Fractionated radioimmunotherapy with 90Y‐clivatuzumab tetraxetan and low‐dose gemcitabine is active in advanced pancreatic cancer

BACKGROUND:

It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single‐dose yttrium‐90‐labeled hPAM4 (⁹⁰Y‐hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low‐dose gemcitabine in this disease.

METHODS:

Thirty‐eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m² weekly for 4 weeks with ⁹⁰Y‐hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2‐4). In the first part of the study, 19 patients received escalating weekly ⁹⁰Y doses of 6.5 mCi/m², 9.0 mCi/m², 12.0 mCi/m², and 15.0 mCi/m². In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m² or 12.0 mCi/m².

RESULTS:

Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single‐dose radioimmunotherapy. The maximum tolerated dose of ⁹⁰Y‐hPAM4 was 12.0 mCi/m² weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m² weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography‐based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses.

CONCLUSIONS:

Fractionated radioimmunotherapy with ⁹⁰Y‐hPAM4 and low‐dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma. Cancer 2012. © 2012 American Cancer Society.     

~(153)Sm-乙二胺四亚甲基膦酸对 Walker 256癌荷瘤大鼠骨侵袭骨溶解的抑制作用

目的研究１５３Ｓｍ－乙二胺四亚甲基膦酸（１５３Ｓｍ－ＥＤＴＭＰ）对荷瘤大鼠骨侵袭、骨溶解的抑制作用。方法运用Ｘ线骨骼照片和胫骨病理切片，观察Ｗａｌｋｅｒ２５６癌大鼠模型的肿瘤骨侵袭和骨溶解情况。结果荷瘤大鼠静脉注射１５３Ｓｍ－ＥＤＴＭＰ７４，１４８ＭＢｇ／ｋｇ后，遭受Ｗａｌｋｅｒ２５６癌侵袭及发生骨溶解的胫骨数减少近一半，３７ＭＢｇ／ｋｇ组对癌的骨侵袭和骨溶解仍有抑制作用。但各组大鼠的移植瘤重量没有差异。结论１５３Ｓｍ－ＥＤＴＭＰ能抑制Ｗａｌｋｅｒ癌模型大鼠骨侵袭和骨溶解，但对移植瘤生长无抑制作用，故其抗癌骨侵袭、骨溶解的作用不是通过抑制动物移植瘤生长来实现的。     

153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients

BackgroundBone metastatic patients with osteosarcoma have a very poor prognosis. Targeted radiation therapy has been pursued as a valid alternative. The primary end point of this study was progression-free survival (PFS) at 4 months.Patients and methodsTwenty-two osteosarcoma patients were treated with Samarium-153 ethylenediaminetetramethylene phosphonic acid (¹⁵³Sm-EDTMP) at various dosages. Administered activities ranged from 150 (3 mCi/kg) to 1140 MBq/kg (30 mCi/kg). Autologous hematopoietic stem cell infusion was carried out on day 14 after the ¹⁵³Sm-EDTMP infusion.ResultsThe median PFS was 61 days (18–436 days) and the median overall survival (OS) was 189 days (31–1175 days). PFS and OS for the entire patient population were 32% [95% confidence interval (CI) 16–50] and 76% (95% CI 52–89) at 4 months, respectively. No statistical differences emerged according to ¹⁵³Sm-EDTMP administered or 24-h retained activity. One-month pain palliation was only observed in a minority of subjects and in none at 4 months.ConclusionsBased on our series, the PFS is dramatically short even when higher activity of ¹⁵³Sm-EDTMP is administered. This would mean that, even at high level, ¹⁵³Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients.     

Safety analysis of repeated high doses of samarium-153 lexidronam in men with hormone-naive prostate cancer metastatic to bone

PURPOSE: The safety and tolerability of repetitive doses of the boneseeking radiopharmaceutical samarium-153 lexidronam (153Sm- EDTMP) were investigated in men with hormone-naive prostate cancer metastatic to bone. PATIENTS AND METHODS: Within 30 days of initiating androgen deprivation, the first of 4 planned doses of 153Sm- EDTMP given every 12 weeks was administered. Growth factors were not permitted. The first cohort of 6 patients received 153Sm-EDTMP at 2 mCi/kg per dose; 3 patients completed all 4 doses and 3 received 3 doses. RESULTS: There were 7 episodes of grade 3 neutropenia and 1 each of grade 3 and 4 thrombocytopenia. Of 6 patients in the second cohort who received 153Sm-EDTMP 2.5 mCi/kg per dose, only 1 received all 4 doses. Four events of grade 3 neutropenia and 2 events of grade 3 thrombocytopenia were reported. The 12-week dose schedule resulted in persistent low-grade thrombocytopenia and/or leukopenia, which prevented administration of all 4 planned doses. As a result, the dose of 153Sm-EDTMP was decreased to 2 mCi/kg for a total of 3 doses administered every 16 weeks. Five of 6 patients in this cohort received all 3 doses of 153Sm-EDTMP. There were 7 episodes of reversible grade 3 neutropenia. For all 18 patients on the study, there were no drug-related serious adverse events or grade 4 nonhemmatologic toxicities. CONCLUSION: In men with hormone-naive prostate cancer metastatic to bone, the feasible dose and schedule for repeated doses of 153Sm-EDTMP is 2 mCi/kg given every 16 weeks for 3 doses.     

Ten‐year follow‐up of a phase 2 study of dose‐intense paclitaxel with cisplatin and cyclophosphamide as initial therapy for poor‐prognosis,advanced‐stage epithelial ovarian cancer

BACKGROUND:

The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced‐stage epithelial ovarian cancer (EOC) who were receiving dose‐intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule.

METHODS:

Patients with stage III/IV EOC received cyclophosphamide 750 mg/m², followed by a 24‐hour infusion of paclitaxel 250 mg/m² and cisplatin 75 mg/m² on Day 2. Filgrastim began on Day 3 at 10 μg/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel.

RESULTS:

Sixty‐two patients were enrolled. Thirty‐two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent‐to‐treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow‐up of 11.4 years, the median progression‐free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel.

CONCLUSIONS:

The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Oncology Group suggest that further study is warranted of dose‐dense or dose‐intense paclitaxel regimens in women with newly diagnosed, advanced‐stage EOC. Cancer 2010. © 2010 American Cancer Society.     

A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent,platinum‐resistant,epithelial ovarian cancer

BACKGROUND:

Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of low‐dose decitabine combined with carboplatin in patients with recurrent, platinum‐resistant ovarian cancer.

METHODS:

Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28‐day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m² (7 patients) or 20 mg/m² (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE‐1 repetitive element) and gene‐specific DNA methylation.

RESULTS:

Dose‐limiting toxicity (DLT) at the 20‐mg/m² dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m². The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1‐2. One complete response was observed, and 3 additional patients had stable disease for ≥6 months. LINE‐1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer‐associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15.

CONCLUSIONS:

Repetitive low‐dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA‐hypomethylating) activity, justifying further testing for clinical efficacy. Cancer 2010. © 2010 American Cancer Society.     

Health‐related quality of life in long‐term breast cancer survivors

BACKGROUND:

The Survivor's Health and Reaction (SHARE) study examined health‐related quality of life (HRQL) in breast cancer patients who had participated in Cancer and Leukemia Group B Trial 8541 from 1985 to 1991.

METHODS:

In total, 245 survivors (78% of eligible patients) who were 9.4 to 16.5 years postdiagnosis (mean, 12.5 years postdiagnosis) completed HRQL surveys relating to 5 domains. Analyses examined HRQL domains according to 3 different chemotherapy dose levels that were administered in the original treatment trial: low‐dose cyclophosphamide, doxorubicin, and fluorouracil (CAF) at 300 mg/m², 30 mg/m², and 300×2 mg/m², respectively, over 4 cycles; standard‐dose CAF at 400 mg/m², 40 mg/m², and 400×2 mg/m², respectively, over 6 cycles; and high‐dose CAF at 600 mg/m², 60 mg/m² and 600×2 mg/m², respectively, over 4 cycles.

RESULTS:

In univariate analyses, a statistically significant difference was observed on the Medical Outcomes Study 36‐item short form Physical Role Functioning subscale by treatment group, with lower mean scores in the standard treatment arm (mean, 65.05) compared with mean scores in the low‐dose arm (mean, 74.66) and the high‐dose arm (mean, 84.94; P.0001). However, multivariate analysis revealed that treatment arm no longer was statistically significant, whereas the following factors were associated with decreased physical role functioning: age ≥60 years (odds ratio [OR], 3.55; P = .006), increased comorbidity interference total score (OR, 1.64; P = .005), lower vitality (OR, 1.05; P = .0002), and increased menopausal symptoms (OR, 1.04 P = .02).

CONCLUSIONS:

At 9.4‐16.5 years after their original diagnosis, differences in physical role functioning among breast cancer survivors who had received 3 different dose levels of chemotherapy were explained by clinical and demographic variables, such as age, fatigue, menopausal symptoms, and comorbidities. Prospective studies are needed to further assess the role of these factors in explaining HRQL and physical role functioning among long‐term survivors. Cancer 2009. © 2009 American Cancer Society.     

Phase 1 study of an oxaliplatin and etoposide regimen in pediatric patients with recurrent solid tumors

BACKGROUND:

The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors.

METHODS:

Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21‐day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m² and etoposide at a dose of 75 mg/m², 2) oxaliplatin at a dose of 130 mg/m² and etoposide at a dose of 100 mg/m², and 3) oxaliplatin at a dose of 145 mg/m² and etoposide at a dose of 100 mg/m². Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single‐agent MTD.

RESULTS:

The 16 patients received a total of 63 courses. At dose level 1, dose‐limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose‐limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose‐limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization.

CONCLUSIONS:

The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m² given on Day 1 and etoposide at a dose of 100 mg/m²/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well‐tolerated and demonstrated antitumor activity. Cancer 2009. © 2008 American Cancer Society.     

A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors

BACKGROUND:

E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids).

METHODS:

In a phase 1 study, E7974 was given intravenously over a 2‐ to 5‐minute infusion on day 1 of every 21‐day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose‐limiting toxicity (DLT).

RESULTS:

Twenty‐eight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m², 0.27 mg/m², 0.36 mg/m², 0.45 mg/m², and 0.56 mg/m²) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m², where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression‐free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95‐147.93 L), slow clearance (2.23‐7.15 L/h), and moderate to slow elimination (time to half‐life, 10.4‐30.5 hours).

CONCLUSIONS:

This study shows that E7974 once every 21‐day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m². Cancer 2012. © 2012 American Cancer Society     

Safety,pharmacokinetics, and activity of EZN‐2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies

BACKGROUND:

EZN‐2208 is a water‐soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN‐2208 in adult patients with advanced solid tumors.

METHODS:

Patients in sequential cohorts (3 + 3 design) received intravenous EZN‐2208 at doses between 1.25 mg/m² and 25 mg/m² once every 21 days.

RESULTS:

Thirty‐nine patients received EZN‐2208. The median number of prior therapies was 2 (range, 0‐10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN‐2208 with (16.5 mg/m²) and without (10 mg/m²) granulocyte‐colony–stimulating factor (G‐CSF). The dose‐limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m² with G‐CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m²). PK analysis indicated a mean terminal half‐life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short‐lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥4 months, 3 had received prior irinotecan, and 1 had KRAS‐positive colorectal cancer.

CONCLUSIONS:

EZN‐2208 was well tolerated and produced stable disease that lasted for ≥4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy. Cancer 2012. © 2012 American Cancer Society.     

Pilot study of huachansu in patients with hepatocellular carcinoma,nonsmall‐cell lung cancer,or pancreatic cancer

BACKGROUND:

Huachansu, a Chinese medicine that comes from dried toad venom from the skin glands of Bufo gargarizans or B. melanostictus, has been used in the treatment of various cancers in China. The authors conducted a pilot study, using a phase 1 trial design, of huachansu in patients with advanced cancer.

METHODS:

Huachansu was administered intravenously for 14 days followed by 7 days off (1 cycle). Without significant adverse events or progressive disease, treatment continued beyond 2 cycles. The dose of huachansu was escalated as follows with 3 patients per cohort: 10 (level 1), 20 (level 2), 40 (level 3), 60 (level 4), and 90 (level 5) mL/m².

RESULTS:

Fifteen patients (hepatocellular cancer, n = 11; nonsmall cell lung cancer, n = 2; pancreatic cancer, n = 2) were enrolled in the trial, and no dose‐limiting toxicities (DLTs) were found. Eleven patients had no drug‐related toxicity greater than grade 1. Six (40%) had stable disease (median duration, 6.0 months; range, 3.5‐11.1 months). One of these patients (with hepatocellular cancer) had 20% regression (duration, 11 months) (dose level 1). Quality of life improved for patients with stable disease. Plasma bufalin concentration reached maximal levels at the end of the 2‐hour infusion and was proportional to the amount of drug being administered (0.81‐3.38 ng/mL).

CONCLUSIONS:

No DLT was observed with the use of huachansu at doses up to 8× higher than typically used in China. Six patients had prolonged stable disease or minor tumor shrinkage. Cancer 2009. © 2009 American Cancer Society.     

帕米膦酸二钠联合153Sm-EDTMP对恶性肿瘤多发骨转移的疗效分析

目的 探讨帕米膦酸二钠（博宁）联合＾１５３Ｓｍ－ＥＤＴＭＰ对恶性肿瘤多发骨转移的临床疗效。方法 ３２例恶性肿瘤多发骨转移患者随机分为２组,每组１６例,分别接受＾１５３Ｓｍ－ＥＤＴＭＰ单独或与帕米膦酸二钠联合治疗。结果 联合组疼痛总缓解率（ＣＲ＋ＰＲ）为９３．８％,单用组为６２．５％,骨病灶控制总有效率（ＣＲ＋ＰＲ）联合组５６．３％,单用组为１８．８％,联合组疗效优于单用组（Ｐ〈０．０５）,两组均无     

Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors

BACKGROUND:

For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors.

METHODS:

Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21‐day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan‐associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotyping were performed.

RESULTS:

Thirteen patients were enrolled. Dose‐limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m²; irinotecan at a dose of 20 mg/m²). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m²/dose oxaliplatin; 15 mg/m²/dose irinotecan) experienced a dose‐limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re‐escalated (60 mg/m²) with irinotecan at a dose of 15 mg/m², 2 of 3 patients had a DLT (1 episode of diarrhea, 1 episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC_0→∞) was 5.9 μg · hour/mL (range, 1.8‐7.6 μg · hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and 1 of 10, respectively.

CONCLUSIONS:

The oxaliplatin MTD was 40 mg/m² per dose on Days 1 and 8 in combination with irinotecan 15 mg/m² per dose on Days 1‐5 and Days 8‐12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed. Cancer 2009. © 2009 American Cancer Society.     

153Sm-EDTMP治疗多发性骨转移癌的疗效分析

目的：评价＾１５３Ｓｍ－ＥＤＴＭＰ对多发性骨转移癌的止痛效果及消作用。方法：首次静脉给药剂量为３７ＭＢｑ／ｋｇ。重复治疗剂量，结合患者病情、病灶数、血象等的情增减。３次为一个疗程，给药间隔平均６周。结果：１５６例骨转移患者，骨痛完全缓痛５２例（３３．３％），部分缓解８１例（５１．９％），无效２３例（２１．２％）。止痛有效率为８５．２％（１３３／１５６），７２例骨转移患者治疗后，病灶骨／全身骨放射睡     

Samarium lexidronam (153Sm-EDTMP): skeletal radiation for osteoblastic bone metastases and osteosarcoma

Radiation therapy can be an effective means to treat bone metastases, which occur in more than 50% of cancer patients. (153)Samarium lexidronam ((153)Sm-EDTMP; Quadramet, Cytogen) is a radiopharmaceutical designed for deposition into bone metastases. Bone scans can identify patients that may benefit from targeted radiation therapy with (153)Sm-EDTMP. As an unsealed source of radiation therapy, (153)Sm-EDTMP is simple to administer: 1 mCi/kg is given in a similar fashion to a bone scan injection ((99m)Tc-MDP bone scan injection is given at 0.2-0.35 mCi/kg. Therefore, both are administered intravenously. However, the radiation-absorbed dose and radiopharmaceutical energy are different). Nevertheless, despite simplicity of administration, (153)Sm-EDTMP is underutilized for improving cancer pain in the skeleton. Repeated cycles and combined treatment with other modalities such as bisphosphonates, chemotherapy and/or external beam radiation are possible. (153)Sm-EDTMP combined with bisphosphonates, chemotherapy and/or radiation may provide better palliation of bone metastases and also in bone-forming tumors (osteosarcoma). Encouraging experience using high-dose (153)Sm-EDTMP for total marrow irradiation in hematologic malignancies involving the bones (e.g., myeloma or acute leukemia) is also reviewed.     

A phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study.     

Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high‐risk osteosarcoma patients

BACKGROUND:

A phase 2 trial was carried out to assess the antineoplastic activity of 2 courses of cyclophosphamide‐etoposide in relapsed osteosarcoma patients.

METHODS:

Twenty‐six relapsed osteosarcoma patients with a median age of 18.5 years (8.3‐47.1) were enrolled. Seven patients were in first relapse (27%), 11 in second relapse (42%), 7 in third relapse (27%), and 1 in fourth relapse (4%). Eighteen patients had bone metastasis at study entry (69%). Cyclophosphamide was given at 4 g/m² on Day 1 followed by etoposide at 200 mg/m² on Days 2, 3, and 4. Second cyclophosphamide and etoposide was planned at 21 days to 28 days from the previous one. The primary endpoint of the study was the clinical benefit at 4 months measured as progression‐free survival.

RESULTS:

Progression‐free survival at 4 months was 42%. Five patients achieved responses (19%), 9 patients had stable disease (35%), and 12 had tumor progression (46%). Overall survival (OS) at 1 year was 50%. The only grade 4 extrahematological toxicities were fever (5%), acute bronchospasm (4%) and stomatitis (18%). Six patients (23%) underwent radical surgery after cyclophosphamide and etoposide ×2.

CONCLUSIONS:

Cyclophosphamide and etoposide ×2 may arrest osteosarcoma progression in a significant number of patients (54%). Osteosarcoma progression arrest after cyclophosphamide and etoposide ×2 translates in a better OS. Cyclophosphamide and etoposide ×2 had good tolerability and the toxicity was time‐limited and resolved in all cases. Cancer 2009. © 2009 American Cancer Society.     

Phase 1 study of concurrent sunitinib and image‐guided radiotherapy followed by maintenance sunitinib for patients with oligometastases

BACKGROUND:

To determine the safety and maximum‐tolerated dose of concurrent sunitinib and image‐guided radiotherapy (IGRT) followed by maintenance sunitinib in oligometastastic patients.

METHODS:

Eligible patients had 1 to 5 sites of metastatic cancer measuring ≤6 cm. The most common treatment sites were bone, liver, and lung. Patients were treated with concurrent sunitinib (Day 1 through Day 28) and IGRT (40‐50 Gy in 10 fractions starting on Day 8) followed by maintenance sunitinib (50 mg daily, 4 weeks on/2 weeks off starting on Day 43). The starting dose was sunitinib 25 mg and IGRT 40 Gy. Doses were escalated in a ping‐pong design with incremental increases in either sunitinib or IGRT.

RESULTS:

Twenty‐one patients with 36 metastatic lesions were enrolled, with a median follow‐up of 10 months. No dose limiting toxicities (DLT) were noted at dose levels 1 or 2 (SU 37.5 mg/RT 40 Gy). One of 10 patients at dose level 3 (SU 37.5 mg/RT 50 Gy) and 2 of 5 patients at dose level 4 (SU 50 mg/RT 50 Gy) experienced DLTs comprising grade 4 myelosuppression and grade 3 nausea. At last follow‐up, 8 patients are alive without evidence of progression. The 1‐year local, progression‐free, and overall survival were 85%, 44%, and 75%, respectively.

CONCLUSIONS:

Addition of SU (25 to 37.5 mg) to IGRT is tolerable in patients with oligometastases, without potentiation of RT toxicity. On the basis of promising antitumor responses observed with this novel combination, a multi‐institutional phase 2 trial using SU 37.5 mg/RT 50 Gy is ongoing. Cancer 2009; 115:3571–80. © 2009 American Cancer Society.     

Samarium lexidronam (153Sm-EDTMP): skeletal radiation for osteoblastic bone metastases and osteosarcoma

Radiation therapy can be an effective means to treat bone metastases, which occur in more than 50% of cancer patients. ¹⁵³Samarium lexidronam (¹⁵³Sm-EDTMP; Quadramet, Cytogen) is a radiopharmaceutical designed for deposition into bone metastases. Bone scans can identify patients that may benefit from targeted radiation therapy with ¹⁵³Sm-EDTMP. As an unsealed source of radiation therapy, ¹⁵³Sm-EDTMP is simple to administer: 1 mCi/kg is given in a similar fashion to a bone scan injection (^99mTc-MDP bone scan injection is given at 0.2–0.35 mCi/kg. Therefore, both are administered intravenously. However, the radiation-absorbed dose and radiopharmaceutical energy are different). Nevertheless, despite simplicity of administration, ¹⁵³Sm-EDTMP is underutilized for improving cancer pain in the skeleton. Repeated cycles and combined treatment with other modalities such as bisphosphonates, chemotherapy and/or external beam radiation are possible. ¹⁵³Sm-EDTMP combined with bisphosphonates, chemotherapy and/or radiation may provide better palliation of bone metastases and also in bone-forming tumors (osteosarcoma). Encouraging experience using high-dose ¹⁵³Sm-EDTMP for total marrow irradiation in hematologic malignancies involving the bones (e.g., myeloma or acute leukemia) is also reviewed.     

[F‐18]‐fluorodeoxy‐D‐glucose–positron emission tomography response is associated with outcome for extremity osteosarcoma in children and young adults

BACKGROUND:

Response to neoadjuvant chemotherapy is 1 of the most powerful prognostic factors for extremity osteosarcoma. [F‐18]‐fluorodeoxy‐D‐glucose–positron emission tomography (FDG‐PET) is a noninvasive imaging modality that is used to predict histopathologic response. To determine the prognostic value of FDG‐PET response for progression‐free survival (PFS) in osteosarcoma, the authors of this report reviewed the University of Washington Medical Center experience.

METHODS:

Forty patients with extremity osteosarcoma were evaluated by FDG‐PET. All patients received neoadjuvant and adjuvant chemotherapy. FDG‐PET standard uptake values (SUVs) before neoadjuvant chemotherapy (SUV1) and after neoadjuvant chemotherapy (SUV2) were analyzed and correlated with histopathologic response.

RESULTS:

The median SUV1 was 6.8 (range, 3.0‐24.1), the median SUV2 was 2.3 (range, 1.2‐12.8), and the median SUV2 to SUV1 ratio (SUV2:1), was 0.36 (range, 0.12‐1.10). A good FDG‐PET response was defined as anSUV2 <2.5 or an SUV2:1 ≤0.5. FDG‐PET responses according to SUV2 and SUV2:1 were concordant with histologic response in 58% and 68% of patients, respectively. SUV2 was associated with outcome (4‐year PFS, 73% for SUV2 <2.5 vs 39% for SUV2 ≥2.5; P = .021). Both the initial disease stage and the histologic response were associated with outcome.

CONCLUSIONS:

FDG‐PET imaging of extremity osteosarcoma was correlated only partially with a histologic response to neoadjuvant chemotherapy. An SUV2 <2.5 was associated with improved PFS. Future prospective studies are warranted to determine whether FDG‐PET imaging may be used as a predictor of outcome independent of initial disease stage. Cancer 2009. © 2009 American Cancer Society.