While internal dosimetric calculations as a result of radioiodine therapy depend on the biodistribution of 131I in the whole-body, thyroid remnant and each organ, biodistribution is characterized by the rate of uptake and clearance. TACs were generated in the anterior positions of the brain, kidneys, liver, LLI, thigh, thyroid remnant, the whole-body and in the posterior position of the kidney (Chen et al., 2003). The Medical Internal Radiation Dose (MIRD) committee of the Society of Nuclear Medicine used the MIRDOSE 3 software to determine the radiation dose of each target organ (Sajjad et al., 2002; Stabin et al., 1999; Stabin, 1996; Loevinger et al., 1988; Cristy and Eckerman, 1987). The reference phantom selected from MIRDOSE 3 was a 57 kg adult female phantom. The residence time (τh) of the whole-body and source organs were fitted by mono-exponential curves based on the pixels of an image captured by Simens E-CAM γ-camera at CSMUH (Stabin, 1996).

The area under the curve of each TAC was measured in two ways.

1. Trapezoidal rule (Parsey et al., 2005):

$$\tau\_{\mathbf{h}} = \frac{1}{2} \int\_{\mathbf{i}}^{\mathbf{n}} \mathbf{f}(\mathbf{t}\_{\mathbf{i}}) \mathbf{dt} + \int\_{\mathbf{n}}^{\mathbf{e}} \mathbf{f}(\mathbf{t}\_{\mathbf{i}}) \mathbf{e}^{-\lambda\_{\text{off}} \mathbf{t}\_{\mathbf{i}}} \mathbf{dt} \tag{8}$$

where *f(ti)* = ID/100 and is the cumulative activity (Ai) for any source organ divided by the total activity A0 administered to the patient at time t (Stabin et al., 1999).

2. The remaining area under the TAC to infinity was determined by the exponential drop in the remaining activity.

The effective dose equivalent (EDE), measured in mGy, in any target organ is,

$$\text{EDE} = \frac{\text{kA}\_{\text{i}} \sum\_{\text{i}} \text{n}\_{\text{i}} \text{E}\_{\text{i}} \text{f}\_{\text{i}}}{\text{m}} \tag{9}$$

where ni is the number of decays with energy Ei emitted per nuclear transition of 131I; Ei, the energy per disintegration (MeV); fi, the fraction of the radiation energy absorbed by the target; m, the mass of the target organ (kg); k, the constant of proportionality (Gy kg/MBq s MeV).

aAVG stands for average; bSD, standard deviation.

Table 2. The average half-life (h) of 131I in each source organ.

#### **3. Results and discussion**

288 Updates in the Understanding and Management of Thyroid Cancer

Table 2 displays the re-estimated Teff for the whole-body and each organ from the five Taiwanese female patients using the gradient of the linear regression of normalized residual

While internal dosimetric calculations as a result of radioiodine therapy depend on the biodistribution of 131I in the whole-body, thyroid remnant and each organ, biodistribution is characterized by the rate of uptake and clearance. TACs were generated in the anterior positions of the brain, kidneys, liver, LLI, thigh, thyroid remnant, the whole-body and in the posterior position of the kidney (Chen et al., 2003). The Medical Internal Radiation Dose (MIRD) committee of the Society of Nuclear Medicine used the MIRDOSE 3 software to determine the radiation dose of each target organ (Sajjad et al., 2002; Stabin et al., 1999; Stabin, 1996; Loevinger et al., 1988; Cristy and Eckerman, 1987). The reference phantom selected from MIRDOSE 3 was a 57 kg adult female phantom. The residence time (τh) of the whole-body and source organs were fitted by mono-exponential curves based on the pixels

eff i n t

(8)

m (9)

1 f(t )dt f(t )e dt 2

where *f(ti)* = ID/100 and is the cumulative activity (Ai) for any source organ divided by the

2. The remaining area under the TAC to infinity was determined by the exponential drop

kA n E f i i i ii EDE

where ni is the number of decays with energy Ei emitted per nuclear transition of 131I; Ei, the energy per disintegration (MeV); fi, the fraction of the radiation energy absorbed by the target; m, the mass of the target organ (kg); k, the constant of proportionality (Gy kg/MBq s

hi i i n

of an image captured by Simens E-CAM γ-camera at CSMUH (Stabin, 1996).

The area under the curve of each TAC was measured in two ways.

total activity A0 administered to the patient at time t (Stabin et al., 1999).

The effective dose equivalent (EDE), measured in mGy, in any target organ is,

 *Wi* =*σi*

The weighted standard error (*σ(Aw)*) is

**2.6 Internal dosimetric calculations**

1. Trapezoidal rule (Parsey et al., 2005):

in the remaining activity.

MeV).

activity.

*σi* %*=*(100 Ai )% (5)

*σ(Aw)=* (Wi )-1/2 (7)

*-2* (6)

**Figure 1** displays radioactivity distribution in the ROIs of a 46-year-old female patient (case no 4) in (a) 3 hours (b) 46 hours and (c) 142 hours after 131I administration. That most of the activity was distributed to the LLI and the thyroid on day 1 indicates the typical distribution of 131I. The blood activity outside by ROIs was not measured. Instead, the activity was determined by subtracting the activity sum of all organs from the whole-body activity. Medical professionals entered the activity into MIRDOSE 3 as the "remainder of the body" and learned that the brain takes up the least. Furthermore, **Table 2** displays the maximum, minimum and the Teff of all five Taiwanese patients. Moreover, **Table 3** and **Figure 2** display the *in vivo* mean τh of the thyroidectomy patients obtained by the γ-camera in various intervals after the 131I administration.

aUptake values are not corrected for physical decay. The results are from a fitted line of five female patients.

Table 3. The calculated 131I residence times (h) using whole-body planar images.

#### **3.1 Biodistributions and dosimetry**

Because the information on the Teff of 131I in the thyroid, as well as other organs, of total or near-total thyroidectomy patients is limited, this study estimates the radiation dose absorbed as a result of 131I administration. The biodistribution pattern of 131I was computed from 14 sequential WBSs of the five female patients. Having fitted the ratio of the activities

Using γ-Camera to Evaluate the *In Vivo* Biodistributions and

exposures were the LLI wall, the kidneys and the ovaries.

**3.2 Teff of whole-body and other organs**

expected to differ significantly due to gender.

**3.3 Internal medical dosimetry**

organ.

Internal Medical Dosimetries of Iodine-131 in Thyroidectomy Patients 291

dosimetric evaluations (mGy/MBq) evaluated from each patient's TACs using MIRDOSE 3 and states the radiation dose absorbed by each organ. The three organs with the highest

According to **Equation 1**, Teff was determined by the biological elimination and physical decay of 131I activity (Chen et al., 2003; Stabin et al., 1999; Berg et al., 1996; Stabin 1996; Synder et al., 1983). An important step in generating the TACs and determining the dose required for thyroidectomy patients is to calculate the exact Teff of each organ of interest. Dunning and Schwarz (1981) determined that large uncertainties might be primarily associated with the patient's age, and the physiological and metabolic characteristics of each

Using planar images to analyze data yields conservative estimates of activities because the large ROIs include overlying tissues, as displayed in **Figure 1**. The Teff of 131I for Graves' disease is 5.0±0.16 days (s.d. = 1.3); toxic nodular goiter, 6.0±0.12 days (s.d = 1.2) as reported by Berg et al. (1996). **Figure 2** shows that 131I-NaI was clearing from the whole-body at an Teff of 22.7±16.3 hour, which is consistent with that obtained by Pacilio et al. (2005), who also found that the median and mean (±1 standard deviation) Tbio distribution of 225 ablation treatments were 0.63 days and 0.70±2.25 days, respectively. In this study, the whole-body Teff values of five female patients who have undergone a total or near-total thyroidectomy ranged from 15.4 to 175.4 hours and Tbio was 31.9±4.8 hours. These data correlated well with 2.18±1.45 days of complete ablation patients, reported by Samuel and Rajashekharrao (1994) as displayed in **Table 5**. Samuel and Rajashekharrao (1994) also reported ranges of 0.83 to 3.7 day for complete ablation patients and 1.6 to 5.0 days for partial ablation patients; these numbers are also displayed in **Table 5**. Furthermore, Samuel and Rajashekharrao (1994) employed a portable β-γ exposure rate meter to measure the 131I activity in residual thyroid tissue in the neck region directly in order to evaluate the Teff of 131I. Using γ-camera *in vivo* at CSMUH may yield more precise results than using a portable β-γ exposure rate meter. North et al. (2001) obtained an Teff of 0.71 days in complete ablation patients who received 1.7-13 GBq of 131I, which is greater than the 1100 MBq dose in this study. Furthermore, this study included only five patients, and therefore the results should be considered as preliminary estimates only. Although the patients were all female, the biodistribution is not

The MIRDOSE 3 software can be used to determine the effective dose as defined by ICRP 23. Internal medical dosimetry was conducted for each subject independently, and the results were averaged. **Table 4** displays the average dose amount absorbed by the six principal target organs in the five female patients. LLI absorbed the most radiation (2.00±0.67 mGy/MBq), ranging from 0.96 to 2.94 mGy/MBq; the kidney (0.89±0.46 mGy/MBq), second; the ovaries (0.41±0.42 mGy/MBq), third. The species as well as physiological and metabolic characteristics may account for the differences. These τh obtained from the fitted lines of individual organs were highest in the LLI wall (3.88±1.15 hours) and then in the liver (2.16±1.14 hours), as displayed in **Table 3**. Self-dose, according to MIRDOSE 3, was the

in individual organs (Ai) after the exponential decay to the first whole-body (A0) decay in **Equation 2**, medical professionals determined the Teff values of these organs. The regional concentrations of 131I changed significantly from hour 1 to hour 4. **Figure 1** shows that a moderate level of background activity remained evident for 32 hours of observation. Furthermore, **Figure 2** shows that the areas known to contain high concentrations of 131I, such as LLI and the liver, exhibited increasing activity. The amount of diagnostic 131I retained by patient no 4 dropped to 1.54% of the initial administered dose after 7 hours, and it did not rise after this initial decline. Whole-body images in **Figure 2** demonstrate persistently high LLI and liver uptake as well as lower brain, kidney and bladder uptake. **Figure 2** also displays the TACs for the whole-body, the bladder, the brain, LLI, the liver and the kidney; it shows that the rate of LLI activity appears to be particularly clean and slow. The biodistribution in the gallbladder, the colon and the esophagus could not be analyzed primarily because the number of pixels and counting statistics were too small. The thyroid remnant uptake in Patient No. 4 declined from 3.69% to 1.54% on day 1, whereas the uptake in the other organs began to fall rapidly at day 2. **Table 4** displays the internal

aLLI stands for lower large intestine; bULI, upper large intestine. cThe units for effective dose and effective dose equivalent are mGy/MBq.

Table 4. The estimated amount of radiation dose absorbed (mGy/MBq) as a result of 131I administration.

dosimetric evaluations (mGy/MBq) evaluated from each patient's TACs using MIRDOSE 3 and states the radiation dose absorbed by each organ. The three organs with the highest exposures were the LLI wall, the kidneys and the ovaries.

#### **3.2 Teff of whole-body and other organs**

290 Updates in the Understanding and Management of Thyroid Cancer

in individual organs (Ai) after the exponential decay to the first whole-body (A0) decay in **Equation 2**, medical professionals determined the Teff values of these organs. The regional concentrations of 131I changed significantly from hour 1 to hour 4. **Figure 1** shows that a moderate level of background activity remained evident for 32 hours of observation. Furthermore, **Figure 2** shows that the areas known to contain high concentrations of 131I, such as LLI and the liver, exhibited increasing activity. The amount of diagnostic 131I retained by patient no 4 dropped to 1.54% of the initial administered dose after 7 hours, and it did not rise after this initial decline. Whole-body images in **Figure 2** demonstrate persistently high LLI and liver uptake as well as lower brain, kidney and bladder uptake. **Figure 2** also displays the TACs for the whole-body, the bladder, the brain, LLI, the liver and the kidney; it shows that the rate of LLI activity appears to be particularly clean and slow. The biodistribution in the gallbladder, the colon and the esophagus could not be analyzed primarily because the number of pixels and counting statistics were too small. The thyroid remnant uptake in Patient No. 4 declined from 3.69% to 1.54% on day 1, whereas the uptake in the other organs began to fall rapidly at day 2. **Table 4** displays the internal

Source organ Internal dosimetry (mGy/MBq)

aLLI stands for lower large intestine; bULI, upper large intestine. cThe units for effective dose and effective dose equivalent are mGy/MBq.

administration.

Table 4. The estimated amount of radiation dose absorbed (mGy/MBq) as a result of 131I

 Minimum Maximum AVG S D Adrenal 0 .040 1 .34 0 .35 0 .40 Brain 0 .039 0 .71 0 .21 0 .20 Breasts 0 .027 1 .09 0 .27 0 .33 Gallbladder Wall 0 .040 1 .32 0 .34 0 .39 LLI Walla 0 .96 2 .94 2 .00 0 .67 Small Intestine 0 .051 1 .35 0 .36 0 .40 Stomach 0 .038 1 .34 0 .34 0 .40 ULI Wallb 0 .042 1 .40 0 .36 0 .40 Heart Wall 0 .034 1 .34 0 .33 0 .40 Kidneys 0 .22 2 .04 0 .89 0 .46 Liver 0 .064 0 .79 0 .32 0 .20 Lungs 0 .032 1 .25 0 .31 0 .38 Muscle 0 .033 1 .21 0 .29 0 .36 Ovaries 0 .07 1 .46 0 .41 0 .42 Pancreas 0 .04 1 .39 0 .35 0 .41 Red Marrow 0 .038 1 .29 0 .32 0 .38 Bone Surfaces 0 .037 1 .38 0 .34 0 .41 Skin 0 .026 1 .03 0 .25 0 .31 Spleen 0 .037 1 .32 0 .34 0 .39 Thymus 0 .032 1 .28 0 .31 0 .39 Thyroid 0 .029 1 .19 0 .29 0 .38 Urine Bladder Wall 0 .042 1 .29 0 .31 0 .42 Uterus 0 .048 1 .42 0 .36 0 .42 Total body 0 .038 1 .20 0 .31 0 .36 Eff Dose Equiv.c 0 .11 1 .42 0 .49 0 .37 Eff Dosec 0 .16 1 .49 0 .55 0 .38 According to **Equation 1**, Teff was determined by the biological elimination and physical decay of 131I activity (Chen et al., 2003; Stabin et al., 1999; Berg et al., 1996; Stabin 1996; Synder et al., 1983). An important step in generating the TACs and determining the dose required for thyroidectomy patients is to calculate the exact Teff of each organ of interest. Dunning and Schwarz (1981) determined that large uncertainties might be primarily associated with the patient's age, and the physiological and metabolic characteristics of each organ.

Using planar images to analyze data yields conservative estimates of activities because the large ROIs include overlying tissues, as displayed in **Figure 1**. The Teff of 131I for Graves' disease is 5.0±0.16 days (s.d. = 1.3); toxic nodular goiter, 6.0±0.12 days (s.d = 1.2) as reported by Berg et al. (1996). **Figure 2** shows that 131I-NaI was clearing from the whole-body at an Teff of 22.7±16.3 hour, which is consistent with that obtained by Pacilio et al. (2005), who also found that the median and mean (±1 standard deviation) Tbio distribution of 225 ablation treatments were 0.63 days and 0.70±2.25 days, respectively. In this study, the whole-body Teff values of five female patients who have undergone a total or near-total thyroidectomy ranged from 15.4 to 175.4 hours and Tbio was 31.9±4.8 hours. These data correlated well with 2.18±1.45 days of complete ablation patients, reported by Samuel and Rajashekharrao (1994) as displayed in **Table 5**. Samuel and Rajashekharrao (1994) also reported ranges of 0.83 to 3.7 day for complete ablation patients and 1.6 to 5.0 days for partial ablation patients; these numbers are also displayed in **Table 5**. Furthermore, Samuel and Rajashekharrao (1994) employed a portable β-γ exposure rate meter to measure the 131I activity in residual thyroid tissue in the neck region directly in order to evaluate the Teff of 131I. Using γ-camera *in vivo* at CSMUH may yield more precise results than using a portable β-γ exposure rate meter. North et al. (2001) obtained an Teff of 0.71 days in complete ablation patients who received 1.7-13 GBq of 131I, which is greater than the 1100 MBq dose in this study. Furthermore, this study included only five patients, and therefore the results should be considered as preliminary estimates only. Although the patients were all female, the biodistribution is not expected to differ significantly due to gender.

#### **3.3 Internal medical dosimetry**

The MIRDOSE 3 software can be used to determine the effective dose as defined by ICRP 23. Internal medical dosimetry was conducted for each subject independently, and the results were averaged. **Table 4** displays the average dose amount absorbed by the six principal target organs in the five female patients. LLI absorbed the most radiation (2.00±0.67 mGy/MBq), ranging from 0.96 to 2.94 mGy/MBq; the kidney (0.89±0.46 mGy/MBq), second; the ovaries (0.41±0.42 mGy/MBq), third. The species as well as physiological and metabolic characteristics may account for the differences. These τh obtained from the fitted lines of individual organs were highest in the LLI wall (3.88±1.15 hours) and then in the liver (2.16±1.14 hours), as displayed in **Table 3**. Self-dose, according to MIRDOSE 3, was the

Using γ-Camera to Evaluate the *In Vivo* Biodistributions and

Vol. 14(2), pp557-565, ISSN 1680-3108

Laboratory, Oak Ridge, Tenn. USA

Society of Nucl Med, New York, USA.

Vol. 81(3), pp.325-329, ISSN 0017-9078.

administer to total thyroidectomy patients.

**5. Acknowledgements**

LSRP099007.

**6. References**

5505

9078

USA

USA.

Internal Medical Dosimetries of Iodine-131 in Thyroidectomy Patients 293

biodistributions and Teff can be easily estimated from medical images obtained using Siemens E-CAM coincidence γ-camera. 1100 MBq of 131I could be safe and sufficient to

Lin Shin Hospital and its staff provided financial support under Contract Number:

Beekhuis, H. (1988). Population radiation absorbed dose from nuclear medicine procedures

Berg, G. E. B. et. al. (1996). Iodine-131 Treatment of Hyperthyroidism: Significance of

Chen, C.Y. et al., (2003). Effective half-life of 131I of whole-body and individual organs for

Chen, C. Y. & Pan, L. K. (2001). Trace elements of race elements of Taiwanese Dioscorea Spp. Using neutron activation analysis. *Food Chem*. Vol. 72, pp255-260, ISSN 0278-6915 Comtois, R.; Theriault, C. & Vecchio, P. D. (1993). Assessment of the efficacy of iodine-131 for thyroid ablation. *J. Nucl. Med.* Vol. 34, pp1927-1930, ISSN 0161-5505. Cristy, M. & Eckerman, K., (1987). Specific absorbed fractions of energy at various ages from

Department of Nuclear Medicine, Chung Shan Medical University Hospital, (2005).

International Commission on Radiological Protection, (1990). Report of the task group on

International Commission on Radiological Protection, (1978). Limits for intakes of

Loevinger, R.; Budinger, T. & Watson E., (1988). *MIRD primer for absorbed dose calculations.*

North, D.L. et al, (2001). Effective Half-Life of 131I in Thyroid Cancer Patients. *Health Phys.*

Rosario, P. W. S. et al., (2004). Efficacy of low and high 131I doses for thyroid remnant

cervical uptake. *Nucl. Med. Commun.* Vol. 25, pp.1077-1081, ISSN 0143-3636. Saha G.B., (1997). *Fundamentals of Nuclear Pharmacy.* 4th ed. P27. ISBN 0-387-98341-4 Springer

reference man. *ICRP Publication 26.* Pergamon Press, Oxford. USA

University Guide. *Chung Shan Medical University Hospital* Taiwan, ROC. Dunning, Jr. D. E. & Schwarz, G. (1981). Variability of Human Thyroid Characteristics and

Effective Half-life Measurements. *J. Nucl. Med.* Vol. 37(2), pp228-232, ISSN 0161-

thyroidectomy patient using scintigraphic images of camera. *Chung Shan Med. J.*

internal photon sources. *ORNL/TM-8381/VII*. P.7-29. Oak Ridge National

Introduction to Radiation Safety in Nuclear Medicine. Chung Shan Medical

Estimates of Dose from Ingested 131I. *Health Phys*. Vol. 40(1), pp. 661-675, ISSN 0017-

radionuclides by workers. ICRP Publication 30 (Part 1). Pergamon Press, Oxford.

ablation in patients with differentiated thyroid carcinoma based on post-operative

in the Netherlands. *Health Phys*. Vol. 54, pp287-291, ISSN 0017-9078

main contributor to the dose absorbed by all of the organs listed in Table 4. The effective dose was 0.55±0.38 mGy/MBq and effective dose equivalent was 0.49±0.37 mGy/MBq, which did not include the effective dose of the thyroid remnant, and was lower the 16.00 mSv/MBq reported by Weng et al. (1989), who determined the values by either EDE per radiopharmaceutical drug or an published procedure of data in Kaohsiung from 1977 to 1988.

Table 5. The effective half-life of 131I for whole-body therapy.

Beekhuis et al. (1988) found large variations among medical internal doses across hospitals that apply various radioactivity dose levels in similar investigations (Beekhuis et al., 1988). Furthermore, Beekhuis et al. (1988) established that EDEs were rough estimates of real radiation burdens. The dose required for ablation is directly related to the mass of the remnant, thus using US, CT or MRI to evaluate organ and tumor mass yields more accurate and reproducible results (Rosario et al., 2004). Published reports by Comtois et al. (1993) also strongly asserted that 1100 MBq of 131I, the dose applied in this study, can ablate residual thyroid tissues completely. Moreover, the 1100 MBq dose reduces the financial burden on the patients who no longer require hospitalization (CSMUH, 2005).

#### **4. Conclusion**

To our knowledge, this study is the first attempt to re-calculate biodistributions, Teff and the internal medical dosimetric data for Taiwanese female 131I patients. The Teff for the thyroid was 22.7±16.3 hours and for the whole-body was 69.5±70.9 hours. **Table 5** shows that the results differ significantly from those reported by ICRP 30, but are consistent with Samuel and Rajashekharrao's (1994) 2.18±1.45 days for patients who exhibited complete ablation. Despite the consideration of thyroid remnant, the medical internal doses in this study were highest in LLI, 2.00±0.67 mGY/MBq, and second highest in the kidney, 0.89±0.46 mGy/MBq as determined by using the trapezoidal rule to evaluate the area under the TACs. Based on an effective dose of 0.55±0.38 mGy/MBq for the five thyroidectomy patients at CSMUH, the biodistributions and Teff can be easily estimated from medical images obtained using Siemens E-CAM coincidence γ-camera. 1100 MBq of 131I could be safe and sufficient to administer to total thyroidectomy patients.

#### **5. Acknowledgements**

Lin Shin Hospital and its staff provided financial support under Contract Number: LSRP099007.

#### **6. References**

292 Updates in the Understanding and Management of Thyroid Cancer

main contributor to the dose absorbed by all of the organs listed in Table 4. The effective dose was 0.55±0.38 mGy/MBq and effective dose equivalent was 0.49±0.37 mGy/MBq, which did not include the effective dose of the thyroid remnant, and was lower the 16.00 mSv/MBq reported by Weng et al. (1989), who determined the values by either EDE per radiopharmaceutical drug or an published procedure of data in Kaohsiung from 1977 to

Effective Half-Life

Extrathyroidal 1.22 GBq 0.32 Model USNRC, 1997

3.4 ± 2.4 GBq 2.18 ± 1.45 Exposure rate

Thyroid cancer 3.7-7.4 GBq 2.2± 0.8 γ-camera Mathieu, 1996

0.5 MBq 6.0± 1.2 2-inch NaI

Beekhuis et al. (1988) found large variations among medical internal doses across hospitals that apply various radioactivity dose levels in similar investigations (Beekhuis et al., 1988). Furthermore, Beekhuis et al. (1988) established that EDEs were rough estimates of real radiation burdens. The dose required for ablation is directly related to the mass of the remnant, thus using US, CT or MRI to evaluate organ and tumor mass yields more accurate and reproducible results (Rosario et al., 2004). Published reports by Comtois et al. (1993) also strongly asserted that 1100 MBq of 131I, the dose applied in this study, can ablate residual thyroid tissues completely. Moreover, the 1100 MBq dose reduces the financial burden on

To our knowledge, this study is the first attempt to re-calculate biodistributions, Teff and the internal medical dosimetric data for Taiwanese female 131I patients. The Teff for the thyroid was 22.7±16.3 hours and for the whole-body was 69.5±70.9 hours. **Table 5** shows that the results differ significantly from those reported by ICRP 30, but are consistent with Samuel and Rajashekharrao's (1994) 2.18±1.45 days for patients who exhibited complete ablation. Despite the consideration of thyroid remnant, the medical internal doses in this study were highest in LLI, 2.00±0.67 mGY/MBq, and second highest in the kidney, 0.89±0.46 mGy/MBq as determined by using the trapezoidal rule to evaluate the area under the TACs. Based on an effective dose of 0.55±0.38 mGy/MBq for the five thyroidectomy patients at CSMUH, the

Tbio =12

Method Reference

This work

Samuel, and Rajashekharrao,

Synde, 1983

Berg, 1996

Berg, 1996

1994

γ-camera

meter

scanner

neck uptake

neck uptake

Model ICRP 30

(day)

Thyroidectomy 1.1 GBq 22.7±16.3 (hr) E-CAM

Total lobectomy 1.1 GBq 5 Rectilinear

Grave's disease 0.5 MBq 5.0± 1.56 2-inch NaI

Table 5. The effective half-life of 131I for whole-body therapy.

the patients who no longer require hospitalization (CSMUH, 2005).

Normal, Adults Trace amount Tbio =120

1988.

Complete ablation

Toxic nodular

**4. Conclusion**

goiter

Pathology Therapeutic dose (131I)

**14**

*Japan*

**Thyroid Cancer:**

Hitoshi Noguchi

**The Evolution of Treatment Options**

Joseph Stalin once said that one death is a tragedy but a million deaths is a statistic. Medical textbooks present percentages and p values, but medical professionals must deal with one death at a time. Textbooks are read in preparation for the profession. The purpose of this chapter is to bridge the gap by presenting an historical overview of the various controversies in the field of thyroid cancer that shaped our current knowledge and thereby assist the student in grasping the underlying structure beneath the vast amount of

A student new to the arena may be surprised at finding the candy box assortment of colorful characters engaged in lively debate within the outwardly staid community. These people are passionate about the arcane details of thyroid carcinoma, a narrow specialty about which most students of medicine are indifferent. But the history of this field is fraught with debate, controversy, confrontations and a legacy of brave souls who dared to fight against

The current opinions, as of 2011, regarding the treatment of differentiated thyroid cancer can roughly be divided into two groups, those that aggressively promote the adoption of total thyroidectomy with radioiodine ablation followed by periodic screening for biochemical recurrence and those that do not. The latter group usually prefers to perform thyroid lobectomy when the gross tumor is small and limited to one lobe of the thyroid, which would automatically rule out post-surgical ablation and the use of recombinant-TSH to screen for thyroglobulin. The option of lobectomy, although still resisted by many in the field, was finally adopted in the 2009 version of the guideline for the treatment of differentiated thyroid carcinoma by the American Thyroid Association1), but only for tumors measuring 10 millimeters or less. The following year, Sonkar et al2) wrote an article titled "Papillary Thyroid Carcinoma: Debate at Rest" writing that "the controversy regarding the extent of thyroidectomy in papillary thyroid carcinoma is relatively settled" with total thyroidectomy and radioiodine ablation being the preferred option for all but the smallest tumors. This announcement, however, proved premature. The 2010 version of the Japanese guideline for the treatment of thyroid tumors declared that papillary carcinomas as large as 30 millimeters were candidates for lobectomy when they were limited to one lobe of the thyroid with little or no extra-capsular invasion and gross lymph node involvement3). As

**1. Introduction**

the tide.

sometimes conflicting data.

*Noguchi Thyroid Clinic and Hospital Foundation*

### **Thyroid Cancer: The Evolution of Treatment Options**

Hitoshi Noguchi *Noguchi Thyroid Clinic and Hospital Foundation Japan*

#### **1. Introduction**

294 Updates in the Understanding and Management of Thyroid Cancer

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patients administered radioactive material. *U.S. Government Printing Office*;

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Thyroid Cancer: A Quantitative Dosimetric Evaluation for Remnant Thyroid Ablation After Surgery. J*. Nucl. Med.* Vol. 35(12), pp,1944-1950, ISSN 0161-5505. Seidlin, S.; Oshry, E. & Yallow, A. A. (1948). Spontaneous and experimentally induced

uptake of radioactive iodine in metastases from thyroid carcinoma. *J. Clin.*

Joseph Stalin once said that one death is a tragedy but a million deaths is a statistic. Medical textbooks present percentages and p values, but medical professionals must deal with one death at a time. Textbooks are read in preparation for the profession. The purpose of this chapter is to bridge the gap by presenting an historical overview of the various controversies in the field of thyroid cancer that shaped our current knowledge and thereby assist the student in grasping the underlying structure beneath the vast amount of sometimes conflicting data.

A student new to the arena may be surprised at finding the candy box assortment of colorful characters engaged in lively debate within the outwardly staid community. These people are passionate about the arcane details of thyroid carcinoma, a narrow specialty about which most students of medicine are indifferent. But the history of this field is fraught with debate, controversy, confrontations and a legacy of brave souls who dared to fight against the tide.

The current opinions, as of 2011, regarding the treatment of differentiated thyroid cancer can roughly be divided into two groups, those that aggressively promote the adoption of total thyroidectomy with radioiodine ablation followed by periodic screening for biochemical recurrence and those that do not. The latter group usually prefers to perform thyroid lobectomy when the gross tumor is small and limited to one lobe of the thyroid, which would automatically rule out post-surgical ablation and the use of recombinant-TSH to screen for thyroglobulin. The option of lobectomy, although still resisted by many in the field, was finally adopted in the 2009 version of the guideline for the treatment of differentiated thyroid carcinoma by the American Thyroid Association1), but only for tumors measuring 10 millimeters or less. The following year, Sonkar et al2) wrote an article titled "Papillary Thyroid Carcinoma: Debate at Rest" writing that "the controversy regarding the extent of thyroidectomy in papillary thyroid carcinoma is relatively settled" with total thyroidectomy and radioiodine ablation being the preferred option for all but the smallest tumors. This announcement, however, proved premature. The 2010 version of the Japanese guideline for the treatment of thyroid tumors declared that papillary carcinomas as large as 30 millimeters were candidates for lobectomy when they were limited to one lobe of the thyroid with little or no extra-capsular invasion and gross lymph node involvement3). As

Thyroid Cancer: The Evolution of Treatment Options 297

It would be easier to compose a narrative if the history of thyroid surgery were a linear progression from "conventional radical neck dissection" to less and less invasive procedures. But the story is more muddled, partly due to the particular characteristics of the organ and also due to entrenched positions of opinionated surgeons and oncologists. The trajectory was also confounded by the periodic infusion of breathtaking new technology for which there was widespread but misguided enthusiasm. There was no consensus for the optimum surgical procedure for thyroid cancer surgery in the early to mid-twentieth century. If the gross tumor was limited to one lobe, some surgeons performed lobectomy, some lobectomy with isthmus, some lobectomy with isthmus and a part of the opposing lobe and some insisted on total thyroidectomy. A few even dared to perform partial lobectomy and preserved most of the thyroid. The extent of lymph node dissection also varied greatly11). Early on, metastasis to the lymph nodes in the neck were mistaken for embryological migration error termed "lateral aberrant thyroid" and believed not to require surgery. Conventional radical dissection may have been a backlash against this initial

During the time Crile was battling conventional radical dissection, others were arguing for more radical surgery. Clark et al performed serial sections of the whole thyroid. He found intraglandular dissemination in 58% of the 79 cases he studied13). Similar studies by Black et al found multicentricity in 20%14), and Underwood et al found contralateral lobe involvement in 32% of cases studied15). Each of these authors advocated total thyroidectomy or more based on their findings. However, Tollefsen, citing these works and others, compared them to the actual clinical recurrence rate in the opposite lobe. He pointed out that his recurrence rate was 3.7% and even Black, a proponent of radical surgery, had reported a recurrence in the opposite lobe in only 7%. In his 1963 report, Tollefsen wrote "The final importance of these histologic observations must rest in the clinical results. All but a small percentage of our patients have remained well for periods up to twenty-five years without clinical recurrence in the remaining lobe. We must, therefore, interpret these histologic cancers in the other lobe as being of slight importance and somewhat analogous to the autopsy incidence of microscopic cancer in the prostate."16) It is surprising today to find that a surgeon in New York had already outlined the position taken by Japanese specialists of the twenty-first century half a century previously. Nobody today questions that papillary thyroid carcinoma is very often multi-focal, although some authors argue that

Care should be taken in reading, and especially in citing, medical reports of this era. Histologic classification and diagnosis did not follow the same criteria as we use today. Statistics were rudimentary and rarely employed anything more sophisticated than simple percentages. Most troublesome of all, such variables as the initial size of the pre-operative tumor or the age of the patient were not taken into account when discussing the merits of one surgical procedure over another. In 1953, Crile reported that patients aged over 40 at initial diagnosis had a poorer prognosis compared to patients aged under 40. He concluded "Since almost all cancers of the thyroid that occur in patients under 40 years of age are of the lowest grade malignancy, the prognosis in this age group is almost universally good if an adequate operation is performed"17). In his 1964 report Tollefsen analyzed 70 fatal cases of

complacency12).

**3. Stratifications**

microscopic multifocal disease is clinically irrelevant.

for papillary carcinoma less than 10 millimeters, some Japanese surgeons are proposing that observation without surgery may be sufficient4). The journey that lead to this schism and how it relates to the current therapeutic options is explained in this chapter as well as the most likely course that future therapy may take.

#### **2. The maverick**

Thyroid surgery was a dangerous endeavor in the 19th century and the French Academy of Medicine officially condemned the practice, but with the introduction of anesthesia, antisepsis techniques and hemostatic forceps, the prognosis improved dramatically. Billroth reported a mortality rate of 40% early in his career which fell to 8% in the 1870s5). Kocher reported a reduction in mortality from 12.6% to 0.2% from the 1870s to the end of the 19th century6). Successful thyroidectomy lead to the discovery of postoperative hypothyroidism which in turn elucidated the true function of the normal thyroid gland7). Klein reported on loss of voice due to injury to the recurrent laryngeal nerves during the removal of goiter8). Tetany was observed in patients who underwent total thyroidectomy, but it was only with the concerted efforts of multiple investigators around the turn of the century that damage to the parathyroid glands was found to be responsible for this condition9). Eventually, these discoveries lead to the reduction of surgical complications in thyroid surgery.

Medical progress has advanced on a precarious balance between the pressing need for immediate solutions and the effort to keep harmful options out of the field. Pioneers of medicine made courageous, sometimes reckless, forays into uncharted territory to which we owe our current technology. But once the frontier was conquered and patient survival improved, more attention was paid to the tradeoffs of treatment, such as compromised quality of life, and efforts were made to diminish them. Surgery in particular has progressed, over the past half century, in the direction of reducing the extent of dissection and thereby lowering the risk of complications.

George "Barney" Crile Jr. stands out as the man who set the field of surgery onto this course. Father of the celebrated journalist George Crile III and son of the venerated founding member of the Cleveland Clinic, George Crile Sr., he is something of an unsung hero of modern surgery. Surgery for thyroid carcinoma of his time, called the "block dissection" or "conventional radical neck dissection", usually sacrificed the sternocleidomastoid muscle, often the accessory nerve and sometimes the inframandibular branch of the facial nerve. He wrote in 1957 "The deformities and dysfunctions which ensue are tragic consequences to teen-age girls and young women who are most commonly affected by papillary cancers of the thyroid. Loss of contour of the neck, paralysis of the muscles of the lower face, shoulder drop, later arthritic changes in the shoulder girdle, hoarseness from unilateral laryngeal nerve injuries, stridor from bilateral injuries, and tetany are serious and often permanent complications. The surgeon who inflicts them must be prepared to defend his position by incontrovertible proof of a higher rate of cure."10) He argued that there was none. He was one of the first surgeons ever to promote the idea that "the less surgery the better", and he campaigned vigorously for the abandonment of the classic block dissection. His ideas on thyroid cancer surgery, and later breast cancer surgery, were reluctantly but steadily adopted by the surgical community and have since shaped the evolution of surgical treatment.

for papillary carcinoma less than 10 millimeters, some Japanese surgeons are proposing that observation without surgery may be sufficient4). The journey that lead to this schism and how it relates to the current therapeutic options is explained in this chapter as well as the

Thyroid surgery was a dangerous endeavor in the 19th century and the French Academy of Medicine officially condemned the practice, but with the introduction of anesthesia, antisepsis techniques and hemostatic forceps, the prognosis improved dramatically. Billroth reported a mortality rate of 40% early in his career which fell to 8% in the 1870s5). Kocher reported a reduction in mortality from 12.6% to 0.2% from the 1870s to the end of the 19th century6). Successful thyroidectomy lead to the discovery of postoperative hypothyroidism which in turn elucidated the true function of the normal thyroid gland7). Klein reported on loss of voice due to injury to the recurrent laryngeal nerves during the removal of goiter8). Tetany was observed in patients who underwent total thyroidectomy, but it was only with the concerted efforts of multiple investigators around the turn of the century that damage to the parathyroid glands was found to be responsible for this condition9). Eventually, these

Medical progress has advanced on a precarious balance between the pressing need for immediate solutions and the effort to keep harmful options out of the field. Pioneers of medicine made courageous, sometimes reckless, forays into uncharted territory to which we owe our current technology. But once the frontier was conquered and patient survival improved, more attention was paid to the tradeoffs of treatment, such as compromised quality of life, and efforts were made to diminish them. Surgery in particular has progressed, over the past half century, in the direction of reducing the extent of dissection

George "Barney" Crile Jr. stands out as the man who set the field of surgery onto this course. Father of the celebrated journalist George Crile III and son of the venerated founding member of the Cleveland Clinic, George Crile Sr., he is something of an unsung hero of modern surgery. Surgery for thyroid carcinoma of his time, called the "block dissection" or "conventional radical neck dissection", usually sacrificed the sternocleidomastoid muscle, often the accessory nerve and sometimes the inframandibular branch of the facial nerve. He wrote in 1957 "The deformities and dysfunctions which ensue are tragic consequences to teen-age girls and young women who are most commonly affected by papillary cancers of the thyroid. Loss of contour of the neck, paralysis of the muscles of the lower face, shoulder drop, later arthritic changes in the shoulder girdle, hoarseness from unilateral laryngeal nerve injuries, stridor from bilateral injuries, and tetany are serious and often permanent complications. The surgeon who inflicts them must be prepared to defend his position by incontrovertible proof of a higher rate of cure."10) He argued that there was none. He was one of the first surgeons ever to promote the idea that "the less surgery the better", and he campaigned vigorously for the abandonment of the classic block dissection. His ideas on thyroid cancer surgery, and later breast cancer surgery, were reluctantly but steadily adopted by the surgical community and have since shaped the evolution of surgical

discoveries lead to the reduction of surgical complications in thyroid surgery.

most likely course that future therapy may take.

and thereby lowering the risk of complications.

**2. The maverick**

treatment.

It would be easier to compose a narrative if the history of thyroid surgery were a linear progression from "conventional radical neck dissection" to less and less invasive procedures. But the story is more muddled, partly due to the particular characteristics of the organ and also due to entrenched positions of opinionated surgeons and oncologists. The trajectory was also confounded by the periodic infusion of breathtaking new technology for which there was widespread but misguided enthusiasm. There was no consensus for the optimum surgical procedure for thyroid cancer surgery in the early to mid-twentieth century. If the gross tumor was limited to one lobe, some surgeons performed lobectomy, some lobectomy with isthmus, some lobectomy with isthmus and a part of the opposing lobe and some insisted on total thyroidectomy. A few even dared to perform partial lobectomy and preserved most of the thyroid. The extent of lymph node dissection also varied greatly11). Early on, metastasis to the lymph nodes in the neck were mistaken for embryological migration error termed "lateral aberrant thyroid" and believed not to require surgery. Conventional radical dissection may have been a backlash against this initial complacency12).

During the time Crile was battling conventional radical dissection, others were arguing for more radical surgery. Clark et al performed serial sections of the whole thyroid. He found intraglandular dissemination in 58% of the 79 cases he studied13). Similar studies by Black et al found multicentricity in 20%14), and Underwood et al found contralateral lobe involvement in 32% of cases studied15). Each of these authors advocated total thyroidectomy or more based on their findings. However, Tollefsen, citing these works and others, compared them to the actual clinical recurrence rate in the opposite lobe. He pointed out that his recurrence rate was 3.7% and even Black, a proponent of radical surgery, had reported a recurrence in the opposite lobe in only 7%. In his 1963 report, Tollefsen wrote "The final importance of these histologic observations must rest in the clinical results. All but a small percentage of our patients have remained well for periods up to twenty-five years without clinical recurrence in the remaining lobe. We must, therefore, interpret these histologic cancers in the other lobe as being of slight importance and somewhat analogous to the autopsy incidence of microscopic cancer in the prostate."16) It is surprising today to find that a surgeon in New York had already outlined the position taken by Japanese specialists of the twenty-first century half a century previously. Nobody today questions that papillary thyroid carcinoma is very often multi-focal, although some authors argue that microscopic multifocal disease is clinically irrelevant.

#### **3. Stratifications**

Care should be taken in reading, and especially in citing, medical reports of this era. Histologic classification and diagnosis did not follow the same criteria as we use today. Statistics were rudimentary and rarely employed anything more sophisticated than simple percentages. Most troublesome of all, such variables as the initial size of the pre-operative tumor or the age of the patient were not taken into account when discussing the merits of one surgical procedure over another. In 1953, Crile reported that patients aged over 40 at initial diagnosis had a poorer prognosis compared to patients aged under 40. He concluded "Since almost all cancers of the thyroid that occur in patients under 40 years of age are of the lowest grade malignancy, the prognosis in this age group is almost universally good if an adequate operation is performed"17). In his 1964 report Tollefsen analyzed 70 fatal cases of

Thyroid Cancer: The Evolution of Treatment Options 299

The use of radioactive isotope of iodine as a tracer for the thyroid was developed during the 1930s and 40s. Eventually, this lead to the treatment of hyperthyroidism using 131-I23). The experimental application of radioiodine on thyroid cancer began almost simultaneously24). It was soon established that replacement thyroid hormones should be withdrawn for the duration of this therapy and that healthy thyroid tissues need to be removed for this method to be effective. The use of thyroglobulin to screen for cancer recurrence was developed later25). It was then established that thyroglobulin measurements yield no useful information in the follow up of thyroid cancer patients in the presence of residual thyroid tissue26). Thus a new rationale for total thyroidectomy was introduced. Thyroid cancer patients would hence forth be given total thyroidectomy not because tumors were found in both lobes, but because it facilitated post-operative screening for recurrence and the treatment of recurrence should any be found. And not only were the thyroid removed surgically, but they were

Although some surgeons were initially skeptical about the utility of radioiodine therapy in the treatment of metastatic thyroid carcinoma, the contrarians were eventually silenced as data mounted supporting its efficacy. By the 1970s few argued against the adoption of radioiodine therapy, and consequently total thyroidectomy, on patients with proven distant metastasis. Routine remnant ablation and thyroglobulin screening, however, was a different matter. Once again, superiority of one regimen over the other was frequently argued without stratifying the cases according to various risk factors. In one example, Snyder pointed out in 1983 that the actual effectiveness of routine remnant ablation in reducing morbidity and mortality was not objectively proven due to this reason27). In a subsequent issue of the same journal, Riccabona published a letter to the editor which included a survival curve comparing the survival of patients who had undergone radioiodine ablation and patients who had not to show that radioiodine ablation indeed had a positive effect28). To this, Snyder replied that this was "yet another testimonial to what has plagued the evaluation of different approaches to the treatment of thyroid cancer patients" and asked "Were Dr. Riccabona's patients randomized as to treatment? Were variables such as age, sex, histological type, histological grade, extent of disease, extent of surgery, and use of thyroid suppression therapy taken into account? What method was used in the detection of postoperative functioning tissue? Was ablation aimed at presumably normal thyroid tissue, or known residual thyroid cancer in the thyroid bed, or extrathyroidal functioning metastasis? Were these variables considered in the survival curve presented?" Few such dialogues were preserved in print, but similar debates occurred frequently in conferences around the world, occasionally accompanied by thunderous arguments and animated gesticulations, throughout the 1980s. Although not entirely as a consequence of such confrontations, the TNM staging system was introduced in 1987, AMES system in 1988,

Randomized prospective trials, had they been performed, may have helped settle many of the disputes. But differentiated thyroid carcinoma is an indolent cancer with a low rate of recurrence regardless of the treatment modality and often remains dormant for many years before tangible physical recurrence can be observed. This means that large numbers of patients would have to be followed for a very long time before a definite conclusion could

completely eradicated by means of "remnant ablation" using 131-I.

AGES system in 1987 and MACIS system in 1993.

**4. Debates**

papillary thyroid carcinoma and isolated age, initial size of tumor over 5 centimeters, recurrent laryngeal nerve palsy and distant metastasis as indicators of poor prognosis18). This was the beginning of the study of risk profiles in thyroid cancer. It was only after the prognostic indicators were clearly identified, and the outcome of treatment was compared among groups with equivalent risk profiles that the debate on surgical procedures rested on firm footing. Statistical techniques such as multivariate analysis were not employed in the study of thyroid cancer until the introduction of practical personal computers in the mid 1980s. Nonetheless, "conventional radical neck dissection" fell out of favor by the early 1970s.

Meanwhile, a remarkable paradigm shift was surrounding the realm of thyroid surgery. The increasing acceptance of iodine prophylaxis markedly decreased the incidence of endemic goiter. Radioiodine and anti-thyroid drugs reduced the number of surgically treated Graves disease. Prior to the development of oral steroid medications, even subacute thyroiditis was often treated by surgery, but this method was completely abandoned. The practice of irradiating children for benign diseases, which apparently increased the incidence of radiation induced thyroid cancer, was no longer performed19). Core needle and fine needle biopsies made preoperative differentiation of benign and malignant tumors possible. Due to these developments and others, the number of thyroid operations performed in the Cleveland Clinic fell from 2,700 in the year 1927 to less than 50 in the late 1960s20). Thyroid cancer effectively became the last bastion of thyroid surgery.

Imaging modalities also influenced surgery. In the late 1940s, ultrasonography was developed simultaneously in the United States, United Kingdom, Sweden and Japan. Although the earliest machines were cumbersome and impractical, the technology eventually improved to incorporate hand held probes which produced acceptably clear images. Fine needle aspiration biopsy was developed in the 1950s and eventually came into wide acceptance. But the combination of the two did not appear until the 1970s and was not widely used in the diagnosis of thyroid diseases until the 1980s. Computerized axial tomography was commercialized in the mid 1970s and magnetic resonance imaging in the early 80s, but neither machines were initially suitable for the examination of the neck area , CAT scan because of image artifacts from the bones and MRI (then called NMR-CT) because of low resolution. Both imaging technologies developed rapidly and became indispensable tools in the examination of the thyroid by the 1990s. The introduction of these diagnostic tools contributed greatly in the early detection of thyroid cancer and the incidence of thyroid cancer steadily increased21) while the size of tumor upon discovery steadily decreased after the mid 1980s3).

Over the years, improvements in anesthesia made it safer for surgeons to take the time to carefully visualize the recurrent laryngeal nerve which was eventually proven to diminish the incidence of paralysis22). The same was true for the parathyroid, which when better preserved caused fewer cases of tetany. This meant that total thyroidectomy could be performed with smaller risk of surgical complications.

So if the tumors were smaller but the complications were fewer, was it more logical to perform more conservative surgery or more radical surgery? Although this was not the question that was openly verbalized, this was the general area where the battle lines were drawn. And the debate was closely linked to the question of radioiodine therapy.

papillary thyroid carcinoma and isolated age, initial size of tumor over 5 centimeters, recurrent laryngeal nerve palsy and distant metastasis as indicators of poor prognosis18). This was the beginning of the study of risk profiles in thyroid cancer. It was only after the prognostic indicators were clearly identified, and the outcome of treatment was compared among groups with equivalent risk profiles that the debate on surgical procedures rested on firm footing. Statistical techniques such as multivariate analysis were not employed in the study of thyroid cancer until the introduction of practical personal computers in the mid 1980s. Nonetheless, "conventional radical neck dissection" fell out of favor by the early

Meanwhile, a remarkable paradigm shift was surrounding the realm of thyroid surgery. The increasing acceptance of iodine prophylaxis markedly decreased the incidence of endemic goiter. Radioiodine and anti-thyroid drugs reduced the number of surgically treated Graves disease. Prior to the development of oral steroid medications, even subacute thyroiditis was often treated by surgery, but this method was completely abandoned. The practice of irradiating children for benign diseases, which apparently increased the incidence of radiation induced thyroid cancer, was no longer performed19). Core needle and fine needle biopsies made preoperative differentiation of benign and malignant tumors possible. Due to these developments and others, the number of thyroid operations performed in the Cleveland Clinic fell from 2,700 in the year 1927 to less than 50 in the late 1960s20). Thyroid

Imaging modalities also influenced surgery. In the late 1940s, ultrasonography was developed simultaneously in the United States, United Kingdom, Sweden and Japan. Although the earliest machines were cumbersome and impractical, the technology eventually improved to incorporate hand held probes which produced acceptably clear images. Fine needle aspiration biopsy was developed in the 1950s and eventually came into wide acceptance. But the combination of the two did not appear until the 1970s and was not widely used in the diagnosis of thyroid diseases until the 1980s. Computerized axial tomography was commercialized in the mid 1970s and magnetic resonance imaging in the early 80s, but neither machines were initially suitable for the examination of the neck area , CAT scan because of image artifacts from the bones and MRI (then called NMR-CT) because of low resolution. Both imaging technologies developed rapidly and became indispensable tools in the examination of the thyroid by the 1990s. The introduction of these diagnostic tools contributed greatly in the early detection of thyroid cancer and the incidence of thyroid cancer steadily increased21) while the size of tumor upon discovery steadily

Over the years, improvements in anesthesia made it safer for surgeons to take the time to carefully visualize the recurrent laryngeal nerve which was eventually proven to diminish the incidence of paralysis22). The same was true for the parathyroid, which when better preserved caused fewer cases of tetany. This meant that total thyroidectomy could be

So if the tumors were smaller but the complications were fewer, was it more logical to perform more conservative surgery or more radical surgery? Although this was not the question that was openly verbalized, this was the general area where the battle lines were

drawn. And the debate was closely linked to the question of radioiodine therapy.

cancer effectively became the last bastion of thyroid surgery.

decreased after the mid 1980s3).

performed with smaller risk of surgical complications.

1970s.

The use of radioactive isotope of iodine as a tracer for the thyroid was developed during the 1930s and 40s. Eventually, this lead to the treatment of hyperthyroidism using 131-I23). The experimental application of radioiodine on thyroid cancer began almost simultaneously24). It was soon established that replacement thyroid hormones should be withdrawn for the duration of this therapy and that healthy thyroid tissues need to be removed for this method to be effective. The use of thyroglobulin to screen for cancer recurrence was developed later25). It was then established that thyroglobulin measurements yield no useful information in the follow up of thyroid cancer patients in the presence of residual thyroid tissue26). Thus a new rationale for total thyroidectomy was introduced. Thyroid cancer patients would hence forth be given total thyroidectomy not because tumors were found in both lobes, but because it facilitated post-operative screening for recurrence and the treatment of recurrence should any be found. And not only were the thyroid removed surgically, but they were completely eradicated by means of "remnant ablation" using 131-I.

Although some surgeons were initially skeptical about the utility of radioiodine therapy in the treatment of metastatic thyroid carcinoma, the contrarians were eventually silenced as data mounted supporting its efficacy. By the 1970s few argued against the adoption of radioiodine therapy, and consequently total thyroidectomy, on patients with proven distant metastasis. Routine remnant ablation and thyroglobulin screening, however, was a different matter. Once again, superiority of one regimen over the other was frequently argued without stratifying the cases according to various risk factors. In one example, Snyder pointed out in 1983 that the actual effectiveness of routine remnant ablation in reducing morbidity and mortality was not objectively proven due to this reason27). In a subsequent issue of the same journal, Riccabona published a letter to the editor which included a survival curve comparing the survival of patients who had undergone radioiodine ablation and patients who had not to show that radioiodine ablation indeed had a positive effect28). To this, Snyder replied that this was "yet another testimonial to what has plagued the evaluation of different approaches to the treatment of thyroid cancer patients" and asked "Were Dr. Riccabona's patients randomized as to treatment? Were variables such as age, sex, histological type, histological grade, extent of disease, extent of surgery, and use of thyroid suppression therapy taken into account? What method was used in the detection of postoperative functioning tissue? Was ablation aimed at presumably normal thyroid tissue, or known residual thyroid cancer in the thyroid bed, or extrathyroidal functioning metastasis? Were these variables considered in the survival curve presented?" Few such dialogues were preserved in print, but similar debates occurred frequently in conferences around the world, occasionally accompanied by thunderous arguments and animated gesticulations, throughout the 1980s. Although not entirely as a consequence of such confrontations, the TNM staging system was introduced in 1987, AMES system in 1988, AGES system in 1987 and MACIS system in 1993.

#### **4. Debates**

Randomized prospective trials, had they been performed, may have helped settle many of the disputes. But differentiated thyroid carcinoma is an indolent cancer with a low rate of recurrence regardless of the treatment modality and often remains dormant for many years before tangible physical recurrence can be observed. This means that large numbers of patients would have to be followed for a very long time before a definite conclusion could

Thyroid Cancer: The Evolution of Treatment Options 301

Other than the lack of prospective trials, varied patient retention, insufficient risk stratification and professional bias, there was also a linguistic problem. The idea that there is always some dissociation between the "signifier" and the "signified" is a relatively new concept that was not widely accepted among medical professionals of the previous generation. Authors almost never gave any thought to it. Noguchi's use of the term "modified radical neck dissection" was just one example of many idiosyncrasies in the use of terminology that hampered understanding and obstructed progress. One of the more glaring examples was Mazzaferri's use of the word "recurrence". He frequently neglected to make the distinction between "recurrence" and "biochemical recurrence"35). In some cases, TSH stimulation produced positive thyroglobulin serum tests in the absence of tangible metastasis on image scans. Recurrence of thyroid cancer was only implied by serum data. Such cases were termed "biochemical recurrence". The assumption was that these test results represented malignant recurrences too small to be visualized. When some doctors heard or read "recurrence" they automatically assumed that there was a detectable physical mass, but Mazzaferri was such an influential and widely cited authority that there would eventually be a school of specialists who used the term "recurrence" interchangeably with "biochemical recurrence". It takes an astute reader to realize that the "recurrence rate" in

one citation is not always the same thing as a "recurrence rate" in another.

to perform total thyroidectomy where its necessity was still in question.

content of the Japanese diet40).

And then, in 1998, human recombinant TSH was approved for thyroglobulin testing. This was truly a product of advanced molecular biology and a cutting edge drug of a new era. It allowed testing for thyroglobulin without withdrawing replacement thyroid hormones. It would eventually be approved for use in radioiodine therapy, for which it had the same advantage. Unfortunately, the enthusiasm that this drug generated also provided incentive

Under the influence of these persistent obstacles, some researchers continued to hone their investigative strategies with ever more refined study designs. Others seemingly decided to take the kick-in-the-teeth approach. Ito et al performed an observational study of papillary microcarcinoma and found that only 15.9% increased in size beyond the margin of error (3mm or more) and only 3.4% presented novel nodal metastasis after 10 years of observation without treatment4). This finding was in line with the data from unsuspected microcarcinomas found in thyroids resected for other reasons36). If this is the malignant potential of clinically tangible tumors, the reasoning implied, what is the clinical significance of microscopic intragrandular focci or invisible biochemical recurrence? Granted that there is evidence that post-ablative serum thyroglobulin is a predictor of recurrence in low risk thyroid carcinoma37), an increasing number of studies suggest that routine ablation does not significantly suppress recurrence in low risk cases38)39). Some experts argue that remnant ablation should be performed anyway in order to prevent what little differentiated cancer that may remain from turning into anaplastic carcinoma, which is universally fatal. But the incidence of anaplastic carcinoma in North America where post-surgical ablation is performed routinely is substantially higher than the incidence in Japan where post-surgical ablation is still uncommon, although this difference has been attributed to the higher iodine

Authors on both sides of the debate have pointed out that not all papillary carcinomas are equally indolent. Some grow rapidly and progress more aggressively than others without obvious histological differences. Histological variations such as tall cell variants and

be reached. Thus, the studies on the optimum treatment for thyroid cancer would be left in the hands of prolific surgeons who would showcase their vast surgical experience in retrospective studies involving large numbers of patients. The field of thyroid cancer is littered with retrospective studies of hundreds, sometimes thousands of cases aimed at demonstrating the validity or otherwise of a given procedure. The extent of surgery is one of many controversial subjects that are so studied and there is a number of retrospective studies, properly stratified with AGES, AMES and pTNM, which demonstrate that total or near-total thyroidectomy reduces recurrence rates compared to lobectomy and similar unilateral resections29)30)31). What is often left unsaid is that patients who undergo near-total or total thyroidectomy must receive oral hormone replacement for a lifetime, while the majority of patients who undergo unilateral lobectomy remain euthyroid without medication. As a consequence, the patients who undergo lobectomy tend to have poor retention in retrospective studies because patients tend to stop visiting their doctors when they are feeling well. The difference in retention between patients of near-total or total thyroidectomy and patients of lobectomy is rarely ever mentioned in retrospective studies. But this helps explain why some investigators found no significant difference in recurrence between the two procedures32)33).

And on top of all this was the professional bias of individual investigators. In the absence of a randomized trial, doctors generally do not perform treatments they do not believe in, due to which single-institution retrospective studies tend to have poorly structured control groups. Shiro Noguchi performed over ten thousand thyroid surgeries during his career by official record, not counting the thousands he hijacked while nominally assisting or overseeing them. He employed clerks whose sole mission was to stay in contact with his postoperative patients by telephone and mail, and to do detective work to track down their ever changing addresses. As a result, he published a number of long-term retrospective studies with large populations and excellent patient retention. His focus, however, was to prove the validity of prophylactic lymph node dissection. He called his procedure "modified radical neck dissection" even though nearly half of his cases involved only lobectomy. His belief was, if the lymph nodes of the neck were properly excised, neither total thyroidectomy nor remnant ablation were necessary in most low-to-moderate risk cases. His support of lobectomy was only secondary to his belief in prophylactic node dissection. Another prolific surgeon Orlo H. Clark, on the other hand, was a proponent of total thyroidectomy and remnant ablation who also happened to be skeptical about the value of prophylactic lymph node dissection. Naturally, Noguchi's reports expounded on the merits of prophylactic node dissection, but compared results in the absence of remnant ablation. Clark's reports stressed the merits of total thyroidectomy with remnant ablation in the absence of prophylactic node dissection. Clark's arguments against prophylactic lymph node dissection rested on the assumption that the patient would receive remnant ablation. Noguchi did not employ radioiodine therapy in any of his cases with rare exceptions, low risk or otherwise, unless there was proven metastasis on image scans such as sonography, CAT, MRI or scintigraphy because he believed ablation was unnecessary and harmed the quality of life of his patients. Clark did not perform neck dissection unless there was proven metastasis on image scans for the same reason. Both surgeons reported excellent prognosis and low incidence of complications. (The two experts once joined hands to create a "definitive text" on thyroid cancer but the book, not surprisingly, was not a commercial success34).) As this example illustrates, each investigator had priorities among different points of controversy that made it difficult to compare the results of one report with another.

be reached. Thus, the studies on the optimum treatment for thyroid cancer would be left in the hands of prolific surgeons who would showcase their vast surgical experience in retrospective studies involving large numbers of patients. The field of thyroid cancer is littered with retrospective studies of hundreds, sometimes thousands of cases aimed at demonstrating the validity or otherwise of a given procedure. The extent of surgery is one of many controversial subjects that are so studied and there is a number of retrospective studies, properly stratified with AGES, AMES and pTNM, which demonstrate that total or near-total thyroidectomy reduces recurrence rates compared to lobectomy and similar unilateral resections29)30)31). What is often left unsaid is that patients who undergo near-total or total thyroidectomy must receive oral hormone replacement for a lifetime, while the majority of patients who undergo unilateral lobectomy remain euthyroid without medication. As a consequence, the patients who undergo lobectomy tend to have poor retention in retrospective studies because patients tend to stop visiting their doctors when they are feeling well. The difference in retention between patients of near-total or total thyroidectomy and patients of lobectomy is rarely ever mentioned in retrospective studies. But this helps explain why some investigators found no significant difference in recurrence

And on top of all this was the professional bias of individual investigators. In the absence of a randomized trial, doctors generally do not perform treatments they do not believe in, due to which single-institution retrospective studies tend to have poorly structured control groups. Shiro Noguchi performed over ten thousand thyroid surgeries during his career by official record, not counting the thousands he hijacked while nominally assisting or overseeing them. He employed clerks whose sole mission was to stay in contact with his postoperative patients by telephone and mail, and to do detective work to track down their ever changing addresses. As a result, he published a number of long-term retrospective studies with large populations and excellent patient retention. His focus, however, was to prove the validity of prophylactic lymph node dissection. He called his procedure "modified radical neck dissection" even though nearly half of his cases involved only lobectomy. His belief was, if the lymph nodes of the neck were properly excised, neither total thyroidectomy nor remnant ablation were necessary in most low-to-moderate risk cases. His support of lobectomy was only secondary to his belief in prophylactic node dissection. Another prolific surgeon Orlo H. Clark, on the other hand, was a proponent of total thyroidectomy and remnant ablation who also happened to be skeptical about the value of prophylactic lymph node dissection. Naturally, Noguchi's reports expounded on the merits of prophylactic node dissection, but compared results in the absence of remnant ablation. Clark's reports stressed the merits of total thyroidectomy with remnant ablation in the absence of prophylactic node dissection. Clark's arguments against prophylactic lymph node dissection rested on the assumption that the patient would receive remnant ablation. Noguchi did not employ radioiodine therapy in any of his cases with rare exceptions, low risk or otherwise, unless there was proven metastasis on image scans such as sonography, CAT, MRI or scintigraphy because he believed ablation was unnecessary and harmed the quality of life of his patients. Clark did not perform neck dissection unless there was proven metastasis on image scans for the same reason. Both surgeons reported excellent prognosis and low incidence of complications. (The two experts once joined hands to create a "definitive text" on thyroid cancer but the book, not surprisingly, was not a commercial success34).) As this example illustrates, each investigator had priorities among different points

of controversy that made it difficult to compare the results of one report with another.

between the two procedures32)33).

Other than the lack of prospective trials, varied patient retention, insufficient risk stratification and professional bias, there was also a linguistic problem. The idea that there is always some dissociation between the "signifier" and the "signified" is a relatively new concept that was not widely accepted among medical professionals of the previous generation. Authors almost never gave any thought to it. Noguchi's use of the term "modified radical neck dissection" was just one example of many idiosyncrasies in the use of terminology that hampered understanding and obstructed progress. One of the more glaring examples was Mazzaferri's use of the word "recurrence". He frequently neglected to make the distinction between "recurrence" and "biochemical recurrence"35). In some cases, TSH stimulation produced positive thyroglobulin serum tests in the absence of tangible metastasis on image scans. Recurrence of thyroid cancer was only implied by serum data. Such cases were termed "biochemical recurrence". The assumption was that these test results represented malignant recurrences too small to be visualized. When some doctors heard or read "recurrence" they automatically assumed that there was a detectable physical mass, but Mazzaferri was such an influential and widely cited authority that there would eventually be a school of specialists who used the term "recurrence" interchangeably with "biochemical recurrence". It takes an astute reader to realize that the "recurrence rate" in one citation is not always the same thing as a "recurrence rate" in another.

And then, in 1998, human recombinant TSH was approved for thyroglobulin testing. This was truly a product of advanced molecular biology and a cutting edge drug of a new era. It allowed testing for thyroglobulin without withdrawing replacement thyroid hormones. It would eventually be approved for use in radioiodine therapy, for which it had the same advantage. Unfortunately, the enthusiasm that this drug generated also provided incentive to perform total thyroidectomy where its necessity was still in question.

Under the influence of these persistent obstacles, some researchers continued to hone their investigative strategies with ever more refined study designs. Others seemingly decided to take the kick-in-the-teeth approach. Ito et al performed an observational study of papillary microcarcinoma and found that only 15.9% increased in size beyond the margin of error (3mm or more) and only 3.4% presented novel nodal metastasis after 10 years of observation without treatment4). This finding was in line with the data from unsuspected microcarcinomas found in thyroids resected for other reasons36). If this is the malignant potential of clinically tangible tumors, the reasoning implied, what is the clinical significance of microscopic intragrandular focci or invisible biochemical recurrence? Granted that there is evidence that post-ablative serum thyroglobulin is a predictor of recurrence in low risk thyroid carcinoma37), an increasing number of studies suggest that routine ablation does not significantly suppress recurrence in low risk cases38)39). Some experts argue that remnant ablation should be performed anyway in order to prevent what little differentiated cancer that may remain from turning into anaplastic carcinoma, which is universally fatal. But the incidence of anaplastic carcinoma in North America where post-surgical ablation is performed routinely is substantially higher than the incidence in Japan where post-surgical ablation is still uncommon, although this difference has been attributed to the higher iodine content of the Japanese diet40).

Authors on both sides of the debate have pointed out that not all papillary carcinomas are equally indolent. Some grow rapidly and progress more aggressively than others without obvious histological differences. Histological variations such as tall cell variants and

Thyroid Cancer: The Evolution of Treatment Options 303

Today there are surgical conferences around the world that no longer hold independent sessions for the discussion of thyroid cancer surgery. As sobering as it may sound, fading from attention is the final reward of great medical progress. We cannot be disappointed that

If the past is any guide, the future of thyroid cancer treatment will most likely evolve in two major directions. One is the treatment of poorly differentiated and unresponsive cancers. The other is the ever earlier diagnosis and increasingly conservative treatment of low malignancy cancers. Endoscopic and robotic surgery that are seeing wider application in the gastroenterological field are being tested in thyroid surgery. Laser ablation and radio frequency ablation, both of which use specialized needles inserted percutaneously to ablate benign thyroid nodules, are also being tested on a limited sub-group of malignant tumors50)51). If more evidence is accumulated that low-risk papillary cancers are as indolent as some researchers claim, such low invasion techniques may see wider application. The current debate on the choice between total thyroidectomy and lobectomy may seem quaint when, in the future, microcarcinomas are treated with needles tipped with thermal

Conservative surgery became possible in other fields of oncology partly due to the development of adjuvant chemotherapy. Though conventional chemotherapy is not effective for differentiated thyroid cancer, tyrosine kinase inhibitors hold some promise. This new class of drugs is being tested, with encouraging results, on radioiodine refractory cases52), medullary carcinoma53) and anaplastic carcinoma54). Combination therapy in the

Molecular biology has enhanced our understanding of thyroid cancer greatly. Genetic testing has allowed for early detection of MEN type 2 and prophylactic thyroidectomy55). Tyrosine kinase inhibitors, histone deacetylase inhibitors56) and nijmegen breakage syndromes57) are being studied as potential new therapies for anaplastic carcinoma. Studies of micro-RNAs have provided some interesting hints in their potential for diagnosis and treatment of cancer58). Further studies may present more focused differentiation of low-risk

In summary, much has been elucidated about thyroid cancer in the past century and a half. We owe our current expertise to those who dared to challenge the status quo. The general direction of the evolution of thyroid cancer treatment has been toward lesser invasion and increasingly tailored therapy as we learned to more correctly differentiate low-risk from high-risk and acquired knowledge and confidence to leave well enough alone. The future will most likely follow this trend, differentiating the risk categories with ever greater accuracy and treating them with increasingly focused therapy. Trends to the contrary are likely to be momentary aberrations or corrections to the course. As prognosis improves and complications diminish, points of controversy in treatment options will be of increasingly smaller universal significance and will inevitably invite greater patient involvement in clinical decision making. There are still frontiers to be conquered in the field of thyroid cancer, though not as wild or lawless as in the past. There will always be room for

innovators in the future. One only needs to proceed in the right direction.

the scope of our arguments has become smaller. Our patients are better for it.

coagulation devises.

**6. Summary**

future may produce even better results.

and high-risk cancers on the molecular level.

columnar cell variants have been identified41)42), but many unusually malignant strains cannot be morphologically identified as any different from other examples of papillary carcinoma. How to identify the rare differentiated cancers that are most likely to take a more malignant course is an important and unanswered question. Clinical risk factors are currently the only guide, although some studies on molecular prognostic markers are being performed43)44).

Proponents of lobectomy point out that only one recurrent laryngeal nerve is at risk when only one lobe of the thyroid is being resected thus the theoretical risk of nerve palsy is halved45). Proponents of total thyroidectomy insist that the increase in complications is minimal at the hands of an experienced surgeon46). Disagreement over the merits of prophylactic central node dissection is argued along similar lines47)48)49). Experience suggests that the incidence of surgical complications is much more dependent on the proficiency of the surgeon than the type of surgery performed. Experts who are experienced enough to publish large retrospective studies invariably report excellent results regardless of the type of surgery they promote.

#### **5. Where we are**

So which is the better option? Is it more practical to allow a small number of recurrences and re-operate on those that recur, or ablate at the first sign of a biochemical recurrence and risk salivary gland damage to prevent re-operation? Is it more economical to periodically check for thyroglobulin with recombinant TSH, or just follow with sonogram and surgically remove the metastasis when they appear? The cost of surgery, radioiodine therapy, image scans and cytology tests vary tremendously in the US, Europe and Japan, to say nothing of the availability of high end care, the social costs of hospitalization, the geographic distance to specialized institutions and the medical legal demands on the doctor. Depending on the location of the patient and the local cost structure of medical care, one option may be more advantageous than another. At the bottom line, the current argument on low risk thyroid cancer is whether or not it is an acceptable tradeoff to allow a minimally increased risk of surgical complications to guard against a minimally increased risk of cancer recurrence when there is no proven difference in prognosis. It is difficult to reach a conclusion because the difference in benefits and demerits are so small, the choice is largely dependent on the preference and socio-economic situation of the patient. Perhaps it is time for this debate to leave the ivory tower and be presented to the patients who are directly affected.

The experts now nearing retirement or who have retired in the past few decades have lived through a vibrant age. Long ago, in an American hospital, two reputable surgeons with conflicting surgical philosophy had an argument in the operating room when, after the initial incision, they found the extent of disease to be not what they expected. Anesthesia was not as stable then as it is today and time was precious. In exasperation, one surgeon punched the other in the face, calmly changed his gloves, and completed the surgery alone while the other lay unconscious on the operating room floor. Such buccaneering days have long since ended. The controversies surrounding thyroid cancer today do not have the consequences of Crile's time when he started his crusade against radical thyroidectomy and radical mastectomy. This is an inevitable result of medical progress. As the prognosis improves and complications diminish, the persisting debates become increasingly pedantic.

columnar cell variants have been identified41)42), but many unusually malignant strains cannot be morphologically identified as any different from other examples of papillary carcinoma. How to identify the rare differentiated cancers that are most likely to take a more malignant course is an important and unanswered question. Clinical risk factors are currently the only guide, although some studies on molecular prognostic markers are being

Proponents of lobectomy point out that only one recurrent laryngeal nerve is at risk when only one lobe of the thyroid is being resected thus the theoretical risk of nerve palsy is halved45). Proponents of total thyroidectomy insist that the increase in complications is minimal at the hands of an experienced surgeon46). Disagreement over the merits of prophylactic central node dissection is argued along similar lines47)48)49). Experience suggests that the incidence of surgical complications is much more dependent on the proficiency of the surgeon than the type of surgery performed. Experts who are experienced enough to publish large retrospective studies invariably report excellent results regardless of the type

So which is the better option? Is it more practical to allow a small number of recurrences and re-operate on those that recur, or ablate at the first sign of a biochemical recurrence and risk salivary gland damage to prevent re-operation? Is it more economical to periodically check for thyroglobulin with recombinant TSH, or just follow with sonogram and surgically remove the metastasis when they appear? The cost of surgery, radioiodine therapy, image scans and cytology tests vary tremendously in the US, Europe and Japan, to say nothing of the availability of high end care, the social costs of hospitalization, the geographic distance to specialized institutions and the medical legal demands on the doctor. Depending on the location of the patient and the local cost structure of medical care, one option may be more advantageous than another. At the bottom line, the current argument on low risk thyroid cancer is whether or not it is an acceptable tradeoff to allow a minimally increased risk of surgical complications to guard against a minimally increased risk of cancer recurrence when there is no proven difference in prognosis. It is difficult to reach a conclusion because the difference in benefits and demerits are so small, the choice is largely dependent on the preference and socio-economic situation of the patient. Perhaps it is time for this debate to

leave the ivory tower and be presented to the patients who are directly affected.

The experts now nearing retirement or who have retired in the past few decades have lived through a vibrant age. Long ago, in an American hospital, two reputable surgeons with conflicting surgical philosophy had an argument in the operating room when, after the initial incision, they found the extent of disease to be not what they expected. Anesthesia was not as stable then as it is today and time was precious. In exasperation, one surgeon punched the other in the face, calmly changed his gloves, and completed the surgery alone while the other lay unconscious on the operating room floor. Such buccaneering days have long since ended. The controversies surrounding thyroid cancer today do not have the consequences of Crile's time when he started his crusade against radical thyroidectomy and radical mastectomy. This is an inevitable result of medical progress. As the prognosis improves and complications diminish, the persisting debates become increasingly pedantic.

performed43)44).

of surgery they promote.

**5. Where we are**

Today there are surgical conferences around the world that no longer hold independent sessions for the discussion of thyroid cancer surgery. As sobering as it may sound, fading from attention is the final reward of great medical progress. We cannot be disappointed that the scope of our arguments has become smaller. Our patients are better for it.

If the past is any guide, the future of thyroid cancer treatment will most likely evolve in two major directions. One is the treatment of poorly differentiated and unresponsive cancers. The other is the ever earlier diagnosis and increasingly conservative treatment of low malignancy cancers. Endoscopic and robotic surgery that are seeing wider application in the gastroenterological field are being tested in thyroid surgery. Laser ablation and radio frequency ablation, both of which use specialized needles inserted percutaneously to ablate benign thyroid nodules, are also being tested on a limited sub-group of malignant tumors50)51). If more evidence is accumulated that low-risk papillary cancers are as indolent as some researchers claim, such low invasion techniques may see wider application. The current debate on the choice between total thyroidectomy and lobectomy may seem quaint when, in the future, microcarcinomas are treated with needles tipped with thermal coagulation devises.

Conservative surgery became possible in other fields of oncology partly due to the development of adjuvant chemotherapy. Though conventional chemotherapy is not effective for differentiated thyroid cancer, tyrosine kinase inhibitors hold some promise. This new class of drugs is being tested, with encouraging results, on radioiodine refractory cases52), medullary carcinoma53) and anaplastic carcinoma54). Combination therapy in the future may produce even better results.

Molecular biology has enhanced our understanding of thyroid cancer greatly. Genetic testing has allowed for early detection of MEN type 2 and prophylactic thyroidectomy55). Tyrosine kinase inhibitors, histone deacetylase inhibitors56) and nijmegen breakage syndromes57) are being studied as potential new therapies for anaplastic carcinoma. Studies of micro-RNAs have provided some interesting hints in their potential for diagnosis and treatment of cancer58). Further studies may present more focused differentiation of low-risk and high-risk cancers on the molecular level.

#### **6. Summary**

In summary, much has been elucidated about thyroid cancer in the past century and a half. We owe our current expertise to those who dared to challenge the status quo. The general direction of the evolution of thyroid cancer treatment has been toward lesser invasion and increasingly tailored therapy as we learned to more correctly differentiate low-risk from high-risk and acquired knowledge and confidence to leave well enough alone. The future will most likely follow this trend, differentiating the risk categories with ever greater accuracy and treating them with increasingly focused therapy. Trends to the contrary are likely to be momentary aberrations or corrections to the course. As prognosis improves and complications diminish, points of controversy in treatment options will be of increasingly smaller universal significance and will inevitably invite greater patient involvement in clinical decision making. There are still frontiers to be conquered in the field of thyroid cancer, though not as wild or lawless as in the past. There will always be room for innovators in the future. One only needs to proceed in the right direction.

Thyroid Cancer: The Evolution of Treatment Options 305

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#### **7. References**

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### *Edited by Thomas J. Fahey*

Thyroid cancer can be either common or rare, and takes several forms in multiple populations, such as children and adolescents. The chapters in this book, which provide state-of-the-art knowledge in understanding and treating the condition, are therefore welcome. Our understanding of thyroid cancer is advanced by several chapters on its incidence in a Spanish population, the functionality of p53 and the use of microarray technology in research. Diagnostic issues include the roles of glycosylation and glycoproteins, and use of a γ-camera to evaluate the in vivo biodistributions and internal medical dosimetries of Iodine-131. The majority of chapters address the range of possible treatment protocols, such as IGF signalling, surgical management, sentinel lymph node biopsy, radioiodine treatment and differentiation therapy.

Updates in the Understanding and Management of Thyroid Cancer

Updates in the Understanding

and Management of

Thyroid Cancer

*Edited by Thomas J. Fahey*

Photo by 7activestudio / iStock