Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial.

PURPOSE: To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study. PATIENTS AND METHODS: Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia. RESULTS: One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity. CONCLUSION: A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded.

Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine 131-labeled bivalent hapten: preliminary results of a phase I/II clinical trial.

The toxicity and therapeutic efficacy of escalating doses of anti-carcinoembryonic antigen x anti-N alpha-(diethylenetriamine-N,N,N',N''-tetraacetic acid)-In bispecific monoclonal antibody (F6-734) and iodine 131-labeled bivalent hapten were determined in a Phase I/II trial. A total of 26 patients with recurrences of medullary thyroid cancer documented by imaging and a rise in serum thyrocalcitonin were enrolled. Twenty to 50 mg of F6-734 and 40-100 mCi of 131I-hapten were injected 4 days apart. Quantitative scintigraphy was performed after the second injection for dosimetry estimations in eight cases. Clinical, biological, and morphological follow-up was carried out for 1 year after treatment. The mean percentage of injected activity per gram of tumor at the time of maximum uptake was 0.08% (range, 0.003-0.26%). The tumor biological half-life ranged from 3 to 95 days, and tumor doses ranged from 2.91 to 184 cGy/mCi. The estimated tumor-to-nontumor dose ratios were 43.8 x 53.4, 29.6 x 35.3, 10.9 x 13.6, and 8.4 x 10.0 for total body, red marrow, liver, and kidney, respectively. Grade III/IV hematological toxicity was observed in seven patients, most of them with bone metastases. Among the 17 evaluable patients, 4 pain reliefs, 5 minor tumor responses, and 4 biological responses with decrease of thyrocalcitonin were observed. Nine patients developed human anti-mouse antibody. Dose-limiting toxicity was hematological, and maximum tolerated activity was 48 mCi/m2 in this group of patients, most of whom had suspected bone marrow involvement. The therapeutic responses observed in patients mainly with a small tumor burden are encouraging for the performance of a Phase II trial with minimal residual disease.

A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases.

One hundred and fourteen patients with painful bone metastases participated in this randomised, dose-controlled study of the efficacy and safety of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP), a systemically administered radiopharmaceutical. Fifty-five patients received single doses of 0.5 mCi/kg and 59 patients received single doses of 1.0 mCi/kg. Treatment with 153-Sm-EDTMP produced improvement from baseline in all patient-rated efficacy assessments, including degree of pain, level of daytime discomfort, quality of sleep and pain relief. During the first 4 weeks after dose administration, when the patients evaluated efficacy daily, there were statistically significant changes from baseline with the 1.0 mCi/kg dose but not with the 0.5 mCi/kg dose. The difference between doses in visual analogue pain scores was statistically significant at week 4 (P = 0.0476). Among subsets of patients examined, female patients with breast cancer receiving 1.0 mCi/kg had the most noticeable improvement. The physicians judged that approximately half of the patients in each dose group were experiencing some degree of pain relief by week 2. This value increased to 55% for the 0.5 mCi/kg group and 70% for the 1.0 mCi/kg group at week 4. More patients in the higher dose group (54%) than in the lower dose group (44%) completed the 16-week study. A predictable level of dose-related marrow suppression was the only toxicity associated with 153Sm-EDTMP treatment. Values for platelets and WBCs reached nadirs at 3 or 4 weeks with both doses and recovered by 8 weeks. Even at their lowest point, the values were generally higher than those associated with infectious or haemorrhagic complications. Myelotoxicity was no greater in female patients than in male patients. Long-term follow-up revealed longer survival among breast cancer patients who had received the higher dose than among those who had received the lower dose. The results suggest that the 1.0 mCi/kg dose of 153Sm-EDTMP is safe and effective for the treatment of painful bone metastases.

[131I]-TYR3-octreotide: clinical dosimetry and use for internal radiotherapy of metastatic paraganglioma and carcinoid tumors.

Dosimetry and therapeutic application of [(131)I]-Tyr3-octreotide were evaluated in three patients with metastatic paraganglioma and carcinoid tumor. The in vitro stability of [(131)I]-Tyr3-octreotide was verified. Tumor uptake and residence time were between 0.02 and 0.1% and 0.5 to 9.8 h, respectively. The calculated tumor radiation doses were between 0.105 and 0.696 mGy.MBq(-1). No intolerance or adverse effects were observed after the therapeutic doses (3.3-6.6 GBq). A partial tumor response was obtained in one patient and no response occurred in two patients.

Thyroglobulin monitoring after treatment of well-differentiated thyroid cancer.

AIMS: The prognosis for well-differentiated thyroid carcinomas is favourable after treatment, but the rate of recurrence is around 20%. Cervical ultrasonography, radio-iodine scans, and monitoring of serum thyroglobulin (Tg) levels allow these recurrences to be diagnosed. The management of patients with isolated elevated Tg levels is controversial in the presence of negative radio-iodine scans. METHODS: The records of 57 patients diagnosed with recurrence of well-differentiated thyroid cancer were reviewed. Serum Tg was not evaluated in 31 of these patients (group 1) and measured in the other 26 cases (group 2). RESULTS: Forty-three recurrence sites were found; four deposits in the thyroid bed and 39 cervical metastatic nodes, with an average of five nodes per patient. The radio-iodine scan was accurate in detecting 10/24 of cases, radiology in 9/17, and elevated Tg levels in 20/25. Thirteen patients with recurrences diagnosed on the basis of Tg levels had negative radio-iodine scans. After surgery, Tg levels were normal in 10 patients from group 1 and 16 patients from group 2 (p=0.0078). CONCLUSIONS: Elevated Tg levels are indicative of disease progression or recurrence in patients who have previously been operated on for well-differentiated thyroid cancer. Even when the radiological study or radio-iodine scan is normal, surgical re-exploration of the neck, with total thyroidectomy and lymphadenectomy, is advisable.

Learning curve for the detection of axillary sentinel lymph node in breast cancer.

AIM: Sentinel axillary lymph node (SALN) detection is a new technique. Surgeons must progress up a learning curve in order to guarantee quality and safety equivalent to axillary lymphadenectomy. To ensure accurate staging of patients this learning curve must include SALN detection and an axillary lymphadenectomy. The aim of our work was to validate the principles and evaluate the consequences of learning curve for SALN detection from a prospective series of 200 consecutive patients. METHOD: Prospective assessment was made of the detection and false negative rates, post operative morbidity as abcess and seroma, and length of hospital stay. RESULTS: We evaluated the performance from the first to the hundredth case for each surgeon. Detection rate improved to 85% after patient number 10. False negative rate was less than 6%. Post operative axillary morbidity included 11% of seromas and 2% of abcess. Mean hospital stay was 2.8 days. CONCLUSION: Multidisciplinary validation of the learning period contributes to an accurate and safe SALN.

Pretargetted imaging of colorectal cancer recurrences using an 111In-labelled bivalent hapten and a bispecific antibody conjugate.

In 11 patients recurrence of colorectal cancer was suspected by a rise in serum carcinoembryonic antigen (CEA) (nine cases), by a subocclusive clinical situation (one case) or by endoscopy (on an anastomosis, one case). Two-step tumour targetting was performed by a first injection of 0.1 mg kg-1 of unlabelled bispecific antibody conjugate (an anti-CEA Fab' fragment chemically coupled to an anti-diethylene triamine pentaacetate (DTPA)-indium fragment) followed 4 to 5 days later by injection of the bivalent DTPA hapten labelled with 5 to 8 mCi 111In. Planar scintigraphy, single photon emission computed tomographic (SPECT) 360 degrees acquisitions and whole-body scans were obtained 4.5 and 24 h after injection of the radiolabelled hapten. Biodistribution was determined for eight patients at 48 h. The final diagnosis was confirmed histologically in nine patients (eight by second-look surgery, one by laparotomy). Overall, results were one true negative (1-year follow-up) and 10 true positive; however, for the three large liver metastases (3 to 6 cm), only the periphery of the metastasis had high uptake compared to normal liver. For pelvic recurrences, immunoscintigraphic (IS) contrast was better for small tumours. The highest tumour uptake was found for a 1 cm diameter pelvic recurrence (7.2% i.d. kg-1). Mean tumour-to-blood ratios were 6.4. Thus, this two-step tumour targetting technique, which uses a bispecific antibody conjugate and an 111In-labelled bivalent hapten injected sequentially without chasing the excess bispecific antibody, provided satisfactory results in this preliminary clinical trial for detection of recurrent colorectal cancers.

A rare gynecological case of paraneoplastic cerebellar degeneration discovered by FDG-PET.

BACKGROUND: PET/CT may be particularly useful to detect the primary cancer in paraneoplastic cerebellar degeneration (PCD) with anti-Yo which is most commonly associated with breast, ovarian and other gynecological cancers. CASE: A 60-year-old woman developed a PCD associated with anti-Yo antibodies in serum and cerebrospinal fluid. Conventional imaging was negative. FDG-PET showed an abnormal hot spot in the right ovarian area associated with lombo aortic lymph nodes. The diagnosis was confirmed by surgery as an ovarian adenocarcinoma. CONCLUSION: In this case report, FDG-PET played a crucial role in detecting the unknown primary tumor in a patient with PCD.

Brown fat in breast cancer patients: analysis of serial (18)F-FDG PET/CT scans.

PURPOSE: It has recently been suggested that FDG accumulation in the brown adipose tissue varies as a function of age, sex and outdoor temperature. The aim of this study was to assess changes in FDG uptake in brown fat in patients based on serial PET/CT scans and to compare our results with previous findings. METHODS: Early response to neoadjuvant chemotherapy in 33 female breast cancer patients was assessed by FDG PET. Five PET/CT scans were performed for each patient. PET/CT images were analysed retrospectively. PET scans were considered positive when diffuse, symmetrical, abnormal "USA" (uptake in supraclavicular area) fat was detected. RESULTS: A total of 163 PET images were analysed. Seventy-four PET scans (45%) revealed abnormal FDG uptake in the supraclavicular area. These foci were present on uncorrected and attenuation-corrected images. FDG uptake was identical on all five scans in only five patients. No significant relationship was found between abnormal FDG uptake and outdoor temperature, age or time interval between chemotherapy and PET. Abnormal FDG uptake in the neck seemed to predominantly occur in patients with a low body mass index (p<0.05). Most significant changes in the PET/CT scan results were observed during chemotherapy with docetaxel (p<0.05). When observed, bilateral uptake in the neck was more intense than background uptake (p<0.00001). CONCLUSION: This study shows that FDG uptake in the neck varies as a function of time, that it is unrelated to age or outdoor temperature, and that bilateral uptake is generally intense.

The impact of nonvisualization of sentinel nodes on lymphoscintigraphy in breast cancer.

BACKGROUND: This study aimed at evaluating the relationship between the nonvisualization of sentinel nodes (SNs) at lymphoscintigraphy and the intraoperative detection rate, radioactive counts in vivo, and histological status of SNs. METHODS: Two hundred eighty patients with infiltrating breast carcinoma (T0, T(1)/T(2)) underwent preoperative lymphoscintigraphy before gamma probe-guided SN biopsy. RESULTS: The surgical identification rate with a gamma probe was 84.6% (56 of 280) in lymphoscintigraphy-negative patients and 93.2% (224 of 280) in lymphoscintigraphy-positive patients (P < .05) after two subdermal periareolar injections. The average number of SNs per patient was 1.7 in lymphoscintigraphy-negative patients and 2.2 in lymphoscintigraphy-positive patients (P < .01), as assessed by gamma detection. The mean age of lymphoscintigraphy-negative patients was 62 +/- 10 years, versus 55 +/- 13 years for lymphoscintigraphy-positive patients (P < .001). The median radioactive count in dissected SNs identified by gamma detection was 204 cps (range, 4-618 cps) in lymphoscintigraphy-negative patients, versus 606 cps (range, 43-16,928 cps) in lymphoscintigraphy-positive patients (P < .001). The rate of macrometastatic SNs was 40% in lymphoscintigraphy-negative patients, versus 30% in lymphoscintigraphy-positive patients (not significant), whereas the size of involved SNs was 16.6 mm in lymphoscintigraphy-negative patients, versus 13.1 in lymphoscintigraphy-positive patients (P < .05). The micrometastasis detection rate in SNs from lymphoscintigraphy-negative patients was 6.25%, versus 23.3% in lymphoscintigraphy-positive patients (P < .01). CONCLUSIONS: Negative lymphoscintigraphy was observed in 20% of patients and was more frequent in elderly patients. Negative lymphoscintigraphy was predictive of a lower surgical identification rate and fewer detected SNs. These SNs had fewer micrometastases, were fairly large, and tended to harbor metastases.

Bone pain palliation with strontium-89 in cancer patients with bone metastases.

Strontium-89 is a pure beta-emitting radioisotope, a chemical analogue of calcium, and it is therefore avidly concentrated by areas of high osteoblastic activity. Selective uptake and prolonged retention at sites of increased bone mineral turnover provide precise bone lesions targeting. 89Sr chloride (commercialised as Metastron) is typically administered in a single 150 MBq parenteral dose. Its radioactive emission poses very little radioprotection concerns. Overall, studies show pain relief in up to 80% of patients, of which 10 to 40% became effectively pain free. The mean duration of palliation was 3-4 months. The mechanism of pain relief is controversial ; it is probably, but not only, related to the absorbed dose in the tumour and bone. There is no clear dose-response relationship. The only reported toxicity is temporary myelosuppression. WBC and platelets should be monitored at least on a weekly basis until they return to baseline. It seems that only patients with a reasonably good general condition stand to benefit from this treatment. In conclusion, systemic radionuclide therapy using 89Sr represents a feasible, safe, effective, well tolerated and cost-effective palliative treatment in patients with refractory bone pain.

Nuclear medicine applications for neuroendocrine tumors.

Sensitive, specific radiopharmaceuticals are available for scintigraphic diagnosis and internal radiotherapy of neuroendocrine tumors. (123)I-MIBG (metaiodobenzylguanidine) scintigraphy is the examination of choice for visualizing tumor sites of pheochromocytoma. In the event of malignant pheochromocytoma or carcinoid tumor, this examination allows assessment of the presence or absence of tumor uptake and can guide radiotherapy with (131)I-MIBG. The peptides secreted by neuroendocrine tumors can be radiolabeled for targeting of their specific receptors. Scintigraphy using a (111)In-labeled somatostatin analog (octreotide) is the examination of choice for diagnosis of the spread of gastroenteropancreatic and carcinoid tumors, as it is more sensitive than morphologic imaging techniques. It can also guide radiotherapy performed with the same pharmaceutical vector. These same two agents (MIBG and octreotide) can be used therapeutically by replacing (123)I with (131)I and (111)In by (90)Y. A transient palliative effect is obtained for a variable number of tumors (most often large ones) that take up the radiopharmaceutic agent well. There is general consensus that, for relatively radioresistant solid tumors, this type of radiotherapy is efficient only in the event of small tumor targets (a few millimeters in diameter) whose uptake is maximal, allowing more homogeneous distribution than that achieved with large tumors. Thus for optimal control of the disease it is recommended first to use scintigraphic imaging to confirm that the tumor takes up the radiopharmaceutical agent in question ((123)I-MIBG or (111)In-octreotide) and then reduce the tumor burden surgically before injecting high therapeutic activity (possibly with reinjection of peripheral stem cells). This treatment can be repeated three times every 3 months before evaluating the response. In these conditions, internal radiotherapy can be beneficial or even determinant for controlling disease progression.

Interest of F-18 fluorodeoxyglucose positron emission tomography in the evaluation of vaginal malignant melanoma.

BACKGROUND: This is the first report of FDG-PET findings in a case of vaginal melanoma. CASE: The tumor arose from the anterior wall of the vaginal canal. As the tumor was limited to the vaginal wall and as there was no evidence of distant metastases, the disease was staged as IIC (AJCC 2002). PET-CT images showed two mediastinal foci localized to the left highest mediastinal and subcarinal nodes on fusion PET/CT images. As it was metastatic, the disease was staged IV (AJCC 2002). CONCLUSION: In comparison to conventional imaging, FDG-PET provides a more accurate assessment of the extent of disease spread in patients with vaginal melanoma as with cutaneous melanoma. Significant alterations in the surgical management and treatment were made based on PET results.

Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement.

This retrospective study evaluated the toxicity and efficacy of strontium-89 chloride (Metastron, Amersham) in 94 patients with painful bone metastases of prostate cancer (117 injections of 150 MBq) and compared the efficacy of treatment in patients with moderate and extensive bone involvement. The predictive value of flare response with regard to analgesic response was also studied. High-grade leukothrombopenias were observed after only 5% of injections. An improvement in quality of life was obtained in 65% of cases, a decrease in pain in 78% (31% complete response) and a reduction of analgesics in 60%. Efficacy was significantly better for pain decrease (P=0.005) and reduction of analgesics (P=0.018), and response was significantly longer (P<0.0035) in patients with moderate than in patients with extensive bone involvement. The flare response observed in 23% of cases was not predictive of pain response (P=0.919) or reduction of analgesics (P=0.353). A second dose prolonged analgesia in three-quarters of cases without any apparent increase in toxicity. These results confirm the benefit of 89Sr chloride for the treatment of metastatic bone pain and suggest that internal radiotherapy should be started earlier. A bone scan could be proposed at the time of hormonal escape resulting in bone pain, and internal radiotherapy could be initiated when several metastatic foci exist, even if only one is painful. In this way, pain-free follow-up could be prolonged, and the transition to other therapeutic approaches, particularly opioids, delayed.

How does iliac crest bone marrow biopsy compare with imaging in the detection of bone metastases in small cell lung cancer?

Iliac crest bone marrow biopsy (BMB) has often been used as the gold standard for the detection of bone marrow metastases in small cell lung cancer (SCLC). However, it is likely to lead to numerous false-negative results. For this reason, we compared the results of bone scintigraphy (BS), magnetic resonance imaging (MRI), and BMB in 48 sequential patients affected with pathologically confirmed SCLC (47 were evaluable; mean age, 58.4 years). The three procedures were carried out within 1 week, no treatment being performed during this period. Whole-body scans and spot views were obtained in the anterior and posterior projections. For MRI, only the thoracolumbar spine, the sternum and the pelvis were scanned, using spin-echo T1-weighted sequences, resulting in an acquisition time of less than 45 min. Only five BMBs were rated as positive. In these cases, both BS and MRI were also positive. The other 42 biopsies were negative. Among them, in ten cases both BS and MRI were positive. In 21 cases, both BS and MRI were negative. In five cases MRI was positive while BS was negative. Finally, in six cases MRI was negative whilst BS was positive. In most cases in which either BS or MRI was positive, follow-up scans confirmed the initial findings. This study suggests that BMB is more invasive and less sensitive than BS or MRI in detecting bone metastases. MRI seems to be more sensitive than BS in detecting small spinal or pelvic metastases. Whole-body bone scintigraphy is more sensitive in detecting skull, costal or peripheral metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphoscintigraphy in the sentinel lymph node technique for breast tumor: value of early and late images for the learning curve.

As the performance of early (H+1 to H+4) and late (D1) lymphoscintigraphic images raises organizational problems in outpatient surgery for breast cancer, only early images are generally obtained. The present study evaluated whether two series of images are better than one and defined the advantages of both methodologies. One hundred and eighteen patients with infiltrating breast carcinoma (T(0), T(1) and T(2)) were included in the study: 87 in group A (early and late images) and 31 in group B (only early images). All patients received two peritumoral injections of (99m)Tc-sulfur colloid, 15-18 MBq (group A) and <15 MBq (group B). During the operation, the patent blue bye technique was associated with radioactivity detection. The two groups were comparable for histological type and tumor size and localization. Successful localization of sentinel nodes on early lymphoscintigraphic images was significantly greater for group B. The identification of a sentinel node focus on early lymphoscintigraphy increased by 10% during the study. Sentinel node detection by the isotopic method alone, or the two methods combined, was comparable for both groups. In radioactivity detection, the count rate for sentinel nodes versus background (contralateral breast) was similar for the two groups. During the learning phase, two series of images gave a definite advantage. Subsequently, lymphoscintigraphy performed at +2 h was sufficient (the results for the two groups became indistinguishable).