ABSTRACT: Despite more than 50 years of research, the overall clinical outcomes of patients afflicted with anaplastic thyroid cancer remain dismal. Survival is limited by the dire consequences of an uncontrolled primary and the prevalence of overt or occult distant metastasis. Local control is influenced by multiple confounding variables, including the inherent biological aggressiveness of the disease and the seemingly insurmountable technical obstacles to both surgery and radiotherapy. In response to these challenges, revolutionary changes in the treatment paradigm over the last 20 years, specifically the adoption of a multimodal treatment strategy, suggest improvements in local control and short-term median survival and have changed the pattern of progression, even for patients presenting with locally advanced disease. For the first time there is attestation of even long-term survivorship for a few patients who harbor advanced local, but nonmetastatic, disease. The current challenge is to address the high incidence of apparent or occult distant metastasis. Newly developed targeted therapies are likely to change the treatment paradigm, and they hold the promise of being able eventually to make treatment with curative intent available to some patients.
Anaplastic thyroid cancer (ATC) remains an almost uniformly fatal disease; there are few long-term survivors (LTSs), with 2-year survival < 10% to 20%.[1-3] Rapid cellular kinetics, with doubling times as short as 24 hours in vitro and 5 days in vivo, as well as multiple genomic derangements, account for ATC’s advanced clinical presentations and rapidly acquired resistance to all treatment modalities.[4,5] Approximately half of patients have distant metastases (DMs) at diagnosis, while 50% to 70% of those with palpable disease likely have occult metastasis, developing DMs within 6 months; once DM develops, survival is reduced to 2 to 3 months.[6,7] ATC does not concentrate iodine(Drug information on iodine), nor does it express thyroglobulin; to date there is no chemotherapy (CTX) that has had an unequivocal impact on DMs.
Despite such dismal survival statistics, local control (LC) remains an important goal so as to prevent death by asphyxiation or hemorrhage, which are historically cited as the causes of death in 50% to 75% of patients.[8-10] LC is ultimately determined by the relative, often interrelated, success of both surgery and radiation therapy (RT). Complete surgical extirpation is limited by the degree of extrathyroidal extension (ETE/ATC) and by the comorbidities typically seen in the affected population, which is largely elderly (< 10% under 50 years of age). Fewer than half of patients undergo resection, and fewer than half of those who do (< 25% to 30% overall) complete a gross total resection (GTR); far fewer (< 15%) achieve a microscopic complete (R0) surgical status.[2,12,13] The success of RT is more difficult to quantitate. Eradication of disease is dependent on the volume of disease irradiated, the total dose applied, and the inherent radiosensitivity of the tumor. In ATC, these variables represent great challenges, since the volume of disease is typically large, the dose is constrained by the tolerance of the nearby anatomical structures (spinal cord, 50 Gy; esophagus, 60 Gy), and the biology is recognized to be one of the most explosive in oncology. Genomic instability leads to frequent mutations, accounting for both accelerated repopulation and acquired radioresistance. Resistance to RT is further enhanced by the hypoxia associated with larger bulk of tumors. Unless an effective dose can be applied such that the entirety of the tumor within the surgical bed is sterilized, mutated residual clonogens will likely require even higher doses per given volume of disease for eradication. Radiocurability is unlikely given the dose-limiting tolerance of the normal tissues; hence, surgery is retained in an aggressive multimodal approach.
A review of the literature regarding the role of RT in the management of ATC is especially tedious given the rarity of ATC (consisting of less than 2% of thyroid cancers) and the availability of only retrospective reviews, with no prospective randomized trials to guide patient care. A review of the literature may seem of questionable value given the apparent lack of change in long-term survival (LTS) over the past 50 years. Nevertheless, in the interest of securing LC, more recent literature attests to significant accomplishments, including changes in the pattern of the cause of death; improvement in the least short-term median survival (ms); and reports that some patients presenting with palpable tumors—and even a few with initially unresectable (R3) tumors—may become long-term, no-evidence-of-disease survivors (LTS/NED). However, these accomplishments have required the adoption of a multimodal strategy (MMS) incorporating surgery, RT, and sensitizing CTX (combined modality therapy [CM]); the efficacy of such a strategy must be individualized in accordance with the likelihood of accomplishing reasonable goals, and must be weighed against the risk of incurring significant acute and late toxicities.
In this article, we endeavor to clarify the role of RT and CTX in the treatment of ATC; we note important contributions of the historical literature, and we review more contemporary strategies adopted by several renowned institutions, each of which in its own way has addressed the challenge of treating locally advanced tumors and of identifying treatment variables that may be predictive of LTS. Given that none of the available studies have stratified patients according to defined prognostic variables, the use of secondary metrics, described herein, may be useful to decipher the literature and extend interpretations so as to make them relative to individual patient care. Furthermore, while achieving “durable” LC (as opposed to only temporary LC) might be irrelevant for patients who may be currently doomed to succumb to initial or occult DMs, such a goal may become imperative should target therapies soon fulfill prospects of having an impact on metastatic disease. The evolving milestones in the development of these novel systemic therapies will also be reviewed.
Contributions From the Historical RT Literature
In order to support the hypothesis that more aggressive MMSs have a favorable impact on outcomes, we have arbitrarily divided this analysis into a review of the “historical literature,” which generally refers to treatment paradigms from before the 1980s but more specifically to those utilizing standard fractionated RT (SF/RT), and a consideration of the more “contemporary literature,” which includes discussion of the incorporation of novel RT strategies within the context of a MMS. However, this distinction is primarily descriptive, rather than a valid comparison, since the earlier literature is notably fraught with serious omissions and lacks standardization of important RT parameters, thereby limiting analysis of the specific merit of RT. On review of the historical literature, with few exceptions, RT parameters (total dose, fractionation, and field definition) were either ambiguous or omitted entirely. If reported, there also was often wide variation in the prescribed total doses, with ranges of 25 to 73 Gy.[7,12,14,15] If a study’s fractionation (FXN) schedule was cited, it was rarely standardized (or stratified); often it consisted of a “hybrid distribution,” with some patients having been treated with SF/RT, defined as 1.8–2.0 Gy per day (QD), while others were prescribed a “hypofractionated” (HYPOFXN/RT) schedule, typically > 3 Gy QD, to a lower total dose.
The historical literature has generally reported on a “single modality” approach, either using surgery alone for the approximately 50% of resectable patients or using primary RT for the treatment of R3 disease. In only 10% of “typical ATC” (palpable tumors with ETE [ETE/ATC]) was an R0 resection achieved. Furthermore, even when a near microscopic complete resection was achieved, almost 40 % of tumors recurred within 2 months. Other-wise, for the majority of patients there was no improvement in even short-term median survival (ms) with either surgery alone (including extensive resections) or RT (occasionally with CTX), vs patients who had biopsy alone (ms 3.5 vs 2.5 months).
The RT literature evolved to validate the importance of securing a curative resection (GTR) coupled with postoperative (postop) RT as predictive of improved LC.[6,13] For patients without overt DMs, there was suggestion of improvement in at least short-term ms.[2,7] Pierie noted that inclusion of “incidental ATC” (iATC)—a small volume of ATC discovered at the time of thyroidectomy for another disease—skewed the survival statistics of relatively small study populations; he noted that more than half of patients in whom an R0 resection was able to be completed had iATC (with a 90% 3-year survival [3YS]), while < 7% (4/57) of the LTSs had more extensive tumor. Haigh redefined a potentially curative surgery as a GTR, ie, resection of all visible disease, not necessarily R0 (microscopically complete), if followed by a minimum of 45 Gy of postop CM. Nearly half of his study population had tumors of < 5 cm, although ETE was seen in over 80%. Of those who received organ-preservation surgery, GTR could be completed in 30% (8/26). This small subgroup, half of whom (4/8) had minimal R1 residuum, showed relatively improved survival, with ms of more than 3 years, and 1-year overall survival of 80%; most likely the population had predominantly intrathyroidal ATCs (IT/ATCs). Notably, four of five LTSs had completed GTRs as well as postop CM. In summary, while a single-modality approach had failed,[6,13,16] a multimodal approach appeared to improve the LC for patients who had IT/ATC or small-volume ETE/ATC[6,17] and who were able to secure a GTR. In comparison, for those with R3 or incompletely excised (gR2) disease who were treated with postop CM, a palliative resection alone, or primary CM, the ms was invariably poor at 3 months—similar to the ms for patients with initial DM. For the approximately 50% to 75% of patients (with or without DMs) who presented with locally advanced tumors, survival remained poor, even after doses “in the range of 45 to 75 Gy” plus CTX.[10,12,14] In a recent review of 188 patients treated from 1972 through 2003 using different treatment tactics, the relative distribution of patients left with R0, R1, R2, and R3 (unresectable) disease were 8%, 8%, 14%, and 69%, and their reported ms were 17, 8, 5, and 2 months, respectively.
Despite the omissions of RT parameters, the historical ATC literature eventually contributed to the identification of important tumor and patient prognostic variables derived from data of large-scale 50-year institutional studies and summarized in Surveillance, Epidemiology, and End Results (SEER) reports. On multivariate analysis, the most consistent adverse prognostic variables included the presence of DMs, age > 60 to 70 years (performance status), and local tumor extent (ETE, size > 5 to 7 cm, volume > 200 cm2, and clinical signs of dysphagia and dysarthria) or rapid tumor kinetics.[1,2,6,8,13]
The historical literature also provided testimony regarding the radiosensitivity of ATC. This is supported by reports of a dose response, a measurable delay in the recurrence of postoperative subclinical disease, and an observed clinical response of gross disease to RT. A dose response has been suggested by multiple authors[7,8,15,19,20]; however, it can be consistently challenged because of the strong selection bias and multiple confounding treatment variables between comparison groups. The most convincing testimony regarding the radioresponsiveness (reflecting radiosensitivity) of ATC was the observation of an initial rapid decrease in the size of visible tumor, defined as the radiation response rate (rRR). At times investigators noted a complete disappearance of gross disease, termed a radiation complete clinical response (r/CCR), observed at or near the completion of RT. Both Tallroth and Mitchell observed that the time at which a maximum response was seen was quite early, on the order of only 2 to 7 weeks (median, 3 weeks) after completion of RT.[21,22] Additionally, McIver noted the impact of adjuvant RT in extending the time to clinical recurrence from 3 to 5 months (P = .08), delaying recurrence but not preventing it. On the other hand, Junor reported a 40% r/CCR after giving a range of “30 to 60 Gy” SF/RT. However, this impact was not sustained for the overall population; the ultimate LC was only 30%, ms was 5 months, and LTS was 10%. Tumor progression was observed for 10% of the overall population, and 70% of patients showed a component of local failure as the cause of death (DcLF). These results are often quoted as a historical reference. Additionally, Levendag noted a strong association for selected patients demonstrating a r/CCR with both an increase in short-term ms and an increase in LC after a dose-equivalent of 40 Gy, irrespective of the initial DM status. Those 15% of patients (8/50) who responded to RT with a r/CCR showed a ms nearly four times that seen in those patients without a r/CCR: 8 months vs < 2 months, with or without DMs. Additionally, half of patients (4/8) who demonstrated a r/CCR and who were without DM showed durable LC (50% LC) and an impressive 40% 1-year survival (1YS). None of those who failed to show a r/CCR survived a year. Importantly, this degree of response, even a complete disappearance of visible gross tumor in response to RT, may not be durable if viable clonogens remain, even on a subclinical basis.