Jonathan Klein

Hepatocellular carcinoma radiation therapy: review of evidence and future opportunities.

Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Curative therapy is not an option for most patients, often because of underlying liver disease. Experience in radiation therapy (RT) for HCC is rapidly increasing. Conformal RT can deliver tumoricidal doses to focal HCC with low rates of toxicity and sustained local control in HCC unsuitable for other locoregional treatments. Stereotactic body RT and particle therapy have been used with long-term control in early HCC or as a bridge to liver transplant. RT has also been effective in treating HCC with portal venous thrombosis. Patients with impaired liver function and extensive disease are at increased risk of toxicity and recurrence. More research on how to combine RT with other standard and novel therapies is warranted. Randomized trials are also needed before RT will be generally accepted as a treatment option for HCC. This review discusses the current state of the literature and opportunities for future research.

The Effects of Marriage, Civil Union, and Domestic Partnership Laws on the Health and Well-being of Children

In 2005, the American Academy of Pediatrics (AAP) Board of Directors commissioned the Committee on Psychosocial Aspects of Child and Family Health, the Committee on Early Childhood, Adoption, and Dependent Care, the Committee on Adolescence, the Committee on State Government Affairs, the Committee on Federal Government Affairs, and the Section on Adoption and Foster Care to develop an analysis examining the effects of marriage, civil union, and domestic partnership statutes and amendments on the legal, financial, and psychosocial health and well-being of children whose parents are gay or lesbian. In developing this analysis, the involved committees and section held before them the AAPs core philosophy—that the family is the principal caregiver and the center of strength and support for children. Together with this philosophy, contributors recognized the reality that our gay and lesbian patients grow up to be gay and lesbian adults. Because many pediatricians are fortunate to care for 2 or more generations of a family, we are likely to encounter and remain involved with our patients, regardless of sexual orientation, as they mature and mark the milestones of establishing a committed partnership with another adult, deciding to raise a family, and entrusting the health and well-being of their own children to us. This analysis explores the unique and complex challenges that same-gender couples and their children face as a result of public policy that excludes them from civil marriage. In compiling this report it became clear to the contributing committees and section that the depth and breadth of these challenges are largely unknown to the general public and perhaps even to many pediatricians. As such, the AAP Board of Directors approved the broad dissemination of this analysis to assist pediatricians with addressing the complex issues related to same-gender couples and their children. It is important to note at … Address correspondence to James G. Pawelski, MS, 141 Northwest Point Blvd, Elk Grove Village, IL 60007. E-mail: jpawelski{at}aap.org

Prospective Longitudinal Assessment of Quality of Life for Liver Cancer Patients Treated With Stereotactic Body Radiation Therapy

PURPOSE To evaluate quality of life (QoL), an important outcome owing to poor long-term survival, after stereotactic body radiation therapy (SBRT) to the liver. METHODS AND MATERIALS Patients (n=222) with hepatocellular carcinoma (HCC), liver metastases, or intrahepatic cholangiocarcinoma and Child-Pugh A liver function received 24-60 Gy of 6-fraction image-guided SBRT. Prospective QoL assessment was completed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30) and/or Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep, version 4) questionnaires at baseline and 1, 3, 6, and 12 months after treatment. Ten HCC patients with Child-Pugh B liver function were also treated. RESULTS The QLQ-C30 was available for 205 patients, and 196 completed the FACT-Hep. No difference in baseline QoL (P = .17) or overall survival (P = .088) was seen between the HCC, liver metastases, and intrahepatic cholangiocarcinoma patients. Appetite loss and fatigue measured by the QLQ-C30 clinically and statistically worsened by 1 month after treatment but recovered by 3 months. At 3 and 12 months after treatment, respectively, the FACT-Hep score had improved relative to baseline in 13%/19%, worsened in 36%/27%, and remained stable in 51%/54%. Using the QLQ-C30 Global Health score, QoL improved in 16%/23%, worsened in 34%/39%, and remained stable in 50%/38% at 3 and 12 months, respectively. Median survival was 17.0 months (95% confidence interval [CI] 12.3-19.8 months). Higher baseline scores on both FACT-Hep and QLQ-C30 Global Health were associated with improved survival. Hazard ratios for death, per 10-unit decrease in QoL, were 0.90 (95% CI 0.83-0.98; P = .001) and 0.88 (95% CI 0.82-0.95; P = .001), respectively. Tumor size was inversely correlated with survival. CONCLUSIONS Liver SBRT temporarily worsens appetite and fatigue, but not overall QoL. Stereotactic body radiation therapy is well tolerated and warrants comparison against other liver-directed therapies.

Stereotactic body radiotherapy: an effective local treatment modality for hepatocellular carcinoma

Although liver-directed therapies such as surgery or ablation can cure hepatocellular carcinoma, few patients are eligible due to advanced disease or medical comorbidities. In advanced disease, systemic therapies have yielded only incremental survival benefits. Historically, radiotherapy for liver cancer was dismissed due to concerns over unacceptable toxicities from even moderate doses. Although implementation requires more resources than standard radiotherapy, stereotactic body radiotherapy can deliver reproducible, highly conformal ablative radiotherapy to tumors while minimizing doses to nearby critical structures. Trials of stereotactic body radiotherapy for hepatocellular carcinoma have demonstrated promising local control and survival results with low levels of toxicity in Child-Pugh class A patients. We review the published literature and make recommendations for the future of this emerging modality.

Strategies to tackle the challenges of external beam radiotherapy for liver tumors

Primary and metastatic liver cancer is an increasingly common and difficult to control disease entity. Radiation offers a non-invasive treatment alternative for these patients who often have few options and a poor prognosis. However, the anatomy and aggressiveness of liver cancer poses significant challenges such as accurate localization at simulation and treatment, management of motion and appropriate selection of dose regimen. This article aims to review the options available and provide information for the practical implementation and/or improvement of liver cancer radiation programs within the context of stereotactic body radiotherapy and image-guided radiotherapy guidelines. Specific patient inclusion and exclusion criteria are presented given the significant toxicity found in certain sub-populations treated with radiation. Indeed, certain sub-populations, such as those with tumor thrombosis or those with larger lesions treated with transarterial chemoembolization, have been shown to have significant improvements in outcome with the addition of radiation and merit special consideration. Implementing a liver radiation program requires three primary challenges to be addressed: (1) immobilization and motion management; (2) localization; and (3) dose regimen and constraint selection. Strategies to deal with motion include simple internal target volume (ITV) expansions, non-gated ITV reduction strategies, breath hold methods, and surrogate marker methods to enable gating or tracking. Localization of the tumor and organs-at-risk are addressed using contrast infusion techniques to take advantage of different normal liver and cancer vascular anatomy, imaging modalities, and margin management. Finally, a dose response has been demonstrated and dose regimens appear to be converging. A more uniform approach to treatment in terms of technique, dose selection and patient selection will allow us to study liver radiation in larger and, hopefully, multicenter randomized studies.

Differentiation of Normal and Radioresistant Prostate Cancer Xenografts Using Magnetization Transfer-Prepared MRI

The ability of MRI to differentiate between normal and radioresistant cancer was investigated in prostate tumour xenografts in mice. Specifically, the process of magnetization exchange between water and other molecules was studied. It was found that magnetization transfer from semisolid macromolecules (MT) and chemical exchange saturation transfer (CEST) combined were significantly different between groups (p < 0.01). Further, the T2 relaxation of the semisolid macromolecular pool (T2,B), a parameter specific to MT, was found to be significantly different (p < 0.01). Also significantly different were the rNOE contributions associated with methine groups at −0.9 ppm with a saturation B1 of 0.5 µT (p < 0.01) and with other aliphatic groups at −3.3 ppm with 0.5 and 2 µT (both p < 0.05). Independently, using a live-cell metabolic assay, normal cells were found to have a greater metabolic rate than radioresistant ones. Thus, MRI provides a novel, in vivo method to quantify the metabolic rate of tumours and predict their radiosensitivity.

Chemical exchange saturation transfer MRI to assess cell death in breast cancer xenografts at 7T

Purpose Detecting cell death and predicting tumor response early in a course of chemotherapy could help optimize treatment regimens and improve clinical outcomes. Chemical exchange saturation transfer (CEST) MRI was investigated in vivo to study properties that may be able to detect cancer death. Results Using a magnetization transfer ratio (MTR) cutoff of 0.12 at 1.8 ppm was able to differentiate between viable tumor and cell death regions. Comparison of MTR values at this frequency showed significant differences (p < 0.0001) between viable tumor and cell death regions, matching patterns seen on histology. Using this cutoff, the mean increase in cell death index (± standard error of the mean) after chemotherapy was 4 ± 4%, 10% ± 7%, 10 ± 8%, and 4 ± 9% at 4, 8, 12, and 24 h, respectively. Conclusions CEST MRI can detect cell death in MDA-231 xenografts but further work is needed to characterize the clinical applications of this finding. Maximum response to chemotherapy occurred at 8–12 h after chemotherapy injection in this in vivo tumor model. Materials and Methods Breast cancer xenografts (MDA-MB-231) were scanned using 7 T MRI before and after chemotherapy. As a measure of CEST effect at 0.5 µT saturation amplitude, MTR values at frequency offsets of 1.8 and −3.3 ppm were evaluated. CEST signals after chemotherapy treatment were compared to cell-death histopathology of tumors.