# Radiation Oncology/Thyroid/Papillary and follicular

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| Thyroid: Main Page | Workup | Staging | Papillary and follicular | Medullary | Hurthle cell | Anaplastic | |

## Clinical features

* Papillary
** most common (75%),
** palpable adenopathy in 33%; 35-50% chance of positive lymph nodes
** extrathyroidal extension 15%
** distant mets in 1-7% at diagnosis
** better 10-year survival (74-93%)
* Follicular
** less common (10%), 10% chance of lymph node involvement (may actually be 1% for pure follicular carcinomas)
** 10-year survival somewhat lower (43-94%)
Risk of distant mets - about 1-2% (papillary) or 2-5% (follicular) at time of diagnosis

## Anatomy

Lymph node groups:
* ATA Consensus Statement (2009): PMID 19860578 PDF — "Consensus statement on the terminology and classification of central neck dissection for thyroid cancer." (Carty SE, Thyroid. 2009 Nov;19(11):1153-8.)

## Pathology

* U Connecticut PMID 15944425 -- Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma. (2005 Shattuck TM, N Engl J Med. 2005 Jun 9;352(23):2406-12.)
** 10 patient samples analyzed, 5 independent clonal origin, 5 either shared or independent clonal origin
** Conclusion: "Individual tumor foci in patients with multifocal papillary thyroid cancer often arise as independent tumors. This provides theoretical support for bilateral thyroidectomy and radioablation of remaining tissue."

## Prognostic indices

AMES (age, metastases, extent of primary cancer, tumor size) ^
* High risk features:
** Age: males > 41, females > 51
** Metastases: distant metastases
** Extent: papillary with extrathryoidal spread or follicular with major capsule invasion
** Size: >= 5 cm
* Risk groups:
** Low risk - not high risk
** High risk - 1) any patient with metastases, or 2) high risk age and either high risk extent or size
* Overall survival:
** Low risk 98% (95% DFS). High risk - 54% (45% DFS)
DAMES - modification of AMES with addition of DNA content measured by flow cytometry ^
* Risk groups:
** Low risk - Low risk AMES + euploid
** Intermediate risk - Low risk AMES + aneuploid
** High risk - High risk AMES + aneuploid
* Disease-free survival:
** Low risk - 92%. Intermediate 45%. High 0%.
AGES - age, tumor grade, tumor extent, tumor size (from Mayo clinic) ^
* Prognostic score = 0.05 x age in years (except in pts < 40, then y=0) +1 (grade 2) or +3 (grade 3 or 4) +1 (if extrathyroidal) or +3 (distant mets) + 0.2 x tumor size in cm
* Risk categories - 0-3.99, 4-4.99, 5-5.99, >6 (median is 2.6)
* 20-year survival:
** <4 (99%), 4-5 (80%), 5-6 (33%), >6 (13%)
MACIS - metastasis, age, completeness of resection, invasion, size ^
* Prognostic score = 3.1 (age < 39 yrs) or 0.08 x age (if >40) + 0.3 x tumor size in cm + 1 (if incompletely resected) +1 (if locally invasive) +3 (if distant mets)
* Risk categories - 0-5.99, 6-6.99, 7-7.99, >8
* 20-year survival:
** <6 (99%), 6-7 (89%), 7-8 (56%), >8 (24%)
Comparison of staging systems:
* 1997: Princess Margaret PMID 9191532 -- "A comparison of different staging systems predictability of patient outcome. Thyroid carcinoma as an example." (Brierley JD, Cancer. 1997 Jun 15;79(12):2414-23.)

## Prognosis

* National Thyroid Cancer Treatment Cooperative Study (NTCTCS) Registry (1987-95)
** 1998 PMID 9731906 -- "Prospective multicenter study of thyroid carcinoma treatment: initial analysis of staging and outcome. National Thyroid Cancer Treatment Cooperative Study Registry Group." (Sherman SI, Cancer. 1998 Sep 1;83(5):1012-21.)
*** 1607 pts. Staged according to NTCTCS system. Papillary carcinoma = 80%, follicular carcinoma = 13% (including oxyphilic / Hurthle), medullary = 4%, anaplastic = 1%. High risk disease (Stages III-IV) was found in 22% of pts with papillary carcinoma and 61% with follicular. For papillary, 49% Stage I, 27% II, 19% III, 4% IV. For follicular, 31% I, 13% II, 44% III, 13% IV.
*** Median f/u 40 months. Disease-specific mortality in 1.6% of papillary, 10.3% of follicular, and 12.9% Hurthle. 5-yr DSS was 99.9% for low risk, 87.5% for high risk. Pts alive without relapse at last follow-up, 93.6% for low risk and 70.5% for high risk.

## Iodine-131

For papillary and follicular. Some Hurthle cell cancers may respond.
Total ablation achieved with either 30 mCi or 100 mCi dose in >80% of the pts who have a complete surgery. For less complete surgery, 30 mCi dose is effective in only 66%. Dose required for total ablation is 300 (Unit ??) to the residual thyroid. I-131 scan postoperatively: 1-5 mCi.
Role for post-operative I-131:
* Ablate residual normal thyroid - increases sensitivity of subsequent I-131 whole body scans and allows measurement of thyroglobulin levels to reflect recurrence disease
* Destroy occult carcinoma - decrease recurrence rate
* Allows post-treatment I-131 whole body scan to detect persistent disease
Procedure:
* Withhold Synthroid (T4; levothyroxine) for 4-6 weeks. Cytomel (T3; liothyronine) can be substituted for 3-4 weeks, but discontinued at least 2 weeks before radioiodine studies.
* TSH should be >25 to 30 at the time of the radioiodine study
* Administer I-131 tracer dose
* If high post-op uptake (>10%), should have completion surgery.
* Others can have treatment dose of I-131.
* Perform total body scan 4-7 days after treatment dose.
* Administer levothyroxine suppressive therapy
* Repeat total body scan in 6 months

### Indications for Postoperative I-131

Strong indications for post-operative treatment:
* Distant metastases
* Incomplete resection
* High risk pts (papillary with MACIS 6+, Stage II-III follicular or Hurthle cell)
Probable indications:
* Papillary/follicular in children < 16 yrs
* Tall cell or columnar cell variant of papillary
Possible indications:
* Diffuse sclerosing variant of papillary
* Bulky bilateral LN mets
* Elevated thyroglobulin at 3 months post-op
No post-operative treatment needed for:
* Low risk pts: papillary with MACIS < 6, or Stage I follicular or Hurthle cell

### Series showing I-131 Efficacy

* U.Michigan - PMID 6502251, 1984 — "An analysis of "ablation of thyroid remnants" with I-131 in 511 patients from 1947-1984: experience at University of Michigan."
** Retrospective. Pts given treatment doses of I-131 after positive uptake postsurgically.
** No difference in rate of successful ablation between groups treated with 100-149 mCi, 150-174 mCi, 179-199 mCi, and 200 mCi or more.
** Conclusion: 100-149 mCi dose is appropriate adjuvant therapy.
* Ohio State - PMID 7977430, 1994 — "Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer."
** Prospective, non-randomized. 1355 pts over 40 yrs.
** I-131 decreases recurrence rate by 33% compared to thyroid hormone therapy alone. No difference in recurrence rate for low doses (29-50 mCi) vs high doses (51-200 mCi).
* Ohio State - PMID 9133698, 1997 — "Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma." Mazzaferri EL et al. Thyroid. 1997 Apr;7(2):265-71.
** Retrospective. 1004 pts. Compared I131 ablation vs thyroid hormone alone or no further treatment.
** Decrease in recurrences by 75%, decreased rate of DM, and decreased cancer deaths after I131. Benefit restricted to those with tumors >=1.5 cm (for recurrence and DM) and for age 40 or older with tumors >=1.5 cm (for cancer deaths). No difference between low and high dose therapy.
** I-131 treatment benefits pts with tumors >=1.5 cm.

### Salivary Gland Protection

* West China Hospital; Chengdu -- Vitamic C after 1 vs 5 vs 13 vs 25 hours after I-131
** Randomized, 4 arms. 72 patients. Effect of sucking Vitamin C after receiving 3.7 Gbq of I-131 at Arm 1) 1 hour vs Arm 2) 5 hours vs Arm 3) 13 hours and Arm 4) 25 hours post treatment. Salivary dose calculated
** 2010 PMID 20237029 -- "Influence of vitamin C on salivary absorbed dose of 131I in thyroid cancer patients: a prospective, randomized, single-blind, controlled trial." (Liu B, J Nucl Med. 2010 Apr;51(4):618-23. Epub 2010 Mar 17.)
*** Outcome: Parotid absorbed dose comparable. Majority (86%) of salivary activity accumulated during first 24 hours
*** Conclusion: Salivary stimulation with vitamin C after I-131 administration doesn't protect salivary glands

### Reviews

* Review, 2005 PMID 15653649 -- "The evolving role of (131)I for the treatment of differentiated thyroid carcinoma." (Robbins RJ, J Nucl Med. 2005 Jan;46 Suppl 1:28S-37S.)
* Review, 2001 Mazzaferri et al, 2001 — "Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer." Mazzaferri EL et al. J Clin Endocrinol Metab. 2001 Apr;86(4):1447-63.

## External beam radiotherapy

Controversial. Early series show no benefit or even had patients who had received radiation doing worse. Modern series appear to show benefit of a combination of RT + radioiodine in some patient populations (e.g. macroscopic residual disease in the neck).

### Post-operative Radiotherapy

* German MSDS Study (1999-2003) -- surgery + I-131 +/- adjuvant RT
** Originally randomized, converted to prospective cohort study. 279 patients met inclusion criteria, 45 consented to randomization, 35 were randomized. T4 tumors (extending beyond capsule with/without LN involvement) treated with surgery and I-131, then Arm 1) observation vs. Arm 2) adjuvant RT. If R0 resection used 59.4/33, if R1 resection used 66.6/37. GTV1 = tumor region, ipsilateral or bilatera. GTV2 = thyroid bed, cervical LNs, infra/supraclavicular LNs, upper mediastinum.
** Acute Toxicity; 2003 PMID 14652672 -- "Acute toxicity of adjuvant radiotherapy in locally advanced differentiated thyroid carcinoma. First results of the multicenter study differentiated thyroid carcinoma (MSDS)." (Schuck A, Strahlenther Onkol. 2003 Dec;179(12):832-9.)
*** Outcome: Grade 3+ in 9% (pharynx, larynx, and skin). Maximal late toxicity Grade 2 in 4 patients, no Grade 3 toxicity
*** Conclusion: Acute toxicity is tolerable
** Conversion; 2003 PMID 14668957 -- "Multicenter study differentiated thyroid carcinoma (MSDS). Diminished acceptance of adjuvant external beam radiotherapy." (Biermann M, Nuklearmedizin. 2003 Dec;42(6):244-50.)
*** Study converted to prospective cohort due to low acceptance of adjuvant RT (only 14% of trial cohort actually assigned)
* Villejuif, France - PMID 3919920 "External radiotherapy in thyroid cancers." Tubiana et al. Cancer. 1985
** 97 pts treated w/ external beam xrt after incomplete resection; 76 pts treated with surgery alone. Low incidence of local recurrence in pts tx'd with xrt (11% at 15 yrs vs 23% for pts treated w/ surgery alone; pts tx'd with xrt had larger/more extensive tumors). Reasons for residual disease included laryngeal, tracheal, esophageal, mediastinal or major vessel involvement.
** Conclusion: Radiotherapy effective means of controlling residual disease after surgery if doses >50 Gy delivered.
* Princess Margaret Hospital, 1998 - PMID 9445196 — "The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma." Tsang RW et al. Cancer. 1998 Jan 15;82(2):375-88.
** 382 pts w/ stage I-IV papillary or follicular thyroid CA w/ median FU of 10.8 yrs. Factors predictive of local relapse were age>60,poor differentiation,>4cm,macroscopic residual,lack of radioiodine. 10 yr OS was 93% for papillary and 86% for follicular. Local control improved in cases of EBRT for microscopic residual disease (93% vs 78% at 10yrs). If macroscopic residual disease, local control 62% at 5yrs if adjuvant EBRT.
** Conclusion: microscopically +margins and macroscopic residual disease both appear to benefit from adjuvant external beam xrt.
* Essen, 1995 - PMID 8630926 "Impact of Adjuvant EBRT in pts with Perithyroidal Infiltration" Farahati et al. Cancer. 1996
** 169 pts with T4 follicular or papillary thyroid and free of mets after 2nd radioiodine tx. Cohorts got either xrt or no xrt; all got surgery, ablative I-131, levothyroxine. Xrt comprised of 50-60 Gy to neck. RFS benefit was seen in pts >40 y/o w/ N+ disease.
** Conclusion: T4N+ should be considered for adjuvant xrt.

### IMRT

* MSKCC, 2005 (2001-4) - PMID 16154712 — "Intensity-modulated radiation therapy for the treatment of nonanaplastic thyroid cancer." Rosenbluth BD et al. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1419-26.
** 20 pts with non-anaplastic thyroid cancer treated with IMRT. Treated microscopic disease to 54 Gy, higher risk areas to 59.4-63 Gy, positive margins to 63-66 Gy, and gross disease to 63-70 Gy. Elective nodal volume extended from the top of level II (sometimes retropharyngeal nodes were included) to below the thoracic inlet to the level of the aortic arch. High risk area was the tumor bed and central neck lymphatics.
** Conclusion: IMRT is feasible for treatment of thyroid cancer

## Follow-up

Monitoring of thyroglobulin:
* Consensus report; 2003 PMID 12679418 -- "A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma." (Mazzaferri EL, J Clin Endocrinol Metab. 2003 Apr;88(4):1433-41.)
** Consensus report of experts, industry sponsored, not representing any official society. Recommendations apply to patients who are low-risk, s/p total or near-total thyroidectomy and I-131 ablation, with no clinical evidence of tumor, undetectable Tg levels (<1 ug/L) during THST. Most of these have tumors <4 cm, not a virulent subtype, with or without positive lymph nodes, no distant metastases. These patients are low-risk by AMES, usually have MACIS scores of <6, and are AJCC Stage I (if age <45) or Stage II (if age >=45).

## Recurrent disease

Excellent prognosis for patients with locoregional recurrences, with 70-90% long-term survivors. For patients who develop distant metastasis, 50-90% die of their disease.
I-131 for ablation (if post-op scan reveals gross residual disease): 100 mCi.
I-131 for recurrent disease, post-op residual in the neck, nodal or distant metastases, or inoperable tumors: 150-250 mCi.
Re-imaging should be done 1-2 days after ablation or therapy.
Recommended maximum dose: 800-1000 mCi.
Estimation of absorbed dose is 0.1 Gy per microcurie per gram of thyroid cancer tissue.

## References

* - PMID 3194846
* - PMID 1455318
* - PMID 3686348
* - PMID 8256208
* Larsen: Williams Textbook of Endocrinology, 10th ed., 2003 Saunders.