Mary V. Graham

CLINICAL DOSE-VOLUME HISTOGRAM ANALYSIS FOR PNEUMONITIS AFTER 3D TREATMENT FOR NON-SMALL CELL LUNG CANCER (NSCLC)

PURPOSE To identify a clinically relevant and available parameter upon which to identify non-small cell lung cancer (NSCLC) patients at risk for pneumonitis when treated with three-dimensional (3D) radiation therapy. METHODS AND MATERIALS Between January 1991 and October 1995, 99 patients were treated definitively for inoperable NSCLC. Patients were selected for good performance status (96%) and absence of weight loss (82%). All patients had full 3D treatment planning (including total lung dose-volume histograms [DVHs]) prior to treatment delivery. The total lung DVH parameters were compared with the incidence and grade of pneumonitis after treatment. RESULTS Univariate analysis revealed the percent of the total lung volume exceeding 20 Gy (V20), the effective volume (Veff) and the total lung volume mean dose, and location of the tumor primary (upper versus lower lobes) to be statistically significant relative to the development of > or = Grade 2 pneumonitis. Multivariate analysis revealed the V20 to be the single independent predictor of pneumonitis. CONCLUSIONS The V20 from the total lung DVH is a useful parameter easily obtained from most 3D treatment planning systems. The V20 may be useful in comparing competing treatment plans to evaluate the risk of pneumonitis for our individual patient treatment and may also be a useful parameter upon which to stratify patients or prospective dose escalation trials.

Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients.

PURPOSE To determine the relation between the incidence of radiation pneumonitis and the three-dimensional dose distribution in the lung. METHODS AND MATERIALS In five institutions, the incidence of radiation pneumonitis was evaluated in 540 patients. The patients were divided into two groups: a Lung group, consisting of 399 patients with lung cancer and 1 esophagus cancer patient and a Lymph./Breast group with 78 patients treated for malignant lymphoma, 59 for breast cancer, and 3 for other tumor types. The dose per fraction varied between 1.0 and 2.7 Gy and the prescribed total dose between 20 and 92 Gy. Three-dimensional dose calculations were performed with tissue density inhomogeneity correction. The physical dose distribution was converted into the biologically equivalent dose distribution given in fractions of 2 Gy, the normalized total dose (NTD) distribution, by using the linear quadratic model with an alpha/beta ratio of 2.5 and 3.0 Gy. Dose-volume histograms (DVHs) were calculated considering both lungs as one organ and from these DVHs the mean (biological) lung dose, NTDmean, was obtained. Radiation pneumonitis was scored as a complication when the pneumonitis grade was grade 2 (steroids needed for medical treatment) or higher. For statistical analysis the conventional normal tissue complication probability (NTCP) model of Lyman (with n=1) was applied along with an institutional-dependent offset parameter to account for systematic differences in scoring patients at different institutions. RESULTS The mean lung dose, NTDmean, ranged from 0 to 34 Gy and 73 of the 540 patients experienced pneumonitis, grade 2 or higher. In all centers, an increasing pneumonitis rate was observed with increasing NTDmean. The data were fitted to the Lyman model with NTD50=31.8 Gy and m=0.43, assuming that for all patients the same parameter values could be used. However, in the low dose range at an NTDmean between 4 and 16 Gy, the observed pneumonitis incidence in the Lung group (10%) was significantly (p=0.02) higher than in the Lymph./Breast group (1.4%). Moreover, between the Lung groups of different institutions, also significant (p=0.04) differences were present: for centers 2, 3, and 4, the pneumonitis incidence was about 13%, whereas for center 5 only 3%. Explicitly accounting for these differences by adding center-dependent offset values for the Lung group, improved the data fit significantly (p < 10(-5)) with NTD50=30.5+/-1.4 Gy and m=0.30+/-0.02 (+/-1 SE) for all patients, and an offset of 0-11% for the Lung group, depending on the center. CONCLUSIONS The mean lung dose, NTDmean, is relatively easy to calculate, and is a useful predictor of the risk of radiation pneumonitis. The observed dose-effect relation between the NTDmean and the incidence of radiation pneumonitis, based on a large clinical data set, might be of value in dose-escalating studies for lung cancer. The validity of the obtained dose-effect relation will have to be tested in future studies, regarding the influence of confounding factors and dose distributions different from the ones in this study.

Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma

PURPOSE Three-dimensional conformal radiation therapy (3D-CRT) has recently become widely available with applications for patients with non-small-cell lung cancer (NSCLC). These techniques represent a significant advance in the delivery of radiotherapy, including improved ability to delineate target contours, choose beam angles, and determine dose distributions more accurately than were previously available. The purpose of this study is to identify prognostic factors in a population of NSCLC patients treated with definitive 3D-CRT. METHODS AND MATERIALS Between March 1991 and December 1998, 207 patients with inoperable NSCLC were treated with definitive 3D-CRT. Tumor targets were contoured in multiple sections from a treatment planning computed tomography (CT) scan. Three-dimensional treatment volumes and normal structures were reconstructed. Doses to the International Commission on Radiation Units and Measurements (ICRU) reference point ranged from 60 to 83.85 Gy with a median dose of 70 Gy. The median dose inhomogeneity was +/- 5% across planning target volume. Outcome was analyzed by prognostic factors for NSCLC including pretreatment patient and tumor-related factors (age, gender, race, histology, clinical stage, tumor [T] stage, and node [N] stage), parameters from our 3D-CRT system (gross tumor volume [GTV] in cm3), irradiation dose prescribed to isocenter, volume of normal lung exceeding 20 Gy (V20), and treatment with or without chemotherapy. The median follow-up time was 24 months (range, 7.5 months to 7.5 years). RESULTS One and two-year overall survival rates for the entire group were 59% and 41%, respectively. Overall survival, cause-specific survival, and local tumor control were most highly correlated with the GTV in cm3. On multivariate analysis the independent variable most predictive of survival was the GTV. Traditional staging such as T, N, and overall clinical staging were not independent prognostic factors. Patients receiving ICRU reference doses > or =70 Gy had better local control and cause-specific survivals than those treated with lower doses (p = 0.05). Increased irradiation dose did not improve overall survival. CONCLUSIONS GTV as determined by CT and 3D-CRT planning is highly prognostic for overall and cause-specific survival and local tumor control and may be important in stratification of patients in prospective therapy trials. T, N, and overall stage were not independent prognostic factors in this population of patients treated nonsurgically. The value of dose escalation beyond 70 Gy should be tested prospectively by clinical trial.

Preliminary results of a prospective trial using three dimensional radiotherapy for lung cancer

PURPOSE To evaluate the preliminary results of a prospective trial using three-dimensional (3D) treatment for lung cancer. METHODS AND MATERIALS Seventy patients with inoperable Stage I through IIIB lung cancer were treated with three-dimensional thoracic irradiation with or without chemotherapy (35% received chemotherapy). Total prescribed dose to the tumor ranged from 60-74 Gy (uncorrected for lung density). All patients were evaluated for local control, survival, and development of pneumonitis. These parameters were evaluated in respect to and compared with three-dimensional parameters used in their treatment planning. RESULTS With a minimum follow-up of 6 to 30 months, the 2-year cause-specific survival rate for Stages I and II was 90% and 53% for Stage III (no difference between Stages IIIA and IIIB). Patients with local tumor control had a better 2-year overall survival rate (47%) than those with local failure (31%). Volumetrically heterogeneously calculated doses were important to the accurate delineation of dose-volume coverage as there was a wide range of discrepancies between a homogeneously prescribed point dose calculation and the heterogeneously calculated volume coverage of that prescription. High-grade pneumonitis was correlated with the location of the tumor with lower lobe tumors having a much higher risk than those with upper lobe tumors. A critical volume effect and threshold dose were apparent in the development of high-grade pneumonitis. CONCLUSIONS Three-dimensional therapy for lung cancer has been practically implemented at the Mallinckrodt Institute of Radiology and shows promising results in our preliminary analysis. The incidence of high-grade pneumonitis, however, warrants careful selection of patients for future dose escalation. Future dose escalation trials in lung cancer should be directed to volumes that limit the amount of elective nodal irradiation. However, the volume of necessary elective nodal irradiation remains unknown and should be studied prospectively. Dose escalation trials are indicated and may be facilitated by smaller target volumes.

Primary Analysis of the Phase II Component of a Phase I/II Dose Intensification Study Using Three-Dimensional Conformal Radiation Therapy and Concurrent Chemotherapy for Patients With Inoperable Non–Small-Cell Lung Cancer: RTOG 0117

PURPOSE Phase I of Radiation Therapy Oncology Group (RTOG) 0117 determined that 74 Gy was the maximum-tolerated dose with concurrent weekly carboplatin/paclitaxel chemotherapy for inoperable non-small-cell lung cancer (NSCLC). Phase II results are reported here. PATIENTS AND METHODS Patients with unresectable stages I-III NSCLC were eligible. Chemotherapy consisted of weekly paclitaxel at 50 mg/m(2) and carboplatin at area under the curve 2 mg/m(2). The radiation dose was 74 Gy given in 37 fractions. Radiation therapy volumes included those of the gross tumor and involved nodes. The volume of lung at or exceeding 20 Gy (V20) was mandated to be <or= 30%. RESULTS Of the combined phase I/II enrollment, a total of 55 patients received 74 Gy, of whom 53 were evaluable. The median follow-up was 19.3 months (range, 0.9 to 57.9 months) for all patients and 25.4 months (range, 13.1 to 57.9 months) for those still alive. The median survival for all patients was 25.9 months. The percentage surviving at least 12 months was 75.5% (95% CI, 65.7% to 85.2%). The median overall survival (OS) and progression-free survival (PFS) times for stage III patients (n = 44) were 21.6 months and 10.8 months, respectively. OS and PFS rates at 12 months were 72.7% and 50.0%, respectively. Twelve patients experienced grade >or= 3 lung toxicity (two patients had grade 5 lung toxicity). CONCLUSION The median survival time and OS rate at 12 months for this regimen are encouraging. These results serve as projection expectations for the high-dose radiation arms of the current RTOG 0617 phase III intergroup trial.

A phase I/II radiation dose escalation study with concurrent chemotherapy for patients with inoperable stages I to III non-small-cell lung cancer: phase I results of RTOG 0117.

PURPOSE In preparation for a Phase III comparison of high-dose versus standard-dose radiation therapy, this Phase I/II study was initiated to establish the maximum tolerated dose of radiation therapy in the setting of concurrent chemotherapy, using three-dimensional conformal radiation therapy for non-small-cell lung cancer. METHODS AND MATERIALS Eligibility included patients with histologically proven, unresectable Stages I to III non-small-cell lung cancer. Concurrent chemotherapy consisted of paclitaxel, 50 mg/m(2), and carboplatin, AUC of 2, given weekly. The radiation dose was to be sequentially intensified by increasing the daily fraction size, starting from 75.25 Gy/35 fractions. RESULTS The Phase I portion of this study accrued 17 patients from 10 institutions and was closed in January 2004. After the initial 8 patients were accrued to cohort 1, the trial closed temporarily on September 26, 2002, due to reported toxicity. Two acute treatment-related dose-limiting toxicities (DLTs) were reported at the time: a case of grade 5 and grade 3 radiation pneumonitis. The protocol, therefore, was revised to de-escalate the radiation therapy dose (74 Gy/37 fractions). Patients in cohort 1 continued to develop toxicity, with 6/8 (75%) patients eventually developing grade >or=3 events. Cohort 2 accrued 9 patients. There was one DLT, a grade 3 esophagitis, in cohort 2 in the first 5 patients (1/5 patients) and no DLTs for the next 2 patients (0/2 patients). CONCLUSIONS The maximum tolerated dose was determined to be 74 Gy/37 fractions (2.0 Gy per fraction) using three-dimensional conformal radiation therapy with concurrent paclitaxel and carboplatin therapy. This dose level in the Phase II portion has been well tolerated, with low rates of acute and late lung toxicities.

THREE-DIMENSIONAL RADIATION TREATMENT PLANNING STUDY FOR PATIENTS WITH CARCINOMA OF THE LUNG

PURPOSE Several reports in the literature suggest that local-regional control and possibly survival could be improved for inoperable nonsmall cell lung cancer if the radiation dose to the target volume could be increased. Higher doses, however, bring with them the potential for increased side effects and complications of normal tissues. Three-dimensional treatment planning has shown significant potential for improving radiation treatment planning in several sites, both for tumor coverage and for sparing of normal tissue from high doses of radiation and, thus, has the potential of developing radiation therapy techniques that result in uncomplicated local-regional control of lung cancer. We have studied the feasibility of large-scale implementation of true three-dimensional technologies in the treatment of patients with cancers of the thorax. METHODS AND MATERIALS CT scans were performed on 10 patients with inoperable nonsmall cell lung cancer to obtain full volumetric image data, and therapy was planned on our three-dimensional radiotherapy treatment planning system. Target volumes were determined using the new ICRU nomenclature--Gross Tumor Volume, Clinical Target Volume, and Planning Target Volume. Plans were performed according to our standard treatment policies based on traditional two-dimensional radiotherapy treatment planning methodologies and replanned using noncoplanar three-dimensional beam techniques. The results were quantitatively compared using dose-volume histograms, dose-surface displays, and dose statistics. RESULTS Target volume delineation remains a difficult problem for lung cancer. Defining Gross Tumor Volume and Clinical Target Volume may depend on window and level settings of the three-dimensional radiotherapy treatment planning system, suggesting that target volume delineation on hard copy film is inadequate. Our study shows that better tumor coverage is possible with three-dimensional plans. Dose to critical structures (e.g., the heart) could often be reduced (or at least remain acceptable) using noncoplanar beams even with dose escalation to 75 to 80 Gy for the planning volume surrounding the Gross Target Volume. CONCLUSION Commonly used beam arrangements for treatment of lung cancer appear to be inadequate to safely deliver tumor doses of higher than 70 Gy. Although conventional treatment techniques may be adequate for tumor coverage, they are inadequate for sparing of normal tissues when the prescription dose is escalated. The ability to use noncoplanar fields for such patients is a major advantage of three-dimensional planning. This capability led to better tumor coverage and reduced dose to critical normal tissues. However, this advantage was achieved at the expense of a greater time commitment by the treatment planning staff (particularly the radiation oncologist) and a greater complexity of treatment delivery. In summary, three-dimensional radiotherapy treatment planning appears to provide the radiation oncologist with the necessary tools to increase tumor dose, which may lead to increased local-regional control in patients with lung cancer while maintaining normal tissue doses at acceptable tolerance levels.

The impact of regional nodal radiotherapy (dose/volume) on regional progression and survival in unresectable non-small cell lung cancer: an analysis of RTOG data

PURPOSE To evaluate in-field progression and survival of patients with unresectable non-small cell lung cancer (NSCLC) in relation to adequacy of coverage of thoracic regional nodal areas in the radiotherapy volume. MATERIALS AND METHODS A total of 1705 patients from four large RTOG trials (78-11, 79-17, 83-11 and 84-07) were analyzed for this purpose. For each of these trials, the dose delivered to nodal regions was recorded and an assessment of adequacy of field borders was made. Each nodal site was assessed for progression, defined as in-field or out-of-field. In patients who had adequate borders on nodal regions, the results were analyzed according to the dose delivered. RESULTS The majority (74%) of patients were between the age of 55-75. Forty-six percent of the patients had KPS of 60-80 and 52% had KPS of 90-100. Sixty percent of patients had a weight loss of less than 5% in the 6 months prior to diagnosis. Deviations from the protocol in field borders (borders not per protocol) were most frequent for the contralateral hilum (25.2%) and least frequent in the ipsilateral hilum (6.3%). The adequacy of ipsilateral hilar coverage was important for preventing the in-field progression (11.6 vs. 22% for adequately vs. inadequately covered ipsilateral hilum, respectively, P=0.01), however, did not influence the 2-year-survival (35 vs. 37%) or median survival (1.3 vs. 1.1 year). Neither the in-field progression nor the 2-year-survival were affected by adequacy of nodal coverage in the mediastinum, ipsilateral supraclavicular area and contralateral hilum, even when different doses were analyzed. CONCLUSION These data suggest that elective irradiation of mediastinal, contralateral hilar and supraclavicular lymph nodes may not be necessary in the treatment of unresectable NSCLC.

IS WEEKLY PORT FILMING ADEQUATE FOR VERIFYING PATIENT POSITION IN MODERN RADIATION THERAPY

PURPOSE The objective of this study is to use daily electronic portal imaging to evaluate weekly port filming in detecting patient set-up position. METHODS AND MATERIALS A computer-based portal alignment method was used to quantify the field displacements on 191 digitized weekly port films and 848 daily electronic portal images in 21 radiation therapy patients. An electronic portal image data set as a control for actual daily treatment position was used to evaluate weekly port films with respect to same-day field displacement, rate of field placement error detection, and prediction of subsequent daily field displacements. RESULTS The field displacements measured on a port film frequently deviated from the corresponding field displacements on the electronic portal image obtained in the same treatment set-up. A linear regression analysis showed that the curves fitted to the same-day field displacements had slopes that differed significantly from unity (p < 0.001). Overall, the respective frequencies of field placement error, beyond clinical tolerance limits of 5, 7, and 10 mm (corresponding to head and neck, thoracic, and pelvic sites) for port filming and electronic portal imaging were 11% and 14% (p = 0.4) in the X-direction (lateral or anteroposterior) and 24% and 13% (p = .0001) in the Y-direction (caphalad-caudad). When the data were broken down by anatomical region, this discrepancy was found to be mainly due to the differences in the thorax, and head and neck image data sets. For thoracic fields, error in Y-shifts was 28% by port filming, but only 9% by portal imaging (p = 0.01). In the head and neck region, 18% of the port films exceeded tolerance, whereas only 6% of the electronic portal images did (p = 0.0001). Field displacements on the treatment set-ups between the acquisition of port films were not predicted by those films. CONCLUSION There are discrepancies between the field displacements and field placement errors detected by weekly port films and daily electronic portal images. This study suggests that improved methods of treatment verification may be necessary in modern radiation therapy.

Phase I/II study of treatment of locally advanced (T3/T4) non-oat cell lung cancer with concomitant boost radiotherapy by the radiation therapy oncology group(RTOG 83-12) : long term results

PURPOSE This pilot study was undertaken to evaluate the effect of high dose-per-fraction radiotherapy given to the tumor primary concurrently with conventional fractionated radiotherapy to the electively irradiated regional lymph nodes (concomitant boost). This article reports the late results of toxicity and survival. METHODS AND MATERIALS Fifty-nine patients with histologically proven clinical Stage T3-T4, N1-3 nonsmall cell lung cancer were prospectively enrolled in this study. Fifty-six were evaluable for late effects. The treatment delivered 2.68 Gy daily to the primary tumor, 5 days a week, to a total dose of 75 Gy in 28 fractions in 5.5 weeks. At the same treatment sessions, the electively irradiated nodal areas received 1.8 Gy daily, 5 days per week, to a total dose of 50.4 Gy. All doses were calculated with heterogeneity corrections for lung density. RESULTS Presently, one patient remains alive at 7.7 years. Median survival was 10.0 months with 1-, 2-, 3-, and 5-year survival rates of 41%, 25%, 18%, and 4%, respectively. Three patients developed severe late complications, including pulmonary fibrosis and osteonecrosis. The remainder of the patients, however, developed only grade 1 or 2 pulmonary fibrosis and/or pneumonitis. CONCLUSION We conclude that concomitant boost radiotherapy in the manner reported resulted in acceptable late toxicity. The 2- and 3-year survivals compared favorably with the best-reported results in the literature with either hyperfractionated or chemoradiotherapy treatment. Studies that deliver higher radiotherapy doses to the gross tumor combined with chemotherapy are in order.