Peter Grupe

Sentinel Node Biopsy in Head and Neck Cancer: Preliminary Results of a Multicenter Trial

Background: The aim was to determine the reliability and reproducibility of sentinel node biopsy (SNB) as a staging tool in head and neck squamous cell carcinoma (HNSCC) for T1/2 clinically N0 patients by means of a standardized technique.Methods: Between June 1998 and June 2002, 227 SNB procedures have been performed in HNSCC cases at six centers. One hundred thirty-four T1/2 tumors of the oral cavity/oropharynx in clinically N0 patients were investigated with preoperative lymphoscintigraphy (LSG), intraoperative use of blue dye/gamma probe, and pathological evaluation with step serial sectioning and immunohistochemistry, with a follow-up of at least 12 months. In 79 cases SNB alone was used to stage the neck carcinoma, and in 55 cases SNB was used in combination with an elective neck dissection (END).Results: In 125/134 cases (93%) a sentinel node was identified. Of 59 positive nodes, 57 were identified with the intraoperative gamma probe and 44 with blue dye. Upstaging of disease occurred in 42/125 cases (34%): with hematoxylin-eosin in 32/125 (26%) and with additional pathological staging in 10/93 (11%). The sensitivity of the technique with a mean follow-up of 24 months was 42/45 (93%). The identification of SNB for floor of mouth (FOM) tumors was 37/43 (86%), compared with 88/91 (97%) for other tumors. The sensitivity for FOM tumors was 12/15 (80%), compared with 30/30 (100%) for other tumor groups.Conclusion: SNB can be successfully applied to early T1/2 tumors of the oral cavity/oropharynx in a standardized fashion by centers worldwide. For the majority of these tumors the SNB technique can be used alone as a staging tool.

Randomized prospective study comparing a single radioiodine dose and a single laser therapy session in autonomously functioning thyroid nodules

OBJECTIVE To compare the efficacy of interstitial laser photocoagulation (ILP) with radioiodine in hot thyroid nodules. DESIGN Thirty consecutive outpatients with subclinical or mild hyperthyroidism and a scintigraphically solitary hot nodule with extraglandular suppression were randomized to either one ILP session or one radioiodine ((131)I) dose. METHODS ILP was performed under continuous ultrasound-guidance and with an output power of 2.5-3.5 W. (131)I was given as a single dose based on thyroid volume and a 24-h thyroid (131)I uptake. Thyroid function and nodule volume were evaluated at inclusion and at 1, 3 and 6 months after treatment. RESULTS Normalization of serum TSH was achieved in 7 out of 14 patients in the ILP group and in all 15 patients in the (131)I group (P=0.0025). In the ILP group, mean thyroid nodule volume reduction was 44+/-5% (s.e.m.; P<0.001), and in the (131)I group 47+/-8% (P<0.001), within 6 months, without between-group difference (P=0.73). The mean reduction of total thyroid volume was 7+/-5% in the ILP group (P=0.20) and 26+/-8% (P=0.006) in the (131)I group (P=0.06 between-group). Two patients in the (131)I group developed hypothyroidism but no major side effects were seen. CONCLUSIONS This first randomized study, comparing ILP with standard therapy, demonstrates that ILP and (131)I therapy approximately halves thyroid nodule volume within 6 months; but in contrast to (131)I, extranodular thyroid volume is unaffected by ILP and no patient developed hypothyroidism. Using the present design, ILP seems inferior to (131)I therapy in normalization of serum TSH. The potential value of ILP as a non-surgical alternative to (131)I needs further investigation.

Modified-Release Recombinant Human TSH (MRrhTSH) Augments the Effect of 131I Therapy in Benign Multinodular Goiter: Results from a Multicenter International, Randomized, Placebo-Controlled Study

BACKGROUND Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.

Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy of Large Nodular Goiters Facilitates Tracheal Decompression and Improves Inspiration

INTRODUCTION The impact on tracheal anatomy and respiratory function of recombinant human (rh)TSH-stimulated (131)I therapy in patients with goiter is not clarified. METHODS In a double-blinded design, patients (age 37-87 yr) with a large multinodular goiter (range, 99-440 ml) were randomized to placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before (131)I therapy. The smallest cross-sectional area of the trachea (SCAT; assessed by magnetic resonance imaging) and the pulmonary function were determined before, 1 wk, and 12 months after therapy. RESULTS Data on goiter reduction have been reported previously. In the placebo group, no significant changes in the lung function or SCAT were found throughout the study. In the rhTSH group, a slight decrease was observed in the forced vital capacity 1 wk after therapy, whereas the mean individual change in SCAT was significantly increased by 10.5% (95% confidence interval = 0.9-20.0%). A further increase in SCAT to 117 +/- 36 mm(2) (P = 0.005 compared with 92 +/- 38 mm(2) at baseline) was seen at 12 months, corresponding to a mean of 31.4% (95% confidence interval = 16.0-46.8%). The expiratory parameters did not change significantly, whereas forced inspiratory flow at 50% of the vital capacity (FIF50%) increased from initially 3.34 +/- 1.33 liters/sec to ultimately 4.23 +/- 1.88 liters/sec (P = 0.015) in the rhTSH group, corresponding to a median increase of 24.6%. By 12 months, the relative improvements in FIF50% and in SCAT were inversely correlated to the respective baseline values (FIF50%: r = -0.47, P = 0.012; SCAT: r = -0.57, P = 0.001). CONCLUSION On average, neither compression of the trachea nor deterioration of the pulmonary function was observed in the acute phase after rhTSH-augmented (131)I therapy. In the long term, tracheal compression is diminished, and the inspiratory capacity improved, compared with (131)I therapy alone.

Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy of Nodular Goiter Allows Major Reduction of the Radiation Burden with Retained Efficacy

CONTEXT AND OBJECTIVE Stimulation with recombinant human TSH (rhTSH) before radioiodine (131I) therapy augments goiter volume reduction (GVR). Observations indicate that rhTSH has a preconditioning effect beyond increasing thyroid (131)I uptake. We test the hypothesis that an equivalent GVR might be obtained by an absorbed thyroid dose well below what has been used previously. PATIENTS AND DESIGN In a double-blinded setup, 90 patients (78 women; median age, 52 yr; range, 22-83) with a nontoxic nodular goiter (median size, 63 ml; range, 25-379 ml) were randomized to either 0.1 mg rhTSH (n=60) followed by a thyroid dose of 50 Gy or placebo followed by 100 Gy (n=30). RESULTS At 12 months, the mean relative GVR in the placebo and the rhTSH group was identical (35+/-3%; P=0.81). The median administered 131I-activity was 170 MBq (45-1269) in the rhTSH group and 559 MBq (245-3530) in the placebo group (70% reduction, P<0.0001). According to the official radiation regulation, hospitalization was required in 14 patients in the placebo group vs. one patient in the rhTSH group (P<0.0001). In both groups, goiter-related symptoms were effectively relieved in the majority of patients. The prevalence of myxedema (10%) did not differ among groups. CONCLUSIONS This is the first study to demonstrate that rhTSH not only increases the thyroid 131I uptake, but per se potentiates the effect of 131I-therapy, allowing a major reduction of the 131I-activity without compromising efficacy. This approach is attractive in terms of minimizing posttherapeutic restrictions and in reducing the potential risk of radiation-induced malignancy.

Optimizing 131I Uptake After rhTSH Stimulation in Patients with Nontoxic Multinodular Goiter: Evidence from a Prospective, Randomized, Double-Blind Study

Prestimulation with recombinant human thyroid-stimulating hormone (rhTSH) augments radioiodine 131I therapy for benign nontoxic multinodular goiter. The purpose of this study was to determine the optimal time interval between rhTSH and 131I administration to enhance thyroid radioactive iodine uptake (RAIU). Methods: Patients were randomized, in a 2-factorial design, to receive either a 0.1-mg dose of rhTSH (n = 60) or placebo (n = 30) and to a time interval of 24, 48, or 72 h before 131I administration. The rhTSH- or placebo-stimulated RAIU study was performed at 4 wk after a baseline RAIU assessment in a tertiary referral center at a university hospital. A total of 90 patients (78 women; median age, 52 y; range, 22–83 y) referred to 131I therapy for symptomatic nontoxic goiter (median goiter volume, 63 mL; range, 25–464 mL) were included in the study. Change in thyroid RAIU was determined at 24 and 96 h after 131I tracer administration. Results: In the placebo subgroups, RAIU did not change significantly from baseline. The mean (±SE) 24-h RAIU increased from 33.8% ± 2.3% to 66.0% ± 1.8% (111.2% increase) with a 24-h interval, from 36.8% ± 2.1% to 64.6% ± 2.7% (83.3% increase) with a 48-h interval, and from 33.0% ± 2.7% to 49.6% ± 2.5% (62.4% increase) with a 72-h interval. All within-group changes were highly significant (P < 0.001). The effect was negatively correlated with initial RAIU (r = −0.703, P < 0.001). The increase in 24- and 96-h RAIU was significantly higher in the rhTSH/24-h group than it was in the rhTSH/72-h group (P = 0.023 and 0.012, respectively) and insignificantly higher than in the rhTSH/48-h group (P = 0.37 and 0.26, respectively). Conclusion: The effect of rhTSH on thyroid RAIU is most pronounced when administered 24 h before 131I administration and declines with longer time intervals. Whether there is a similar time dependency for goiter reduction after rhTSH-stimulated 131I-therapy remains to be clarified.

Prestimulation with Recombinant Human Thyrotropin (rhTSH) Improves the Long-Term Outcome of Radioiodine Therapy for Multinodular Nontoxic Goiter

OBJECTIVE The objective of the study was to evaluate the long-term outcome of recombinant human TSH (rhTSH)-augmented radioiodine ((131)I) therapy for benign multinodular nontoxic goiter. PATIENTS AND METHODS Between 2002 and 2005, 86 patients with a multinodular nontoxic goiter were treated with (131)I in two randomized, double-blind, placebo-controlled trials. (131)I-therapy was preceded by 0.3 mg rhTSH (n = 42) or placebo (n = 44). In 2009, 80 patients completed a follow-up (FU) visit, including determination of thyroid volume, thyroid function, and patient satisfaction by a visual analog scale. RESULTS In both groups, thyroid volume was further reduced from 1 yr to final FU (71 months). The mean goiter volume reductions obtained at 1 yr and final FU [59.2 ± 2.4% (sem) and 69.7 ± 3.1%, respectively] in the rhTSH group were significantly greater than those obtained in the (131)I-alone group (43.2 ± 3.7 and 56.2 ± 3.6%, respectively, P = 0.001 and P = 0.006), corresponding to a gain of 24% at final FU. At last FU the mean reduction in compression visual analog scale score was significantly greater in patients receiving rhTSH (P = 0.049). Additional therapy (thyroid surgery or (131)I) was required more often in the placebo group (nine of 44) compared with the rhTSH group (two of 42) (P = 0.05). The prevalence of hypothyroidism at 1 yr [9 and 43% in the placebo and rhTSH groups, respectively (P < 0.0001)] increased to 16 and 52%, respectively, at final FU (P = 0.001). CONCLUSION Enhanced goiter volume reduction with rhTSH-augmented (131)I therapy improves the long-term reduction in goiter-related symptoms and reduces the need for additional therapy compared with plain (131)I therapy. Overall patient satisfaction is benefited, despite a higher rate of permanent hypothyroidism.

Staging N0 Oral Cancer: Lymphoscintigraphy and Conventional Imaging

Purpose: To compare sentinel lymph node biopsy, magnetic resonance imaging (MRI), Doppler ultrasonography, and palpation as staging tools in patients with T1/T2 N0 cancer of the oral cavity. Material and Methods: Forty consecutive patients were enrolled (17 F and 23 M, aged 32–90 years), 24 T1 and 16 T2 cN0 squamous cell carcinoma of the oral cavity. Palpation was carried out by two observers prior to inclusion. MRI, gray-scale and Doppler ultrasonography were performed. Lymphoscintigraphies were done after peritumoral injections of 99mTc labelled rheniumsulphide nanocolloid, followed by sentinel lymph node biopsy guided by a gamma probe and Patent Blue. Palpation, Doppler ultrasonography, MRI, and sentinel lymph node biopsy were compared to a combination of histopathology and follow-up. Diagnostic testing was performed using the x2 test. Results: Histopathological examination revealed metastatic spread to the neck in 14 of 40 patients. One patient had bilateral neck disease. Sentinel lymph node biopsy and ultrasonography were performed in 80 neck sides of 40 patients and MRI in 70 neck sides (5 patients were claustrophobic). SN revealed suspicious lymph nodes in 12 necks, ultrasonography in 23 necks, and MRI in 9 necks. The positive predictive value of sentinel lymph node biopsy was 100%, ultrasonography 57%, and MRI 56%. The respective negative predictive values were 96%, 96%, and 85%. The sensitivity of sentinel lymph node biopsy 80% was comparable to ultrasonography 87%, but the sensitivity of MRI 36% was low. The specificities were 100%, 85%, and 93%, respectively. By combined sentinel lymph node biopsy and ultrasonography the overall sensitivity could have been 100%. Conclusion: Sentinel lymph node biopsy improved staging of patients with small N0 oral cancers. Combined sentinel lymph node biopsy and Doppler ultrasonography may further improve staging. MRI and simple palpation results were poor.

Long-Term Efficacy of Modified-Release Recombinant Human Thyrotropin Augmented Radioiodine Therapy for Benign Multinodular Goiter: Results from a Multicenter, International, Randomized, Placebo-Controlled, Dose-Selection Study

BACKGROUND Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy. METHODS In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2 ± 9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 mL; range 31.9-242.2 mL) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30), or 0.03 mg MRrhTSH (n=33) 24 hours before a calculated (131)I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. RESULTS At six months, TV reduction was enhanced in the 0.03 mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01 mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH group, and 53 ± 18.6% in the 0.03 mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03 mg MRrhTSH group, the subset of patients with basal (131)I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03 mg MRrhTSH group (13.4 ± 23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01 mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01 mg, and 0.03 mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. CONCLUSIONS When used as adjuvant to (131)I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤ 0.03 mg, indicating that the lower threshold for efficacy is around this level.

Sentinel Lymph Node Biopsy in Oral Cancer: Validation of Technique and Clinical Implications of Added Oblique Planar Lymphoscintigraphy and/or Tomography

Purpose: To validate lymphatic mapping combined with sentinel lymph node biopsy as a staging procedure, and to evaluate the possible clinical implications of added oblique lymphoscintigraphy and/or tomography and test the intra- and interobserver reproducibility of lymphoscintigraphy. Material and Methods: Forty patients (17 F and 23 M, aged 32–90) with 24 T1 and 16 T2 squamous cell carcinoma of the oral cavity. Planar lymphoscintigraphy, emission and transmission tomography were performed. Detection and excision of the sentinel nodes were guided by a gamma probe. The sentinel nodes were step-sectioning and stained with hematoxylin and eosin and cytokeratin (CK 1). Histology and follow-up were used as “gold standard”. Tumor location, number of sentinel lymph nodes, metastasis, and recurrences were registered. Two observers evaluated the lymphoscintigraphic images to assess the inter-rater agreement. Results: Eleven (28%) patients were upstaged. The sentinel lymph node identification rate was 97.5%. Sentinel lymph node biopsy significantly differentiated between patients with or without lymph node metastasis (P = 0.001). Lymphatic mapping revealed 124 hotspots and 144 hot lymph nodes were removed by sentinel lymph node biopsy. Three patients developed a lymph node recurrence close to the primary tumor site during follow-up. Added oblique lymphoscintigraphic images and/or tomography revealed extra hotspots in 15/40 (38%) patients. In 4/40 (10%), extra contralateral hotspots were detected. Conclusion: Sentinel lymph node biopsy upstaged 28% of the patients. Sentinel lymph nodes close to the primary tumor were difficult to find. Added oblique planar images and/or tomographic images revealed extra clinical relevant hotspots in 38% of patients. Reproducibility proved excellent.