J Turner

Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients.

Radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) has achieved objective response rates in clinical trials comparable with standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, but is relatively underused in routine practice. In this article, we report our clinical experience in 142 consecutive patients who received iodine-131 rituximab radioimmunotherapy for low-grade, predominantly follicular, relapsed NHL. Objective response rates of 67%, with complete response (CR) in 50% and median overall survival of 32 months, matched the response rates in a phase 2 clinical trial of (131)I-rituximab radioimmunotherapy and compares favorably with those reported for (131)I-tositumomab or (90)Y-ibritumomab tiuxetan. Progression-free survival was 18 months overall and 32 months in CR or CR-unconfirmed patients. Our patients comprised 107 (75%) follicular lymphoma, 21 (15%) small lymphocytic lymphoma, 6 (4%) mucosa-associated lymphoid tissue/marginal zone lymphoma, and 8 (6%) mantle-cell lymphoma, with median follow-up of 32 months and 8-year overall survival of 48%. Toxicity was limited to hematologic grade 4 neutropenia, occurring in 10% and thrombocytopenia in 6%. There were no episodes of bleeding or infection requiring hospital admission. Radioimmunotherapy with (131)I-rituximab in routine clinical outpatient practice provides cost-effective, safe treatment of relapsed/refractory indolent NHL, with half of patients achieving durable, complete remission with potential for repeat radioimmunotherapy on relapse.

Outpatient therapeutic nuclear oncology

In the beginning, nuclear medicine was radionuclide therapy, which has evolved into molecular tumour-targeted control of metastatic cancer. Safe, efficacious, clinical practice of therapeutic nuclear oncology may now be based upon accurate personalised dosimetry by quantitative gamma SPECT/CT imaging to prescribe tumoricidal activities without critical organ toxicity. Preferred therapy radionuclides possess gamma emission of modest energy and abundance to enable quantitative SPECT/CT imaging for calculation of the beta therapy dosimetry, without radiation exposure risk to hospital personnel, carers, family or members of the public. The safety of outpatient radiopharmaceutical therapy of cancer with Iodine-131, Samarium-153, Holmium-166, Rhenium-186, Rhenium-188, Lutetium-177 and Indium-111 is reviewed. Measured activity release rates and radiation exposure to carers and the public are all within recommendations and guidelines of international regulatory agencies and, when permitted by local regulatory authorities allow cost-effective, safe, outpatient radionuclide therapy of cancer without isolation in hospital.

Repeat treatment with iodine-131-rituximab is safe and effective in patients with relapsed indolent B-cell non-Hodgkin's lymphoma who had previously responded to iodine-131-rituximab

BACKGROUND Small series suggest retreatment of indolent lymphomas with murine anti-CD20 radioimmunotherapy is effective. The longer half-life of iodine-131 ((131)I)-rituximab may result in increased bone marrow exposure, with greater toxicity on repeat administration. We examined the effects of a second (131)I-rituximab in patients with indolent lymphoma following relapse. PATIENTS AND METHODS We analyzed two institutional databases from January 2000 to July 2007 for retreatment with (131)I-rituximab. The severity of cytopenia, development of myelodysplasia (MDS), acute myeloid leukemia (AML) and hypothyroidism was noted. We compared response duration and toxicity of the treatments. RESULTS Fourteen of 16 patients responded with nine complete responses (CRs), with a median duration of 10.5 months in responders. Six of 13 reresponders had the same or a longer response and six more remain in complete response. The median event-free survival was not significantly different for the two treatments. There was no significant difference in the severity of myelosuppression. Four patients developed hypothyroidism with three requiring thyroxine. One patient developed AML, with no other cases of MDS. The actuarial progression-free survival rate at 12 months was 36%. CONCLUSIONS Repeat (131)I-rituximab induces high response rates, some of which result in durable remissions in patients who had previously responded.

Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy

Extrapolation to humans from experimental radioimmunotherapy in nude mouse xenograft models is confounded by large relative tumour size and small volume of distribution in mice allowing tumour uptake of radiolabelled antibodies unattainable in patients. Our large animal model of human tumours in cyclosporin-immunosuppressed sheep demonstrated tumour uptake of targeted radiolabelled monoclonal antibodies comparable with uptakes reported in clinical trials. Sheep immunosuppression with daily intravenous cyclosporin augmented by oral ketoconazole maintained trough blood levels of cyclosporin within the range 1000-1500 ng ml(-1). Human tumour cells were transplanted orthotopically by inoculation of 10(7) cells: SKMEL melanoma subcutaneously; LS174T and HT29 colon carcinoma into bowel, peritoneum and liver; and JAM ovarian carcinoma into ovary and peritoneum. Tumour xenografts grew at all sites within 3 weeks of inoculation, preserving characteristic morphology without evidence of necrosis or host rejection. Lymphatic metastasis was demonstrated in regional nodes draining xenografts of melanoma and ovarian carcinoma. Colonic LS1 74T xenografts produced mucin and carcinoembryonic antigen (CEA). The anti-CEA IgG1 monoclonal antibody A5B7 was radiolabelled with iodine-131 and administered intravenously to sheep. Peak uptake at 5 days in orthotopic human tumour transplants in gut was 0.027% DI g(-1) (percentage of injected dose per gram) and 0.034% DI g(-1) in hepatic metastases with tumour to blood ratios of 2-2.5. Non-specific tumour uptake in melanoma was 0.003% DI g(-1). Uptake of radiolabelled monoclonal antibody in human tumours in our large animal model is comparable with that observed in patients and may be more realistic than nude mice xenografts for prediction of clinical efficacy of radioimmunotherapy.

Phase II study of first-line 131I-rituximab radioimmunotherapy in follicular non-Hodgkin lymphoma and prognostic 18F-fluorodeoxyglucose positron emission tomography

Abstract First-line 131I-anti-CD20 radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) achieves durable remission with low toxicity. The phase II INITIAL study comprised 68 patients with follicular NHL followed up to 7 years (median 4 years) after outpatient 131I-rituximab radioimmunotherapy (RIT) in conjunction with rituximab, followed by maintenance therapy for 1 year. Baseline and 3-month 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging, analyzed according to Deauville criteria, was used to evaluate response and predict prognosis. The overall response rate at 3 months was 99%, with 88% achieving Deauville category 1–3. These satisfactory responders did not reach median time-to-next-treatment, versus a median of 29 months for a category 4–5 response (p < 0.0001). Grade IV hematological toxicity (9%) was self-limited without clinical sequelae. 131I-rituximab radioimmunotherapy in newly diagnosed, advanced stage, symptomatic follicular NHL is an effective, practical and affordable alternative to existing conventional chemotherapies, with lower toxicity and durable remissions. Response assessment at 3 months by 18F-FDG PET Deauville five-point scale permits prognostic stratification.

Outpatient 131I-rituximab radioimmunotherapy for non-Hodgkin lymphoma: a study in safety.

Purpose This study aimed to establish the safety of outpatient 131I-rituximab radioimmunotherapy by measuring the radiation exposure of hospital staff, carers, and members of the public and by estimating the environmental impact of radioactive urinary excretion. Methods Two hundred consecutive outpatients treated with 131I-rituximab radioimmunotherapy of non-Hodgkin lymphoma (NHL) with therapeutic activities between 1 and 4.5 GBq (mean, 2.3 GBq; or between 27 and 121 mCi; mean, 62 mCi) predicated on a prescribed whole-body radiation-absorbed dose of 0.75 Gy were studied. Their 279 family members/carers and 432 visitors wore thermoluminescent dosimeter badges for the week during which the patients were confined to their home after treatment. Results All 200 patients received 131I-rituximab activities according to the prescribed dose of 0.75 Gy to the whole body. From 200 consecutive patients, over the 7 days after therapy, mean radiation exposure of adult carers was 0.49 mSv (range, <0.01 to 3.67 mSv). To other coresiding family members, mean exposure was 0.23 mSv (range, <0.01 to 1.20 mSv), and for visitors sharing badges, the mean exposure was 0.17 mSv (range, <0.01 to 0.73 mSv). Urinary activity excreted over the week after 131I-rituximab therapy was typically less than 25% of the administered activity. Conclusions 131I-rituximab radioimmunotherapy for non-Hodgkin lymphoma may be safely administered on an outpatient basis. The median radiation exposure of carers, cohabitants of the patient, and visitors is well within the limits recommended by international guidelines. Local regulatory agency–designated patient release rate limit of less than 25 &mgr;Sv/h at 1 m was attained within 1 week of therapeutic 131I-rituximab administration.

Defining Pharmacokinetics for Individual Patient Dosimetry in Routine Radiopeptide and Radioimmunotherapy of Cancer: Australian Experience

Determination of individual pharmacokinetics in patients undergoing radiopharmaceutical therapy is essential to define critical normal organ dosimetry. Review of a 20 year single institution experience demonstrates practical methodology for routinely characterising pharmacokinetics in each patient and calculating safe, effective therapeutic activities predicated upon prescribed radiation absorbed doses to the critical organs. In particular the results achieved in over 100 unselected consecutive clinic patients treated with (131)I-rituximab radioimmunotherapy for relapsed/refractory non-Hodgkins lymphoma have matched the ORR of 75% and CR 50% achieved in formal phase II clinical trial. The low level of myelotoxicity was attributed to prospective dosimetry in each patient and prescribed dose of 0.75 Gy to whole body. Radiopeptide therapy of progressive neuroendocrine tumours with (177)Lu-octreotate, illustrates application of practical dosimetry using retrospective quantitative imaging to define individual pharmacokinetics. Further challenges of multimodality combination therapy using radionuclide cocktails, chemotherapy and antivascular therapy, which will perturb pharmacokinetics, will require creative dosimetric methodology for continued safe, effective clinical practice of therapeutic nuclear oncology.: Determination of individual pharmacokinetics in patients undergoing radiopharmaceutical therapy is essential to define critical normal organ dosimetry. Review of a 20 year single institution experience demonstrates practical methodology for routinely characterising pharmacokinetics in each patient and calculating safe, effective therapeutic activities predicated upon prescribed radiation absorbed doses to the critical organs. In particular the results achieved in over 100 unselected consecutive clinic patients treated with (131)I-rituximab radioimmunotherapy for relapsed/refractory non-Hodgkins lymphoma have matched the ORR of 75% and CR 50% achieved in formal phase II clinical trial. The low level of myelotoxicity was attributed to prospective dosimetry in each patient and prescribed dose of 0.75 Gy to whole body. Radiopeptide therapy of progressive neuroendocrine tumours with (177)Lu-octreotate, illustrates application of practical dosimetry using retrospective quantitative imaging to define individual pharmacokinetics. Further challenges of multimodality combination therapy using radionuclide cocktails, chemotherapy and antivascular therapy, which will perturb pharmacokinetics, will require creative dosimetric methodology for continued safe, effective clinical practice of therapeutic nuclear oncology.

Optimization of technetium-99m Sestamibi single-photon emission tomography to define multidrug resistance with confidence

BackgroundThe efflux rate of technetium-99m Sestamibi (99mTc-Sestamibi) is a kinetic phenomenon related to the response of cancer cells to chemotherapy, and may be used to determine drug resistance. Measurement of the efflux rate requires accurate quantitative single-photon emission tomography (SPET) imaging within the time constraints imposed by the kinetics of the process. MethodsA phantom study, at activity concentrations typically found with 99mTc-Sestamibi in vivo, was undertaken to optimize the SPET parameters and, in particular, to determine whether 180° acquisition arcs with heads in ‘L’ configuration could be used for accurate quantification. Following the development of the most appropriate SPET protocol, a small patient pilot study was undertaken. ResultsStudies designed to evaluate statistical uncertainty (noise), contrast restitution and spatial resolution of the data sets, using different acquisition and reconstruction parameters, showed that 180° SPET using a 64×64 matrix, 6° angular sampling and iterative reconstruction was optimal. Finer linear and/or angular sampling afforded negligible improvement in resolution, but markedly increased the statistical uncertainty. Comparison of 360° and 180° acquisitions, utilizing conventional filtered backprojection and iterative reconstruction algorithms, demonstrated that the statistical uncertainty was reduced to a greater extent for 180° data collection. For 360° (64×64) data acquisition, statistical uncertainty decreased from 15% to 11% using the iterative algorithm, whilst the 180° (64×64) data showed a reduction from 20% to 7%, and approached values obtained by planar imaging. The efflux measurements obtained in the patient pilot study were consistent with the observed chemotherapy response. ConclusionOur study shows that 180° acquisition arcs are a practical option for accurate quantitative SPET kinetic imaging for potential studies of chemotherapy response in patients with lung cancer.

Cyclosporin immunosuppression of sheep: pharmacokinetics and allograft survival

A chronically immunosuppressed sheep model was established using a regimen of cyclosporin A (CsA; 2-3mg/kg twice daily) and ketoconazole (10mg/kg twice daily). Blood CsA concentrations reached a steady-state after 17 days of treatment. The clearance of CsA decreased from a mean (95% CI) of 9.47 (6.2-12.7)ml/min/kg after a single (first) dose (3mg/kg i.v.) to 1.62 (1.38-1.86)ml/min/kg after 18 days of CsA (3mg/kg i.v. twice daily) co-administration with ketoconazole. These data indicated that the combination of CsA and ketoconazole could be used to give stable high concentrations of CsA in the sheep. Using this regimen in the sheep, the long-term survival of skin allografts was monitored as an indicator of effective immunosuppression. CsA in blood was measured daily and CsA dose adjusted to various target concentration ranges. Provided that the trough concentration of blood CsA was maintained between 1500-2500 mg/l, long-term healthy skin allografts were maintained on the sheep without significant adverse effects on haematological or biochemical parameters.

Imaging of Early Response to Predict Prognosis in the First-Line Management of Follicular Non-Hodgkin Lymphoma with Iodine-131-Rituximab Radioimmunotherapy

The purpose of this study was to evaluate prediction of prognosis after first-line radioimmunotherapy (RIT) of advanced follicular non-Hodgkin lymphoma (FL), by imaging with fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG-PET/CT) three months after induction treatment by Iodine-131-rituximab (131I-rituximab). Objective response was determined using the Deauville 5-point scale in 68 prospective clinical trial patients. Baseline 18F-FDG-PET/CT studies were used to calculate total-metabolic-tumor-volume (TMTV). Non-imaging studies included the Follicular lymphoma international prognostic index (FLIPI) and absolute baseline monocyte and lymphocyte counts. Patients were monitored for over ten years (median follow-up 59 months), and no patient was lost to follow-up. Complete response (CR) of 88% predicted excellent prognosis with median time-to-next-treatment (TTNT) not yet reached. Those patients (12%) who failed to achieve CR (Deauville ≤ 3) on 18F-FDG-PET/CT at three months had significantly poorer outcomes (p < 0.0001) with a median TTNT of 41 months. Requirement for re-treatment was predicted by FLIPI and absolute baseline monocyte count but not lymphocyte count. The TTNT was accurately predicted by 18F-FDG-PET/CT Deauville response at three months following first-line therapy of FL with RIT. Early response demonstrated by imaging does, therefore, foretell prognosis in the individual FL patients.