Progress toward a thermal dosimetry system.
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Hyperthermia, Induced↗
Biomedical subjects
L R Prosnitz
Publications and source records attributed to L R Prosnitz.
The role of three dimensional functional lung imaging in radiation treatment planning: the functional dose-volume histogram.
PURPOSE: During thoracic irradiation (XRT), treatment fields are usually designed to minimize the volume of nontumor-containing lung included. Generally, functional heterogeneities within the lung are not considered. The three dimensional (3D) functional information provided by single photon emission computed tomography (SPECT) lung perfusion scans might be useful in designing beams that minimize incidental irradiation of functioning lung tissue. We herein review the pretreatment SPECT scans in 86 patients (56 with lung cancer) to determine which are likely to benefit from this technology. METHODS AND MATERIALS: Prior to thoracic XRT, SPECT lung perfusion scans were obtained following the intravenous injection of approximately 4 mCi of 99mcTc-labeled macro-aggregated albumin. The presence of areas of decreased perfusion, their location relative to the tumor, and the potential clinical usefulness of their recognition, were scored. Patients were grouped and compared (two-tailed chi-square) based on clinical factors. Conventional dose-volume histograms (DVHs) (DVFHs) are calculated based on the dose distribution throughout the computed tomography (CT)-defined lung and SPECT-defined perfused lung, respectively. RESULTS: Among 56 lung cancer patients, decreases in perfusion were observed at the tumor, adjacent to the tumor, and separate from the tumor in 94%, 74%, and 42% of patients, respectively. Perfusion defects adjacent to the tumor were often large with centrally placed tumors. Hypoperfusion in regions separate from the tumor were statistically most common in patients with relatively poor pulmonary function and chronic obstructive pulmonary disease (COPD). Considering all SPECT defects adjacent to and separate from the tumor, corresponding CT abnormalities were seen in only approximately 50% and 20% of patients, respectively, and were generally not as impressive. Following XRT, hypoperfusion at and separate from the tumor persisted, while defects adjacent to the tumor improved in several patients. In four patients who achieved a complete response scored by CT with chemotherapy prior to XRT, persistent hypoperfusion was present at and adjacent to the tumor site in three. Among 30 patients with cancers not arising in the lung (14 breast, 12 lymphoma, 4 others), perfusion defects were seen in only 4 (2 adjacent and 2 apart). Recognition of decreases in perfusion mainly impacted on treatment planning for a few patients with poor pulmonary function and limited target volumes. DVFHs have been useful in beam selection for patients with marked perfusion heterogeneities. CONCLUSIONS: Lung perfusion scans provide functional information not provided by CT scans that can be useful in designing radiation treatment beams that minimize incidental irradiation of the function regions of the lung. This approach appears to be most helpful in patients with gross intrathoracic lung cancer, especially those with small targets and relatively poor pulmonary function. One limitation of this approach is that some of the defects adjacent to the tumor site reperfuse following treatment, indicating that these scans identify perfusion rather than potential perfusion. Three dimensional functional data can be used to generate DVFHs that may be more predictive of the physiological consequences of the radiation than conventional DVHs. Additional work is currently underway to test this hypothesis.
Forced Expiratory Volume↗
Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases.
PURPOSE: The validity of tumor pO2 measurement as a predictive outcome assay depends upon demonstrating that intrapatient pO2 variation is less than interpatient variation. No consensus exists regarding the appropriate distance between individual measurements. This distance could affect the calculation of the hypoxic fraction (% pO2s < 5 mm Hg) and the assessment of intra/interpatient heterogeneity. This study was performed to evaluate tumor oxygenation and to assess the effects of two different measurement intervals on pO2 heterogeneity in three different sets of patients. MATERIALS AND METHODS: Fifteen patients with soft tissue sarcoma, nine patients with cervical carcinoma, and eight patients with squamous carcinoma metastatic to lymph nodes underwent pretreatment polarographic pO2 measurements. Two grossly distinct sites were studied in each tumor, and 2-3 linear tracks were measured at each site. Track lengths varied from 20-36 mm. Distance between measured points was either 0.7-0.8 mm or 0.4 mm. Mean pO2, median pO2, and hypoxic fraction were calculated for each track. Data for each patient were also averaged across all tracks obtained for that patient. Track-specific data were used to evaluate intrapatient variation. The range of average values for each patient was used to assess interpatient heterogeneity. The ratio of these measures provided an assessment of within- vs. between-patient heterogeneity. RESULTS: The median number of pO2 measurements/patient was 200 (range: 88-356). The average length of hypoxic regions varied from 4.5-5.6 mm. Median tumor pO2s for the cervix, lymph node, and sarcoma patients were 4.5 mm Hg, 12.6 mm Hg, and 18.0 mm Hg, respectively (p = 0.07). Median hypoxic fractions were 0.61, 0.36, and 0.31, respectively (p = 0.07). Intrapatient heterogeneity was less than interpatient heterogeneity for all parameters in all patients, except for mean pO2 for the cervix patients measured at 0.7-mm increments (1.51). Assessment of oxygenation was not affected by the distance between samples. CONCLUSIONS: Heterogeneity of tumor oxygenation within tumors is less than that between tumors. Both 0.4 mm and 0.7-0.8 mm sampling increments provide similar data. Longer term follow-up of large numbers of uniformly treated patients is required to define the value of tumor oxygen measurement as a predictor of treatment outcome.
Carcinoma, Squamous Cell↗
Estrogen replacement therapy in breast cancer survivors.
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Breast Neoplasms↗
Second solid malignancies after combined modality therapy for Hodgkin's disease.
PURPOSE: To determine the actuarial incidence (AI) and relative risk (RR) of second solid malignancies (SSM; solid tumors and non-Hodgkin's lymphoma) in patients with Hodgkin's disease who were treated with chemotherapy and adjuvant, low-dose radiation (combined modality therapy; CMT). PATIENTS AND METHODS: From 1969 to 1983, 102 patients with previously untreated advanced Hodgkin's disease (group A) and 81 patients with recurrent disease after radiation (group B) were treated with CMT. Patients were observed for the development of solid tumors (ST) and non-Hodgkin's lymphoma (NHL), and the AI and RR were calculated. RESULTS: Nearly half of the patients entering remission were observed for greater than 15 years. At 20 years, the AI for SSM was 12% in group A versus 41% in group B (P = .009). The overall RR for developing a ST in group A was 1.88 (not significant) versus 8.84 in group B (95% confidence interval, 5.3 to 15.4). The difference in the RR between groups A and B was significant (P < .001). The RR for developing NHL was significantly increased in both groups, but the difference between groups was not significant. CONCLUSION: Previously untreated patients with advanced disease who were treated with CMT (group A) had a modest but not significant increase in the RR of ST; however, patients treated with CMT for recurrent disease (group B) had a highly significant increase in the RR of ST. Possible explanations for the increase in ST in group B include more cumulative radiation or a greater carcinogenic effect of chemotherapy in previously irradiated patients, but it also is possible that the increase is due to a longer follow-up time.
Adolescent↗
The impact of conventional plus high dose chemotherapy with autologous bone marrow transplantation on hematologic toxicity during subsequent local-regional radiotherapy for breast cancer.
BACKGROUND: Forty patients with Stage II-III breast cancer with 10 or more positive axillary nodes were treated with mastectomy followed by four cycles of standard dose CAF (cytoxan, Adriamycin, 5-FU), followed by high dose cytoxan, cisplatin, carmustine (HDCT) with autologous bone marrow transplant support (ABMT), and local-regional radiotherapy (LR XRT). During LR XRT, the hematologic toxicity experienced by these patients appeared more severe than that usually seen in patients not heavily pretreated with chemotherapy. Radiation therapy was interrupted in four patients (10%) because of thrombocytopenia and leukopenia. This observation prompted a comparison of the hematologic changes seen in this group with those seen in patients not treated previously with chemotherapy. METHODS: A detailed analysis of changes in hematologic parameters during LR XRT was performed in 33 evaluable patients who received CAF-HDCT/ABMT and compared with a "control" group of 17 women who did not receive prior chemotherapy. RESULTS: The mean pretreatment leukocyte, platelet, and hematocrit counts were lower in the CAF-HDCT/ABMT group than in the control group, with the differences indicating statistical significance for the latter two (P = 0.17, P < 0.001, and P = 0.001, respectively). None of the control patients required a treatment interruption because of hematologic toxicity, whereas four of the CAF-HDCT/ABMT patients did. Among the CAF-HDCT/ABMT patients, a leukocyte count nadir of less than 2.0, a platelet nadir of less than 50,000, and a hematocrit nadir of less than 25 occurred in 12%, 19%, and 9%, respectively. The corresponding rates of control patients were 6%, 0%, and 0%, respectively. Relative to their pretreatment levels, however, both groups experienced similar declines in platelet and leukocyte counts. CONCLUSION: The higher rate of hematologic toxicity observed in the patients who previously received conventional chemotherapy plus HDCT/ABMT appears to have been due primarily to lower preradiotherapy blood counts.
Adenocarcinoma↗
Pretreatment oxygenation profiles of human soft tissue sarcomas.
PURPOSE: Tumor oxygenation is thought to influence the radiocurability of many malignancies. Advances in polarographic electrode technology have facilitated the in situ measurement of human tumor pO2. The optimal method of defining a "hypoxic" tumor is not known. Characterization of intra-tumor and intertumor pO2 heterogeneity could help with this process. This study was performed to evaluate pretreatment tumor oxygenation status and pO2 heterogeneity in patients with soft tissue sarcoma. METHODS AND MATERIALS: Nine patients with soft tissue sarcomas underwent pretreatment pO2 measurements with the Eppendorf pO2 histograph. Two grossly distinct anatomic sites within each tumor were measured in all but one patient; these were localized under computerized tomography guidance to ensure that all measurements were obtained from tumor tissue. Multiple probe tracks were studied at each site. Measurements were performed in resting, awake patients. RESULTS: A total of 1588 pO2 readings was obtained (mean = 176/patient). Measurement path lengths ranged from 22-36 mm. The average hypoxic fraction (pO2 < 5 mm Hg) was 29% (range 0-76%). Arterial pO2 was positively correlated with mean and median tumor pO2. Tumor hypoxic fraction increased with increasing tumor volume. Linear pO2 profiles and frequency histograms provided similar estimates of the extent of hypoxia in individual tumors. Marked variation in oxygenation existed both within and between individual tumors. The intertumor variation was greater than the intratumor variation. CONCLUSION: Radiobiologic hypoxia exists in human soft tissue sarcomas. The pO2 variation within individual tumors is less than the variation between tumors. Further study is necessary to identify the best parameter for defining tumor hypoxia and to discern the relationship between tumor pO2 and treatment outcome.
Cell Hypoxia↗
Is there a role for radiotherapy in the "curative" management of patients with metastatic cancer?
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Breast Neoplasms↗
A pilot study of etoposide, vinblastine, and doxorubicin plus involved field irradiation in advanced, previously untreated Hodgkin's disease.
BACKGROUND: Advanced stage Hodgkin's disease (HD) usually is treated with combination chemotherapy with or without supplemental irradiation. The risk of significant acute and long term toxicity when the chemotherapy regimen contains alkylating agents has provided the impetus for the development of systemic combinations that do not include alkylating agents. This trial was designed to assess the toxicity and efficacy of a regimen of etoposide, vinblastine, and doxorubicin (EVA) as part of a combined modality approach in patients with moderate to high risk HD. METHODS: This was a prospective pilot study that included 26 previously untreated patients. They received 6 cycles of EVA, and complete responders received low dose (1500-2500 cGy) involved field radiation. RESULTS: Four patients were hospitalized for sepsis during chemotherapy. Complete response was achieved in 54% of patients, and 46% patients experienced induction failures. Two year failure-free survival is 44%, while 2 year overall survival is 86%. Median follow-up is 27 months. CONCLUSIONS: The EVA regimen is no more efficacious than other programs already in use and may be less so. It also is potentially leukemogenic because of the presence of etoposide. New combinations that do not contain etoposide should be explored in therapy programs for advanced HD in the hopes of discovering an efficacious treatment program that has minimal long term side effects.
Adolescent↗
To treat or not to treat the internal mammary nodes: a possible compromise.
PURPOSE: A method for designing partly wide tangential fields that irradiate the superiorly placed internal mammary nodes, yet exclude the inferiorly placed internal mammary nodes and the cardiac tissue, is described for patients receiving tangential radiation for breast cancer. METHODS AND MATERIALS: Patients are immobilized in hemibody foam cradles. A CT study is performed with a series of fiducial markers. The CT data set can then either be transferred to the three-dimensional treatment planning computer for sophisticated treatment planning, or can be viewed to design partly wide tangential fields "by hand." This latter method is far less time consuming and, we believe, usually adequate, given the uncertainties in identifying the location of the internal mammary nodes. RESULTS: This technique has been implemented in our clinic and has been used to treat approximately 15 patients. In four of these patients, a formal dose-volume histogram analysis revealed that these partly wide tangential fields can adequately exclude the cardiac volume and include the superiorly placed internal mammary nodes. Modest reductions in the pulmonary volume that is incidentally irradiated are seen compared to conventional wide tangents that irradiate the entire length of the internal mammary chain. CONCLUSION: While controversy remains regarding the appropriateness of internal mammary nodal irradiation for patients with breast cancer, the technique described represents an attractive compromise. Selective irradiation of the superiorly placed internal mammary nodes (which are those at greatest risk for involvement) with customized "partly wide" tangential fields is possible. This treatment technique may provide the survival advantage that might be seen with internal mammary node irradiation, yet avoid the possible cardiac morbidity.
Breast Neoplasms↗
Estimation of normal tissue complication probabilities with three-dimensional technology.
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Humans↗
Correlation of mid-sternum and mid-spine positions in 82 patients irradiated for breast cancer.
The validity of designing anterior internal mammary node (IMN) radiation therapy fields based on vertebral body landmarks was tested by reviewing computer tomography (CT) images in 82 patients treated for breast cancer. The horizontal distance between the geometric center of the sternum and the vertebral body was 0-5, 6-10 and > 10 mm in approximately 30%, 25%, and 45% of patients, respectively. This suggests that using the projection of the vertebral bodies to design an anterior internal mammary node field is frequently inaccurate and may lead to inadequate coverage of these lymph nodes.
Breast Neoplasms↗
Prognostic importance of restaging gallium scans following induction chemotherapy for advanced Hodgkin's disease.
PURPOSE: This study was intended to assess the ability of restaging gallium scanning to distinguish between patients with residual radiographic abnormalities who still have active Hodgkin's disease (HD) and those who are truly complete responders. Early identification of the former patients might increase the success of secondary salvage therapy. MATERIALS AND METHODS: The charts of all patients with advanced HD treated at Duke University Medical Center during the years 1983 to 1991 who underwent gallium scanning were reviewed. Thirty-three patients were identified who had gallium scans performed as part of restaging following induction combination chemotherapy; no patient had other signs or symptoms of active or progressive HD. RESULTS: Thirteen of 33 patients had positive restaging gallium scans; 20 patients had negative scans. The 4-year actuarial relapse-free survival (RFS) rate was 75% for patients with negative restaging gallium scans compared with 8% for those with positive restaging scans (P < .001). The 4-year actuarial overall survival (OS) rate was 100% for those with negative scans compared with 51% for gallium-positive patients (P = .001). Twenty-four patients had residual chest x-ray or computed tomographic scan abnormalities. Calculated negative and positive predictive values for gallium scanning are 92% and 90%, respectively, compared with values of 48% and 83% for computed tomographic scanning. CONCLUSION: Restaging gallium scans separate complete responders from induction failures with a high degree of accuracy. Gallium scanning is clearly superior to computed tomography in this regard. Patients with advanced HD who have positive restaging gallium scans after induction chemotherapy should be classified as induction failures and are highly unlikely to be cured with involved-field low-dose radiotherapy.
Actuarial Analysis↗
Postmastectomy radiotherapy.
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Breast Neoplasms↗
Prognostic significance of extent of nodal involvement in stage D1 prostate cancer treated with radiotherapy.
The records of 107 patients with newly diagnosed adenocarcinoma of the prostate irradiated with curative intent at Duke University Medical Center from 1970 through 1983 were reviewed. Forty patients (37%) underwent standard bilateral pelvic lymph node dissection (PLND) prior to beginning irradiation. Twenty-four patients (22%) were found to have pelvic nodal metastases (Stage D1). Those found to have a single microscopically positive node at PLND may be curable with irradiation. In contrast, those with more extensive nodal metastases appear to be incurable with radiotherapy. Additional studies are needed to confirm or refute these findings.
Adenocarcinoma↗
Relationships among tumor temperature, treatment time, and histopathological outcome using preoperative hyperthermia with radiation in soft tissue sarcomas.
The lack of an unambiguous thermal dosimetry continues to impede progress in clinical hyperthermia. In an attempt to define better this dosimetry, a model based on the cumulative minutes during which arbitrary percentages of measured tumor temperature points exceeded an index temperature was tested in patients with soft tissue sarcomas treated with preoperative hyperthermia and conventional radiation therapy. Patients received 5000-5040 cGy at 180-200 cGy per fraction. Hyperthermia was delivered 30-60 minutes after radiation therapy and given for 60 minutes. Patients were randomized between one and two hyperthermia treatments per week for a total of five or 10 treatments, respectively. Lesions were excised 4-6 weeks after completion of hyperthermia/radiation therapy. Successful treatment outcome was considered to be the finding of greater than 80% necrosis of the sarcoma upon histopathologic examination of the resected specimen. Forty-five patients were eligible with thermometry data available in 44 patients. An average of 19 interstitial sites were monitored each treatment per tumor. Sixty percent of tumors had a successful histopathologic outcome. Univariate analysis demonstrated that several descriptors of the temperature distribution were strongly related to treatment outcome; more strongly than nonthermometric factors, such as the number of treatments per week, tumor volume and patient age and more strongly than the commonly used temperature descriptors Tmin and Tmax. Descriptors that incorporated both temperature and time were also superior to the more commonly used descriptors Tmin and Tmax. Multivariate stepwise logistic regression analysis revealed that a descriptor of both the hyperthermia treatment time and the frequency distribution of intratumoral temperatures was the strongest predictor of histopathologic outcome and that the best predictive model combined this time/temperature descriptor and one versus two treatment per week grouping. The more conventional temperature descriptor, minimum measured tumor temperature, did not significantly enhance the predictive power of treatment group. Based on these results, we recommend that descriptors based on both the frequency distribution of intratumoral temperatures and hyperthermia treatment time be tested for relationships with treatment outcome in other clinical data bases. Furthermore, we recommend that temperature descriptors that are less sensitive to catheter placement and tumor boundary identification than Tmin and Tmax (such as T90, T50, and T10) be tested prospectively along with other important thermal variables in Phase II trials in further efforts to define a thermal dosimetry for spatially nonuniform temperature distributions.
Combined Modality Therapy↗
Post-mastectomy radiotherapy following adjuvant chemotherapy and autologous bone marrow transplantation for breast cancer patients with greater than or equal to 10 positive axillary lymph nodes. Cancer and Leukemia Group B.
Between 2/87 and 2/91, 49 women with operable breast cancer involving greater than or equal to 10 axillary nodes were treated following mastectomy, with four cycles of Cyclophosphamide, Adriamycin, 5FU, followed by high doses of Cyclophosphamide, Cisplatin, Carmustine (HDCT) with autologous bone marrow transplant support. Forty patients received local-regional radiotherapy (generally to the chest wall, internal mammary, supraclavicular, +/- axillary nodal areas; minimum 44-50 Gy, 1.8-2 Gy/fraction, +/- 10-15 Gy scar boost; standard radiation techniques). The first nine patients did not receive local-regional radiotherapy. Three developed a local-regional failure (6-12 months after HDCT); six are without evidence of disease. Local-regional radiotherapy (LR XRT) was delivered to the subsequent 40 patients following HDCT+autologous bone marrow transplant. Six received less than 44 Gy of the planned local-regional radiotherapy due to significant toxicity and one of these failed locally. Only one local failure was observed among the 34 patients who received greater than or equal to 44 Gy. Two additional patients developed distant metastases. None of these 40 patients have failed in the axilla despite the fact that the axilla was irradiated in only 18 cases. Overall, 36/40 (90%) of these patients are without evidence of disease 4-30 months following HDCT (approximately 10-36 months after mastectomy, median 22 months). Radiotherapy was interrupted or discontinued because of progressive dyspnea, thrombocytopenia, or neutropenia in nine patients. Further studies to determine the roles of local-regional radiotherapy and HDCT in the development of these toxicities are underway. These encouraging results suggest that HDCT + autologous bone marrow transplant+local-regional radiotherapy may improve the survival rate in these high risk patients. A national randomized study to test the efficacy of this HDCT regimen is currently underway (Cancer and Leukemia Group B#9082 and Southwest Oncology Group #9114).
Adenocarcinoma↗
Combined chemotherapy and radiotherapy for Hodgkin's disease.
This paper reviews the treatment of advanced and intermediate stage Hodgkin's disease with combination chemotherapy alone and combined chemotherapy and radiation. Relapse following complete remission with chemotherapy occurs principally at initial sites of disease; its occurrence will be reduced by radiotherapy to those sites. There is disagreement regarding the frequency of relapse and hence the impact of consolidation radiotherapy. Our interpretation of the literature is that relapse occurs in approximately 25% to 50% of all patients achieving complete response with chemotherapy, and that consolidation radiation reduces relapse frequency with a resultant increase in survival. The addition of low dose, involved field radiotherapy is generally free of significant adverse effects. In particular, there appears to be no increase in second malignant neoplasms. The risk: benefit ratio for adding radiotherapy to chemotherapy in patients with advanced Hodgkin's disease is, therefore, quite favorable. We believe that combined modality therapy should become the standard treatment.
Antineoplastic Combined Chemotherapy Protocols↗