Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is increasing in incidence and the majority of patients are not candidates for radical therapies. Therefore, interest in minimally invasive therapies in growing. METHODS: A Phase I dose escalation trial was conducted at Indiana University to determine the feasibility and toxicity of stereotactic body radiation therapy (SBRT) for primary HCC. Eligible patients had Child-Turcotte-Pugh's Class (CTP) A or B, were not candidates for resection, had 1-3 lesions and cumulative tumour diameter less than or equal to 6 cm. Dose escalation started at 36 Gy in 3 fractions (12 Gy/fraction) with a subsequent planned escalation of 2 Gy/ fraction/level. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events v3.0 grade 3 or greater toxicity. RESULTS: Seventeen patients with 25 lesions were enrolled. Dose was escalated to 48 Gy (16 Gy/fraction) in CTP-A patients without DLT. Two patients with CPC-B disease developed grade 3 hepatic toxicity at the 42-Gy (14 Gy/fraction) level. The protocol was amended for subsequent CTP-B patients to receive a regimen of 5 fractions starting at 40 Gy (8 Gy/fraction) with one patient experiencing progressive liver failure. Four additional patients were enrolled (one died of unrelated causes after an incomplete SBRT course) without DLT. The only factor related to more than one grade 3 or greater liver toxicity or death within 6 months was the CTP score (p=0.03). Six patients underwent a liver transplant. Ten patients are alive without progression with a median FU of 24 months (10-42 months), with local control/stabilisation of the disease of 100%. One and two-year Kaplan-Meier estimates for overall survival are 75% and 60%, respectively. CONCLUSIONS: SBRT is a non-invasive feasible and well tolerated therapy in adequately selected patients with HCC. The preliminary local control and survival are encouraging. A confirmatory Phase II trial is currently open to accrual.

Treatment of anal carcinoma in immune-compromised patients.

BACKGROUND: Immune-compromised populations show an increased incidence of anogenital tract neoplasms. This study was undertaken to evaluate local control (LC), overall survival (OS) and toxicity in immune-compromised patients with anal carcinoma treated with radiotherapy with or without chemotherapy. METHODS: We identified 25 patients with anal carcinoma and human immunodeficiency virus (HIV) infection or history of solid-organ transplant on chronic medical immune-suppression. Median age and follow-up were 44 years and 26 months respectively. AJCC T-stages were Tis (4%), T1 (8%), T2 (58%) and T3 (29%). N-stages were N0 (79%), N1 (4%), N2 (13%) and N3 (4%). One patient had metastatic disease at diagnosis. Seventy-five percent received concurrent chemoradiotherapy. Median radiation dose to the primary tumour was 50 Gy. RESULTS: One-, 3- and 5-year LC without salvage therapy was 87%, 87% and 70% respectively. One-, 3- and 5-year actuarial OS was 96%, 73% and 61% respectively. One-, 3- and 5-year OS was 100% for treatment time (TT) <50 days and 57%, 38% and 0% for TT > or =50 days (p=0.0009). All patients had acute grade 2-3 skin toxicity. Acute grade 3-4 gastrointestinal (GI), genitourinary (GU) and haematological toxicity occurred in 8%, 0% and 38%. Late grade 3-4 skin, GI and GU toxicity occurred in 8%, 4% and 0%. CONCLUSIONS: Most HIV-positive and organ transplant patients receiving radiotherapy with or without chemotherapy experience acute toxicity but few have chronic complications. T-stage and CD4 level in HIV-positive patients predict for LC. T-stage and TT predict for OS.

Molecular alterations in the pathogenesis of endometrial adenocarcinoma. Therapeutic implications.

Molecular genetic evidence indicates that endometrial carcinoma likely develops as the result of a multistep process of oncogene activation and tumor suppressor gene inactivation. These molecular alterations appear to be specific for Type I (endometrioid) and Type II (non endometrioid) cancers. Type I cancers are characterized by mutation of PTEN, KRAS2, defects in DNA mismatch repair, as evidenced by the microsatellite instability phenotype, and a near diploid karyotype. Type II cancers often contain mutations of TP53 and Her-2/neu and are usually nondiploid. The clinical value of many of these molecular markers is now being tested and it may help to refine diagnosis and establish an accurate prognosis. Furthermore, some of these tumor biomarkers constitute the targets for emerging therapies. Transtuzumab against Her-2/neu and bevacizumab against VEGF overexpressing carcinomas are among the promising novel treatments. Additional translational research is needed to identify molecular and genetic alterations with potential for therapeutic interventions.