Professor Huang Donghang
The most effective and primary treatment for thyroid cancer is surgery. The appropriate scope of surgery is the key to success or failure. However, there is no denying that postoperative adjuvant non-surgical treatment has a great impact on long-term survival and recurrence rate, especially for patients in high-risk group. For some thyroid cancers that cannot be completely resected, such as local fixation, or highly malignant thyroid cancers that cannot be resected, such as those that have infiltrated extra-glandular tissues, or those that have distant metastases or local recurrence that cannot be resected, non-surgical adjuvant treatment can still have the effect of relieving symptoms and prolonging life. (1) Thyrotropin suppression therapy for differentiated thyroid cancer: The correct application of thyrotropin (TSH) suppression therapy after DTC can lead to good results in most patients, and the local recurrence rate and distant metastasis rate are significantly reduced. 30-year survival rate is also significantly improved. Huang Donghang, Department of Basic Surgery, Fujian Provincial Hospital
The mechanism of TSH inhibition therapy: Although many factors that stimulate thyroid growth and genes related to thyroid tumors have been identified, such as epidermal growth factor (EGF) and its receptor (EGFr), TSH is still the most important. TSH inhibitory therapy has no therapeutic effect on established carcinomas, but it can slow down their development. Inhibitory therapy may be effective only if the primary site is removed.
It has been shown that TSH receptors are present in follicular cell-derived DTC, and in vitro experiments have found that these receptors respond to TSH stimulation. TSH inhibition with thyroxine can prevent thyroid tumors from developing, and TSH can also stimulate the phosphate-dylinositol phophokinase C (PKC) system, especially in iodine deficiency, and contribute to thyroid nodule formation.
Dunhill (1937) first proposed the application of TSH inhibition in the treatment of thyroid cancer, and it is widely used in DTC with existing metastases and to prevent recurrence of resected tumors.
Thyroxine has a negative feedback effect on TSH, which is the basis for the implementation of suppressive therapy, but the physiological function is equivalent to 3-5 times that of T4, which can cause osteoporosis or heart rate disorders, some scholars oppose suppressive therapy, but comparing the 30-year survival rate, the suppressive therapy group is significantly higher than the control group.
② Implementation of TSH suppression therapy.
A. Indications for treatment: Since the prognosis of differentiated thyroid cancer in the high-risk group is not as good as that in the low-risk group, and thyroxine increases oxygen consumption in the heart and causes osteoporosis, the best indication for suppressive therapy is differentiated thyroid cancer aged <65 years without cardiovascular disease, especially in the high-risk group and premenopausal women. Secondly, suppressive therapy is also indicated after total thyroidectomy for differentiated thyroid cancer, especially within 5 years after surgery when the cancer is prone to recurrence. When there are some poor prognostic factors, suppressive therapy should be given to those who are >40 years old, with masses >4 cm in diameter, invading the envelope, etc.
B. Choice of preparation: The commonly used preparation is levothyroxine sodium (1evothyroxine, L-T4), which has a long half-life of about 7 days, while iodoserine (T3, triiodothyronine liothyronien) has a half-life of only 24h, which is beneficial for patients in the high-risk group who must undergo a nuclear scan at any time, in order to shorten the time to stop the drug before the examination and make the scan in time.
Sodium levothyroxine (L-T4) is a pure preparation with accurate thyroxine content and no risk of allergic reactions, but it is expensive. Biological thyroid powder (tablets), although rough in its preparation, is still valuable because of its low cost, and it is convenient to interchange thyroid powder (tablets) with sodium levothyroxine (L-T4). The equivalent dose for both is about 40mg of thyroid powder (tablet) equivalent to 100μg of levothyroxine sodium (L-T4).
C. Dosage control: It should be decided according to the concentration of TSH (S-TSH) and the concentration of T3, T4, FT3, especially FT4, measured by high-sensitivity immunoassay in serum. S-TSH is required to be reduced to a certain value, while T3, T4, FT3 and FT4 are maintained within the normal range. Depending on the need, suppressive therapies are divided into two types: total suppressive therapy and partial suppressive therapy. The former requires S-TSH to be below the normal low value, usually <0.3 μIU/ml or even <0.01 μIU/ml, while the latter requires S-TSH to be within the normal low value, often 0.3-1 μIU/m1 (the normal reference value of S-TSH is 0.3-6.3 μIU/ml).
The effective dose of LT4 is <60 years: >60 years: 1.5-1.8 μg/kg.d. The usual initial dose is about 50-100 μg/d of LT4 or 20-40 mg/d of thyroid tablets, but the sensitivity varies individually and the dose should be adjusted according to the thyroid function measurements. Patients in the low-risk group require only partial suppression therapy. In addition, the dose of thyroxine should be reduced with increasing age to avoid osteoporosis and increased myocardial oxygen consumption. However, the dose should be increased when the following factors are present: 1. gastrointestinal malabsorption: such as hepatic sclerosis, short bowel syndrome, etc. 2. concomitant use of certain drugs that block T4 absorption: such as aluminum hydroxide, aluminum thioglycollate, ferrous sulfate, lovastatin, biliary amines, etc. 3. pregnancy, etc.
D. Treatment time frame: When to give medication after surgery has not been unified, regardless of unilateral or bilateral thyroid lobectomy, the serum thyroxine level is basically within the normal range within 3 weeks after surgery and will not produce clinical manifestations of hypothyroidism, especially in unilateral resection, and T4 and FT4 are not significantly reduced about 5 days after surgery, and S-TSH is still in a transient suppressed state in some patients for a short period after surgery. In terms of suppression, the drug should be started after the effect of intraoperative hormone release has disappeared. In patients with unilateral thyroidectomy, TSH is twice the upper limit of the normal range at 3 weeks after surgery, so it is recommended that suppressive therapy be given from 2 to 3 weeks after surgery, i.e. 3 weeks after unilateral thyroidectomy and 2 weeks after bilateral thyroidectomy.
As for the duration of administration, patients in the high-risk group should preferably take it for life, while the low-risk group is prone to recurrence during the first 5 years after surgery. Therefore, total suppressive therapy can be administered within 5 years after surgery and followed up closely with regular ultrasound, nuclear scan, chest X-ray, CT, ECT and other imaging examinations of the neck. If there is no recurrence, partial suppressive treatment or no treatment can be performed after 5 years. In case of metastasis or recurrence, surgical resection or other non-surgical treatment will be performed. If the initial surgery is a total thyroidectomy or if the residual thyroid gland has been completely destroyed by nuclear iodine ablation, monitoring of serum thyroglobulin (TG) levels at follow-up is of great interest. TG should not be increased when suppressive therapy is effective. Once serum TG increases >5 ng/day after 4-6 weeks of cessation of effective suppressive therapy as indicated by S-TSH measurement, it is important to be alert for tumor recurrence or metastasis. Serum TG levels are more sensitive than nuclear scans after total thyroidectomy for non-functioning thyroid cancer.
Since TG is caused by TSH stimulation of the thyroid follicles, it can be increased by any disease that increases thyroid function, such as nodular goiter and thyroiditis. Therefore, when there is a functioning thyroid follicle, an increase in TG does not indicate a malignant tumor.
(iii) Adverse effects of suppressive therapy: As long as the dose of thyroxine is appropriate, most of the adverse effects are not significant. 1. Hyperthyroidism (hyperthyroidism) or subclinical hyperthyroidism: this can be avoided by regular review of thyroid function to keep T3, T4, FT3, and especially FT4 within normal limits. 2. Osteoporosis: It is characterized by bone pain, increased blood calcium, urinary calcium and osteoporosis, and decreased serum parathyroid hormone, especially in patients with insufficient calcium intake, alcohol consumption, tobacco addiction, hormone dependence and menopausal women. 3. Increased myocardial oxygen consumption, promoting angina pectoris and even myocardial infarction. Therefore, suppressive therapy must be used with caution or abandoned in patients with coronary arteriosclerotic heart disease, hypertensive heart disease or elderly patients, as well as in patients with atrial fibrillation.
(4) Efficacy of suppressive therapy: Suppressive therapy has been shown to reduce the recurrence rate of papillary and follicular adenocarcinoma and the mortality associated with thyroid cancer, even in elderly patients with progressive disease. However, the efficacy of suppressive therapy for advanced lesions is not as good as for the earlier ones. A recent retrospective analysis summarizing 683 cases from 14 centers according to the international classification suggested that it significantly reduced recurrence rates and prolonged survival in both stage III and IV versus stage I and II papillary carcinomas. In addition, although there was no significant difference in the 10-year survival rate between the suppressive therapy group and the control group, the 30-year survival rate showed that the suppressive therapy group was significantly higher than the control group.
(2) Nuclide iodine therapy: Nuclide iodine (131I) can be detected by γ-camera, and the absorption of γ-rays by tissues is minimal, while the destructive effect on thyroid follicles or carcinomas is caused by high-energy β-rays with a range of only 0.5 cm.
After oral administration of nuclear iodine, it is rapidly absorbed in the upper gastrointestinal tract, reaches certain tissues through blood circulation and concentrates, and is finally excreted in urine. Differentiated carcinoma has better iodine uptake and better therapeutic effect; medullary carcinoma has little or no iodine uptake, so the therapeutic effect is poor; undifferentiated carcinoma does not uptake iodine, so nuclear iodine therapy is hardly used.
Nuclide iodine therapy for differentiated thyroid cancer: Nuclide iodine therapy has good efficacy in differentiated thyroid cancer, but it can only be used as an adjuvant therapy for DTC after at least de-loading surgery.
According to the purpose of treatment, nuclear iodine treatment can be divided into two types: ablation therapy after thyroidectomy and internal irradiation therapy when metastasis is found and no more surgery is possible.
A. Ablation therapy: Ablation therapy is used to destroy the residual normal thyroid gland after near-total thyroidectomy for DTC to achieve the purpose of total thyroidectomy. The significance of ablation therapy: 1) remove the residual lesions and subclinical metastases after surgery; 2) reduce the recurrence rate and mortality rate in high-risk patients; 3) facilitate post-treatment follow-up by measuring thyroglobulin (Tg) in blood to monitor the presence of recurrence and metastases; 4) whole-body iodine-131 scan after iodine-131 treatment can detect new metastases that cannot be found by surgery or by other imaging examinations; 5) facilitate 131I treatment. 5. It is beneficial to treat metastases with 131I.
The indications for the elimination of residual thyroid tissue with 131I vary among scholars as follows: some believe that 131I should be performed on all patients with DTC who have residual thyroid tissue measured after surgery; most believe that 131I should be performed on high-risk patients with residual thyroid tissue. The majority of scholars believe that 131I to eliminate residual thyroid tissue in high-risk patients can reduce the recurrence rate and prolong survival. All patients with extra-thyroidal invasion visible to the naked eye, or tumors larger than 4 cm, or distant metastases should be treated with radioactive iodine 131 therapy to remove the residual thyroid gland and possible micro-metastases. For patients with cancer foci larger than 2 cm but limited to the thyroid gland, or with microscopic thyroid cancer infiltration, or with cervical lymph node metastasis, or with other high-risk recurrence factors such as high-risk histological types or vascular invasion, radioiodine 131 therapy is also feasible. Iodine 131 therapy is not routinely recommended for patients with papillary carcinoma with tumors less than 2 cm confined to the thyroid gland and without lymph node and distant metastases, regardless of whether the carcinoma is multiple. Follicular carcinoma and Hurthle cell carcinoma are generally considered to be high-risk tumors and should be recommended for RAI treatment. However, follicular thyroid carcinoma with only envelope invasion and no vascular invasion (also called “minimal invasive follicular carcinoma”) has a very good prognosis with surgical resection, and these patients do not need iodine 131 therapy.
Contraindications to 131I for elimination of remaining thyroid tissue: pregnant and lactating women; white blood cells <3.0 X 109/L, platelets <90 X 109/L; severe liver and kidney dysfunction.
b. Ablation timing: Usually 2-3 weeks after surgery is the most appropriate time, when TSH increases up to 30 μU/ml. At this time, limited metastases or residual lesions have the strongest iodine uptake capacity, and TSH >50 μU/ml inhibits the uptake of nuclear iodine instead.
c. Ablation dose.
The indicators of successful ablation are: iodine uptake <1% at 48h; no thyroid scan after ablation.
Within a certain range, the dose of nuclear iodine is positively correlated with the efficiency of ablation, ranging from 85% to 95% for 100-150 mCi. Since the higher the initial dose, the higher the ablation efficiency and the lower the number of repeat treatments, Balc et al. suggested that the appropriate dose for the initial application of nuclear iodine should be ≥30 mCi. Beieraltes suggested that a high dose of 100-149 mci of nuclear iodine should be applied when 1-5 mCi of nuclear iodine is taken and a diagnostic scan cannot reveal occult metastases, especially when the preoperative iodine uptake rate is <4%. treatment. If necessary, after 6-12 months of the initial nuclear iodine treatment, additional 75-100mci or fractionated ablative treatment should be applied in order to be safe and effective.
B. 131I treatment for recurrent metastases of differentiated thyroid cancer
Indications for 131I treatment of recurrent metastases of differentiated thyroid cancer: 131I can be administered to recurrent metastases of differentiated thyroid cancer without severe bone marrow suppression and liver and kidney dysfunction.
If surgical resection is possible, surgical resection should be performed first to reduce the tumor load, followed by 131I therapy after surgery.
The efficacy of 131I treatment varies depending on the tissue. Small cervical lymph nodes have good efficacy with complete remission rates up to 70%, lung metastases have the second best efficacy with complete remission rates up to 45%, and bone and brain metastases have poorer efficacy. There are many factors affecting the efficacy of 131I treatment, such as age at presentation, type of pathology, size and number of metastases, degree of 131I uptake by metastases, location of metastases, and duration of treatment. The iodine uptake rate of thyroid cancer obviously affects the efficacy of nuclear iodine.
When the cancer recurs in the residual gland, although the C cells that cause medullary carcinoma do not take up iodine, the normal thyroid follicles have iodine uptake function and can irradiate the nearby C cells, so the so-called bystander effect can achieve certain therapeutic effect. However, some people are against this effect.
If the tumor is found to be confined to the gland during the initial surgery, and total thyroidectomy is not performed, but the postoperative serum calcitonin is increased, it means that there may be occult lesions in the residual gland, and nuclear iodine can still be a valuable adjuvant therapy and can mostly prolong survival. Residual focal lesions are treated with 150 mCi of nuclear iodine, but the efficacy is not reliable. In metastases, iodine therapy is not indicated because the metastases contain only non-iodine-intake cancerous C cells and no normal thyroid follicles with iodine uptake.
(iii) Complications of nuclear iodine therapy.
A. Early complications: They occur within three weeks after drug administration and rarely occur with small doses (<30mci) of nuclear iodine therapy. The incidence increases when the dose is >150-200 mCi. a. Acute radiculopathy: incidence <1%, usually within 12 h after drug administration. It may occur immediately or several days after taking the drug, and in severe cases there may be parotid glands, and the change in taste may last for weeks or months. c. Transient radiation gastritis: It is rare and occurs within 1/2 to 1h after taking the drug orally, and manifests as nausea. d. Radiation cystitis: It manifests as bladder irritation, keeping the bladder emptying once every 2 to 3 hours. If the patient does not drink enough water within 24h of taking the drug, or if the bladder is not emptied in time, radiation cystitis may occur. e. Abdominal discomfort and mild diarrhea: Occurs on the 1st to 2nd day after taking the drug. f. Neck edema: Common after ablation therapy, occurs when the residual thyroid gland is high and iodine uptake is good, and manifests as angioneurotic-like neck edema. g. Transient hyperthyroidism: Nuclear iodine causes massive destruction of the thyroid gland. Transient hyperthyroidism can be caused by rapid release of thyroxine when the tumor regresses. h. Myelosuppression: almost always occurs, especially at high doses, and can lead to severe myelosuppression. i. Transient recurrent laryngeal nerve palsy: occurs during nuclear ablation therapy after near-total thyroidectomy. k. Hemorrhage from tumor metastases, which can also cause fatal cerebral edema, should be treated with adrenal Corticosteroids should be used for prevention before applying nuclear iodine therapy for brain metastasis.
B. Late complications: Complications arising after 3 months of treatment are late complications. a. Radiation pneumonitis and pulmonary fibrosis: Occurs in patients with extensive lung metastases with good iodine uptake, especially when the dose is too high. Prevention methods include: control of nuclear iodine dose within 80mCi within 48h; application of adrenocorticotropic hormone before treatment. b. Persistent bone marrow suppression: Very rare. It occurs only when the dose of nuclear iodine applied to bone metastases is too high. c. Sperm (oocyte) reduction or non-functioning syndrome: Prevalent in patients under 20 years of age, 12% infertility can be found at long-term follow-up. Therefore, it is recommended that pregnancy should be carried out only 6 months after treatment.
In the early days of 131I treatment, due to the lack of attention to the maximum safe dose experience, some serious side effects were reported, such as: leukemia, suppressed reproductive function, second primary cancer, pulmonary fibrosis, degenerative developmental changes, etc. Now, due to the emphasis on the maximum safe dose experience, the reports of serious side effects after 131I treatment have been greatly reduced.
(3) Radiation therapy: Radiation therapy (i.e. external irradiation therapy) is effective in controlling residual lesions and certain metastases of thyroid cancer, especially for some lesions that do not take up nuclear iodine, such as spindle cell and giant cell carcinoma, which is an ideal treatment method.
(4) Chemotherapy: The sensitivity and efficacy of chemotherapy for thyroid cancer are not as good as those of nuclear iodine and radiation therapy, and most of them can only provide local relief. For those who are not sensitive to nuclear iodine and radiation therapy, it can be used for comprehensive palliative treatment of thyroid cancer. For advanced thyroid cancer or undifferentiated cancer, cyclophosphamide can be tried.
Manumycin, a famesyl-protein transferase inhibitor, is often used alone or in combination with other drugs (e.g. paclitaxel) for the treatment of undifferentiated thyroid cancer.
Targeted therapy of monoclonal antibodies, which has been tried in recent years, may be a new way to treat thyroid cancer (mainly medullary carcinoma) (e.g., anti-CEA radiolabeled antibodies).
The combination of chemotherapeutic drugs and immunomodulatory drugs can improve the immunity of the body and strengthen the anti-cancer effect.
Chemotherapy for ①differentiated thyroid carcinoma: for progressive DTC that is insensitive to nuclear iodine and radiation therapy, or with surgical counter-indication, especially with pulmonary metastasis, chemotherapy has certain efficacy, with an effective rate of 17%, but there is no one case with significant effect, and the survival rate of more than 2 years is 10%, and 5% of patients still survive after stopping the drug.
Burgess et al. (1978) treated 53 cases of thyroid carcinoma with doxorubicin (Adriamycin) alone, 2/3 were effective, the mass was stable or shrunken, and the survival was prolonged, especially the differentiated type and medullary carcinoma were more sensitive, the efficacy of undifferentiated carcinoma was poor, the median validity was 8 months, and the survival was 17 months.
Medullary carcinoma chemotherapy: Most medullary carcinoma of thyroid has a good prognosis, but about 20% of patients have rapid progression and distant metastasis, so the prognosis is not good. Doxorubicin (Adriamycin), with an efficacy of up to 15%-30%, is less effective than the combination of monotherapy.
Wu treated with vincristine (1.4 mg/m2), qd×2 intravenous drip, 1 course every 3-4 weeks) with pulmonary metastasis, 4 cases were effective, 2 of which saw significant decrease and shrinkage of serum calcitonin and masses, which lasted for 14-19 months, with an efficiency of 57%, of which 28% were effective, with only mild to moderate gastrointestinal symptoms, and a few (2/7) with moderate hemoglobin reduction.
Petursson treated a 20-year-old medullary carcinoma with pulmonary metastases with streptozotocin (streptozotocin), starting with streptozotocin (streptozotocin) (500 mg/m2) qd×5 and doxorubicin (adriamycin) (60 mg/m2) every 3 weeks intravenously for 1 course every 6 weeks, and then switched to dacarbazine (azelenimib) (250 mg/m2) and fluorouracil when the pulmonary metastases were controlled (5-Fu) (450mg/m2) qd×5, followed by a 75% dose every 4 weeks for 1 course, resulting in shrinkage of the mass that lasted for up to 10 months and eventual death due to recurrence of the lung lesion 21 months after treatment.
(iii) Chemotherapy for undifferentiated thyroid cancer: The prognosis of undifferentiated thyroid cancer is extremely poor, and although it is less effective in chemotherapy, it still responds to some extent, with a response rate of 33%. Therefore, for progressive undifferentiated carcinoma where treatment methods are scarce, chemotherapy is a possible effective method when radiotherapy is ineffective or inappropriate to apply.
(4) Chemotherapy for primary thyroid lymphoma: Chemotherapy for primary thyroid lymphoma is similar to that for lymphoma.
(5) Biologic therapy for medullary carcinoma: Medullary thyroid carcinoma develops from parafollicular cells and is a neuroendocrine tumor. In addition to calcitonin, it also secretes other peptides, such as serotonin and substance P, which cause certain clinical symptoms unique to medullary carcinoma.
Somatostatin inhibits the secretion of several growth factors and hormones in tumor cells, and since 50% of myeloid carcinomas have growth inhibitor receptors, growth inhibitors can relieve symptoms caused by these hormones, such as diarrhea. IFN also has some efficacy in APUD tumors with metastases, blocking the division of tumor cells in the G0-G1 phase and activating the immunomodulatory system. 64% improvement in major symptoms was observed with interferon in the treatment of neuroendocrine tumors.
①Growth inhibitors: The half-life of natural growth inhibitors is only 3min, the efficacy is short, and the drug must be administered continuously and uninterruptedly to maintain the effective blood concentration, so it is difficult to promote clinically.
Growth inhibitor derivatives: The commonly used growth inhibitor derivatives include Octreotide, which have a significantly longer half-life and have been used in clinical practice.
The mechanisms of growth inhibitor derivatives to inhibit tumor growth are: A. Inhibit the mediators that promote tumor growth; B. Inhibit the vascular growth of tumor; C. Regulate the immune activity; D. Prevent the mitosis of tumor cells through the growth inhibitor receptor of tumor cells.
③Otrastatin combined with interferon: 8 cases of sporadic medullary thyroid carcinoma with unresectable metastases (mediastinum) and growth inhibitory receptors confirmed by 111In-DTPA, otrastatin 300μg/d subcutaneously for 6 months and interferon (r-IFN-α-2b) 5 million U/d intramuscularly 3 times a week for 12 months, of which 5 cases of flushing and 6 cases of serum calcitonin decreased from 32% to 88% of the original, suggesting that the tumor was suppressed, but the metastases did not shrink. However, octreotide must be injected daily, which is costly.
The half-life of slow-release octreotide is greatly prolonged after chelation with slow-release agent, and the effective blood concentration can be maintained by one injection in 10-14 days, and the intra-muscular injection of slow-release octreotide is 30mg/2 weeks. In 7 cases of myeloid carcinoma, r-IFN-α-2b was administered intramuscularly for 12 months and r-IFN-α-2b for 11 months, with significant efficacy.
In conclusion, the combination of growth inhibitor derivatives and interferon (recombinant interferon) can alleviate the symptoms caused by tumor secreting peptide hormones, reduce the level of serum tumor markers and suggest tumor suppression, but the control effect on tumor itself is still relatively weak.
(6) Percutaneous ethanol injection therapy: It is mainly used for the treatment of solid small to medium nodules. After finding the most vascularized area in the nodule, ethanol is injected with a 21-22 gauge needle. TSH should be followed before and after treatment. this method can have a cure rate of about 60%.
Ethanol injection is mainly used to treat non-functional thyroid nodules, especially in those with metastases and local pressure symptoms.