Abstract
A 46-year-old woman with history of radioiodine-refractory follicular thyroid carcinoma (FTC) presented with locally recurrent, high-risk, invasive disease. She was treated with paclitaxel/carboplatin concomitant chemoradiotherapy (CRT), which was well tolerated, resulting in complete remission and freedom from residual or recurrent FTC for longer than 5 years until her last follow-up at age 52. This case highlights the possibility of combining taxane-based chemotherapy with definitive radiotherapy (as CRT) for the management of locally aggressive recurrences in poorly differentiated thyroid carcinoma, thereby resulting in rapid and persistent disease eradication. Even in the light of recent data on the potential benefit of novel targeted therapy agents in poorly differentiated thyroid carcinoma, this approach in similar clinical settings deserves future investigation.
Thyroid cancer accounts for about 1%-2% of all malignancies, with non-medullary differentiated thyroid carcinoma (DTC) accounting for ~93% of all cases (1). Although DTC is not associated with significant mortality, it demonstrates a high rate of local recurrence (2). Involvement of the aerodigestive tract by DTC via direct extension of either the primary tumor (at the time of initial presentation) or locally recurrent disease deposits is rare. Furthermore, there is no consensus on the optimal management of such patients, as they also typically harbor disease that is refractory to radioiodine (RAI; 131I) therapy (1, 3) and their surgical curability is low (3).
We present the case of a patient who developed RAI-refractory, locally recurrent, invasive de-differentiated follicular thyroid carcinoma (FTC) which responded fully and in a sustained fashion to a concomitantly administered combination of taxane-based chemotherapy and radiotherapy (RT).
Case Report
A Caucasian woman presented with a T4aN0M0 FTC in June 1996, at the age of 41. She had neither previous exposure to ionizing radiation nor family history of thyroid disease or tumors. The patient underwent a total thyroidectomy for the resection of a right-sided 5.5-cm primary malignancy. The tumor extended to the resection margins, and showed evidence of both vascular and capsular invasion; no pathological findings were noted in 4/4 resected small nodes. The tumor histology was typical for well-differentiated FTC with typical DTC marker immunocytochemistry, with the exception of focal positivity for p53 and ~55% positivity for Ki-67. Her subsequent clinical course, imaging findings and serum thyroglobulin (Tg) levels over time are summarized in Table I. A locally invasive macroscopic recurrence at the level of the lower larynx/trachea was detected in March 2001, when the patient was 46 years old. The computed tomography (CT) of the neck without i.v. iodinated contrast, as well as the corresponding neck magnetic resonance imaging (MRI) scan at the time of diagnosis of the recurrence are shown in Figure 1. The 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) scan is shown in Figure 2; this demonstrated a single focus of increased uptake in the right anterior neck with a high standard uptake value (SUV) of 10.2, corresponding to the abnormality depicted on both the MRI and ultrasound (US) examinations. An US-guided fine-needle aspiration biopsy of the paralaryngeal mass confirmed FTC recurrence. Of note, direct laryngoscopy revealed no evidence of vocal cord paralysis or erosion of the mass into the laryngeal mucosa.
At that juncture, the patient had already undergone three previous neck operations, and the risk of significant morbidity from damage to the recurrent laryngeal nerve, or the larynx itself, in another surgery could not be overlooked; furthermore, the surgical curability of the lesion with a functionally sparing procedure was deemed low. A diagnostic 131I whole-body scan showed no elevated RAI uptake and the patient already had history of RAI-non-avid disease deposits, as demonstrated by the previously resected lung solitary metastasis. Considering that the absence of RAI uptake on a diagnostic 131I whole-body scan usually suggests little or no fractional iodine uptake by the tumor deposits (4), it was predicted that the patient's response to yet another maximally safe dose 131I therapy (under whole-blood/bone marrow RAI dosimetry guidance) would be minimal to none. Furthermore, administering RAI therapy under dosimetric guidance could have led to potential delays in the initiation of a more definitive therapy and/or some risk of more prolonged or severe myelosuppression due to bone marrow irradiation (5). Of note, the patient had an ECOG performance status of 0, and was otherwise completely asymptomatic. Definitive external beam RT to the recurrent mass was certainly considered as a possible option at that time (6), with a suggested field coverage extending to the rest of the neck and upper mediastinum, which were territories at high risk for future recurrences. In addition, administration of the radiosensitizing chemotherapy during RT delivery was also considered. More specifically, the doublet of paclitaxel (Ptx)/carboplatin (Cb) was chosen to be administered concomitantly with definitive RT with curative intent. At the time of the patient's evaluation, Ptx, a taxane, had been used as a radiosensitizing agent in the treatment of assorted solid organ malignancies (7).
The CRT regimen was as follows: Chemotherapy: On day 1 of each cycle and concomitantly with RT, the patient received 60 mg/m2 of Ptx administered over a 1-hour infusion. Premedication included dexamethasone, ranitidine, and diphenhydramine. The Ptx dose on the day of infusion was scheduled to start at least 2 hours before the RT fraction for that day, thus leaving a 1-hour gap between the end of Ptx infusion and the RT fraction. Cb was administered also concomitantly with RT on day 1 of each cycle as a 30-min infusion administered 3 to 4 hours after the RT fraction at a dose of an area under the concentration × time curve (AUC) of 2.0 (using the Calvert dosing formula) (8). Each Ptx/Cb cycle was 1 week in duration, and a total of 6 cycles were delivered.
RT: RT started from day 2 onward, and continued on a 5-day/week schedule with an initially planned total duration of 6 weeks (42 days). RT was delivered with a linear accelerator using 10-MV photons and suitable electron energies, via parallel-opposed lateral fields and an anterior field that allowed shielding of the spinal cord, and appropriate tangential laryngopharyngeal/tracheal doses. Using the above conventional 3-D conformal technique and once-daily standard fractionation, RT was administered to the primary tumor volume (paralaryngeal mass with appropriate margins) at a daily dose of 2.0 Gy/fraction on a 5-day/week schedule in a series of 30 fractions, plus 12 additional boost fractions of 0.85 Gy/fraction (total of 42 fractions at an average of 1.67 Gy/fraction) to a total of 70.2 Gy over a period of 52 days (initially planned RT treatment duration: 6 weeks: 42 days); the bilateral neck lymphatic fields received a total of 46.2 Gy.
The patient's treatment was complicated by oropharyngeal candidiasis, dysphagia, and hyperemia of the skin of the neck and upper chest (the latter anatomically defined by the margins of the radiation therapy fields). However, these effects were promptly managed and did not exceed NCI-CTC grade 2; furthermore, these adverse events did not necessitate therapy interruption, although there was a total delay of 10 days in the delivery of combination chemoradiotherapy (CRT). No hematological or other significant toxic reactions ensued. The patient was fed via a percutaneous endoscopic gastrostomy (PEG) tube for 3 weeks during her CRT; the PEG tube was placed prophylactically, was used successfully when needed, and was eventually removed without complications within 4 weeks after the completion of CRT (total duration of PEG tube dependence: 6.5 weeks). The patient did not experience severity of cytopenia greater than grade 2, and did not require transfusions or bone marrow growth factor support.
The patient's clinical course after completion of Ptx/Cb CRT is shown in Table I. By Mar. 2006, the patient was considered as having achieved no evidence of disease (NED) status for 5 years since completion of CRT. Ever since, the patient has been followed by a local oncologist. She remains recurrence-free to date, for a total duration of longer than 8 years.
Discussion
DTC is the second most common endocrine organ malignancy (after ovarian carcinoma) (1). Although not associated with significant mortality, DTC demonstrates a high rate of local recurrence (2). Involvement of the aerodigestive tract by DTC via direct extension of either the primary tumor (at the time of initial presentation) or locally recurrent disease deposits is rare. However, such locoregional recurrences, together with distant metastases (M1 status), represent the most frequent causes of death directly attributable to this malignancy (9-12), and are associated with aggressive features (such as the tall-cell or columnar variant of papillary thyroid carcinoma, poorly-differentiated FTC, and Hürthle-cell carcinomas) (13).
Literature on the clinical experience in the management of thyroid carcinoma involving the aerodigestive tract and/or large vessels of the neck remains sparse. Relevant reports combine patients with both undifferentiated (or poorly differentiated) and well-differentiated histologies, tumors at various initial stages, tumors that were invasive since initial presentation vs. those that demonstrated invasiveness only at the time of local recurrence, as well as varying levels of involvement of critical midline neck structures by the offending recurrence(s). Not surprisingly, there is no consensus on the optimal means of managing a patient with thyroid carcinoma who presents with invasion of the aerodigestive tract (3).
In cases similar to the one described here, deciding the direction of the management plan toward a specific single modality (surgery or definitive RT) or CRT is challenging. The goal of oncologically sound surgical treatment is to “provide adequate locoregional control, while minimizing not only the morbidity of the tumor, but also the morbidity of the surgical treatment” (3, 14). In cases where no evidence of intraluminal involvement exists, surgical resection to remove macroscopic disease (shave excision) is generally considered to be as effective (15). For invasive thyroid carcinoma (TC), adjuvant treatment with either high-dose 131I therapy, RT, or a sequence of both is typically required to manage microscopic disease, which usually remains in the surgical bed and/or the surrounding lymphatic territories. This is required for the prevention of the emergence of the postoperative tumor repopulation effect, which is a theoretical possibility based data on this phenomenon in solid malignancies other than thyroid carcinoma (16). Incomplete excision of gross tumor in locally invasive thyroid carcinoma cases is associated with a worse prognosis, mainly due to increased risk of local complications (13). If a decision is made to resect a part of the aerodigestive tract, partial rather than radical procedures are currently preferred, with the hope of preserving an acceptable degree of function (14).
For our patient, with aggressive recurrent disease and three previous neck surgeries, when a high-impact, invasive paralaryngeal locoregional recurrence was identified, the risks associated with surgery outweighed the anticipated benefits. In addition, because the offending lesion was rather small, had not penetrated the larynx transmurally, did not involve any major vascular organs, and had not undergone complete dedifferentiation into a frankly anaplastic phenotype, alternative non-surgical modalities were considered. Treatment with 131I therapy was discussed, despite a negative diagnostic RAI whole-body scan. However, on average, less than 10% of similar patients would experience some benefit (typically partial response or maintenance of stable disease) from the administration of high-dose (~11 GBq) 131I therapy (17). In our case, there was almost certainty regarding the refractoriness of the recurrence to RAI therapy, in view of the previous history of a RAI-non-avid pulmonary metastatic FTC deposit.
In patients with locoregional recurrence from thyroid carcinoma, definitive RT alone has been traditionally used for treatment of disease deposits that are not amenable to surgical resection and/or are no longer 131I avid (6, 18-20). Over the last decade, RT has been used by some as an adjuvant modality after primary or secondary surgery (with/without 131I therapy), particularly if there is evidence of a carcinoma with aggressive features, by either extent of disease or histologic type or grade (e.g. tumor harboring microscopic anaplastic components) (19, 20). The ability to administer an effective dose of RT may be limited by the risk of damage to surrounding structures, such as the spinal cord in the case of recurrences in the neck. Although this concern may have been lessened in the current era of intensity-modulated radiation therapy (IMRT), it continues to exist (21).
Chemotherapy agents, administered at lower doses than are typically used systemically for cytoreductive purposes in the context of treatment of distant metastases, have been attempted in combination with RT to improve the tumor's response to treatment in patients with anaplastic thyroid carcinoma (22-24). This combination is defined as concomitant chemoradiation, and its effectiveness has also reported in a single case series from the late 1980s by Kim and Leeper (25), who reported a 91% objective response rate (ORR) to a combination of weekly doxorubicin and RT, the latter targeted to the bulk of the tumor mass and the neck territories. This series was of consecutive (i.e. non-randomized) cases of either advanced DTC or less differentiated subtypes of TC — including mixed histologies (e.g. papillary “in transformation” toward anaplastic); the series did not include RT-only controls. The usefulness of doxorubicin in this report reflects the benefit from this agent in anaplastic thyroid carcinoma (26). Nevertheless, the response to doxorubicin-based CRT was short-lived. Side-effects included pharyngoesophagitis, tracheitis, and erythema of the irradiated skin. In some cases, RT had to be discontinued or given in a hypofractionated manner, particularly in elderly patients (25). Notably, the RT technology used at the time of this report was frankly suboptimal as compared to today's standards (even with 3-D conformal techniques without IMRT). With doxorubicin-containing CRT, 77% of DTC patients were deemed tumor free 2 years after their initial treatment (25). The definition of tumor-free status in this study was based solely on anatomical criteria, considering the lack of application, or crudity, of the imaging techniques available at the time. It is likely that a lower ORR would be observed currently, considering the availability of highly sensitive and reliable methods for identification of persistent/recurrent disease (27-29).
Ptx, as well as its newer congener, docetaxel, are semisynthetic broad-activity antineoplastic agents that can be used alone or in combination for the treatment of solid tumors, including breast, lung, ovarian, and squamous cell head and neck carcinomas (22-24), including the locally advanced context (30-37). As microtubule-active drugs, taxanes act by inducing cell arrest in the G2/M phase, which is the most radiosensitive phase of the cell cycle, but may also have a cell cycle-independent effect through stimulation of apoptosis (38, 39). Ptx arrests the development of anaplastic malignant thyrocytes in vitro (40) and reduces the size of anaplastic thyroid carcinoma deposits in vivo (41). The above notwithstanding, Ptx has been much less effective in inducing a measurable clinical response when administered as monotherapy to patients with anaplastic thyroid carcinoma in a phase II trial, but this may be a result of the dosing schedules of the agent used in that particular study (41). With the exception of a report on the beneficial effect of docetaxel CRT in a single case of anaplastic thyroid carcinoma (42), to date there are no reports of the use of either taxane as a radiosensitizer in the context of CRT for locally advanced DTC (either in the primary or locally recurrent setting). The demonstration of activity of the latter approach would provide proof-of-principle, and could potentially provide a CRT paradigm to build upon with the addition of novel agents (administered either synchronously or metachronously) (43-45). Although in our patient a Ptx/Cb combination was used for CRT, future phase I or II studies in similar patients may consider using docetaxel as the agent of choice. This suggestion is based on the latter agent's manageable safety profile and superior efficacy as a radiosensitizer when used in CRT for squamous cell carcinoma of the head and neck (33-35, 46-50).
Several clinicopathological features in our patient, such as the type of her carcinoma (de-differentiated FTC), the size of the initial lesion, and the presence of vascular, capsular, and surrounding soft tissue invasion at presentation, pointed to the need for more aggressive initial management of her disease than would routinely be used in a patient with low-risk DTC. In retrospect, in our patient, the early use of RT (6, 18-20) or taxane-based CRT (23, 42, 43) delivered mainly to the surgical bed, as well as surrounding neck and mediastinal lymph node territories soon after initial total thyroidectomy and 131I remnant ablation may have resulted in a more expeditious eradication of her disease.
We thus suggest that taxanes (with or without platinum; both at radiosensitizing doses) be considered in combination with external beam definitive RT for the treatment of an unresectable, RAI-refractory locally invasive locoregional recurrence in DTC.
Acknowledgements
We would like to thank the American Thyroid Association for a THY-CA grant to L.S., Dr. N.J. Patronas, Department of Radiology, and Dr. J.C. Reynolds, Nuclear Medicine Department, both at the Clinical Center, NIH, and Drs. R.M. Altemus and A.T. Fojo of the National Cancer Institute (NCI), NIH, for their expert consultations. Dr. M.J. Merino, Laboratory of Pathology, NCI, NIH, performed the pathology review of all tumor specimens in this case. We also appreciate the critical comments and suggestions provided by Drs. F.C. Holsinger of the University of Texas - M. D. Anderson Cancer Center and M.R. Posner of the Dana-Farber Cancer Institute.
Footnotes
-
↵† Current address: Epidemiology Research Unit, TMRI, University of West Indies, Kingston, Jamaica, West Indies.
-
↵# Department of Medical Affairs - Oncology, Sanofi-Aventis US, Bridgewater, NJ, U.S.A.
-
Disclosures/Potential Conflicts of Interest
Dr. Nicholas J. Sarlis is an employee of Sanofi-Aventis US, the manufacturer of docetaxel. He also holds stock options in the same company. The other authors have nothing to disclose.
- Received June 5, 2009.
- Revision received September 4, 2009.
- Accepted September 14, 2009.
- Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved