In-field Response Research Articles

Early radiotherapy versus late radiotherapy after incomplete transarterial chemoembolization in hepatocellular carcinoma.

459 Background: To investigate the efficacy of early RT (ERT) in comparison to late RT (LRT) in HCC patients after incomplete TACE. Methods: Between January 2006 and December 2011, 99 BCLC B and C stage HCC patients were reviewed. We defined ERT as curative aimed additional RT after the first TACE, and LRT was defined as salvage aimed additional RT for recurrent or re-growing remnant tumors after repeated TACE. The median prescribed dose was 45 Gy (range, 21.6 Gy–60 Gy) given in daily dose of 1.8 Gy–3 Gy. Three-dimensional conformal RT or intensity modulated RT was used for all patients. The in-field tumor response rate (IFTR) was evaluated using the modified response evaluation criteria in solid tumors. Results: Fifty eight (58.6%) patients received ERT and 41 (41.4%) patients received LRT. All patients had BCLC B-C stage HCC and the characteristics between two groups were not different significantly. However, vessel invasion was observed more often in the LRT group (p=0.039). The median interval between last TACE and RT was 2weeks in the ERT group, and 4 weeks in the LRT group. The IFTR at one month and three months were significantly higher in the ERT group. The one-year in-field progression-free survival rates were 79.5% and 45.9% in the ERT and LRT groups, respectively (p=0.007).The one-year overall survival rates were 75.9% and 48.8% in the ERT and LRT groups, respectively (p = 0.01). In the multivariate analysis, vessel invasion and treatment group (ERT vs.LRT) were independent predictor of OS (p=0.039 and p=0.035). PVTT and treatment group (ERT vs.LRT) showed correlation with IFPFS in the multivariate analysis (p=0.002 and p=0.01). Conclusions: While this finding may reflect differences in biological characteristics between the two groups, ERT within 2weeks after incomplete TACE should be considered.

A Prospective Phase 2 Multicenter Study for the Efficacy of Radiation Therapy Following Incomplete Transarterial Chemoembolization in Unresectable Hepatocellular Carcinoma

The purpose of this study was to investigate the efficacy and toxicity of radiation therapy (RT) following incomplete transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). The study was designed as a prospective phase 2 multicenter trial. Patients with unresectable HCC, who had viable tumor after TACE of no more than 3 courses, were eligible. Three-dimensional conformal RT (3D-CRT) was added for HCC treatment with incomplete uptake of iodized oil, and the interval from TACE to RT was 4 to 6 weeks. The primary endpoint of this study was the tumor response after RT following incomplete TACE in unresectable HCC. Secondary endpoints were patterns of failure, progression-free survival (PFS), time to tumor progression (TTP), overall survival (OS) rates at 2 years, and treatment-associated toxicity. Survival was calculated from the start of RT. Between August 2008 and December 2010, 31 patients were enrolled. RT was delivered at a median dose of 54 Gy (range, 46-59.4 Gy) at 1.8 to 2 Gy per fraction. A best objective in-field response rate was achieved in 83.9% of patients, with complete response (CR) in 22.6% of patients and partial response in 61.3% of patients within 12 weeks post-RT. A best objective overall response rate was achieved in 64.5% of patients with CR in 19.4% of patients and PR in 45.1% of patients. The 2-year in-field PFS, PFS, TTP, and OS rates were 45.2%, 29.0%, 36.6%, and 61.3%, respectively. The Barcelona Clinic liver cancer stage was a significant independent prognostic factor for PFS (P=.023). Classic radiation-induced liver disease was not observed. There were no treatment-related deaths or hepatic failure. Early 3D-CRT following incomplete TACE is a safe and practical treatment option for patients with unresectable HCC.

A Prospective Phase II Multicenter Study for the Efficacy of Radiotherapy Following Incomplete Transarterial Chemoembolization in Unresectable Hepatocellular Carcinoma

The purpose of this study was to investigate the efficacy and toxicity of radiotherapy (RT) following incomplete transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). The study was designed as a prospective phase II multicenter trial. Patients with unresectable HCC, who has viable tumor after TACE of no more than 3 courses, were eligible. Three dimensional-conformal RT (3D-CRT) was added for HCC with incomplete uptake of iodized oil, and the interval from TACE to RT was 4-6 weeks Prescribed total doses were up to 60 gray (Gy) in the absence of a no dose limitation to normal tissues near the RT site but were reduced by 46 Gy until normal tissue constraints were allowed. The primary endpoint of this study was the tumor response according to the modified Response Evaluation Criteria in Solid Tumors criteria after RT following incomplete TACE in unresectable HCC. Secondary endpoints were patterns of failure, progression-free survival (PFS), time to tumor progression (TTP), overall survival (OS) rates at 2 years, and treatment-associated toxicity. Survival was calculated from the start of RT using the Kaplan-Meier method. Any factor that influenced prognosis in univariate analyses were subjected to multivariate analyses using the Cox proportional hazards regression model. Between August 2008 and December 2010, 31 patients were enrolled. RT was delivered with a median total dose 54 Gy (range, 46-59.4 Gy) in 1.8 to 2 Gy per fraction. Most patients (29 patients, 93.5%) received RT with a total dose ≥ 54 Gy. A best objective in-field response rate was achieved in 83.9% of patients with complete response (CR) in 22.6% of patients and partial response (PR) in 61.3% of patients within 12 weeks post-RT. A best overall response rate was achieved in 64.5% of patients with CR in 19.4% of patients and PR in 45.1% of patients. The 2-year IFPFS, PFS, TTP, and OS rates were 45.2%, 29.0%, 36.6%, and 61.3%, respectively. The Barcelona-Clinic Liver Cancer stage was identified as significant independent prognostic factor for PFS (P = 0.023). Overall, 22 patients (59.1%) had treatment failures. Hepatic in-field failure occurred in 10 patients (32.3%), hepatic out-of-field failure occurred in 11 patients (35.5%), and extrahepatic failure (distant metastasis) occurred in 13 patients (41.9%). The lung was the most common site for distant metastases. Classic radiation-induced liver disease was not observed. There was no treatment-related death or hepatic failure. Three-dimensional-CRT following incomplete TACE achieves a promising objective response rate and is a safe and practical treatment option for patients with unresectable HCC.

Radiation therapy is an effective modality in the treatment of mantle cell lymphoma, even in heavily pretreated patients.

Mantle cell lymphoma has an aggressive clinical course and continuous relapse pattern with a median survival of 3 to 7 years. Multiple courses of chemotherapy are the basis of treatment. Radiotherapy is underutilized in this disease. We undertook this study to assess the role of radiation therapy. A total of 41 consecutive patients with mantle cell lymphoma diagnosed from December, 1999 to January, 2010 who received radiation therapy were reviewed retrospectively. The main endpoint was in-field lymphoma response at each irradiated disease site. There were 39 evaluable patients (68 symptomatic sites). Sites treated included: nodal stations (n = 31), soft tissue (n = 13), mucosal sites (n = 11), central nervous system (n = 10), gastrointestinal tract (n = 2), and bone (n = 1). Median maximum tumor size at presentation was 3.5 cm (range, 1.3 cm-9.6 cm). The median dose of radiation was 30.6 Gy (range 18-40 Gy). Median follow-up post radiation per site was 12.3 months (range, 0.6-80.9 months). Response to treatment was complete in 47 sites (69.1%), partial in 16 sites (23.5%), and 5 sites (7.4%) had stable disease. In 9 (13.2%) sites local relapse occurred (median 7 months; range 2-21). The mean size of lymphoma at time of RT correlated with relapse, with tumors with local relapse larger than those without a local relapse (P = .005). Our data add to accumulating evidence that mantle cell lymphoma is a radio-sensitive disease with excellent responses to relatively low radiation doses, even in patients with chemo-refractory disease.

Effect of dynamic characteristics of building envelope on thermal-energy performance in winter conditions: In field experiment

Research about building strategies for energy saving is taking a growing interest worldwide. New solutions for building envelopes require increasingly sophisticated investigation to analyze the thermal-energy in-field dynamic response of constructions. Moreover, in-lab experiments are difficultly able to represent real environment boundary conditions. In this paper, effect of dynamic properties of building opaque envelope is investigated in winter conditions through an extensive continuous monitoring campaign of a dedicated experimental field. The field consists of: two full-scale buildings, an outdoor weather station, and two indoor microclimate stations. The two buildings were designed with the same stationary envelope characteristics, but different envelope technologies, materials and, therefore, different dynamic properties. Nevertheless, following Italian regulations about building energy performance in winter, they should behave the same. With the purpose to verify this hypothesis, a continuous long-term comparative monitoring is developed. The results only partly confirm that simplified hypothesis. In fact, in winter, while the two buildings exhibit equivalent long-term energy behavior, a weak difference is registered in terms of air temperature in free-floating, transient, and operative HVAC systems’ regime. Additionally, non-negligible discrepancies are registered in terms of mean radiant temperature, indoor humidity and internal–external envelope surface temperature, given the different transpiration rate of the two envelope systems and different solar reflectance values of the roofs.

External Beam Radiation Therapy With or Without 131I-MIBG Systemic Radiation Therapy in the Therapy of Patients With Malignant Pheochromocytoma and Paraganglioma

Patients with malignant pheochromocytoma (PCC) and paraganglioma (PGL) of the thorax, abdomen and pelvis are often not considered for external beam radiation therapy (EBRT) due to concerns that these tumors are not radiosensitive. Therefore, we have reviewed our institutional experience with EBRT with particular attention to a subset of patients treated with combined 131I-MIBG systemic radionuclide therapy and EBRT to areas of bulky disease. Forty-nine consecutive patients with a diagnosis of PCC or PGL treated with EBRT at the University of Pennsylvania from 1984 to 2012 were reviewed in an IRB-approved retrospective study. Response rate was evaluated by RECIST v1.1 criteria as stable disease and partial responses. Of the 24 patients with tumors in the thorax, abdomen or pelvis, the median dose/fractionation was 50 Gy/25 fractions. 20 patients received megavoltage photons and 4 patients received protons. The in-field objective response rate in evaluable patients was 85% with 75% of patients maintaining local control at 12 months. Treatment toxicity was related to irradiation of tumor-adjacent normal tissues without clinically significant hematologic toxicity in the 16 patients receiving only EBRT. Because of non-overlapping toxicity of EBRT and 131I-MIBG and the potential for radiosensitization from combined low dose rate-high dose rate therapy, 8 patients with widespread systemic metastases were treated with external beam radiation therapy to 12 sites of bulky, symptomatic tumor in conjunction with systemic 131I-MIBG (2 mCi/kg per treatment, median 2 cycles 3 months apart and radiation typically given immediately after second cycle). In these patients, all areas irradiated with EBRT showed durable objective tumor response despite all patients eventually experiencing out-of-field systemic progression at a median time of 11.9 months. The median survival in the combined modality cohort is 29 months. Four of these patients remain alive with excellent performance status 27, 29, 35 and 36 months after EBRT. EBRT can be highly effective in local management of PCC and PGL. EBRT can be used safely in conjunction with 131I-MIBG due to non-overlapping toxicities with excellent control of locally bulky tumors. Based on these results, a clinical protocol with combined 131I-MIBG and EBRT is currently being designed.

Is Stereotactic Body Radiation Therapy an Attractive Option for Unresectable Liver Metastases? A Preliminary Report From a Phase 2 Trial

To evaluate the feasibility of high-dose stereotactic body radiation therapy (SBRT) in the treatment of unresectable liver metastases. Patients with 1 to 3 liver metastases, with maximum individual tumor diameters less than 6 cm and a Karnofsky Performance Status of at least 70, were enrolled and treated by SBRT on a phase 2 clinical trial. Dose prescription was 75 Gy on 3 consecutive days. SBRT was delivered using the volumetric modulated arc therapy by RapidArc (Varian, Palo Alto, CA) technique. The primary end-point was in-field local control. Secondary end-points were toxicity and survival. Between February 2010 and September 2011, a total of 61 patients with 76 lesions were treated. Among the patients, 21 (34.3%) had stable extrahepatic disease at study entry. The most frequent primary sites were colorectal (45.9%) and breast (18%). Of the patients, 78.7% had 1 lesion, 18.0% had 2 lesions, and 3.3% had 3 lesions. After a median of 12 months (range, 2-26 months), the in-field local response rate was 94%. The median overall survival rate was 19 months, and actuarial survival at 12 months was 83.5%. None of the patients experienced grade 3 or higher acute toxicity. No radiation-induced liver disease was detected. One patient experienced G3 late toxicity at 6 months, resulting from chest wall pain. SBRT for unresectable liver metastases can be considered an effective, safe, and noninvasive therapeutic option, with excellent rates of local control and a low treatment-related toxicity.

Feasibility of Sorafenib Combined with Local Radiotherapy in Advanced Hepatocellular Carcinoma

PurposeSorafenib is an effective systemic agent for advanced hepatocellular carcinoma. To increase its efficacy, we evaluated the feasibility and benefit of sorafenib combined with radiotherapy.Materials and MethodsFrom July 2007 to July 2011, 31 patients were treated with a daily dose of 800 mg of sorafenib and radiotherapy. Among them, 13 patients who received radiotherapy on the bone metastasis were excluded. Thirteen patients received 30-54 Gy of radiotherapy on the primary tumor (primary group) and 5 patients received 30-58.4 Gy on the measurable metastatic lesions (measurable metastasis group). Tumor responses at 1 month after the completion of radiotherapy and overall survival were evaluated.ResultsThe in-field response rate was 100% in the primary group and 60% in the measurable metastasis group. A decrease of more than 80% in the tumor marker α-fetoprotein was observed in 7 patients in the primary group (54%). Toxicities of grades 3-4 were hand-foot syndrome in 3 (17%) patients, duodenal bleeding in 1 (6%) patient, thrombocytopenia in 3 (17%) patients and elevation of aspartate transaminase in 1 (6%) patient. The median overall survival was 7.8 months (95% confidence interval, 3.0-12.6).ConclusionThe combined treatment of sorafenib and radiotherapy was feasible and induced substantial tumor responses in the target lesions. The results of this study emphasize the importance of individualized approach in the management of advanced hepatocellular carcinoma and encourage the initiation of a controlled clinical trial.

The use of isolated limb infusion in limb threatening extremity sarcomas

This paper reports a single-institution experience with the use of isolated limb infusion for limb salvage in locally advanced, unresectable, recurrent limb threatening soft tissue sarcomas.Background: Locally advanced, limb threatening soft tissue sarcomas (STS) pose a significant treatment challenge. We report our experience using isolated limb infusion (ILI) in patients with unresectable extremity STS.Methods: A total of 22 patients with extremity STS underwent 26 ILIs with melphalan and dactinomycin. Patient characteristics, intra-operative parameters and toxicity were recorded. Outcome measures included limb-salvage and in-field response rates.Results: Of the 19 lower and 7 upper extremity ILIs, Wieberdink grade III toxicity or less was observed in all. Median followup was 11 months. A total of 17 patients were evaluable at 3 months post-ILI with an overall response rate of 42%. Four (24%) had complete response (CR), three (18%) partial response (PR), three (18%) stable disease (SD) and seven (41%) progressive disease (PD). Twelve of 17 (71%) underwent successful limb preservation at a median of 9 months post-ILI. Two (12%) were downstaged to resectable disease and remain showing no evidence of disease (NED) after surgery at 30 and 22 months post-ILI.Conclusions: ILI is an attractive modality that provides regional disease control and limb preservation in patients with limb threatening sarcoma. Although short-term results appear encouraging, long-term follow-up is needed to fully assess the role of ILI in unresectable extremity STS.

Radiation therapy for the management of patients with HTLV-1–associated adult T-cell leukemia/lymphoma

AbstractHuman T-cell leukemia virus type 1–associated adult T-cell leukemia/lymphoma (ATL) typically has survivals measured in months with chemotherapy. One prior published series (1983-1991) assessed local radiotherapy for ATL. Ten consecutive patients with pathologically confirmed ATL treated with radiotherapy were reviewed. Subtypes included acute (n = 7), smoldering (n = 2), and lymphomatous (n = 1). Patients received an average of 2.5 systemic therapy regimens before radiotherapy. Twenty lesions (cutaneous = 10, nodal = 8, extranodal = 2) were treated to a mean of 35.4 Gy/2-3 Gy (range, 12-60 Gy). At 9.0-month mean follow-up (range, 0.1-42.0 months), all lesions symptomatically and radiographically responded, with in-field complete responses in 40.0% (nodal 37.5% vs cutaneous 50.0%; P = .62). No patient experienced in-field progression. Nine patients developed new/progressive out-of-field disease. Median survival was 17.0 months (3-year survival, 30.0%). No Radiation Therapy Oncology Group acute grade ≥ 3 or any late toxicity was noted. This report is the first to use modern radiotherapy techniques and finds effective local control across ATL subtypes. Radiotherapy should be considered for symptomatic local progression of ATL.

Prehospital trauma systems reduce mortality in developing countries

The majority of trauma deaths in the developing world occur outside of the hospital. In the mid-1990s, preliminary studies of prehospital trauma systems showed improvements in mortality. However, no empirical data are available to assess the overall benefit of these systems. We undertook a systematic review and meta-analysis to assess the effectiveness of prehospital trauma systems in developing countries. We conducted multiple database and bibliography searches (from inception until December 2010) to identify articles assessing the effectiveness of prehospital trauma systems in developing countries. The primary outcome was mortality. Secondary outcomes were physiologic severity score, Injury Severity Score, and prehospital time. We calculated relative risks (95% confidence intervals [CIs]), performed a sensitivity analysis, and pooled estimates using a fixed effects method. Fourteen studies met our inclusion criteria for qualitative analysis. Eight studies representing seven countries (n = 5,607) were included in the meta-analysis. Our pooled estimates show a 25% decreased risk of dying from trauma in areas that have prehospital trauma systems (relative risk [RR], 0.75; 95% CI, 0.66-0.85), with no significant heterogeneity (χ = 3.71, p = 0.72). Rural settings showed slightly enhanced treatment effect compared with urban settings (RR, rural 0.71; 95% CI, 0.59-0.86 vs. urban 0.79; 95% CI, 0.65-0.94). In-field response time was reduced in both rural (without an ambulance system, 66 minutes, 95% CI: 24-108) and urban (with an ambulance system, 6 minutes, 95% CI: 5.47 to 6.53, p < 0.0005) settings. Prehospital trauma systems in developing countries, particularly middle-income countries, reduce mortality. These data should inform and encourage developing countries to adopt prehospital trauma systems at the policy level. Meta-analysis, level III+.

Limb Preservation With Isolated Limb Infusion for Locally Advanced Nonmelanoma Cutaneous and Soft-Tissue Malignant Neoplasms

To demonstrate the efficacy of isolated limb infusion (ILI) in limb preservation for patients with locally advanced soft-tissue sarcomas and nonmelanoma cutaneous malignant neoplasms. Locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms, including soft-tissue sarcomas of the extremities, can pose significant treatment challenges. We report our experience, including responses and limb preservation rates, using ILI in cutaneous and soft-tissue malignant neoplasms. We identified 22 patients with cutaneous and soft-tissue malignant neoplasms who underwent 26 ILIs with melphalan and dactinomycin from January 1, 2004, through December 31, 2009, from 5 institutions. Outcome measures included limb preservation and in-field response rates. Regional toxic effects were measured using the Wieberdink scale and serum creatinine phosphokinase levels. The median age was 70 years (range, 19-92 years), and 12 patients (55%) were women. Fourteen patients (64%) had sarcomas, 7 (32%) had Merkel cell carcinoma, and 1 (5%) had squamous cell carcinoma. The median length of stay was 5.5 days (interquartile range, 4-8 days). Twenty-five of the 26 ILIs (96%) resulted in Wieberdink grade III or less toxicity, and 1 patient (4%) developed grade IV toxicity. The median serum creatinine phosphokinase level was 127 U/L for upper extremity ILIs and 93 U/L for lower extremity ILIs. Nineteen of 22 patients (86%) underwent successful limb preservation. The 3-month in-field response rate was 79% (21% complete and 58% partial), and the median follow-up was 8.6 months (range, 1-63 months). Five patients underwent resection of disease after an ILI, of whom 80% are disease free at a median of 8.6 months. Isolated limb infusion provides an attractive alternative therapy for regional disease control and limb preservation in patients with limb-threatening cutaneous and soft-tissue malignant neoplasms. Short-term response rates appear encouraging, yet durability of response is unknown.

Prospective Multicenter Phase II Trial of Systemic ADH-1 in Combination With Melphalan via Isolated Limb Infusion in Patients With Advanced Extremity Melanoma

Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity. Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one). To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.

Highly Conformal Partial Liver Irradiation for Chemorefractory Unresectable Colorectal Liver Metastases

There is limited safety data regarding liver irradiation in patients that have been extensively pretreated for metastatic liver disease. The aim is to report toxicity and response data from a phase I study of partial liver irradiation using highly conformal radiotherapy (CRT) for unresectable colorectal liver metastases (CRLM) that have received all lines of therapy available. Eligible patients had unresectable or medically inoperable CRLM and received all standard therapies (chemotherapy, surgery, radiofrequency ablation), Childs score A and KPS > 60 and signed informed consent. CRT was delivered hypofractionated in 10 fractions over 2 weeks. Adaptive radiotherapy management was used with planning target volume being patient specific according to tumor motion characterized on 4DCT and cine MRI. Delivered dose was individualized according to volume of uninvolved liver irradiated to the prescribed dose in 3 dose bins: <30% = 40 Gy, 30-50% = 35 Gy, 50-70% = 30 Gy and to maintain the estimated risk of liver toxicity <5%. Six patients were entered in each dose bin. The primary endpoints were feasibility and toxicity, secondary local control, and survival. The toxicity was assessed using CTCAE v 3.0 scale: weekly during CRT, and at 1 month, then 3 monthly assessments also with imaging. Radiation induced liver disease (RILD) grade 4 within 12 weeks of radiation would have stopped recruitment. From Nov 2006 to March 2010, 18 patients were recruited and all completed CRT. Mean age 70 year (range, 44-85). Eight patients had metastatic disease at initial diagnosis. All patients had combination chemotherapy and or biological agents: median 2 lines (range, 1-4), 5 patients had hepatic resection and 7 also had radiofrequency ablation. The mean tumor volume was 85 cc (range, 3 cc to 395 cc). A total of 26 metastases were treated. The CRT tumor dose ranged from 30 Gy to 40 Gy (average 35 Gy. No grade 3/4/5 related acute toxicity was observed. No radiation-induced liver disease (RILD) was observed. Other toxicity within 3 months following CRT included grade 2: anemia (1), liver capsular pain (1), nausea (1) fatigue (2) and skin toxicity (1). Fifteen patients had at least 3 months of follow-up, in-field response assessed using CT at 3 months was: PR (6), MR/SD (5), PD (4). Median follow-up was 8.7 months (1.5 to 40 months). Median in field progression-free survival was 8.9 months. Median overall survival (OS) 17.7 months; 1 year OS 42% (95% CI 18-64%). On progression, 6 patients were re-challenged with chemotherapy. No late toxicities grades 3-5 were seen. In a heavily pretreated population with large liver burden disease this approach of individual dose CRT appears safe; with no additional toxicity observed in higher dose bin (40 Gy).

Helical tomotherapy with concurrent capecitabine for the treatment of inoperable pancreatic cancer

BackgroundHelical tomotherapy, an advanced intensity-modulated radiation therapy with integrated CT imaging, permits highly conformal irradiation with sparing of normal tissue. Capecitabine, a pro-drug of 5-FU that induces thymidine phosphorylase can achieve higher levels of intracellular 5-FU when administered concurrently with radiation. We evaluated the feasibility as well as the clinical outcome of concurrent administration of capecitabine with tomotherapy in patients with advanced pancreatic cancer.MethodsNineteen patients with advanced pancreatic cancer including primarily unresectable disease and recurrence after curative surgery were included in the study. Two planning target volumes (PTV) were entered: PTV1 is gross tumor volume; and PTV2, the volume of the draining lymph nodes. The total doses to target 1 and target 2 were 55 and 50 Gy, respectively. Capecitabine at 1600 mg/m2/day was administered on each day of irradiation.ResultsTwenty six measurable lesions were evaluated. Overall in-field response rate was 42.3%; partial responses were achieved in 53.3% of the pancreatic masses, 28.6% of distant metastatic lesions and 25.0% of regional lymph nodes. The median duration of follow-up after tomotherapy was 6.5 months. None of the lesions showed in-field progression. Treatment was well tolerated with only minor toxicities such as grade 1 nausea (one patient), grade 1 hand-foot syndrome (one patient) and grade 1/2 fatigue (three patients).ConclusionsHelical tomotherapy with concurrent capecitabine is a feasible option without significant toxicities in patients with advanced pancreatic cancer. We achieved excellent conformal distribution of radiation doses and minimal treatment-related toxicities with promising target volume responses.

A phase 1 study of systemic ADH‐1 in combination with melphalan via isolated limb infusion in patients with locally advanced in‐transit malignant melanoma

Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed. Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors. Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n=14) and pain (n=12). Grade 3 toxicities included shortness of breath (n=1), hypertension (n=1), serologic toxicities (n=4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels. Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.

Dose Escalated, Hypofractionated Radiotherapy Using Helical Tomotherapy for Inoperable Non-Small Cell Lung Cancer: Preliminary Results of a Risk-Stratified Phase I Dose Escalation Study

To improve local control for inoperable non-small cell lung cancer (NSCLC), a phase I dose escalation study for locally advanced and medically inoperable patients was devised to escalate tumor dose while limiting the dose to organs at risk including the esophagus, spinal cord, and residual lung. Helical tomotherapy provided image-guided IMRT, delivered in a 5-week hypofractionated schedule to minimize the effect of accelerated repopulation. Forty-six patients judged not to be surgical candidates with Stage I-IV NSCLC were treated. Concurrent chemotherapy was not allowed. Radiotherapy was delivered via helical tomotherapy and limited to the primary site and clinically proven or suspicious nodal regions without elective nodal irradiation. Patients were placed in 1 of 5 dose bins, all treated for 25 fractions, with dose per fraction ranging from 2.28 to 3.22 Gy. The bin doses of 57 to 80.5 Gy result in 2 Gy/fraction normalized tissue dose (NTD) equivalents of 60 to 100 Gy. In each bin, the starting dose was determined by the relative normalized tissue mean dose modeled to cause < 20% Grade 2 pneumonitis. Dose constraints included spinal cord maximum NTD of 50 Gy, esophageal maximum NTD < 64 Gy to < or = 0.5 cc volume, and esophageal effective volume of 30%. No grade 3 RTOG acute pneumonitis (NCI-CTC v.3) or esophageal toxicities (CTCAE v.3.0 and RTOG) were observed at median follow-up of 8.1 months. Pneumonitis rates were 70% grade 1 and 13% grade 2. Multivariate analysis identified lung NTD(mean) (p=0.012) and administration of adjuvant chemotherapy following radiotherapy (p=0.015) to be independent risk factors for grade 2 pneumonitis. Only seven patients (15%) required narcotic analgesics (RTOG grade 2 toxicity) for esophagitis, with only 2.3% average weight loss during treatment. Best in-field gross response rates were 17% complete response, 43% partial response, 26% stable disease, and 6.5% in-field thoracic progression. The out-of-field thoracic failure rate was 13%, and distal failure rate was 28%. The median survival was 18 months with 2-year overall survival of 46.8% +/- 9.7% for this cohort, 50% of whom were stage IIIB and 30% stage IIIA. Dose escalation can be safely achieved in NSCLC with lower than expected rates of pneumonitis and esophagitis using hypofractionated image-guided IMRT. The maximum tolerated dose has yet to be reached.

Phase I study of stereotactic radiotherapy for unresectable hepatobiliary cancer and liver metastases

4590 Background: Safety of stereotactic radiotherapy (SRT) for unresectable hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CC) and liver metastases (LM) has not been well established. Results from a phase I study of 6 fraction SRT are reported. Methods: Eligible patients had unresectable or medically inoperable HCC, CC or LM, liver enzymes &lt; 6 fold higher than normal, platelets &gt; 80,000 bil/L, Child score A, &gt; 800 cc uninvolved liver, KPS = 60 and unsuitability for standard therapies. Patients were treated with breath hold and image guided 6 fraction SRT. Dose was individualized to maintain the same risk of liver toxicity at three risk levels (I-5%, II-10%, III-20%). Escalation to level II and III occurred once at least 3 patients had been followed for &gt;3 months without dose limiting toxicity (grade 4/5 &lt; 1 month or grade 4/5 liver &lt; 3 months) for each stratum. Stratification was based on diagnosis and liver volume irradiated (low &lt;20%, mid 20–50%, high 50–80%). Results: From Aug. 2003 to Dec. 2006, 82 patients initiated SRT. Two patients discontinued SRT after 1 fraction for progressive disease (LM) and a variceal bleed (HCC). 80 patients completed SRT (38 LM, 32 HCC, 10 CC). Median age was 64 years (38–92 years). Median tumor volume was 293 cc (3–3088 cc). 24 patients (30%) had extra-hepatic disease. 17 HCC patients had portal vein thrombosis (53%), 14 HBV, 12 HCV and 4 alcoholic cirrhosis. The median prescribed dose was 40 Gy (24 Gy - 60 Gy) in 6 fractions. Within 3 months post SRT, no dose-limiting grade 4/5 toxicity or classic radiation liver toxicity was observed. Grade 3 liver enzymes (2 new, 9 pre-existing), thrombocytopenia (3), nausea (3) and fatigue (1) was observed. Child score declined in 8 patients (5 HCC, 2 CC, 1 LM), 6 with progressive disease. Late toxicity included 1 tumor-duodenal fistula, 1 bowel obstruction and 2 GI bleeds. The in-field response rate was 60% (LM 57%, CC 50%, HCC 67%): CR 14%, PR 46%, SD 23%, PD 17%. Actuarial 12 month local control was 78% (95% CI: 58- 90%). The median survival for LM, CC and HCC was 16.6 months (7.9–25.6), 13.1 months (6.0–28.4) and 11.0 months (8.6–20.8) respectively. Conclusions: Individualized SRT is a safe, promising treatment for unresectable liver cancer. No significant financial relationships to disclose.

A phase I dose-escalating study of combination pemetrexed-based chemotherapy and concomitant radiotherapy for locally advanced or metastatic non-small cell lung or esophageal cancer

7062 Background: Pemetrexed (pem, Alimta) is a multitargeted antifolate approved for second-line treatment of metastatic non-small cell lung cancer (NSCLC). Treatment failure with chemoradiotherapy (CRT) is frequently due to development of distant metastasis suggesting a potential need for more effective systemic therapy. The primary objective was to determine whether pem based CRT allows administration of systemically active chemotherapy doses. Methods: Patients (pts) with locally advanced or metastatic (dominant local symptoms) NSCLC or esophageal cancer (ca) were enrolled in a phase I dose-escalating study with chemotherapy delivered on day 1, every 21 days for 2 cycles. Schedule 1 was pem (200–600 mg/m2) with concurrent radiotherapy (RT) 40–66Gy (2 Gy/d). Schedule 2 was pem fixed at recommended single-agent dose (500 mg/m2) and escalating carboplatin doses (AUC 4–6) + concomitant RT (40–66Gy). Results: 30 pts (18 locally advanced, 12 metastatic disease) were enrolled. ECOG performance status was 0 (8 pts, 26.7%), 1 (21 pts, 70.0%), and 2 (1 pt, 3.3%). Schedule 1 enrolled 18 pts (15 NSCLC, 3 esophageal ca); all dose levels were tolerable. One DLT (Grade [Gr] 4 esophagitis) was reported. One pt developed Gr 4 pulmonary embolism (PE) at the end of therapy. Gr 3 toxicities were leukopenia (n=3), dysphagia (1), and dehydration (1). Schedule 2 enrolled 12 NSCLC pts; all dose levels were tolerated. One DLT (Gr 4 PE) was reported at 500 mg/m2 + AUC 6. One pt had Gr 4 leukopenia at 500 mg/m2 + AUC 5. Treatment-related grade 3 toxicities were leukopenia (n=3), dehydration (1), and fatigue (1). Overall responses for Schedule 1 were PR (n=5), SD (5), PD (6), and unknown (2); for Schedule 2, pts had CR (1), PR (3), SD (4), PD (1), and unknown (3). Study is on-going. 3 pts had Gr 1/2 radiation pneumonitis (8 d - 8 w) after RT. Several pts underwent curative intent surgery. In-field responses are being assessed. Conclusions: The combination of pemetrexed (500 mg/m2) with carboplatin (AUC 6) day 1 every 21 days for 2 cycles with concurrent radiotherapy is feasible, allows administration of systemically active doses, and warrants examination in a phase II trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly

Preliminary results of a phase I study of stereotactic radiotherapy for unresectable primary and metastatic liver cancer

4127 Purpose: To report initial toxicity and response data from a phase I study of stereotactic radiotherapy (SRT) for unresectable liver cancer. Methods: Eligible patients have unresectable or medically inoperable primary or metastatic liver cancer, Childs score A and KPS ≥ 60. Standard treatment options have been explored. Patients are stratified based on diagnosis (metastases vs. primary cancer) and volume of uninvolved liver treated (< 20%, 20–50%, 50–80%). SRT is delivered in 6 fractions/2 weeks to maximize patient convenience, resource utilization and therapeutic gain. Dose is individualized to maintain the same estimated risk of liver toxicity for patients at each level (level I - 5% risk, level II - 10% risk, level III - 20%, max. dose 60 Gy in 6 fractions). Escalation to level II and III occurs once at least 3 patients have been followed for >3 months without dose limiting toxicity for each stratum at the previous level. Patients are treated during breath hold to reduce organ motion, with daily imaging and repositioning to reduce setup error. Acute toxicity scored using CTC v3.0. Results: From Aug 2003 to Dec 2004, 36 patients completed SRT at levels I and II (14 hepatocellular carcinoma, 6 cholangiocarcinoma, 16 metastases). The median tumor volume was 213.9 cm3 (range 9.2 to 3088cm3). The average SRT dose to tumor was 35.7 Gy (range: 24 to 56.3 Gy). Median follow-up was 5.5 months (1.4 to 14.9 months). No grade 4/5 related toxicity was seen. At 1 month, 4 patients with HCC had a decline in liver function to Child B. No radiation-induced liver disease (RILD) was observed. Toxicity within 3 months included: grade 3 fatigue (1), vomiting (1); grade 2: thrombocytopenia (2), gastritis (4), pruritis (2), vomiting (2), nausea (6), anorexia (2) fatigue (8), hepatic pain (2). One gastrointestinal bleed occurred 6.4 months following SRT in a patient with tumor extension to the stomach on endoscopy. In 28 evaluable patients, in-field response assessed using CT at 3 months was: CR (1), PR (9), MR/SD (14), PD (4) Conclusion: This approach of individualized dose SRT appears safe, with no severe liver toxicity observed to date. More patients and longer follow up are required for a further assessment of late toxicity and efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ASCO CDA, Canadian Institutes of Health Research, NIH (US)/ NCI, NIH (US)/ Ontario portion/year, Ontario Cancer Research Network, Lustgarten Foundation for Pancreatic Cancer Research