Charlie Pan

Phase II Trial of High-Dose Conformal Radiation Therapy With Concurrent Hepatic Artery Floxuridine for Unresectable Intrahepatic Malignancies

PURPOSE A phase II trial was conducted to determine if high-dose radiation with concurrent hepatic arterial floxuridine would improve survival in patients with unresectable intrahepatic malignancies. PATIENTS AND METHODS Three-dimensional conformal high-dose radiation therapy was delivered concurrently with hepatic arterial floxuridine in 128 patients. The radiation dose was based on a normal-tissue complication probability model and subjected the patient to an estimated maximum risk of radiation-induced liver disease of 10% to 15%. The study design provided more than 80% power to detect a two-fold increase in median survival compared with historical controls at a 5% significance level. RESULTS The median radiation dose delivered was 60.75 Gy (1.5-Gy fractions bid). At a median follow-up time of 16 months (26 months in patients who were alive) the median survival was 15.8 months (95% CI, 12.6 to 18.3 months), significantly longer than in the historical control. The actuarial 3-year survival was 17%. The total dose was the only significant predictor of survival. Primary hepatobiliary tumors had a significantly greater tendency to remain confined to the liver than did colorectal cancer metastases. Overall toxicity was acceptable, with 27 patients (21%) and 11 patients (9%) developing grade 3 and 4 toxicity, respectively, and one treatment-related death. CONCLUSION The results suggest that, compared with historical controls, high-dose focal liver irradiation with hepatic artery floxuridine prolongs survival in patients with unresectable chemotherapy-refractory metastatic colorectal cancer and primary hepatobiliary tumors. This provides a rationale for intensification of local therapy for unresectable hepatobiliary cancers and integration of this regimen with newer systemic therapy for patients with colorectal cancer.

Radiation-Associated Kidney Injury

The kidneys are the dose-limiting organs for radiotherapy to upper abdominal cancers and during total body irradiation. The incidence of radiotherapy-associated kidney injury is likely underreported owing to its long latency and because the toxicity is often attributed to more common causes of kidney injury. The pathophysiology of radiation injury is poorly understood. Its presentation can be acute and irreversible or subtle, with a gradual progressive dysfunction over years. A variety of dose and volume parameters have been associated with renal toxicity and are reviewed to provide treatment guidelines. The available predictive models are suboptimal and require validation. Mitigation of radiation nephropathy with angiotensin-converting enzyme inhibitors and other compounds has been shown in animal models and, more recently, in patients.

Influence of 3D-CRT pelvic irradiation on outcome in prostate cancer treated with external beam radiotherapy

PURPOSE The role of pelvic irradiation (PRT) in the treatment of prostate cancer remains unclear. We reviewed our institutions experience with three-dimensional conformal external beam radiotherapy (3D-CRT) during the prostate-specific antigen era to determine the influence of PRT on the risk of biochemical recurrence in patients who have a predicted risk of lymph node involvement. METHODS AND MATERIALS Between March 1985 and January 2001, 1832 patients with clinically localized prostate cancer were treated with definitive 3D-CRT. All treatments involved CT planning to ensure coverage of the intended targets. Treatment consisted of prostate-only treatment, prostate and seminal vesicle treatment, or PRT of lymph nodes at risk followed by a boost. To create relatively homogenous analysis groups, each patients percentage of risk of lymph node (%rLN) involvement was assigned by matching the patients T stage, Gleason score, and initial prostate-specific antigen level to the appropriate value as described in the updated Partin tables. Three categories of %rLN involvement were defined: low, 0-5%; intermediate, >5-15%; and high, >15%. Biochemical recurrence was defined as the first occurrence of either the American Society for Therapeutic Radiology and Oncology consensus definition of prostate-specific antigen failure or the initiation of salvage hormonal therapy for any reason. RESULTS The risk status (%rLN) could be determined for 709 low-risk, 263 intermediate-risk, and 309 high-risk patients. The actuarial freedom from biochemical recurrence (bNED) and the log-rank test for the similarity of the control and treatment survival functions are reported for each risk group. Multivariate analysis demonstrated a statistically significant benefit for the entire population treated with PRT, with a relative risk reduction of 0.72 (95% confidence interval 0.54-0.97). Although the multivariate analysis could not determine the patient population that would most benefit from PRT, the beneficial effect appeared to be most pronounced within the intermediate-risk group. Univariate analysis revealed that the intermediate-risk patients treated with PRT had an improved 2-year bNED rate, 90.1% vs. 80.6% (p = 0.02), and both low-risk and high-risk patients treated with PRT had statistically similar 2-year bNED rates compared with those who did not receive it. CONCLUSION Pelvic 3D-CRT appears to improve bNED in prostate cancer patients. Additional studies are needed to elucidate the %rLN population for which this treatment should be recommended.

Prediction of liver function by using magnetic resonance-based portal venous perfusion imaging.

PURPOSE To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning. METHODS AND MATERIALS Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model. RESULTS There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT. CONCLUSIONS This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.

Randomized phase II trial of urethral sparing intensity modulated radiation therapy in low-risk prostate cancer: implications for focal therapy

BackgroundLow-risk prostate cancer (PCa) patients have excellent outcomes, with treatment modality often selected by perceived effects on quality of life. Acute urinary symptoms are common during external beam radiotherapy (EBRT), while chronic symptoms have been linked to urethral dose. Since most low-risk PCa occurs in the peripheral zone (PZ), we hypothesized that EBRT using urethral sparing intensity modulated radiation therapy (US-IMRT) could improve urinary health-related quality of life (HRQOL) while maintaining high rates of PCa control.MethodsPatients with National Comprehensive Cancer Network (NCCN) defined low-risk PCa with no visible lesion within 5 mm of the prostatic urethra on MRI were randomized to US-IMRT or standard (S-) IMRT. Prescription dose was 75.6 Gy in 41 fractions to the PZ + 3–5 mm for US-IMRT and to the prostate + 3 mm for S-IMRT. For US-IMRT, mean proximal and distal urethral doses were limited to 65 Gy and 74 Gy, respectively. HRQOL was assessed using the Expanded Prostate Cancer Index (EPIC) Quality of Life questionnaire. The primary endpoint was change in urinary HRQOL at 3 months.ResultsFrom June 2004 to November 2006, 16 patients were randomized, after which a futility analysis concluded that continued accrual was unlikely to demonstrate a difference in the primary endpoint. Mean change in EPIC urinary HRQOL at 3 months was −0.5 ± 11.2 in the US-IMRT arm and +3.9 ± 15.3 in the S-IMRT arm (p = 0.52). Median PSA nadir was higher in the US-IMRT arm (1.46 vs. 0.78, p = 0.05). At 4.7 years median follow-up, three US-IMRT and no S-IMRT patients experienced PSA failure (p = 0.06; HR 8.8, 95% CI 0.9–86). Two out of 3 patients with PSA failure had biopsy-proven local failure, both located contralateral to the original site of disease.ConclusionsCompared with S-IMRT, US-IMRT failed to improve urinary HRQOL and resulted in higher PSA nadir and inferior biochemical control. The high rate of PSA failure and contralateral local failures in US-IMRT patients, despite careful selection of MRI-screened low-risk patients, serve as a cautionary tale for focal PCa treatments.

The prediction of radiation-induced liver dysfunction using a local dose and regional venous perfusion model.

We have shown that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. The ability to safely deliver higher doses is primarily limited by the development of radiation-induced liver disease, characterized by venous occlusion. In this study, we investigated whether portal venous perfusion measured prior to the end of radiation therapy (RT) together with dose could predict liver venous perfusion dysfunction after treatment. Ten patients with unresectable intrahepatic cancer participated in an IRB-approved computer tomography (CT) perfusion study. Hepatic arterial and portal vein perfusion distributions were estimated by using dynamic contrast enhanced CT and the single compartmental model. Scans were obtained at four time points: prior to treatment, after 15 and 30 fractions of 1.5 Gy treatments, and one month following the completion of RT. Multivariant linear regression was used to determine covariances among the first three time point measurements plus dose for prediction of the post RT measurement. The reduction in the regional venous perfusion one month following RT was predicted by the local accumulated dose and the change in the regional venous perfusion after -30 fractions (F=90.6,p <0.000 01). Each Gy produced an approximately 1.2% of reduction in the venous perfusion. This local dose and venous perfusion model has the potential to predict individual sensitivity to radiation. This is the first step toward developing a method to deliver higher and potentially more curative radiation doses to the patients who can safely receive these higher doses.

The influence of 3D-CRT pelvic irradiation on outcome in intermediate-risk prostate cancer treated with external beam radiotherapy

Purpose/Introduction: The role of pelvic irradiation in the treatment of prostate cancer remains unclear. While prospective data has yet to prove an advantage with pelvic irradiation, conflicting data suggest both no benefit with pelvic irradiation and some benefit with pelvic irradiation in select subsets of patients. One potential reason why pelvic therapy has not been demonstrated to be clearly beneficial is that pelvic lymphatics may have been under treated in traditional, non-conformal pelvic treatment plans [Forman JD et al. Radiology. 1993; 186:889-892]. We reviewed our PSA-era experience with conformal, external beam radiotherapy to determine the influence of pelvic irradiation on the risk of PSA-failure in patients with an intermediate predicted risk of lymph node involvement.

MO‐D‐204B‐04: A Quantitative Metric Derived from DCE MRI for Assessment of Liver Response to Radiation Therapy

Purpose: To investigate a quantitative metric derived from dynamic contrast enhanced (DCE) liver MR imaging for hepatic perfusion response to radiation therapy (RT). Materials and Methods: Ten patients with intrahepatic cancers were treated by fractionated conformai RT in a dose range of 48–82 Gy, and imaged with DCE MRI before, during, 1 month and 2 month after the therapy. Voxel‐by‐voxel hepatic arterial perfusion (Fa) and portal venous perfusion (Fp) were estimated using a dual‐input single‐compartment model. To overcome some of the challenges in estimation of hepatic perfusion from DCE MRI, a portal venous perfusion ratio (PVPR) (100×Fp/(Fa+Fp)) was evaluated for liver perfusion dose‐response. Hepatic perfusion maps were co‐registered to the dose distribution via registration with the treatment planning CT. The liver voxels having PVPR between 80% and 95% before RT were considered as “normal” tissue. The relation between perfusion and dose in the “normal” liver was assessed by the venous‐perfusion‐ratio dose‐response function. Results: The PVPR in the “normal” liver regions 1 month after RT decreased compared to pre RT. The extent of the decrease was linearly correlated with the dose accumulated to the end of RT (R2=0.93). Substantial individual variations of the PVPR decreases were observed 1 month after RT. Conclusions: Our study shows dose‐dependent perfusion changes in local liver regions. There is substantial variability in the sensitivity of liver perfusion to irradiation. The PVPR may characterize the liver perfusion change in response to radiation and might be a metric for predicting radiation toxicity in the liver. The study is supported in part by R21 CA126137 and 3 P01 CA59827.