Mary F. Mulcahy

Clinical practice guidelines in oncology

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Radioembolization for Hepatocellular Carcinoma Using Yttrium-90 Microspheres: A Comprehensive Report of Long-term Outcomes

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) has limited treatment options; long-term outcomes following intra-arterial radiation are unknown. We assessed clinical outcomes of patients treated with intra-arterial yttrium-90 microspheres (Y90). METHODS Patients with HCC (n = 291) were treated with Y90 as part of a single-center, prospective, longitudinal cohort study. Toxicities were recorded using the Common Terminology Criteria version 3.0. Response rate and time to progression (TTP) were determined using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. Survival by stage was assessed. Univariate/multivariate analyses were performed. RESULTS A total of 526 treatments were administered (mean, 1.8; range, 1-5). Toxicities included fatigue (57%), pain (23%), and nausea/vomiting (20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30-day mortality rate was 3%. Response rates were 42% and 57% based on WHO and EASL criteria, respectively. The overall TTP was 7.9 months (95% confidence interval, 6-10.3). Survival times differed between patients with Child-Pugh A and B disease (A, 17.2 months; B, 7.7 months; P = .002). Patients with Child-Pugh B disease who had portal vein thrombosis (PVT) survived 5.6 months (95% confidence interval, 4.5-6.7). Baseline age; sex; performance status; presence of portal hypertension; tumor distribution; levels of bilirubin, albumin, and alpha-fetoprotein; and WHO/EASL response rate predicted survival. CONCLUSIONS Patients with Child-Pugh A disease, with or without PVT, benefited most from treatment. Patients with Child-Pugh B disease who had PVT had poor outcomes. TTP and overall survival varied by patient stage at baseline. These data can be used to design future Y90 trials and to describe Y90 as a potential treatment option for patients with HCC.

Gemcitabine Plus Bevacizumab Compared With Gemcitabine Plus Placebo in Patients With Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303)

PURPOSE The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients. PATIENTS AND METHODS Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m(2) over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days. RESULTS Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P < .001) and proteinuria (5% v 1%; P = .002); venous thrombosis grade > or = 3 was equivalent in both arms (14% and 15%, respectively). CONCLUSION The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients.

Safety and Efficacy of 90Y Radiotherapy for Hepatocellular Carcinoma With and Without Portal Vein Thrombosis

This study was undertaken to present data from a phase 2 study in which patients with unresectable hepatocellular carcinoma (HCC) with and without portal vein thrombosis underwent radioembolization with Yttrium (90Y) microspheres. Patients treated were stratified by Okuda, Child‐Pugh, baseline bilirubin, tumor burden, Eastern Cooperative Oncology Group (ECOG), presence of cirrhosis and portal vein thrombosis (PVT) (none, branch, and main). Clinical and biochemical data were obtained at baseline and at 4‐week intervals following treatment for up to 6 months. Tumor response was obtained using computed tomography (CT). Patients were followed for survival. One hundred eight patients were treated during the study period. Thirty‐seven (34%) patients had PVT, 12 (32%) of which involved the main PV. The cumulative dose for those with and without PVT was 139.7 Gy and 131.9 Gy, respectively. The partial response rate using world Health Organization (WHO) criteria was 42.2%. Using European Association for the Study of the Liver (EASL), the response rate was 70%. Kaplan‐Meier survival varied depending on location of PVT and presence of cirrhosis. The adverse event (AE) rates were highest in patients with main PVT and cirrhosis. There were no cases of radiation pneumonitis. Conclusion: The use of minimally embolic 90Y glass microspheres to treat patients with HCC complicated by branch/lobar PVT may be clinically indicated and appears to have a favorable toxicity profile. Further investigation is warranted in patients with main PVT. (HEPATOLOGY 2007.)

Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma

BACKGROUND & AIMS Chemoembolization is one of several standards of care treatment for hepatocellular carcinoma (HCC). Radioembolization with Yttrium-90 microspheres is a novel, transarterial approach to radiation therapy. We performed a comparative effectiveness analysis of these therapies in patients with HCC. METHODS We collected data from 463 patients who were treated with transarterial locoregional therapies (chemoembolization or radioembolization) over a 9-year period. We excluded patients who were not appropriate for comparison and analyzed data from 245 (122 who received chemoembolization and 123 who received radioembolization). Patients were followed for signs of toxicity; all underwent imaging analysis at baseline and follow-up time points. Overall survival was the primary outcome measure. Secondary outcomes included safety, response rate, and time-to-progression. Uni- and multivariate analyses were performed. RESULTS Abdominal pain and increased transaminase activity were more frequent following chemoembolization (P < .05). There was a trend that patients treated with radioembolization had a higher response rate than with chemoembolization (49% vs 36%, respectively, P = .104). Although time-to-progression was longer following radioembolization than chemoembolization (13.3 months vs 8.4 months, respectively, P = .046), median survival times were not statistically different (20.5 months vs 17.4 months, respectively, P = .232). Among patients with intermediate-stage disease, survival was similar between groups that received chemoembolization (17.5 months) and radioembolization (17.2 months, P = .42). CONCLUSIONS Patients with HCC treated by chemoembolization or radioembolization with Yttrium-90 microspheres had similar survival times. Radioembolization resulted in longer time-to-progression and less toxicity than chemoembolization. Post hoc analyses of sample size indicated that a randomized study with > 1000 patients would be required to establish equivalence of survival times between patients treated with these two therapies.

A Comparative Analysis of Transarterial Downstaging for Hepatocellular Carcinoma: Chemoembolization Versus Radioembolization

Chemoembolization and other ablative therapies are routinely utilized in downstaging from United Network for Organ Sharing (UNOS) T3 to T2, thus potentially making patients transplant candidates under the UNOS model for end‐stage liver disease (MELD) upgrade for hepatocellular carcinoma (HCC). This study was undertaken to compare the downstaging efficacy of transarterial chemoembolization (TACE) versus transarterial radioembolization. Eighty‐six patients were treated with either TACE (n = 43) or transarterial radioembolization with Yttrium‐90 microspheres (TARE‐Y90; n = 43). Median tumor size was similar (TACE: 5.7 cm, TARE‐Y90: 5.6 cm). Partial response rates favored TARE‐Y90 versus TACE (61% vs. 37%). Downstaging to UNOS T2 was achieved in 31% of TACE and 58% of TARE‐Y90 patients. Time to progression according to UNOS criteria was similar for both groups (18.2 months for TACE vs. 33.3 months for TARE‐Y90, p = 0.098). Event‐free survival was significantly greater for TARE‐Y90 than TACE (17.7 vs. 7.1 months, p = 0.0017). Overall survival favored TARE‐Y90 compared to TACE (censored 35.7/18.7 months; p = 0.18; uncensored 41.6/19.2 months; p = 0.008). In conclusion, TARE‐Y90 appears to outperform TACE for downstaging HCC from UNOS T3 to T2.

Complications Following Radioembolization with Yttrium-90 Microspheres: A Comprehensive Literature Review

The past decade has seen significant advancement in the locoregional management of liver tumors; novel and promising therapies such as transarterial chemoembolization, radioembolization, and radiofrequency ablation are now available. The development of new techniques and devices has led to the improved safety and efficacy profiles of external-beam radiation. Radioembolization with yttrium-90 ((90)Y) microspheres has emerged as a safe and efficacious treatment modality for liver malignancies. The purpose of this article is to present a comprehensive evidence-based review of the complications and adverse events that may be associated with radioembolization with (90)Y microspheres. Strategies to mitigate these adverse events are also discussed.

A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma

BackgroundWe report the results of a multi-institutional phase II trial that used preoperative full-dose gemcitabine and radiotherapy for patients with potentially resectable pancreatic carcinoma.MethodsPatients were treated before surgery with three cycles of full-dose gemcitabine (1000 mg/m2 intravenously), with radiation during the second cycle (36 Gy in daily 2.4-Gy fractions). Patients underwent surgery 4 to 6 weeks after the last gemcitabine infusion.ResultsThere were 10 men and 10 women, with a median age of 58 years (range, 50–80 years). Nineteen patients (95%) completed therapy without interruption, and one experienced grade 3 gastrointestinal toxicity. The mean weight loss after therapy was 4.0%. Of 20 patients taken to surgery, 17 (85%) underwent resections (16 pancreaticoduodenectomies and 1 distal pancreatectomy). The complication rate was 24%, with an average length of stay of 13.5 days. There were no operative deaths. Pathologic analysis revealed clear margins in 16 (94%) of 17 and uninvolved lymph nodes in 11 (65%) of 17 specimens. One specimen contained no residual tumor, and three specimens revealed only microscopic foci of residual disease. With a median follow-up of 18 months, 7 (41%) of the 17 patients with resected disease are alive with no recurrence, 3 (18%) are alive with distant metastases, and 7 (41%) have died.ConclusionsPreoperative gemcitabine/radiotherapy is well tolerated and safe when delivered in a multi-institutional setting. This protocol had a high rate of subsequent resection, with acceptable morbidity. The high rate of negative margins and uninvolved nodes suggests a significant tumor response. Preliminary survival data are encouraging. This regimen should be considered in future neoadjuvant trials for pancreatic cancer.

Radiologic–pathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium‐90 microspheres

We present the correlation between radiologic and pathologic findings in HCC patients who underwent radioembolization with yttrium‐90 (90Y) microspheres prior to resection or transplantation. Thirty‐five patients with a total of 38 lesions who underwent liver explantation after 90Y radioembolization were studied. Imaging surrogates following treatment were evaluated; the explants were examined for assessment of necrosis by pathology. The correlation betwen radiologic and histologic findings of the treated lesions was analyzed. Twenty‐three of 38 (61%) target lesions showed complete pathologic necrosis. All target lesions demonstrated some degree of histologic necrosis at explant. Complete histologic necrosis was seen in 89% of lesions with pretreatment size <3 cm. Complete pathologic necrosis was seen in 100%, 78%, and 93% of the lesions that were shown to have complete response by European Association for the Study of the Liver (EASL) necrosis criteria, partial response by World Health Organizaton (WHO) criteria, or thin rim enhancement on posttreatment imaging, respectively. In contrast, complete pathologic necrosis was seen in only 52% and 38% of the lesions that showed partial response by EASL criteria and peripheral nodular enhancement, respectively. Conclusion: Post‐radioembolization imaging findings of response by EASL and WHO criteria are predictive of the degree of pathologic necrosis. Rim enhancement was an imaging characteristic that correlated well with histologic necrosis. (HEPATOLOGY 2009.)

Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres--safety, efficacy, and survival.

PURPOSE To prospectively evaluate the safety, efficacy, and survival of patients with chemorefractory liver metastases who have been treated with yttrium 90 ((90)Y) glass microspheres. MATERIALS AND METHODS Institutional review boards from two institutions approved the HIPAA-compliant study; all patients provided informed consent. One hundred thirty-seven patients underwent 225 administrations of (90)Y microspheres by using intraarterial infusion. Primary sites (origins) included colon, breast, neuroendocrine, pancreas, lung, cholangiocarcinoma, melanoma, renal, esophageal, ovary, adenocarcinoma of unknown primary, lymphoma, gastric, duodenal, bladder, angiosarcoma, squamous cell carcinoma, thyroid, adrenal, and parotid. Patients underwent evaluation of baseline and follow-up liver function and tumor markers and computed tomographic or magnetic resonance imaging. Patients were observed for survival from first treatment. Median survival (in days) and corresponding 95% confidence intervals were computed by using the Kaplan-Meier method. The log-rank statistic was used for statistical significance testing of survival distributions between various subgroups of patients. RESULTS There were 66 men and 71 women. All patients were treated on an outpatient basis. Median age was 61 years. The mean number of treatments was 1.6. The median activity and dose infused were 1.83 GBq and 112.8 Gy, respectively. Clinical toxicities included fatigue (56%), vague abdominal pain (26%), and nausea (23%). At follow-up imaging, according to World Health Organization criteria, there was a 42.8% response rate (2.1% complete response, 40.7% partial response). There was a biologic tumor response (any decrease in tumor size) of 87%. Overall median survival was 300 days. One-year survival was 47.8%, and 2-year survival was 30.9%. Median survival was 457 days for patients with colorectal tumors, 776 days for those with neuroendocrine tumors, and 207 days for those with noncolorectal, nonneuroendocrine tumors. CONCLUSION (90)Y hepatic treatments are well tolerated with acceptable toxicities; tumor response and median survival are promising.