Review
Management of advanced medullary thyroid cancer Julien Hadoux, Furio Pacini, R Michael Tuttle, Martin Schlumberger
Abstract Medullary thyroid cancer arises from calcitonin-producing C-cells and accounts for 3–5% of all thyroid cancers. The discovery of a locally advanced medullary thyroid cancer that is not amenable to surgery or of distant metastases needs careful work-up, including measurement of serum calcitonin and carcinoembryonic antigen (and their doubling times), in addition to comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for any treatment. In the past, cytotoxic chemotherapy was used for treatment but produced little benefit. For the past 10 years, tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors and RET (rearranged during transfection) have been used when a systemic therapy is indicated for large tumour burden and documented disease progression. Vandetanib and cabozantinib have shown benefits on progression-free survival compared with placebo in this setting, but their toxic effect profiles need thorough clinical management in specialised centres. This Review describes the management and treatment of patients with advanced medullary thyroid cancer with emphasis on current targeted therapies and perspectives to improve patient care. Most treatment responses are transient, emphasising that mechanisms of resistance need to be better understood and that the efficacy of treatment approaches should be improved with combination therapies or other drugs that might be more potent or target other pathways, including immunotherapy.
Introduction Medullary thyroid cancer arises from calcitoninproducing C-cells and accounts for 3–5% of all thyroid cancers. About 75% of medullary thyroid cancer cases present in sporadic form and the remainder in a hereditary pattern. A germline activating mutation in the RET (rearranged during transfection) proto-oncogene (RET) is reported in nearly all cases of hereditary medullary thyroid cancer and a somatic RET mutation in up to 50% of sporadic tumours.1–5 At initial diagnosis, neck disease is usually amenable to surgery but recurrences are frequent and are often associated with, or precede, the discovery of distant metastases. Advanced medullary thyroid cancer includes patients with a locally advanced disease not amenable to surgery and those with distant metastases. Clinically detected distant metastases are present at diagnosis of medullary thyroid cancer in 4–17% of patients.4–12 Although distant metastases are often not clinically detectable they might be present initially in an even larger proportion of patients with medullary thyroid cancer; this might account for persistent high calcitonin levels after complete surgery. Distant metastases will be detected during follow-up in another 18–38% of patients.9,13 In retrospective series, survival after the discovery of distant metastases is 26% at 5 years and 10% at 10 years.6,10 Currently, distant metastases are often found at an early stage when small and could have an indolent course over years or decades, but patients with an aggressive disease might need treatment.
Clinical presentation Clinical medullary thyroid cancer usually presents as a thyroid nodule that can be associated with palpable lymph node metastases; initial treatment includes a total thyroidectomy and a neck lymph node dissection. Recurrence in the neck after initial surgery occurs mostly
in lymph nodes, and more rarely in the thyroid bed and in soft tissues. In some patients with extensive neck disease at the time of initial treatment or at recurrence, surgical resection is not feasible. Many distant metastases are often noted in involved organs and metastases can simultaneously affect several organs, such as the liver, lungs, and bones and, less frequently, the brain and soft tissues. Symptoms might be associated with local invasion and metastatic sites should be regularly assessed to anticipate and manage any complications. Furthermore, symptoms can also be associated with tumour hormone production—eg, diarrhoea, flushes, or (less frequently) Cushing’s syndrome—but quality of life is usually acceptable. Other patients might be asymptomatic and the presence of distant metastases is shown by imaging approaches in the presence of raised serum calcitonin and carcinoembryonic antigen (CEA) concentrations.
Lancet Diabetes Endocrinol 2015 Published Online October 23, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00337-X Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris Sud, Villejuif, France (J Hadoux MD, Prof M Schlumberger MD); Department of Medical, Surgical and Neurological Sciences, University of Siena, Via Bracci, Siena, Italy (Prof F Pacini MD); and Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA (Prof R M Tuttle MD) Correspondence to: Prof Martin Schlumberger, Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, 94805 Villejuif Cedex, France martin.schlumberger@ gustaveroussy.fr
Laboratory and radiological assessment Serum markers: calcitonin and CEA doubling times Calcitonin is a monomeric peptide that is secreted by both normal and neoplastic thyroid C-cells. It is a highly sensitive and specific tumour marker. CEA, which is produced only by neoplastic C-cells, is a less sensitive and less specific tumour marker than calcitonin, but high CEA concentrations are associated with a poor outcome of rapidly progressing disease. Serial (at least four) measurements of calcitonin and CEA allow the determination of their doubling time (defined as the interval of time in which the level has doubled). Doubling times might vary widely among patients with medullary thyroid cancer, from a few months to several years, but doubling time mostly remains unchanged in a specific patient during their life time. Because serum calcitonin concentration is closely associated with tumour volume, the doubling time is a
www.thelancet.com/diabetes-endocrinology Published online October 23, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00337-X
1
Review
Patient with medullary thyroid carcinoma shows evidence of disease
Work-up: • Calcitonin, CEA, and doubling times • Neck ultrasonography • Total body CT scan • MRI (liver, bones, and brain) • 18F-DOPA PET scan
Local and regional recurrence
Raised calcitonin concentrations and no evidence of disease
Metastatic disease
Surgery with or without external radiation therapy
Repeat work-up every 6 months or as according to calcitonin and CEA doubling times
Assess: • Tumour progression • Tumour burden • Local symptoms or risk of complication • Diarrhoea or secretion of hormonal peptides (eg, ACTH)
Low tumour burden; no progression; or no local symptom
Oligometastases amenable to focal treatment
Local symptoms or risk of local complication
Focal treatment: Surgery, radiofrequency ablation, cryoablation, or radiation therapy
Progression in
Management of advanced medullary thyroid cancer Julien Hadoux, Furio Pacini, R Michael Tuttle, Martin Schlumberger
Abstract Medullary thyroid cancer arises from calcitonin-producing C-cells and accounts for 3–5% of all thyroid cancers. The discovery of a locally advanced medullary thyroid cancer that is not amenable to surgery or of distant metastases needs careful work-up, including measurement of serum calcitonin and carcinoembryonic antigen (and their doubling times), in addition to comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for any treatment. In the past, cytotoxic chemotherapy was used for treatment but produced little benefit. For the past 10 years, tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors and RET (rearranged during transfection) have been used when a systemic therapy is indicated for large tumour burden and documented disease progression. Vandetanib and cabozantinib have shown benefits on progression-free survival compared with placebo in this setting, but their toxic effect profiles need thorough clinical management in specialised centres. This Review describes the management and treatment of patients with advanced medullary thyroid cancer with emphasis on current targeted therapies and perspectives to improve patient care. Most treatment responses are transient, emphasising that mechanisms of resistance need to be better understood and that the efficacy of treatment approaches should be improved with combination therapies or other drugs that might be more potent or target other pathways, including immunotherapy.
Introduction Medullary thyroid cancer arises from calcitoninproducing C-cells and accounts for 3–5% of all thyroid cancers. About 75% of medullary thyroid cancer cases present in sporadic form and the remainder in a hereditary pattern. A germline activating mutation in the RET (rearranged during transfection) proto-oncogene (RET) is reported in nearly all cases of hereditary medullary thyroid cancer and a somatic RET mutation in up to 50% of sporadic tumours.1–5 At initial diagnosis, neck disease is usually amenable to surgery but recurrences are frequent and are often associated with, or precede, the discovery of distant metastases. Advanced medullary thyroid cancer includes patients with a locally advanced disease not amenable to surgery and those with distant metastases. Clinically detected distant metastases are present at diagnosis of medullary thyroid cancer in 4–17% of patients.4–12 Although distant metastases are often not clinically detectable they might be present initially in an even larger proportion of patients with medullary thyroid cancer; this might account for persistent high calcitonin levels after complete surgery. Distant metastases will be detected during follow-up in another 18–38% of patients.9,13 In retrospective series, survival after the discovery of distant metastases is 26% at 5 years and 10% at 10 years.6,10 Currently, distant metastases are often found at an early stage when small and could have an indolent course over years or decades, but patients with an aggressive disease might need treatment.
Clinical presentation Clinical medullary thyroid cancer usually presents as a thyroid nodule that can be associated with palpable lymph node metastases; initial treatment includes a total thyroidectomy and a neck lymph node dissection. Recurrence in the neck after initial surgery occurs mostly
in lymph nodes, and more rarely in the thyroid bed and in soft tissues. In some patients with extensive neck disease at the time of initial treatment or at recurrence, surgical resection is not feasible. Many distant metastases are often noted in involved organs and metastases can simultaneously affect several organs, such as the liver, lungs, and bones and, less frequently, the brain and soft tissues. Symptoms might be associated with local invasion and metastatic sites should be regularly assessed to anticipate and manage any complications. Furthermore, symptoms can also be associated with tumour hormone production—eg, diarrhoea, flushes, or (less frequently) Cushing’s syndrome—but quality of life is usually acceptable. Other patients might be asymptomatic and the presence of distant metastases is shown by imaging approaches in the presence of raised serum calcitonin and carcinoembryonic antigen (CEA) concentrations.
Lancet Diabetes Endocrinol 2015 Published Online October 23, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00337-X Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris Sud, Villejuif, France (J Hadoux MD, Prof M Schlumberger MD); Department of Medical, Surgical and Neurological Sciences, University of Siena, Via Bracci, Siena, Italy (Prof F Pacini MD); and Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA (Prof R M Tuttle MD) Correspondence to: Prof Martin Schlumberger, Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, 94805 Villejuif Cedex, France martin.schlumberger@ gustaveroussy.fr
Laboratory and radiological assessment Serum markers: calcitonin and CEA doubling times Calcitonin is a monomeric peptide that is secreted by both normal and neoplastic thyroid C-cells. It is a highly sensitive and specific tumour marker. CEA, which is produced only by neoplastic C-cells, is a less sensitive and less specific tumour marker than calcitonin, but high CEA concentrations are associated with a poor outcome of rapidly progressing disease. Serial (at least four) measurements of calcitonin and CEA allow the determination of their doubling time (defined as the interval of time in which the level has doubled). Doubling times might vary widely among patients with medullary thyroid cancer, from a few months to several years, but doubling time mostly remains unchanged in a specific patient during their life time. Because serum calcitonin concentration is closely associated with tumour volume, the doubling time is a
www.thelancet.com/diabetes-endocrinology Published online October 23, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00337-X
1
Review
Patient with medullary thyroid carcinoma shows evidence of disease
Work-up: • Calcitonin, CEA, and doubling times • Neck ultrasonography • Total body CT scan • MRI (liver, bones, and brain) • 18F-DOPA PET scan
Local and regional recurrence
Raised calcitonin concentrations and no evidence of disease
Metastatic disease
Surgery with or without external radiation therapy
Repeat work-up every 6 months or as according to calcitonin and CEA doubling times
Assess: • Tumour progression • Tumour burden • Local symptoms or risk of complication • Diarrhoea or secretion of hormonal peptides (eg, ACTH)
Low tumour burden; no progression; or no local symptom
Oligometastases amenable to focal treatment
Local symptoms or risk of local complication
Focal treatment: Surgery, radiofrequency ablation, cryoablation, or radiation therapy
Progression in
