Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

BACKGROUND AND PURPOSE: Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. MATERIALS AND METHODS: Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. RESULTS: Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from nonpseudoprogression (true progression and mixed) with an area under the curve of 0.807. CONCLUSIONS: DTI and DSC perfusion imaging can improve accuracy in assessing treatment response and may aid in individualized treatment of patients with glioblastomas.

The effects of titanium mesh on passive-scattering proton dose.

High-density metallic implants can introduce considerable uncertainties in proton therapy treatment planning. These uncertainties eventually translate into proton range errors, which may cause significant underdosing to the target volume or overdosing to normal tissue beyond the target. This study investigated the dosimetric impact of a 0.6 mm titanium (Ti) mesh implant in passive-scattering proton beam therapy through the study of the depth dose and output in water, and the dose profiles in solid water at various depths. The measurements were performed for a beam with a range of 8.5 cm and a modulation of 7.5 cm. The titanium mesh was placed at a depth of 1 cm below the surface of the phantom for all measurements. A range reduction of 0.5 ± 0.1 mm was observed for a beam perpendicular to the mesh, with no further reductions when the incident angle increased to 60°. We conclude that the dosimetric effect of a 0.6 mm titanium mesh implant is small for a passive scattering proton beam. With proper correction applied to metal artifacts, consistent results were observed in the phantom study in the treatment planning system.

A Phase II safety and effect on time to tumor progression study of intratumoral light infusion technology using talaporfin sodium in patients with metastatic colorectal cancer.

BACKGROUND AND OBJECTIVES: Twenty-seven patients with refractory liver metastases from colorectal cancer took part in a Phase II study of the light infusion technology (Litx) light-activated drug/device system to assess safety and evaluate time to tumor progression (TTP). METHODS: Litx consists of the light-activated drug, talaporfin sodium (LS11), activated intratumorally by a catheter-like array of light-emitting diodes (LEDs). After placement of the array via ultrasound or computed tomography (CT) guidance, LS11 was administered intravenously, followed 15-60 min later by light infusion for 2.8 hr. Patients were assessed for adverse events and tumor response using physical examination, laboratory values, and CT scan evaluation over a period of 60 days. RESULTS: The observed occurrence of Litx treatment-related adverse events was minimal and cumulative toxicity did not occur when combined with chemotherapy. Assessment of TTP and tumor response rate, although statistically non-robust, suggest potential improvement. CONCLUSIONS: The Litx system was shown to be safe for treating liver metastases from colorectal cancer and there was no cumulative toxicity when combined with standard systemic therapy. Preliminary assessments of TTP and tumor response rate justify further evaluation in a Phase III follow-up study.

Complete remission of nonresectable pancreatic cancer after infusional colloidal phosphorus-32 brachytherapy, external beam radiation therapy, and 5-fluorouracil: a preliminary report.

This is a preliminary report of five patients diagnosed with locally advanced nonresectable pancreatic cancer who achieved improved quality of life, delay of local progression, and reduction of biomarker CA 19-9 after infusion of colloidal phosphorus 32 (32P) and administration of combined chemoradiotherapy. A phase II trial using intratumoral colloidal 32P delivery for nonresectable pancreatic cancer without metastases is in progress. Patients initially were given infusions of decadron followed by macroaggregated albumin and 30 mCi colloidal 32P to the interstitial space of the tumor by two infusions 1 week apart. Through this method, doses ranging from 750,000 to 1,800,000 cGy were delivered. After administration of colloidal 32P, external radiation to a dose of 6000 cGy minimum tumor dose, including regional lymph nodes, was given concomitantly with four intravenous infusions of 500 mg bolus 5-fluorouracil on alternating days within the first 2 weeks after initiation of external radiation. All five of these patients demonstrated cessation of local tumor growth or regression of disease on serial computed tomography scans for a minimum of 10 months from completion of therapy. Three of these patients have survived without local disease progression over 24 months from initiation of therapy, with one patient approaching 36 months. CA 19-9 values for all patients declined within weeks after completion of therapy. This new method of isotope delivery has resulted in reduction of tumor volume, normalization of the biomarker CA 19-9, and improved performance status in those patients who have localized nonresectable disease without dissemination.

Changes in high-dose-rate tandem and ovoid applicator positions during treatment in an unfixed brachytherapy system.

PURPOSE: To measure the change in applicator position during treatment in an unfixed high-dose-rate (HDR) brachytherapy system and to evaluate the effect of the shifts on dose calculations. MATERIALS AND METHODS: Posttreatment localization radiographs were obtained for 47 HDR treatments (26 tandem and ovoid applicators, 21 ovoids-only applicators). The authors measured the change in applicator position relative to the patient's bone anatomy. Doses to the target and critical structures were calculated for posttreatment applicator positions for comparison. RESULTS: Average displacements of the tandem and ovoid applicators in anteroposterior dimension were 5 and 4 mm for the tandem and ovoids, respectively. Anterior displacement occurred twice as often as posterior displacement. The average lateral and longitudinal shifts were less. Less displacement was observed with ovoids-only insertions. The largest displacement for ovoids-only applicators was 3 mm in the anteroposterior dimension. A high bladder dose difference (17.4%) for tandem and ovoid applications correlated with anterior shifts of the applicators. CONCLUSION: Patient movement in an unfixed HDR brachytherapy system can displace the applicators, especially the tandem. Anterior shifts correlate with high bladder dose differences. Immobilization of the patient's hips and legs, as well as stabilization of applicators, would reduce these shifts.

A new method for delivering radioactive cytotoxic agents in solid cancers.

PURPOSE: Therapeutic agents such as monoclonal antibodies, radiopharmaceuticals, and radioactive growth factors are limited in effectiveness due to the inability to deposit significant quantities of the agents and for limited periods of time in solid cancer. A new technique based on knowledge of the pathophysiology of solid tumors allows for significant concentration of these agents to accumulate and for a prolonged period of time, thus allowing interaction with the tumor for potentially increased effectiveness. METHODS AND MATERIALS: Three agents have been studied: 131I antiferritin monoclonal antibody, colloidal 32P chromic phosphate, and 131I transferrin. The time required for maximal tumor uptake was determined in vitro in tissue culture and was 10 min, 25 min, and 40 min, respectively. The new method of in vivo tumor infusion consisted of a direct intratumoral injection of macroaggregated albumin (MAA) 10,000 particles, followed by the radioactive agents under study. Tumors were infused in vivo using the new technique and compared to intratumoral infused controls. In the instance of radiolabeled antiferritin antibody, intraperitoneal administration and intratumoral infusion were compared to the new technique. In the other two instances, intratumoral infusion was compared to the new method. RESULTS: In all instances the direct vascular blockade caused by MAA led to greater deposition of the agent under study for at least 24 h. These results were clinically applied with MAA followed by 32P colloidal chromic phosphate and were consistent with the experimental findings. CONCLUSION: A new technique is described that may be carried out in the experimental laboratory and clinic by direct tumor infusion of macroaggregated albumin (MAA), followed by other radioactive agents that will remain localized in solid cancers and will allow for high tumor dose deposition for potentially increased therapeutic efficacy.

Improvements observed in care and outcome in carcinoma of the larynx.

The 1978 Patterns of Care Studies (PCS) survey of carcinoma of the larynx reviewed the process (pre-treatment evaluation and treatment) and outcome of 521 patients. When compared to results from the 1973 PCS survey, several important changes have been observed. The use of surgery in conjunction with radiation therapy (RT) increased in Stage III cases from less than 30% to greater than 60% and in Stage IV cases from 48% to greater than 70%. This change in therapy was associated with a decline in locoregional failure in this patient group. Among Stage I and II supra- and subglottic carcinomas, an improvement in 3-year local tumor control (Stage I: 78 to 100% and Stage II: 54 to 74%) and overall freedom from recurrence (Stage I: 78 to 100% and Stage II: 45 to 73%) was seen over this 5-year period with no identifiable change in process for this subgroup. Also noted was an improvement in the freedom from recurrence rate for Stage III and IV patients receiving treatment at facilities with low process scores. The 1978 PCS survey confirmed the presence of superior patient outcome in several subgroups and the relationship of this improvement to patient process.

Effect of Fluosol-DA 20% and oxygen on response of C57BL/6 mice to whole-body irradiation.

Normal tissue effects in mice due to combinations of a perfluorochemical emulsion, Fluosol-DA 20%, 100% oxygen, and whole-body irradiation were investigated. Eight-to-10-week-old C57BL/6 male mice were injected via the tail vein with 10 ml/kg of Fluosol-DA with and without subsequent exposure to oxygen for 60 minutes. Animals then received graded doses of whole-body radiation (4 MV photons) at a dose rate of 2.85 +/- .015 Gy/minute. Using linear regression analysis, the lethal doses of radiation to 50% and 10% of the animals within 30 days in the absence of Fluosol-DA and oxygen were 8.35 Gy (95% c.l.:7.77-8.93 Gy) and 6.73 Gy (95% cl.:6.21-7.25 Gy), respectively, and were unaffected by Fluosol-DA and/or oxygen pre-treatment. However, Fluosol-DA given alone or in combination with oxygen produced increased balding and decreased graying incidence in mice within 60 days, and resulted in depressed weight gain 15 to 60 days post-treatment. Normal tissue effects due to administration of Fluosol-DA and oxygen in combination with whole-body irradiation have been demonstrated but appear minimal compared to other anti-tumor modalities currently under investigation.

Impact of initial quality control review on study outcome in lung and head/neck cancer studies--review of the Radiation Therapy Oncology Group experience.

The Radiation Therapy Oncology Group (RTOG) initiated cooperative clinical trials in 1971. In 1978, RTOG developed a formalized program of Quality Control (QC) divided into initial and final phases. The initial review process consisted of two steps. The first phase of review is an evaluation performed by a radiation oncologist to verify treatment plan and field borders. The second portion of the initial review process originally consisted of dosimetry calculation verification based on machine data provided by the regional Radiological Physics Center and treatment planning data provided by the accessioning institution. Between 1978 and December 31, 1987, a total of 11,343 cases in 96 RTOG protocols, excluding particle studies, underwent initial review. Of this number, 2227 patients were entered in lung cancer studies and 1341 patients were entered in head/neck cancer studies. Initial review was carried out in 2089 (93.8%) of the lung cancer cases. Missing or delayed data accounted for 138 (6.2%) cases not reviewed initially. In head/neck cancer trials, 1251 (93.2%) received initial review and 90 (6.8%) did not. Our findings suggest that there are sharply defined but long lasting learning experiences involved in clinical trial participation. Consideration may be given to modifying the initial review process to use random sampling of cases accessioned by experienced investigators in ongoing clinical trials and to continuing the total case evaluation on all new studies and cases entered by inexperienced investigators or investigators/institutions with unsatisfactory performance. Recommendations regarding initial review of other sites will await evaluation of the impact of initial review on those sites.

The effect of fraction size on control of early glottic cancer.

A retrospective analysis of 600 patients treated for head and neck malignancy at the Cooper Hospital/University Medical Center was undertaken. Patients who had surgical intervention (excluding biopsy) were withdrawn from this review. Fifty-eight patients with Stage I Glottic Laryngeal Carcinoma were identified and constitute the basis of this report. Various parameters were analyzed to assess their impact on local control. These include age, sex, serum hemoglobin, tumor bulk, differentiation, field size, total dose, total treatment time, and fraction size. Overall local control was 87% with a median follow-up of 63 months. The only factor that influenced local control was fraction size. Of 28 patients treated with 180 cGy fractions, seven (25%) had a local recurrence within 3 years. Twenty-eight patients treated with 200 cGy or greater fractions have had no failures to date. The difference in control rate when comparing the two treatment schema was significant (p less than 0.01). The median dose in the controlled 180 cGy group was 6660 cGy (range, 6300-7020 cGy). In the patients who failed in the 180 cGy group the median dose was 6660 cGy (range, 6480-6840 cGy). The patients receiving 200 cGy fractions or greater had a median dose of 6600 cGy (range, 6000-6950 cGy) and an average dose of 6507 cGy. The mean NSD in the 180 cGy group failing was 1787 RET (range, 1735-1843 RET). Patients who were controlled and received 180 cGy fractions had a median NSD of 1796 RET (range, 1743-1868). The mean NSD in the 200 cGy group was 1847 RET. The median TDF in the 180 cGy group of patients controlled was 102. Those failing also had a TDF of 102 (range, 101-105). Patients receiving 200 cGy fractions or greater had a median TDF of 109. It appears from this data that fraction size is a highly significant factor in our ability to control glottic laryngeal cancer.

The Patterns of Care Outcome Studies: results of the National practice in carcinoma of the larynx.

The Patterns of Care Study conducted a survey of patients with glottic and supraglottic carcinomas treated in 1973 and 1974. Patients for this study were randomly selected from all types of treatment facilities, including those with full and part-time therapists and large and small institutions. Detailed evaluation and treatment parameters were recorded for a total of 707 patients. Overall three-year recurrence free survival for glottic carcinoma was: Stage I, 90%; Stage II, 78%; Stage III, 65%; and Stage IV, 23%. For supraglottic carcinoma the rates are: Stage I 78%, Stage II, 60%, Stage III, 34% and Stage IV, 30%. The use of surgery in this study for advanced lesions varied among different departments. For advanced lesions, those treated with combined radiation and surgery had improved survival; this was also related to completeness of work-up and departmental equipment.

Adjuvant methotrexate in the radiotherapeutic management of advanced tumors of the head and neck.

Oral methotrexate (MTX) was administered to a group of 48 patients with advanced head and neck tumors prior to radiation therapy in a nonrandomized manner. A second group of 75 similar patients were randomized to intravenous (i.v.) MTX plus radiation or radiation alone. Three-year survival rates by life table analysis show no significant statistical difference between i.v. MTX plus radiation or radiation alone. Those treated with oral MTX plus radiation have a statistically significant improved survival. The degree of tumor regression in the oral MTX group was correlated with survival. No similar correlation could be found in the intravenous MTX group. The use of either form of MTX correlated with a lower rate of distant metastasis.