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Originally published as JCO Early Release 10.1200/JCO.2005.04.4917 on March 20 2006 © 2006 American Society of Clinical Oncology. Survival Improvement in Patients With Medullary Thyroid Carcinoma Who Undergo Pretargeted Anti–Carcinoembryonic-Antigen Radioimmunotherapy: A Collaborative Study With the French Endocrine Tumor Group
From the Department of Nuclear Medicine, Institut Régional du Cancer; Department of Endocrinology, University Hospital; Inserm U601, Université de Nantes, Nantes; Department of Nuclear Medicine, Centre François Baclesse, Caen; Department of Nuclear Medicine, University Hospital, Grenoble; Department of Endocrinology, University Hospital, Angers, France; IBC Pharmaceuticals Inc; Immunomedics Inc, Morris Plains; and the Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ. Address reprint requests to to Jean-François Chatal, PhD, MD, Research Unit INSERM U 601, 9 Quai Moncousu, 44093 Nantes Cedex 1, France; e-mail: jfchatal{at}nantes.inserm.fr
PURPOSE: No effective therapy is currently available for the management of patients with metastatic medullary thyroid carcinoma (MTC). The efficacy of pretargeted radioimmunotherapy (pRAIT) with bispecific monoclonal antibody (BsMAb) and a iodine-131 (131I) –labeled bivalent hapten is evaluated. PATIENTS AND METHODS: Twenty-nine patients with advanced, progressive MTC, as documented by short serum calcitonin doubling times (Ct DTs), received an anti–carcinoembryonic antigen (CEA)/anti–diethylenetriamine pentaacetic acid (DTPA) –indium BsMAb, followed 4 days later by a 131I-labeled bivalent hapten. Overall survival (OS) was compared with 39 contemporaneous untreated MTC patients with comparable prognostic indicators. RESULTS: OS was significantly longer in high-risk, treated patients (Ct DT < 2 years) than in high-risk, untreated patients (median OS, 110 v 61 months; P < .030). Forty-seven percent of patients, defined as biologic responders by a more than 100% increase in CtDT, experienced significantly longer survival than nonresponders (median OS, 159 v 109 months; P < .035) and untreated patients (median OS, 159 v 61 months; P < .010). Treated patients with bone/bone-marrow disease had a longer survival than patients without such involvement (10-year OS, 83% v 14%; P < .023). Toxicity was mainly hematologic and related to bone/bone-marrow tumor spread. CONCLUSION: pRAIT against CEA induced long-term disease stabilization and a significantly longer survival in high-risk patients with Ct DTs less than 2 years, compared with similarly high-risk, untreated patients. Ct DT and bone-marrow involvement appear to be prognostic indicators in MTC patients who undergo pRAIT.
The prognosis of medullary thyroid carcinoma (MTC) varies from long-term survival to a much shorter duration in patients with poor prognostic factors, including age greater than 45 years, initial stage, and biochemical markers.1 Saad et al2 observed that the slope of the curve for serum carcinoembryonic antigen (CEA) concentrations over time and its doubling time (DT) correlate well with the course of the disease. Recently, we confirmed this observation, and demonstrated that calcitonin doubling time (Ct DT) was a significant prognostic factor for survival, independently of age, TNM stage, or European Organisation for Research and Treatment of Cancer (EORTC) score.3 In the absence of treatment, patients with longer Ct DT survive longer, with 25% and 8% 5- and 10-year survival in the high-risk group, and 92% and 37% 5- and 10-year survival in the intermediate-risk group, respectively; all patients with a Ct DT more than 2 years (low-risk group) were alive at the end of the study.3 In two successive phase I pretargeted radioimmunotherapy (pRAIT) studies using an 131I-labeled bivalent hapten and conducted between 1996 and 1999 in 26 patients (group I with a murine anti-CEA/anti–diethylenetriamine pentaacetic acid [DTPA)] –indium bispecific monoclonal antibody [BsMAb]), and between 2001 and 2002 in eight patients (group II with a humanized anti-CEA murine anti–DTPA-indium BsMAb), five minor responses, three with a more than 50% decrease of Ct serum concentrations, and 12 patients with morphologic and biomarker stabilization were observed.4,5 Six years after the first study and 3 years after the second one, long-term disease stabilization was observed in 53% of patients, as documented by morphologic imaging (computed tomography and magnetic resonance imaging [MRI]) and serial Ct and CEA serum measurements. The purpose of this study was to compare the survival of patients who underwent pRAIT with that of contemporaneous untreated patients for whom data were collected by the French Endocrine Tumor Group (GTE). A second objective was to examine whether post-pRAIT variations of Ct DT could be used as surrogate markers of survival by comparing, among treated patients, the survival of biologic responders with that of nonresponders, defining a responder as showing at least a 100% increase in Ct DT.
Patients In the first trial (group I), 26 patients were enrolled between April 1996 and February 1999. Eligibility criteria included histologically proven MTC and a recurrence documented by a rise in serum Ct concentration and conventional imaging. Five patients had no pre-pRAIT sequential serum Ct measurements, including three with clinically rapidly progressing high tumor burden; these patients were not included in this analysis. In the second trial (group II), eight patients with MTC were enrolled between April 2001 and February 2002. Eligibility criteria were the same as in the group I study. All treated patients (groups I and II) had serum Ct DTs less than 5 years, including 19 with DTs less than 2 years and 10 with DTs more than 2 but less than 5 years. The decision to stratify patients according to Ct DT (< 2 years v 2-5 years) was made on the basis of a previous study showing that Ct DTs less than 2 years correspond to high-risk patients with a poor prognosis.3 Signed informed consent was obtained, and the protocol was approved by the responsible ethics committee. The survival of all 29 treated patients (21 assessable in group I and eight in group II) was compared to that of a contemporaneous control group of 39 untreated patients, who were selected from the database of the French GTE only on the basis of serum Ct DTs' being less than 5 years, thus being comparable to the treated group, and who were not included in the two successive phase I/II trials that enrolled a limited number of patients in only three investigational centers.
Drug Infusions In group II patients, 40 mg/m2 of a humanized anti-CEA/murine anti–DTPA-indium BsMAb (hMN14-734) was infused slowly in three patients, followed 5 days later by infusion of 2.7 GBq (73 mCi) of 131I-labeled bivalent hapten. In the other five patients, 75 mg/m2 of BsMAb hMN14-734 was followed, 5 days later, by infusion of 1.9 to 3.1 GBq (51 to 84 mCi) of 131I-labeled bivalent hapten (mean, 2.75 GBq or 74 mCi).
Follow-Up Measurement of blood biomarkers (CEA and Ct) was performed before administration of the BsMAb/hapten, 1, 3, 6, and 12 months later, and then twice annually. Blood CEA concentrations were measured using the Kryptor rapid random-access immunoassay analyzer (Brahms Diagnostica GmbH, Berlin, Germany), with a normal cutoff of 10 ng/mL. Blood Ct concentrations were measured by a radioimmunoassay (Schering-CIS Bio International, Saclay, France), with normal values below 10 pg/mL. Single exponentials were fitted to serum Ct and CEA concentrations by nonlinear least-square regression. Data were weighted by the inverse of the measured concentrations, and standard deviations were calculated as asymptotic SEs. A biologic response was arbitrarily defined as at least a doubling (> 100% increase) of pre-pRAIT Ct DT. Disease progression was defined, by conventional imaging, as an increase of more than 25% in the sum of the products of the longest perpendicular diameters of all measured lesions, whereas stabilization was defined as no modification of more than 25%. Whole-body immunoscintigraphy images were visually analyzed by two nuclear medicine physicians blinded to outcome. They ranked the results into 5 categories from no (–) or faint (±) uptake, to moderate (+), intense (++), or very intense (+++) uptake. For statistical analysis, two groups were considered: one negative (– and ±) and one positive (+, ++, +++).
Human Antimouse and Human Antihuman Antibodies
Data Analysis Cause-specific survival curves for each scoring system were calculated using the Kaplan-Meier survival estimates method, and compared by the log-rank test, with P < .05 being significant. All P values are the results of two-sided tests. Statistical analysis was performed using the SAS 8.2 software package (SAS Inc, Cary, NC). Prognostic values for age, sex, TNM staging, EORTC score, inverse values of Ct DTs, and bone-marrow immunoscintigraphy status (BMIS) were first determined by means of univariate analysis. Parameters with a significant influence in univariate analysis were further subjected to multivariate analysis by using Cox's forward stepwise proportional hazards regression model.
Patients Within the treated group of 29 patients, there was no significant difference between those treated in the first (n = 21) and second clinical trials (n = 8) with regard to age, sex, TNM and EORTC staging, and pre-pRAIT Ct DT. Nineteen patients (68%) had a pretreatment Ct DT less than 2 years, which corresponds to the high-risk (< 6 months) and intermediate-risk (> 6 months and < 2 years) subgroups in our previous study.3 Because of the relatively small number of treated patients, patients with Ct DT less than 2 years were considered here as a single high-risk subgroup. Nine patients had Ct DT more than 2 years and less than 5 years (low-risk subgroup). Similarly, in the control group, 24 (62%) of 39 patients had a Ct DT less than 2 years (high-risk subgroup) and 15 had a Ct DT more than 2 years and less than 5 years (low-risk subgroup). Thus, the entire population of 68 patients (29 treated and 39 untreated), and a subgroup of 43 high-risk patients (19 treated and 24 untreated), was analyzed. In the comparison between control patients (n = 39) and treated patients (n = 29), no significant differences were found for five prognostic variables, including age, sex, TNM staging, EORTC staging, postoperative CEA serum levels and pre-pRAIT Ct DT. Because long-term changes in Ct serum level kinetics were observed after pRAIT, a biologic response was arbitrarily defined as at least a doubling (> 100% increase) of pre-pRAIT Ct DT. This resulted in 18 biologic responders and 11 nonresponders for whom no significant difference was found for pre-pRAIT CEA serum levels. Among these 18 biologic responders, nine had a pretreatment Ct DT less than 2 years (high-risk subgroup). All patients with Ct DT more than 2 years and less than 5 years (n = 9; low-risk subgroup) were biologic responders.
Survival
In order to determine the independent prognostic value of RAIT, a multivariate analysis was performed, and showed that pRAIT (adjusted HR = 0.44; 95% CI, 0.19 to 0.98; P = .046) and Ct DT (adjusted HR = 0.26; 95% CI, 0.12 to 0.56; P = .001) were both independent, significant predictors of survival. When comparing patients within the treated group, biologic responders (n = 9) and nonresponders (n = 10), as defined herein on the basis of Ct DT change, no significant difference was found for age, sex, TNM, EORTC staging, Ct DT, conventional imaging (progression or stabilization), or bone-marrow involvement (as assessed by whole-body scans; Table 1). The median interval between diagnosis and pRAIT was 30 months (range, 7 to 92 months) for responders versus 41 months (range, 6 to 124 months) for nonresponders (P = .87). The median postoperative serum Ct level was 5,520 pg/mL (range, 19 to 20,820 pg/mL) for responders versus 161 pg/mL (range, 5 to 16,280 pg/mL) for nonresponders (P = .075); the median postoperative serum CEA level was 24 ng/mL (range, 2 to 433 ng/mL) for responders and 19 ng/mL (range, 1 to 335 ng/mL) for nonresponders (P = .90); and the median cumulative injected activity was 2.96 GBq (range, 1.55 to 3.9 GBq) for responders and 2.66 GBq (range, 1.41 to 3.03 GBq) for nonresponders (P = .14). Despite the high similarity between the two groups, OS was significantly longer for biologic responders (median OS, 159 months; 5- and 10-year survival, 89% [95% CI, 43% to 98%] and 89% [95% CI, 43% to 98%], respectively), than for nonresponders (median OS, 109 months; 5- and 10-year survival, 70% [95% CI, 33% to 89%] and 15% [95% CI, 1% to 47%], respectively; P = .035) or for the untreated group (median OS, 64 months; 5- and 10-year survival, 58% [95% CI, 36% to 75%] and 24% [95% CI, 8% to 44%], respectively; P = .010; Fig 2), indicating a significant survival advantage for the treated biologic responders.
Bone/bone marrow uptake was frequently visible on post-pRAIT whole-body scans (20 of 29 patients), and MRI of the spine and pelvis also showed tumor involvement in 19 of 25 patients. Diffuse bone-marrow uptake was estimated on posterior views of the whole-body scans, and allowed identification, in the treated patients, of one subgroup with negative BMIS (no or faint bone-marrow uptake; Fig 3) and one with positive BMIS (moderate to intense uptake; Fig 4). Univariately determined OS from date of diagnosis was longer in the positive BMIS subgroup (did not reach median OS [56%] at 172 months of follow-up; 5- and 10-year survival at 83% [95% CI, 48% to 96%]) than in the negative BMIS subgroup (median OS, 109 months; 5- and 10-year survival, 71% [95% CI, 26% to 92%] and 14% [95% CI, 1% to 47%], respectively; P = .023; Fig 5). Multivariate analysis confirmed the independent prognostic value of BMIS (adjusted HR = 0.19; 95% CI, 0.04 to 0.94; P = .042).
Toxicity A transient grade 1 to 2 hepatic toxicity was observed in five group II patients. Two had known liver metastases. Five had grade 4 thrombocytopenia (all in group I) and four experienced grade 4 neutropenia (two each in groups I and II). The duration of grade 4 toxicities was 20 days (standard deviation, 16 days). Three patients received blood-product transfusions and/or hematopoietic growth factors. One group I patient developed myelodysplasia. He had been treated previously with three injections of 131I–metaiodobenzylguanidine (cumulative activity 11.1 GBq) and underwent two courses of pRAIT (cumulative activity, 5.8 GBq).
HAMA and HAHA Responses
On the basis of our recent finding that Ct DT is an effective prognostic factor of survival in MTC,3 the present analysis of long-term efficacy of pRAIT compared treated patients to a contemporaneous untreated group of 39 patients with similar Ct DT of less than 5 years, using overall survival as the primary end point. Consideration of pretreatment Ct DT should avoid the bias that could be caused by those MTC patients, even with progressive disease, that benefit from long periods of survival in the absence of treatment. Considering the entire group of treated patients, there was a strong tendency toward a longer survival in the treated patients (P = .059). This can be explained by the fact that all patients who had Ct DTs of more than 2 years (low-risk patients; 10 [34%] of 29 in the treated group and 15 [38%] of 39 in the control group) were still alive at analysis. Indeed, median OS was significantly longer in rapidly progressing pRAIT-treated patients with a Ct DT less than 2 years (high-risk) than in the corresponding untreated control subgroup (110 v 61 months; P < .030), emphasizing that pRAIT was effective in this high-risk population. Conventionally, imaging-based tumor response has been used as a surrogate for survival, but tumor shrinkage can be difficult to evaluate, requiring other criteria.8,9 Recently, serum CA-125 response was reported to be a better surrogate marker for survival than the commonly used RECIST (Response Evaluation Criteria in Solid Tumors) imaging-based response criteria in the treatment of ovarian carcinoma.10 Here, biologic response was defined arbitrarily as at least a doubling (> 100% increase) of serum Ct DT after pRAIT, so that with the high-risk subgroup of 19 treated patients, nine patients (47%) were biologic responders and 10 were nonresponders. We found that survival was significantly longer in responders than in nonresponders (159 v 109 months; P = .035; Fig 2). Whereas no convincing long-term efficacy of RAIT in confirmed metastatic solid tumors has been observed, an indication of a survival advantage for RAIT in the occult disease setting of colorectal liver metastases was reported recently.11 Here, we describe improved survival after pRAIT in MTC that resulted from disease stabilization of long duration in patients with macroscopically rapidly progressing tumors. To our knowledge, this is the first report of long-term efficacy in terms of a survival benefit of radioimmunotherapy in solid-tumor patients with confirmed metastatic disease. However, we appreciate that this retrospective analysis and comparison with historical and contemporaneous control groups should be confirmed in a prospective, randomized study; such a trial would require at least a decade to be completed in this rare disease. We were surprised to find high-grade hematologic toxicity with moderate doses of 131I when we expected the opposite situation with pRAIT. The bone/bone marrow was frequently visible on post-pRAIT scans, unlike scans for patients with colorectal carcinoma included in the same second phase I study and for whom bone/bone-marrow metastases are known to be infrequent.12 In the majority of patients with bone/bone-marrow scintigraphic visualization, MRI of the spine and pelvis also indicated positive results.12 Unexpectedly, we have now observed that OS is significantly longer in patients with positive post-pRAIT bone-marrow immunoscintigraphy than in those without bone/bone-marrow uptake of radioactivity. Thus, we speculate that pRAIT efficacy in MTC could be related in part to tumor bone-marrow response, because of findings in animal and clinical studies that the best indication for pRAIT is in disseminated microscopic disease, in which a much higher uptake and consequently higher tumor dose of the radiotherapeutic are achieved.13,14 Currently, the best-documented systemic treatment for patients with rapidly progressing metastatic MTC is chemotherapy. In a total of 87 patients treated with different chemotherapeutic regimens,15-18 the progression-free survival or response duration reported for 22 patients ranged from 4 to 29 months (median, 10 months). The OS reported in 20 patients ranged from 8.5 to 33 or more months (median, 17.5 months) for responders and from 3 to 20 months (median, 12 months) for nonresponders.16 Thus, response duration of chemotherapy appears to be markedly shorter than that of pRAIT. In conclusion, two-step pRAIT against CEA induced long-term disease stabilization and a significantly longer survival in a high-risk group of MTC patients, as compared with similarly high-risk, untreated patients. In the treated group, 47% of high-risk patients (Ct DT < 2 years) were considered as biologic responders and survived significantly longer than the biologic nonresponders or the contemporaneous untreated MTC patients.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
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Bispecific monoclonal antibody: A modified monoclonal antibody that has two binding arms, one to a tumor antigen and the other to a hapten. Bivalent hapten: Two incomplete, covalently linked antigens that are incapable of causing the production of antibodies but capable of combining with a specific antibody. Pretargeted radioimmunotherapy: A multistep targeting procedure that starts by administering an unlabeled bi-specific antibody that is given time to localize to the tumor sites. This bispecific antibody is able to bind to the tumor, but also has the ability to bind to a small bivalent hapten that can be radiolabeled for use in tumor therapy. Immunoscintigraphy: An imaging scintigraphic procedure that uses a radiolabeled antibody as the radiopharmaceutical for the detection of an antigen expressed by a lesion.
Supported by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique 1996). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Van Heerden JA, Grant CS, Gharib H, et al: Long term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 212:395-400, 1990[Medline] 2. Saad MF, Fritsche HA, Samaan NA: Diagnostic and prognostic values of carcinoembryonic antigen in medullary carcinoma of the thyroid. J Clin Endocrinol Metab 58:889-894, 1984[Abstract] 3. Barbet J, Campion L, Kraeber-Bodéré F, et al: Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab 90:6077-6084, 2005 4. Kraeber-Bodéré F, Bardet S, Hoefnagel CA, et al: Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine-131-labeled bivalent hapten: Preliminary results of a phase I/II clinical trial. Clin Cancer Res 5:3190s-3198s, 1999[Medline] 5. Kraeber-Bodéré F, Faivre-Chauvet A, Ferrer L, et al: Pharmacokinetics and dosimetry studies for optimization of anti-carcinoembryonic antigen x anti-hapten bispecific antibody-mediated pretargetring of iodine-131-labeled hapten in a phase I radioimmunotherapy trial. Clin Cancer Res 9:3973s-3981s, 2003[Medline] 6. Le Doussal JM, Chetanneau A, Gruaz-Guyon A, et al: Bispecific monoclonal antibody-mediated targeting of an indium-111-labeled-DTPA dimer to primary colorectal tumors: Pharmacokinetics, biodistribution, scintigraphy and immune response. J Nucl Med 34:1662-1671, 1993 7. Hansen HJ, Sullivan CL, Sharkey RM, Goldenberg DM: HAMA interference with murine monoclonal antibody-based immunoassays. J Clin Immunoassay 16:294-299, 1993 8. Therasse P, Arbuck S, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 9. Husband JE, Schwartz LH, Spencer J, et al: Evaluation of the response to treatment of solid tumors: A consensus statement of the international cancer imaging society. Br J Cancer 90:2256-2260, 2004[Medline] 10. Gronlund B, Hogdall C, Hilden J, et al: Should CA-125 response criteria be preferred to response evaluation criteria in solid tumors (RECIST) for prognostication during second-line chemotherapy of ovarian carcinoma? J Clin Oncol 22:4051-4058, 2004 11. Liersch T, Meller J, Kulle B, et al: Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: Five-year safety and efficacy results. J Clin Oncol 23:6763-6770, 2005 12. Mirallie E, Vuillez JP, Bardet S, et al: High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer. J Clin Endocrinol Metab 90:779-788, 2005 13. Sharkey RM, Goldenberg DM: Perspectives on cancer therapy with radiolabeled monoclonal antibodies. J Nucl Med 46:115s-125s, 2005[Medline] 14. Sharkey RM, Karacay H, Chang CH, et al: Improved therapy of non-Hodgkin's lymphoma xenografts using radionuclides pretargeted with a new anti-CD20 bispecific antibody. Leukemia 19:1064-1069, 2005[CrossRef][Medline] 15. Wu LT, Averbuch SD, Ball DW, et al: Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Cancer 73:432-436, 1994[CrossRef][Medline] 16. Schlumberger M, Abdelmoumene N, Delisle MJ, et al: Treatment of advanced medullary thyroid carcinoma. Br J Cancer 71:363-365, 1995[Medline] 17. Petursson SR: Metastatic thyroid carcinoma: Complete response to combination chemotherapy with dacarbazine and 5-fluorouracil. Cancer 62:1899-1903, 1988[CrossRef][Medline] 18. Shimaoka K, Schoenfeld DA, Dewys WD, et al: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56:2155-2160, 1985[CrossRef][Medline] Submitted October 14, 2005; accepted December 21, 2005. Related Editorial
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