Gregory S. Sibley

Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck

PURPOSE Tumor hypoxia adversely affects short term clinical radiation response of head and neck cancer lymph node metastases and long term disease-free survival (DFS) in cervix carcinoma. This study was performed to evaluate the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS Pretreatment tumor pO2 was assessed polarographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measurements taken from locally advanced primaries (T3 or T4) or neck nodes > or = 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66-70 Gy) or twice daily irradiation (1.25 Gy B.I.D. to 70-75 Gy) +/- planned neck dissection (for > or = N2A disease) according to institutional treatment protocols. RESULTS Twenty-eight patients underwent tumor pO2 measurement. The average pre-treatment median pO2 was 11.2 mm Hg (range 0.4-60 mm Hg). The DFS at 12 months was 42%. The DFS was 78% for patients with median tumor pO2 > 10 mm Hg but only 22% for median pO2 < 10 mm Hg (p = 0.009). The average tumor median pO2 for relapsing patients was 4.1 mm Hg and 17.1 mm Hg in non-relapsing (NED) patients (p = 0.007). CONCLUSION Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relationship between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

Clinical and dosimetric predictors of radiation-induced esophageal toxicity

PURPOSE To evaluate the incidence, severity, and clinical/dosimetric predictors of acute and chronic esophageal toxicities in patients with non-small cell lung cancer (NSCLC) treated with high-dose conformal thoracic radiation. METHODS AND MATERIALS Ninety-one patients with localized NSCLC treated definitively with high-dose conformal radiation therapy (RT) at Duke University Medical Center (DUMC) were reviewed. Patient characteristics were as follows: 53 males and 38 females; median age 64 yr (range 46-82); stage I--16, II--3, IIIa--40, IIIb--30, X--2; dysphagia pre-RT--6 (7%). Treatment parameters included: median corrected dose-78.8 Gy (range 64.2-85.6); BID fractionation-58 (64%); chemotherapy-43 (47%). Acute and late esophageal toxicities were graded by RTOG criteria. Using 3D treatment planning tools, the esophagus was contoured in a uniform fashion, the 3D dose distribution calculated (with lung density correction), and the dose-volume (DVH) and dose-surface histograms (DSH) generated. At each axial level, the percentage of the esophageal circumference at each dose level was calculated. The length of circumferential esophagus and the maximum circumference treated to doses >50 Gy were assessed. Patient and treatment factors were correlated with acute and chronic esophageal dysfunction using univariate and multivariate logistic regression analyses. RESULTS There were no acute or late grade 4 or 5 esophageal toxicities. Ten of 91 patients (11%) developed grade 3 acute toxicity. On univariate analysis of clinical parameters, both dysphagia pre-RT (p = 0.10) and BID fractionation (p = 0.11) tended toward significantly predicting grade 3 acute esophagitis. None of the dosimetric parameters analyzed significantly predicted for grade 3 acute esophagitis. Twelve of 66 assessable patients (18%) developed late esophageal toxicity. Of the clinical parameters analyzed, only dysphagia pre-RT (p = 0.06) tended toward significantly predicting late esophageal toxicity. On univariate analyses, the effects of percent organ volume treated >50 Gy (p = 0.05), percent surface area treated >50 Gy (p = 0.05), length of 100% circumference treated >50 Gy (p = 0.04), and maximum percent of circumference treated >80 Gy (p = 0.01) significantly predicted for late toxicity of all grades. On multivariate analysis, percent organ volume treated >50 Gy (p = 0.02) and maximum percent of circumference treated >80 Gy (p = 0.02) predicted for late toxicity. CONCLUSIONS Late esophageal toxicity following aggressive, high-dose conformal radiotherapy is common but rarely severe. Dosimetric variables addressing the longitudinal and circumferential character of the esophagus have biologic rationale and are predictive of late toxicity. Further studies are needed to assess whether these parameters are better predictors than those derived from traditional DVHs.

Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation : a new paradigm for destruction of therapeutically intractable tumors

Human U-87 malignant glioma xenografts in mice were exposed to ionizing radiation, inoculated with a herpes simplex virus 1 mutant R3616 lacking both copies of the γ134.5 gene, or received both virus and radiation. Dual treatment caused a significantly greater reduction in volume or total regression of tumors than either radiation or infection alone. The significantly enhanced oncolytic effects of the combined treatment correlate with two- to five-fold enhanced replication in irradiated tumor cells than in tumors receiving virus only. In addition, in situ hybridization with viral DNA probes showed that infected tumor cells were the dominant landscape of irradiated tumors and much less apparent in the nonirradiated tumors administered this virus.

Conservative surgery and adjuvant radiation therapy in the management of adult soft tissue sarcoma of the extremities: Clinical and radiobiological results

PURPOSE The outcome of adult patients with soft tissue sarcoma of the extremities treated with conservative surgery and adjuvant irradiation was evaluated to (a) determine the appropriate treatment volume and radiation dosage in the postoperative setting, and (b) correlate in vitro radiobiological parameters obtained prior to therapy with clinical outcome. METHODS AND MATERIALS Sixty-four consecutive adult patients with soft tissue sarcoma of the extremities (40 lower, 24 upper) who underwent conservative surgery and adjuvant irradiation 7 preoperative, 50 postoperative, 7 perioperative) between 1978 and 1991 were reviewed. The initial radiation field margin surrounding the tumor bed/scar was retrospectively analyzed in all postoperative patients. Initial field margins were < 5 cm in 12 patients, 5-9.9 cm in 32 and > or = 10 cm in 6. Patients with negative pathological margins were initially treated with traditional postoperative doses (64-66 Gy); however, in later years the postoperative dose was reduced to 60 Gy. Thirteen cell lines were established prior to definite therapy, and radiobiological parameters (multitarget and linear-quadratic) were obtained and correlated with outcome. RESULTS Postoperative patients treated with an initial field margin of < 5 cm had a 5-year local control of 30.4% vs. 93.2% in patients treated with an initial margin of > or = 5 cm (p = 0.0003). Five-year local control rates were similar in patients treated with initial field margins of 5-9.9 cm (91.6%) compared with those treated with > or = 10 cm margins (100%) (p = 0.49). While postoperative patients receiving < 60 Gy had a worse local control than those receiving > or = 60 Gy (p = 0.08), no difference was seen in local control between patients receiving less than traditional postoperative doses (60-63.9 Gy) (74.4% vs. those receiving 64-66 Gy (87.0%) (p = 0.5). The local control of patients treated in the later years of the study, with strict attention to surgical and radiotherapeutic technique, was 87.6%. Severe late sequelae were more frequent in patients treated with doses > or = 63 Gy compared to patients treated with lower doses (23.1% vs. 0%) (p < 0.05). Mean values for Do, alpha, beta, D, n and SF2 obtained from the 13 cell lines were 115.7, 0.66, 0.029, 2.15, 0.262, respectively. Four of the 13 cell lines established prior to therapy ultimately failed locally. The radiobiological parameters of these cell lines were similar to the other nine cell lines in terms of radiosensitivity. CONCLUSIONS Our data confirm the importance of maintaining an initial field margin of at least 5 cm around the tumor bed/scar in the postoperative setting. No benefit was seen with the use of margins > or = 10 cm. In addition, patients undergoing wide local excision with negative margins can be treated with lower than traditional postoperative doses (60 Gy) without compromising local control and with fewer chronic sequelae. Finally, it does not appear that inherent tumor cell sensitivity is a major determinant of local failure following radiation therapy and conservative surgery in soft tissue sarcoma.

73.6 Gy and Beyond: Hyperfractionated, Accelerated Radiotherapy for Non–Small-Cell Lung Cancer

PURPOSE To assess results with twice-daily high-dose radiotherapy (RT) for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Between 1991 and 1998, 94 patients with unresectable NSCLC were prescribed > or = 73.6 Gy via accelerated fractionation. Fifty were on a phase II protocol (P group); 44 were similarly treated off-protocol (NP group). The clinical target volume received 45 Gy at 1.25 Gy bid (6-hour interval). The gross target volume received 1.6 Gy bid to 73.6 to 80 Gy over 4.5 to 5 weeks using a concurrent boost technique. Overall survival (OS) and local progression-free survival (LPFS) were calculated by the Kaplan-Meier method. Median follow-up durations for surviving P and NP patients were 67 and 16 months, respectively. RESULTS Total doses received were > or = 72 Gy in 97% of patients. The median OS by stage was 34, 13, and 12 months for stages I/II, IIIa, and IIIb, respectively. LPFS was significantly longer for patients with T1 lesions (median, 43 months) versus T2-4 (median, 7 to 10 months; P =.01). Results were similar in the P and NP groups. Acute grade > or = 3 toxicity included esophagus (14 patients; 15%), lung (three patients; 3% [one grade 5]), and skin (four patients; 4%). Grade > or = 3 late toxicity in 86 assessable patients included esophagus (three patients; 3%), lung (15 patients; 17% [three grade 5]), skin (five patients; 6%), heart (two patients; 2%), and nerve (one patient; 1%). CONCLUSION This regimen yielded favorable survival results, particularly for T1 lesions. Acute grade > or = 3 toxicity seems greater than for conventional RT, though most patients recovered. Late grade > or = 3 pulmonary toxicity occurred in 17%. Because of continued locoregional recurrences, we are currently using doses > or = 86 Gy.

Patterns of failure following high-dose chemotherapy and autologous bone marrow transplantation with involved field radiotherapy for relapsed/refractory Hodgkin's disease

PURPOSE To evaluate the patterns of failure and outcome of patients undergoing high-dose chemotherapy and autologous bone marrow transplantation for relapsed/refractory Hodgkins disease with emphasis on the impact of involved-field radiotherapy. METHOD AND MATERIALS Fifty-four adult patients with refractory (25) or relapsed (29) Hodgkins disease underwent high-dose chemotherapy with either autologous bone marrow (32) or peripheral stem cell (23) transplantation. Twenty patients received involved-field radiotherapy either prior to (7) or following (13) high-dose chemotherapy. Patients treated prior to the high-dose chemotherapy received radiation to bulky or symptomatic sites, and those treated following the transplantation were treated to sites of disease persistence (10) or to consolidate a complete response (3). Twenty-six patients had purely nodal disease, 10 had lung involvement, 7 liver, 5 bone, and 3 bone marrow. A total of 147 sites were present prior to high-dose chemotherapy. Nineteen were bulky (> or = 5 cm), and 42 arose in a previous radiotherapy field. RESULTS Twenty-five of the 54 patients (46.3%) relapsed. Seventeen (68.0%) relapsed in sites of disease present prior to high-dose chemotherapy. Patients treated with involved-field radiotherapy had a lower rate of relapse in sites of prior disease involvement (26.3 vs. 42.8%) (p < 0.05) than those not treated with radiotherapy. Twenty-one patients had disease persistence following high-dose chemotherapy, of which 10 received involved-field radiotherapy and were converted to a complete response. Patients with disease persistence who received involved-field radiotherapy had a better progression-free survival (40.0 vs. 12.1%) (p = 0.04) than those who did not. Moreover, the patients converted to a complete response had similar progression-free and cause-specific survival as those patients achieving a complete response with high-dose chemotherapy alone. Of the initial 147 sites, 142 (97.3%) were amenable to involved-field radiation therapy. The addition of involved-field radiotherapy improved the 5-year local control of all sites (p = 0.008), nodal sites (p = 0.01), and sites of disease persistence (p = 0.0009). CONCLUSIONS Patients with relapsed/refractory Hodgkins disease undergoing high-dose chemotherapy and autologous bone marrow rescue have a high rate of relapse in sites of prior disease involvement. Involved-field radiotherapy is capable of improving the control of these sites, the majority of which are amenable to radiotherapy. In addition, the use of radiotherapy to sites of disease persistence following high-dose chemotherapy may improve the outcome of these patients.

Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction?

PURPOSE To determine whether changes in whole-lung pulmonary function test (PFT) values are related to the sum of predicted radiation therapy (RT)-induced changes in regional lung perfusion. PATIENTS AND METHODS Between 1991 and 1998, 96 patients (61% with lung cancer) who were receiving incidental partial lung irradiation were studied prospectively. The patients were assessed with pre- and post-RT PFTs (forced expiratory volume in one second [FEV1] and diffusion capacity for carbon monoxide [DLCO]) for at least a 6-month follow-up period, and patients were excluded if it was determined that intrathoracic recurrence had an impact on lung function. The maximal declines in PFT values were noted. A dose-response model based on RT-induced reduction in regional perfusion (function) was used to predict regional dysfunction. The predicted decline in pulmonary function was calculated as the weighted sum of the predicted regional injuries: equation [see text] where Vd is the volume of lung irradiated to dose d, and Rd is the reduction in regional perfusion anticipated at dose d. RESULTS The relationship between the predicted and measured reduction in PFT values was significant for uncorrected DLCO (P = .005) and borderline significant for DLCO (P = .06) and FEV1 (P = .08). However, the correlation coefficients were small (range,.18 to.30). In patients with lung cancer, the correlation coefficients improved as the number of follow-up evaluations increased (range,.43 to.60), especially when patients with hypoperfusion in the lung adjacent to a central mediastinal/hilar thoracic mass were excluded (range,.59 to.91). CONCLUSION The sum of predicted RT-induced changes in regional perfusion is related to RT-induced changes in pulmonary function. In many patients, however, the percentage of variation explained is small, which renders accurate predictions difficult.

THE TREATMENT OF STAGE III NONSMALL CELL LUNG CANCER USING HIGH DOSE CONFORMAL RADIOTHERAPY

PURPOSE To review our experience using conformal treatment planning and high-dose radiotherapy for Stage IIIa and IIIb nonsmall cell lung cancer (NSCLC), and to identify a subset of patients best suited for this approach by analyzing multiple pretreatment patient and tumor characteristics. METHODS AND MATERIALS Between December 1987 and June 1992, 37 patients with Stage III NSCLC treated with high-dose radiotherapy using conformal radiotherapy were reviewed. The patient characteristics were as follows: Stage IIIa (18 patients), IIIb [19]; T1-2 [13], T3-4 [24]; N0-1 [8], N2-3 [29]; and median age 63. All patients were treated with 1.8-2.0 Gy fractions to a median dose of 66 Gy (range 60-70 Gy). Outcome was analyzed by multiple pretreatment variables including age, sex, Karnofsky performance score, pretreatment symptoms, stage group, T and N stage, tumor volume (calculated from computed tomography (CT) contours), presence of atelectasis, and tumor histology. Outcome was also analyzed by total radiotherapy dose. RESULTS The median, 1-year and 2-year survival rates for the entire group were 19.5 months, 75 and 37%, respectively. The median, 1-year, and 2-year local progression-free survival rates are 15.6 months, 62 and 23%. There was no difference in survival by stage group (IIIa vs. IIIb) or by T or N stage. Tumor volumes ranged from 47-511 cc in the patients without atelectasis and were not a significant prognostic factor. Histology was found to be a significant prognostic factor, with squamous cell carcinoma having a better overall survival and local progression-free survival than other histologies. No other patient characteristic was found to be significant by either univariate or multivariate analysis. When outcome was analyzed by radiotherapy dose, no dose response was evident in the narrow dose range studied (60-70 Gy). Toxicity included two cases of pneumonitis, which resolved with conservative therapy. CONCLUSION High-dose conformal radiotherapy, in our experience, results in overall survival rates that compare favorably with trials of chemoradiotherapy or conventional radiotherapy with a low treatment-associated morbidity. However, local progression remains a significant problem despite median radiotherapy doses of 66 Gy. Future trials using escalating radiotherapy doses with conformal radiotherapy are therefore, indicated.

The effect of patient-specific factors on radiation-induced regional lung injury

PURPOSE To assess the impact of patient-specific factors on radiation (RT)-induced reductions in regional lung perfusion. METHODS Fifty patients (32 lung carcinoma, 7 Hodgkins disease, 9 breast carcinoma and 2 other thoracic tumors) had pre-RT and > or = 24-week post-RT single photon emission computed tomography (SPECT) perfusion images to assess the dose dependence of RT-induced reductions in regional lung perfusion. The SPECT data were analyzed using a normalized and non-normalized approach. Furthermore, two different mathematical methods were used to assess the impact of patient-specific factors on the dose-response curve (DRC). First, DRCs for different patient subgroups were generated and compared. Second, in a more formal statistical approach, individual DRCs for regional lung injury for each patient were fit to a linear-quadratic model (reduction = coefficient 1 x dose + coefficient 2 x dose2). Multiple patient-specific factors including tobacco history, pre-RT diffusion capacity to carbon monoxide (DLCO), transforming growth factor-beta (TGF-beta), chemotherapy exposure, disease type, and mean lung dose were explored in a multivariate analysis to assess their impact on the coefficients. RESULTS None of the variables tested had a consistent impact on the radiation sensitivity of regional lung (i.e., the slope of the DRC). In the formal statistical analysis, there was a suggestion of a slight increase in radiation sensitivity in the dose range >40 Gy for nonsmokers (vs. smokers) and in those receiving chemotherapy (vs. no chemotherapy). However, this finding was very dependent on the specific statistical and normalization method used. CONCLUSION Patient-specific factors do not have a dramatic effect on RT-induced reduction in regional lung perfusion. Additional studies are underway to better clarify this issue. We continue to postulate that patient-specific factors will impact on how the summation of regional injury translates into whole organ injury. Refinements in our methods to generate and compare SPECT scans are needed.

Can Angiotensin-Converting Enzyme Inhibitors Protect against Symptomatic Radiation Pneumonitis?

Abstract Wang, L. W., Fu, X-L., Clough, R., Sibley, G., Fan, M., Bentel, G. C., Marks, L. B. and Anscher, M. S. Can Angiotensin-Converting Enzyme Inhibitors Protect against Symptomatic Radiation Pneumonitis? This study was designed to determine whether patients taking angiotensin-converting enzyme (ACE) inhibitors while receiving radiation therapy for lung cancer are protected from developing symptomatic radiation pneumonitis. The records of 213 eligible patients receiving thoracic irradiation for lung cancer with curative intent at Duke University Medical Center from 1994–1997 were reviewed. Of the 213 patients, 26 (12.2%) were on ACE inhibitors (usually for the management of hypertension) during radiotherapy (group 1); the remaining 187 patients (group 2) were not. Patients were irradiated, with fields shaped to protect normal tissues, with total doses of 50–80 Gy. After treatment, patients were generally followed every 3 months for 2 years, then every 6 months thereafter. Symptomatic radiation pneumonitis was scored according to modified National Cancer Institute Common Toxicity Criteria (i.e., radiographic changes alone were not sufficient for the diagnosis of pneumonitis). There was no difference in the incidence of pneumonitis between the two groups (P = 0.75). Fifteen percent of the patients on ACE inhibitors (group 1) developed symptomatic radiation-induced lung injury compared to 12% of the patients not receiving these drugs (group 2). Although patients in group 1 tended to develop pneumonitis slightly sooner than did patients in group 2, this difference also was not significant (P = 0.8). Within the dose range prescribed for treating hypertension, ACE inhibitors do not appear to either decrease the incidence or delay the onset of symptomatic radiation pneumonitis among lung cancer patients receiving thoracic irradiation.