Andrew T. Turrisi

RANDOMIZED TRIAL OF PREOPERATIVE CHEMORADIATION VERSUS SURGERY ALONE IN PATIENTS WITH LOCOREGIONAL ESOPHAGEAL CARCINOMA

PURPOSEnA pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone.nnnMATERIALS AND METHODSnOne hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42.nnnRESULTSnAt median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power.nnnCONCLUSIONnThis randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

Dose Escalation in Non–Small-Cell Lung Cancer Using Three-Dimensional Conformal Radiation Therapy: Update of a Phase I Trial

PURPOSEnHigh-dose radiation may improve outcomes in non-small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose could be safely escalated.nnnMATERIALS AND METHODSnA standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes >or= 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine.nnnRESULTSnAt the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions.nnnCONCLUSIONnDose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.

Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients

Tumor control probability (TCP) model calculations may be used in a relative manner to evaluate and optimize three-dimensional (3-D) treatment plans. Using a mathematical model which makes a number of simplistic assumptions, TCPs can be estimated from a 3-D dose distribution of the tumor given the dose required for a 50% probability of tumor control (D50) and the normalized slope (gamma) of the sigmoid-shaped dose-response curve at D50. The purpose of this work was to derive D50 and gamma from our clinical experience using 3-D treatment planning to treat non-small cell lung cancer (NSCLC) patients. Our results suggest that for NSCLC patients, the dose to achieve significant probability of tumor control may be large (on the order of 84 Gy) for longer (> 30 months) local progression-free survival.

Dose-volume histogram and 3-D treatment planning evaluation of patients with pneumonitis

PURPOSEnTolerance of normal lung to inhomogeneous irradiation of partial volumes is not well understood. This retrospective study analyzes three-dimensional (3-D) dose distributions and dose-volume histograms for 63 patients who have had normal lung irradiated in two types of treatment situations.nnnMETHODS AND MATERIALSn3-D treatment plans were examined for 21 patients with Hodgkins disease and 42 patients with nonsmall-cell lung cancer. All patients were treated with conventional fractionation, with a dose of 67 Gy (corrected) or higher for the lung cancer patients. A normal tissue complication probability description and a dose-volume histogram reduction scheme were used to assess the data. Mean dose to lung was also calculated.nnnRESULTSnFive Hodgkins disease patients and nine lung cancer patients developed pneumonitis. Data were analyzed for each individual independent lung and for the total lung tissue (lung as a paired organ). Comparisons of averages of mean lung dose and normal tissue complication probabilities show a difference between patients with and without complications. Averages of calculated normal tissue complication probabilities for groups of patients show that empirical model parameters correlate with actual complication rates for the Hodgkins patients, but not as well for the individual lungs of the lung cancer patients treated to larger volumes of normal lung and high doses.nnnCONCLUSIONnThis retrospective study of the 3-D dose distributions for normal lung for two types of treatment situations for patients with irradiated normal lung gives useful data for the characterization of the dose-volume relationship and the development of pneumonitis. These data can be used to help set up a dose escalation protocol for the treatment of nonsmall-cell lung cancer.

Dose escalation for non-small cell lung cancer using conformal radiation therapy

PURPOSEnImproved local control of non-small cell lung cancer (NSCLC) may be possible with an increased dose of radiation. Three-dimensional radiation treatment planning (3D RTP) was used to design a radiation therapy (RT) dose escalation trial, where the dose was determined by (a) the effective volume of normal lung irradiated, and (b) the estimated risk of a complication. Preliminary results of this trial were reviewed.nnnMETHODS AND MATERIALSnA graph of the iso-normal tissue complication probability (NTCP) levels associated with a dose and effective volume (V(eff)) was derived, using normal tissue parameters derived from the literature. This led to a dose escalation schema, where patients were sorted into 1 of 5 treatment bins, determined by the V(eff) of the best possible treatment plan. The starting doses ranged from 63 to 84 Gy. Each treatment bin was then escalated separately, as in Phase I dose escalation fashion, with Grade > or = 3 radiation pneumonitis defined as dose limiting. To allow for dose escalation, we required patient follow-up to be > or = 6 months for at least three patients. 3D treatment planning was used to irradiate only the radiographically abnormal areas, with 2.1 Gy (corrected for lung inhomogeneity)/day. Clinically uninvolved lymph nodes were not treated prophylactically.nnnRESULTSnA total of 48 NSCLC patients have been treated (Stage I/II: 18 patients; Stage III: 28 patients; mediastinal recurrence postsurgery: 2 patients). No radiation pneumonitis has been observed in the 30 patients currently evaluable beyond the 6-month time point. All treatment bins have been escalated at least once. Current doses in the five treatment bins are 69.3, 69.3, 75.6, 84, and 92.4 Gy. None of the 15 evaluable patients in any bin with > or = 30% NTCP experienced clinical radiation pneumonitis, implying that the actual risk is < 20% (beta error rate 5%). Despite the observation of the clinically negative lymph nodes at high risk, there has been no failure in the untreated mediastinum as the sole site of first failure. Three of 10 patients receiving > or = 84 Gy have had biopsy proven residual or locally recurrent disease.nnnCONCLUSIONnSuccessful dose escalation in a volume-dependent organ can be performed using this technique. By incorporating the effective volume of irradiated tissue, some patients have been treated to a total dose of radiation over 50% higher than traditional doses. The literature-derived parameters appear to overestimate pneumonitis risk with higher volumes. There has been no obvious negative effect due to exclusion of elective lymph node radiation. When completed, this trial will have determined the maximum tolerable dose of RT as a single agent for NSCLC and the appropriate dose for Phase II investigation.

Use of Veff and iso-NTCP in the implementation of dose escalation protocols

PURPOSEnThis report investigates the use of a normal tissue complication probability (NTCP) model, 3-D dose distributions, and a dose volume histogram reduction scheme in the design and implementation of dose escalation protocols for irradiation of sites that are primarily limited by the dose to a normal tissue which exhibits a strong volume effect (e.g., lung, liver).nnnMETHODS AND MATERIALSnPlots containing iso-NTCP contours are generated as a function of dose and partial volume using a parameterization of a NTCP description. Single step dose volume histograms are generated from 3-D dose distributions using the effective-volume (Veff) reduction scheme. In this scheme, the value of Veff for each dose volume histogram is independent of dose units (Gy, %). Thus, relative dose distributions (%) may be used to segregate patients by Veff into bins containing different ranges of Veff values before the assignment of prescription doses (Gy). The doses for each bin of Veff values can then be independently escalated between estimated complication levels (iso-NTCP contours).nnnRESULTS AND CONCLUSIONnGiven that for the site under study, an investigator believes that the NTCP parameterization and the Veff methodology at least describe the general trend of clinical expectations, the concepts discussed allow the use of patient specific 3-D dose/volume information in the design and implementation of dose escalation studies. The result is a scheme with which useful prospective tolerance data may be systematically obtained for testing the different NTCP parameterizations and models.

Results of high-dose thoracic irradiation incorporating beam's eye view display in non-small cell lung cancer: A retrospective multivariate analysis

PURPOSEnTo review the University of Michigan clinical experience in nonsmall cell lung cancer using high-dose thoracic irradiation (> or = 60 Gy) so that a starting dose for our prospective dose-escalation study could be determined.nnnMETHODS AND MATERIALSnEighty-eight consecutive patients diagnosed with medically inoperable or locally advanced, unresectable nonsmall cell lung cancer were identified who were treated with thoracic irradiation alone to a minimum total dose of 60 Gy (uncorrected for lung density). All patients except four (95%) underwent computed tomography scanning for treatment planning that included beams eye view display for tumor and critical structure localization. All patients were treated with standard fractionation in a continuous course to uncorrected total doses ranging from 60 to 74 Gy (median, 67.6 Gy).nnnRESULTSnThe median follow-up exceeds 24 months for all surviving patients (range, 12 to 78 months). The median survival time was 15 months, and the 2- and 3-year overall actuarial survival rates were 37% and 15%, respectively. Survival was significantly different between stage of disease (p = .004) and N-stage (p = .002) by univariate analysis. In a multivariate analysis, stage becomes the only characteristic significantly associated with outcome. The median time to local progression for 86 evaluable patients was 29 months. Stage (p = .0003), T-stage (p = .0095) and N-stage (p = .027) were significantly different with respect to local progression-free survival by univariate analysis. However, only stage was prognostic for local progression-free survival by multivariate analysis. There was no difference between large volume treatment (inclusion of the contralateral hilar and supraclavicular lymph nodes) and small volume treatment (exclusion of these elective nodal sites) with respect to local progression-free survival (p = .507) or survival (p = .520). With regard to dose, there was no significant difference between patients who received > 67.6 Gy and patients who received < or = 67.6 Gy with respect to local progression-free survival (p = .094) or survival (p = .142). Within the Stage III subgroup, local progression-free survival (p = .018) and survival (p = .061) were longer favoring the high-dose group of patients. Despite these doses, disease progression within the irradiated field was the predominant first site of treatment failure.nnnCONCLUSIONnThis retrospective study has shown that it is feasible to deliver uncorrected tumor doses as high as 70 Gy using standard fractionation in NSCLC with acceptable morbidity. Local control remains a significant problem. These data indicate justification for a starting dose in a prospective radiation dose-escalation study.

Results of primary and adjuvant CT-based 3-dimensional radiotherapy for malignant tumors of the paranasal sinuses.

PURPOSEnThis study reports our clinical experience supporting the normal tissue-sparing capability of 3-dimensional (3-D) treatment planning when applied to advanced neoplasms of the paranasal sinuses.nnnMETHODS AND MATERIALSnBetween 1986 and 1992, computed tomography (CT)-based 3-D radiotherapy was used to treat 39 patients with advanced stage malignant tumors of the paranasal sinuses as all or part of initial treatment. Fifteen unresectable patients were treated with primary radiotherapy to a median prescribed total dose of 68.4 Gy. Twenty-four patients were treated with postoperative adjuvant radiotherapy for close margins (< 5 mm), microscopic or gross residual disease. The median prescribed total doses were 55.8 Gy, 59.4 Gy and 67.8 Gy, respectively. Globe-sparing fields were used in the primary treatment plans of 37 patients (95%). The median follow-up is 4.5 years (range, 19-86 months).nnnRESULTSnFor the unresectable patients who were treated with radiotherapy alone, the local control rate at 3 years is 32%. The actuarial overall survivals at 3 and 4 years are 32%. For the patients who received postoperative adjuvant radiotherapy, none of the five patients irradiated for close surgical margins recurred locally. Three of the 14 with microscopic residual (21%) recurred locally at 26, 63, and 74 months from the start of irradiation. Four of the five with gross residual (80%) recurred locally with a median time to recurrence of 2 years. The local control rates at 3 and 5 years for the adjuvant group are 75% and 65%, respectively. The actuarial overall survival at 3 and 5 years are 65% and 60%, respectively. None of the first sites of local disease progression were judged to have occurred outside the high-dose region. There was one case of mild osteoradionecrosis successfully treated with conservative treatment, one case of limited optic neuropathy and one case of possible radiation-induced cataract. There was no blindness related to irradiation.nnnCONCLUSIONnThis study indicates that computed tomography-based 3-D radiotherapy can preserve critical structures unaffected by tumor invasion and achieve the generally expected local control rates when it is used as all or part of initial treatment for extensive malignant tumors of the paranasal sinus. The presence of gross disease was a major adverse prognostic factor in this study. Additional therapeutic maneuvers are essential to improve the local control and survival rate in patients with advanced paranasal sinus carcinomas.

Volume and dose parameters for survival of non-small cell lung cancer patients

BACKGROUND AND PURPOSEnTo determine the effect of tumor volume and dose factors derived from 3-D treatment planning dose distributions on survival outcome for non-small cell lung cancer patients.nnnMATERIALS AND METHODSnSeventy-six consecutive patients diagnosed with medically inoperable or locally advanced, unresectable non-small cell lung cancer planned with 3-D treatment planning between 1986 and 1992 were the subject of this retrospective study. Patient characteristics and dosimetric parameters were analyzed for influence on overall survival and local progression-free survival (LPFS) using univariate and multivariate analysis.nnnRESULTSnNodal stage and stage were the most significant factors for overall survival and LPFS duration on both univariate and multivariate analysis. We found a wide range of primary tumor volume sizes for each stage. Patients with tumor volumes <200 cm3 had longer survival (P = 0.047). In an analysis stratifying patients into four groups by tumor volume (<200 cm3 versus >200 cm3) and nodes (negative versus positive), patients in the group with no nodal disease and <200 cm3 tumor volumes survived longer than patients in any other group (P = 0.046). No dose factors were statistically significant for longer survival. Longer LPFS was seen for (a) isocenter dose >70 Gy (P = 0.055) for the overall group of patients, (b) within a subgroup with no nodal disease and >73 Gy (P = 0.054), and (c) within a subgroup with no nodal disease and tumor volume <200 cm3 receiving >73 Gy (P = 0.086).nnnCONCLUSIONSnSeveral findings from the volume and dosimetric analysis in this study are noteworthy. Stage was found to be a poor predictor of primary tumor volume size. Also, tumor volume size (<200 cm3) in conjunction with nodal status (negative nodes) had an impact on survival though there was a mix of stage (I, IIIa, IIIb) in this group of patients. Finally, dose appears to influence local control (LPFS) for the overall group of patients and when tumor volumes are <200 cm3. Our data indicate that outcome following radiation may be better predicted by a staging system that takes into account tumor volume and nodal spread rather than a system that is largely based on anatomic location of disease. Dose prescription for lung cancer treatment might better be written based on tumor volume size.

Pediatric Midbrain Tumors: A Benign Subgroup of Brainstem Gliomas

The presentation, radiographic findings and course of 17 children with MRI-documented intrinsic midbrain lesions are reviewed. The anatomic centers of all the lesions were tectal, peritectal, or tegmental. Lesions centered at the pineal gland were excluded. Signs of increased intracranial pressure from hydrocephalus requiring shunt placement were present in 14 patients. Histopathological diagnosis was confirmed in three tumors; these were low grade astrocytomas and all received focal irradiation, as did one unbiopsied tumor. The remaining 13 patients with no histopathological diagnosis received no therapy other than shunt placement in 11. All but one of the lesions have remained clinically and radiographically stable, with a 4-year progression-free and total survival of 94 and 100%, respectively. We conclude that mass lesions originating in the upper midbrain are a subset of intrinsic brainstem tumors with a relatively benign course, usually presenting with hydrocephalus after infancy. They may remain stable for considerable periods and may require no further therapy after treatment of hydrocephalus. Surgical biopsy and/or resection can usually be reserved for progressive or atypical lesions which may also require further adjuvant therapy.