Role of Stereotactic Body Radiation Therapy Before Orthotopic Liver Transplantation: Retrospective Evaluation of Pathologic Response and Outcomes.

PURPOSE: To analyze the results of stereotactic body radiation therapy (SBRT) in patients with early-stage, localized hepatocellular carcinoma who underwent definitive orthotopic liver transplantation (OLT). METHODS AND MATERIALS: The subjects of this retrospective report are 38 patients diagnosed with hepatocellular carcinoma who underwent SBRT per institutional phase 1 to 2 eligibility criteria, before definitive OLT. Pre-OLT radiographs were compared with pathologic gold standard. Analysis of treatment failures and deaths was undertaken. RESULTS: With median follow-up of 4.8 years from OLT, 9 of 38 patients (24%) recurred, whereas 10 of 38 patients (26%) died. Kaplan-Meier estimates of 3-year overall survival and disease-free survival are 77% and 74%, respectively. Sum longest dimension of tumors was significantly associated with disease-free survival (hazard ratio 1.93, P=.026). Pathologic response rate (complete plus partial response) was 68%. Radiographic scoring criteria performed poorly; modified Response Evaluation Criteria in Solid Tumors produced highest concordance (κ = 0.224). Explants revealed viable tumor in 74% of evaluable patients. Treatment failures had statistically larger sum longest dimension of tumors (4.0 cm vs 2.8 cm, P=.014) and non-statistically significant higher rates of lymphovascular space invasion (44% vs 17%), cT2 disease (44% vs 21%), ≥pT2 disease (67% vs 34%), multifocal tumors at time of SBRT (44% vs 21%), and less robust mean α-fetoprotein response (-25 IU/mL vs -162 IU/mL). CONCLUSIONS: Stereotactic body radiation therapy before to OLT is a well-tolerated treatment providing 68% pathologic response, though 74% of explants ultimately contained viable tumor. Radiographic response criteria poorly approximate pathology. Our data suggest further stratification of patients according to initial disease burden and treatment response.

ACR Appropriateness Criteria® Ductal Carcinoma in Situ.

Ductal carcinoma in situ (DCIS) is a breast neoplasm with potential for progression to invasive cancer. Management commonly involves excision, radiotherapy, and hormonal therapy. Surgical assessment of regional lymph nodes is rarely indicated except in cases of microinvasion or mastectomy. Radiotherapy is employed for local control in breast conservation, although it may be omitted for select low-risk situations. Several radiotherapy techniques exist beyond standard whole-breast irradiation (ie, partial-breast irradiation [PBI], hypofractionated whole-breast radiation); evidence for these is evolving. We present an update of the American College of Radiology (ACR) Appropriateness Criteria® for the management of DCIS. The ACR Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions, which are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi technique) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria®-Anal Cancer.

The management of anal cancer is driven by randomized and nonrandomized clinical trials. However, trials may present conflicting conclusions. Furthermore, different clinical situations may not be addressed in certain trials because of eligibility inclusion criteria. Although prospective studies point to the use of definitive 5-fluorouracil and mitomycin C-based chemoradiation as a standard, some areas remain that are not well defined. In particular, management of very early stage disease, radiation dose, and the use of intensity-modulated radiation therapy remain unaddressed by phase III studies. The American College of Radiology (ACR) Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Evaluation of superficial dosimetry between treatment planning system and measurement for several breast cancer treatment techniques.

PURPOSE: Dosimetric accuracy in radiation treatment of breast cancer is critical for the evaluation of cosmetic outcomes and survival. It is often considered that treatment planning systems (TPS) may not be able to provide accurate dosimetry in the buildup region. This was investigated in various treatment techniques such as tangential wedges, field-in-field (FF), electronic compensator (eComp), and intensity-modulated radiotherapy (IMRT). METHODS: Under Institutional Review Board (IRB) exemption, radiotherapy treatment plans of 111 cases were retrospectively analyzed. The distance between skin surface and 95% isodose line was measured. For measurements, Gafchromic EBT2 films were used on a humanoid unsliced phantom. Multiple layers of variable thickness of superflab bolus were placed on the breast phantom and CT scanned for planning. Treatment plans were generated using four techniques with two different grid sizes (1 × 1 and 2.5 × 2.5 mm(2)) to provide optimum dose distribution. Films were placed at different depths and exposed with the selected techniques. A calibration curve for dose versus pixel values was also generated on the same day as the phantom measurement was conducted. The DICOM RT image, dose, and plan data were imported to the in-house software. On axial plane of CT slices, curves were drawn at the position where EBT2 films were placed, and the dose profiles on the lines were acquired. The calculated and measured dose profiles were separated by check points which were marked on the films before irradiation. The segments of calculated profiles were stretched to match their resolutions to that of film dosimetry. RESULTS: On review of treatment plans, the distance between skin and 95% prescribed dose was up to 8 mm for plans of 27 patients. The film measurement revealed that the medial region of phantom surface received a mere 45%-50% of prescribed dose. For wedges, FF, and eComp techniques, region around the nipple received approximately 80% of prescribed dose, although only IMRT showed inhomogeneous dose profile. At deeper depths mainly (6-11 mm depths), film dosimetry showed good agreement with the TPS calculation. In contrast, the measured dose at a 3-mm depth was higher than TPS calculation by 15%-30% for all techniques. For the tangential and IMRT techniques, 1 × 1 mm(2) grid size showed a smaller difference than that with a 2.5 × 2.5 mm(2) grid size compared to the measurements. CONCLUSIONS: In general, TPS even with advanced algorithms do not provide accurate dosimetry in the buildup region, as verified by EBT2 film for all treatment techniques. For all cases, TPS and measured doses were in agreement from 6 mm in depth but differed at shallower depths. Grid size plays an important role in dose calculation. For accurate dosimetry small grid size should be used where differences are lower between TPS and measurements.

ACR appropriateness criteria® resectable rectal cancer.

The management of resectable rectal cancer continues to be guided by clinical trials and advances in technique. Although surgical advances including total mesorectal excision continue to decrease rates of local recurrence, the management of locally advanced disease (T3-T4 or N+) benefits from a multimodality approach including neoadjuvant concomitant chemotherapy and radiation. Circumferential resection margin, which can be determined preoperatively via MRI, is prognostic. Toxicity associated with radiation therapy is decreased by placing the patient in the prone position on a belly board, however for patients who cannot tolerate prone positioning, IMRT decreases the volume of normal tissue irradiated. The use of IMRT requires knowledge of the patterns of spreads and anatomy. Clinical trials demonstrate high variability in target delineation without specific guidance demonstrating the need for peer review and the use of a consensus atlas. Concomitant with radiation, fluorouracil based chemotherapy remains the standard, and although toxicity is decreased with continuous infusion fluorouracil, oral capecitabine is non-inferior to the continuous infusion regimen. Additional chemotherapeutic agents, including oxaliplatin, continue to be investigated, however currently should only be utilized on clinical trials as increased toxicity and no definitive benefit has been demonstrated in clinical trials. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria®-Recurrent Rectal Cancer.

The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions. These Criteria are reviewed every 2 years by a multidisciplinary expert panel. The development and review of these guidelines includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.Local recurrence of rectal cancer can result in devastating symptoms for patients, including intractable pain and discharge. Prior treatment can limit subsequent treatment options. Preoperative 5-FU based chemoradiotherapy is the treatment of choice for patients with a local recurrence who did not receive adjuvant therapy after initial resection or who might have received chemotherapy alone. Chemoradiotherapy followed by evaluation for surgery is the preferred treatment for patients who have undergone previous radiotherapy after surgery. The inclusion of surgery has resulted in the best outcomes in a majority of studies. Palliative chemoradiotherapy is appropriate for patients who have received previous radiotherapy whose recurrent disease is considered inoperable. Radiotherapy can be delivered on a standard or hyperfractionated treatment schedule.Newer systemic treatments have improved response rates and given physicians more options for treating patients in this difficult situation. The use of induction chemotherapy prior to radiotherapy is an evolving treatment option. Specialized treatment modalities should be used at institutions with experience in these techniques and preferably in patients enrolled in clinical trials.

Primary radiation therapy for medically inoperable patients with clinical stage I and II endometrial carcinoma.

OBJECTIVE: To determine the outcomes associated with primary radiation therapy for medically inoperable, clinical stage I and II, endometrial adenocarcinoma (EAC). METHODS: A multi-institution, retrospective chart review from January 1997 to January 2009 was performed. Overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS) and time to progression (TTP) were assessed using the Kaplan-Meier method. Disease-specific survival was analyzed using a competing risks approach. RESULTS: Seventy-four patients were evaluable. The median age and BMI were 65 years (range 36-92 years) and 46 kg/m(2) (range 23-111 kg/m(2)), respectively. 85.1% had severe systemic disease, most frequently cardiopulmonary risk and morbid obesity. With a mean follow-up of 31 months, 13 patients (17.6%) experienced a recurrence. The median PFS and OS were 43.5 months and 47.2 months, respectively. Overall, 35 women died, including 4 women who died of unknown cause. Of the remaining 31 women, 7 patients (9.5%) died of disease, while 24 died of other causes (32.4%). The hazard ratio comparing the risk of death due to other causes to the risk of death due to disease was 3.4 (95% CI 1.4-9.4, p=0.003). Among patients who are alive three years after diagnosis, 14% recurred and the conditional recurrence estimate did not exceed 16%. CONCLUSIONS: Primary radiation therapy for clinical stage I and II EAC is a feasible option for medically inoperable patients and provides disease control, with fewer than 16% of surviving patients experiencing recurrence.

Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is increasing in incidence due to hepatitis C. Stereotactic body radiotherapy (SBRT) is a noninvasive, effective therapy in the management of liver malignancies. The authors evaluated radiological response in 26 patients with HCC treated with SBRT at Indiana University. METHODS: Between March 2005 and June 2008, 26 patients with HCC who were not surgical candidates were enrolled in a phase 1 to 2 trial. Eligibility criteria included solitary tumors ≤ 6 cm or up to 3 lesions with sum diameters ≤ 6 cm, and well-compensated cirrhosis. All patients had imaging before, at 1 to 3 months, and every 3 to 6 months after SBRT. RESULTS: Patients received 3 to 5 fractions of SBRT. Median SBRT dose was 42 Gray (Gy) (range: 24-48 Gy). Median follow-up was 13 months. Per Response Evaluation Criteria in Solid Tumors (RECIST), 4 patients had a complete response (CR), 15 had a partial response (PR), and 7 achieved stable disease (SD) at 12 months. One patient with SD experienced progression marginal to the treated area. The overall best response rate (CR + PR) was 73%. In comparison, by European Association for the Study of the Liver (EASL) criteria, 18 of 26 patients had ≥ 50% nonenhancement at 12 months. Thirteen of 18 demonstrated 100% nonenhancement, being > 50% in 5 patients. Kaplan-Meier 1- and 2-year survival estimates were 77% and 60%, respectively. CONCLUSIONS: SBRT is effective therapy for patients with HCC with an overall best response rate (CR + PR) of 73%. Nonenhancement on imaging, a surrogate for ablation, may be a more useful indicator than size reduction in evaluating HCC response to SBRT in the first 6 to 12 months, supporting EASL criteria.

Stereotactic body radiotherapy for primary hepatocellular carcinoma.

PURPOSE: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of primary hepatocellular carcinoma (HCC). METHODS AND MATERIALS: From 2005 to 2009, 60 patients with liver-confined HCC were treated with SBRT at the Indiana University Simon Cancer Center: 36 Child-Turcotte-Pugh (CTP) Class A and 24 CTP Class B. The median number of fractions, dose per fraction, and total dose, was 3, 14 Gy, and 44 Gy, respectively, for those with CTP Class A cirrhosis and 5, 8 Gy, and 40 Gy, respectively, for those with CTP Class B. Treatment was delivered via 6 to 12 beams and in nearly all cases was prescribed to the 80% isodose line. The records of all patients were reviewed, and treatment response was scored according to Response Evaluation Criteria in Solid Tumors v1.1. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Local control (LC), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were calculated according to the method of Kaplan and Meier. RESULTS: The median follow-up time was 27 months, and the median tumor diameter was 3.2 cm. The 2-year LC, PFS, and OS were 90%, 48%, and 67%, respectively, with median TTP of 47.8 months. Subsequently, 23 patients underwent transplant, with a median time to transplant of 7 months. There were no ≥Grade 3 nonhematologic toxicities. Thirteen percent of patients experienced an increase in hematologic/hepatic dysfunction greater than 1 grade, and 20% experienced progression in CTP class within 3 months of treatment. CONCLUSIONS: SBRT is a safe, effective, noninvasive option for patients with HCC ≤6 cm. As such, SBRT should be considered when bridging to transplant or as definitive therapy for those ineligible for transplant.

Imaging changes after stereotactic body radiation therapy for lung and liver tumors.

Stereotactic body radiation therapy (SBRT) is gaining wide acceptance as a treatment modality for lung and liver tumors, and it is crucial to make an accurate evaluation of the local effects of ablative doses of radiation in terms of local tumor control and normal tissue reaction or damage. The very complex radiation dose distribution of SBRT, the use of a large number of non-opposing and noncoplanar beams, and the delivery of individual ablative doses of radiation may cause substantially different radiographic appearance on diagnostic imaging compared with conventional radiation therapy. Different patterns of radiographic changes have been observed in the lung and liver after SBRT. This article reviews the post-SBRT imaging changes in the lung and liver. Since computed tomography and PET are the most commonly used diagnostic imaging tools for monitoring lung tumor and computed tomography for liver tumors, this article will focus on the changes observed on those imaging modalities.

Intra-articular chromic phosphate (³²P) in the treatment of diffuse pigmented villonodular synovitis.

PURPOSE: Pigmented villonodular synovitis (PVNS) is an uncommon proliferative lesion of synovial tissue. In diffuse PVNS, recurrence rates are high after resection alone. Adjuvant external beam radiation therapy contributes to improved local control. Limited data exist for intra-articular radioisotope therapy after surgical resection. We report institutional experience with intra-articular chromic phosphate ((32)P). METHODS AND MATERIALS: Records were reviewed from the Department of Radiation Oncology at Indiana University. Nine cases of PVNS treated with (32)P were identified (mean age=40). Seven patients were treated at time of recurrence and 2 patients were treated prophylactically. Intra-articular injections were performed by accessing the joint space, aspirating joint fluid, reinjecting 1-2 mCi of (32)P, and barbitaging to ensure good distribution in the joint space. No external beam radiation therapy was delivered. One patient was lost to followup. Mean followup of remaining patients was 20 months (range, 2-48). RESULTS: Eleven injections were performed in 9 patients. Eight had PVNS in the knee(s) and 1 patient had involvement of the hip. Two patients were treated more than once, one for a recurrence in the same joint at 13 months and another for PVNS of a contralateral joint. Three clinical recurrences (2, 13, and 28 months) were noted. Two of three recurrences were in patients who had bulky diffuse PVNS at the time of injection. Overall local control was 70%. In patients without bulky diffuse PVNS at the time of injection, local control was 88%. CONCLUSION: We report success using intra-articular injections of (32)P after synovectomy in patients with PVNS.

ACR Appropriateness Criteria: local excision in early-stage rectal cancer.

Low anterior resection or abdominoperineal resection is considered standard treatment for early rectal cancer. These procedures, however, carry a risk of morbidity and mortality that may not be warranted for early distal lesions, which may be treated with local excision. Emerging data has investigated the efficacy of local excision in patients with early stage rectal cancers. An expert panel designated by the American College of Radiology has reviewed supporting data, from a few prospective multi-institutional trials and a number of single-institution, retrospective reviews. The consensus recognizes the importance of accurate staging to identify patients who may be candidates for a local excision approach. Optimal candidates for local excision alone include small, low-lying T1 tumors, without adverse pathologic features. A number of procedures may be safely used including transanal, posterior trans-sphincteric, posterior proctotomy, transanal excision, or transanal microsurgery. It is important to note that none of these include lymph node evaluation, and depending on the risk of lymph node metastases, adjuvant radiation with or without chemotherapy may be warranted. Patients with positive margins or T3 lesions are at high risk of local recurrence and should be offered immediate APR or LAR. However, patients with high-risk T1 tumors, T2 tumors, or those who are not amenable to more radical surgery may benefit from adjuvant treatment. Data have also reported excellent local control rates for neoadjuvant radiation +/- chemotherapy followed by local excision in higher risk patients, but it is not yet clear if this approach reduces recurrence rates over surgery alone.

ACR Appropriateness Criteria: rectal cancer-metastatic disease at presentation.

In 2009, an estimated 40,870 new cases of rectal cancer will be diagnosed in the USA. After decades of treating metastatic colorectal cancer (CRC) with 5-fluorouracil alone, newer agents have resulted in significant improvements in disease-free and overall survival rates. These improvements stem from combinations of newer cytotoxic agents and targeted therapies. Based on performance status and burden of disease, metastatic CRC patients are generally treated with either a curative or palliative intent. Curative paradigm patients often have low burden liver or lung metastases which are technically resectable. Patients with resectable colorectal liver metastases and no evidence of any extrahepatic metastases have impressive 5-year survival rates of 30%-70% following resection. Unfortunately, only 20%-30% of patients with colorectal liver metastases are candidates for resection at initial presentation. Patients with unresectable liver or lung metastasis are candidates for local therapies including radioablation, chemoembolization, radioembolization, and stereotactic radiation therapy. In select patients with metastatic CRC, neoadjuvant or adjuvant pelvic chemoradiation (CRT) is indicated to prevent local recurrence. Patients who have resectable metastatic disease with symptomatic, obstructive, Stage T3-4 and N1, or low-lying (

Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients.

BACKGROUND: Low voriconazole levels have been associated with a higher failure rate in patients with confirmed fungal infections. METHODS: Steady-state plasma trough voriconazole levels were measured after at least 5 days of therapy in 87 patients with hematologic malignancies on 201 separate occasions (1-5 levels per patient; median, 2). Most patients (90%) had undergone allogeneic hematopoietic stem cell transplantation. The daily voriconazole dose, administered in 2 divided doses, was 200 mg (n = 4), 400 mg (n = 151), 500 mg (n = 20), 600 mg (n = 18), and 800 mg (n = 8); corresponding to 2.0-16.3 (median, 5.4) mg/kg. Plasma voriconazole levels were 0-12.5 microg/mL (median, 1.2). Voriconazole was undetectable (<0.2 mug/mL) in 15%. RESULTS: The correlation between dose and levels was weak (r = 0.14; P = .045). The median absolute daily drug dose (400 mg) was identical in groups of patients with levels of 0, 0.2 to 0.5, >0.5 to 2.0, >2.0 to 5.0, and >5.0. Whereas the daily drug dose in mg/kg was significantly higher when the levels were >5.0 microg/mL, there was no consistent relation between dose and level below that threshold. In adult patients getting standard doses of voriconazole orally, the drug levels are highly variable. Based on limited available data, between a quarter and two-thirds of these levels could potentially be associated with a lower likelihood of response or a higher likelihood of failure. CONCLUSIONS: Future voriconazole studies should incorporate prospective therapeutic drug monitoring and consideration should be given to checking levels in patients receiving the drug for confirmed, life-threatening fungal infections.