'these real-world data suggest that clinicians may be cautious' when resuming therapy. An analysis of the FDA AE database focused on cardiac AEs linked to pembrolizumab. The study looked at 6719 ICI-related cardiac AEs, more than one third (34.3%) of which were fatal. The analysis found that 17.3% of all pembrolizumab-associated AEs were cardiac in nature. Pembrolizumab was found to be more often reported with myocarditis, pericardial disease, heart failure, and atrial fibrillation than other drugs in the FDA database, with myocarditis being the most significant. However, the study did not specify cancer types or stages. In melanoma, the safety profile of pembrolizumab is comparable to that of other checkpoint inhibitors. The pivotal CheckMate 067 trial, which evaluated the combination of nivolumab, an anti–PD-1 agent like pembrolizumab, and ipilimumab against either drug alone in patients with melanoma, reported grade 3 or higher treatment-related AEs in approximately 59% of patients on combination therapy, with nearly 10% having to stop treatment. Survival Outcomes and AEs In the phase 2 SWOG S1801 trial, the incidence of AEs of grade 3 or higher was similar in both neoadjuvant-adjuvant and adjuvant-only treatment groups (12% and 14%, respectively), and significantly lower than other studies have found, study leader Patel said. The study did not specify irAEs. Hamid said that most pembrolizumab-related AEs 'are manageable and can get back to baseline.' Symptoms of irAEs can occur at 10 weeks into therapy or later, he said. Adrenal insufficiency, for example, occurred within about 6 months. The most commonly reported irAEs were hypothyroidism, pneumonitis, hyperthyroidism, colitis, and severe skin reactions, Hamid said. 'Any symptom needs to be looked at and considered in the setting of an immune-mediated toxicity,' Hamid said. Alternative to Pembrolizumab When pembrolizumab may not be optimal for treating melanoma, the use of first-line immunotherapy with alternative treatments and regimens might be. Hamid noted the phase 2 SECOMBIT trial showed that first-line immunotherapy followed by combination BRAF and MEK inhibition provided a survival benefit in patients with untreated BRAFV600 -metastatic melanoma. SECOMBIT included a treatment arm in which patients received 8 weeks of the BRAF inhibitor encorafenib with the MEK inhibitor binimetinib, followed by the combination of nivolumab with ipilimumab until PD — a regimen the study termed the 'sandwich' arm. That arm had a 4-year total progression survival rate of 54% vs 29% for the arm taking encorafenib plus binimetinib until PD followed by ipilimumab and nivolumab, and 55% for the arm that started with ipilimumab and nivolumab until PD then switched to encorafenib and binimetinib. 'It's the fact that immunotherapy takes time to work, so patients with aggressive high-tumor fraction growth may want to initially involve some form of priming dose,' Hamid said. 'For those who are BRAF -mutated, a lead-in with BRAF inhibition, with BRAF and MEK combination therapy as per the SECOMBIT trial, may be indicated.' Another option is what Patel called 'flipped dosing,' which involves nivolumab plus ipilimumab for two doses. Another alternative to pembrolizumab in advanced melanoma is nivolumab plus relatlimab, a checkpoint inhibitor that targets the lymphocyte-activation gene 3, Patel said. 'Treatment for melanoma has dramatically changed over the past 10-15 years, moving from a general lack of treatment options to now a plethora of options,' Luke said. He noted the multitude of options, besides the ICIs such as pembrolizumab and nivolumab, include combinations of anti–PD-1 with anti-CTLA4 and anti-LAG3 agents, BRAF and MEK inhibition as targeted therapy, adoptive cell transfer of tumor-infiltrating lymphocytes, oncolytic viruses, and CD3-bispecific therapies. The choices can be 'daunting' for patients, according to Luke. While there are several treatment options, overall, there is strong evidence supporting the life-extending effects of pembrolizumab despite the drug's potential side effects. Hamid disclosed having financial relationships with Alkermes, Amgen, Bactonix, BeiGene, BioAtla, Bristol Myers Squibb, Eisai Biotech, Roche/Genentech, Georgiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instil Bio, IO Biotech, Iovance, Janssen, KSQ, Merck, Moderna, NGM Bio, Novartis, Obsidian, Pfizer, Regeneron, Sanofi, Seattle Genetics, Tempus, Vial Health Tech, and Zelluna. Luke disclosed having financial relationships with AbbVie, Agenus, AstraZeneca, Bayer, Bristol Myers Squibb, Clasp, Curadev, Eisai, EMD Serono, Geneos, Gilead, HotSpot, Krystal, Janssen, Ikena, Immatics, Incyte, IO Biotech, iTeos, LegoChem, Lyvgen, Merck, Mersana, Novartis, Pfizer, Pioneering Medicines, Regeneron, Replimune, Storm, Sumitomo, Synlogic, and Teva. Patel disclosed having financial relationships with Bristol Myers Squibb, Cardinal Health, Ideaya, IO Biotech, Merck Sharpe and Dohme, Natera, Novartis, OncoSec, Pfizer, Replimune, Scancell, TriSalus, Veda Trials, Foghorn Therapeutics, InxMed, Lyvgen, Provectus Biopharmaceuticals, Seagen, Syntrix Bio, and TriSalus Life Sciences. No funding details were reported by the authors of the Northern Island study. One author of that paper disclosed receiving honoraria from DePuy companies and having other ties with various organizations. Another author reported having a consulting or advisory role with Bristol Myers Squibb UK.
