Multidisciplinary treatment of olfactory neuroblastoma: Patterns of failure and management of recurrence.

PURPOSE: Esthesioneuroblastoma is an uncommon malignancy of the head and neck for which there is no defined treatment protocol. The purpose of this study is to report our experience with the treatment and patterns of failure of this disease. METHODS AND MATERIALS: From 1994 to 2012, 37 previously unreported patients with esthesioneuroblastoma were evaluated, and 32 eventually treated for cure at 2 academic medical centers. All patients were staged with Kadish criteria. The mean and median follow-ups were 96.1 and 76.5 months respectively (range 6-240 months). RESULTS: The Kadish stage was A in 6 patients, B in 13 patients, and C in 13 patients. Four patients were initially treated with concurrent chemo-radiation therapy. Twenty-eight patients were treated with primary surgery. Two (2) underwent open medial maxillectomy and 26 underwent craniofacial resection (open - 17, endoscopic - 9). Three patients received curative surgical resection only. Seven patients failed either within the cranial axis or distantly, 6 of the 7 are dead of disease, 10-194 months following initial treatment. Six patients had isolated neck recurrences, 4/6 were salvaged with neck dissection and additional chemo-radiation and remain alive 30-194 months following initial treatment. Estimated overall survival rate at 10 years was 78% based on Kadish and T stages. CONCLUSION: In this retrospective analysis of 32 patients, Kadish stage C and stage T3/T4 tumors were associated with worse outcome. Total radiation dose of 60 Gy, margin status, patient age, were not found to have significant prognostic value.

Tissue perfusion rate determined from the decay of oxygen-15 activity after photon activation in situ.

Rates of cerebral perfusion were obtained from measurements of the disappearance (wash-out) of oxygen-15 after in situ tissue activation with 45-million-volt x-rays. In an anesthetized cat, typical values were 90 milliliters per minute per 100 grams of tissue, with 55 percent wash-out. In a specific radiotherapy patient, the value was 65 milliliters per minute per 100 grams of tissue, with 63 percent wash-out of oxygen-15 through incorporation into tissue water.

Multiple members of the retinoic acid receptor family are capable of mediating the granulocytic differentiation of HL-60 cells.

The complex and diverse biological effects of retinoic acid (RA) are mediated through specific receptors that are members of the steroid hormone family of nuclear transcription factors. The RA receptor family consists of multiple structurally distinct RA receptors, which diverge primarily at the NH2-terminal domain. The evolutionary conservation of this divergent region in individual RA receptors among different species together with their tissue-specific patterns of expression suggest that the biological function and activity of the individual RA receptors may be confined to specific tissues. To test this hypothesis in hematopoietic cells, we used retrovirus-mediated gene transduction to introduce the RA receptors RAR-alpha, RAR-beta, and RAR-gamma as well as RXR-alpha into a mutant subclone of the HL-60 promyelocytic leukemia cell line (designated HL-60R) that is relatively resistant to RA-induced granulocytic differentiation. We found that each of these structurally distinct RA receptors could restore sensitivity of the HL-60R cells to RA. A critical threshold number of transduced receptors per cell appears to be necessary to restore this functional activity. Thus, the capability to mediate granulocytic differentiation of HL-60 cells is shared among distinctly different RA receptors.

Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer.

BACKGROUND: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. PURPOSE: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. METHODS: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29 and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). RESULTS: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy--46%, 11.4 months; chemotherapy plus radiotherapy--60%, 13.8 months; and hyperfractionated radiation therapy--51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). CONCLUSIONS: In "good-risk" patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.

Sequencing of the total course of hyperthermia and irradiation.

The effect of sequencing of the total course of hyperthermia and irradiation on local tumor control was studied on a murine tumor system (RIF). The results showed a 20% control rate for the treatment arms: (a) total course of irradiation followed by total course of hyperthermia; or (b) total course of hyperthermia followed by total course of irradiation. A superior (70%) control rate was achieved when irradiation and heat were given close to each other on each session. The detailed results are presented.

Design and fabrication of a nanofibrous polycaprolactone tubular nerve guide for peripheral nerve tissue engineering using a two-pole electrospinning system.

Nerve guidance conduits are considered to be the new generation of scaffolds designed for nerve disorders. A tubular construct with a highly aligned fibrous structure, mimicking the endoneurium layer surrounding inner axons of a nerve fascicle, is a suitable candidate for a nerve guide. In this paper a new approach for the fabrication of 3D tubular nerve guides is introduced using simulation of a two-pole electrospinning system and describing its mechanism. The structure of this scaffold is then optimized using the Taguchi statistical method and after morphological studies by scanning electron microscopy, the crystallinity, tensile strength and protein adsorption of these highly aligned fibres are investigated, comparing them with semi-aligned and random fibres produced via conventional mandrel electrospinning. Cell attachment, proliferation and migration of PC12 neuronal like cells are studied on highly aligned, semi aligned and random structures, and morphological change and elongation are observed in PC12 cells. The results of these studies suggest that conduits fabricated using two-pole electrospinning are a suitable and promising scaffold for peripheral and even spinal nerve regeneration. This nerve guide has a great potential for further advanced modifications and regeneration in higher levels.

A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11.

A phase Ilate/II trial of hyperfractionated (HFX) radiation therapy for non-small-cell carcinoma of the lung (NSCCL) was conducted by the Radiation Therapy Oncology Group (RTOG) between 1983 and 1987. Fractions of 1.2 Gy were administered twice daily with greater than or equal to 4 hours between fractions. Patients were randomized to receive minimum total doses of 60.0, 64.8, and 69.6 Gy. After acceptable risks of acute and late effects were found, 74.4 Gy and 79.2 Gy arms were added, and the lowest total dose arms were closed. No significant differences in the risks of acute or late effects in normal tissues were found among the 848 patients analyzed in the five arms; risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among 350 patients who had the same criteria as Cancer and Leukemia Group B (CALGB) protocol 84-33 (American Joint Committee on Cancer Staging [AJCCS], 1984, stage III; Karnofsky performance status [KPS] 70 to 100; less than 6% weight loss), there was a dose response for survival: survival with 69.6 Gy (median, 13.0 months; 2 years, 29%) was significantly (P = .02) better than the lower total doses. There were no differences in survival among the three highest total-dose arms. Comparisons with results in similar patients treated with 60 Gy in 30 fractions of 2.0 Gy 5 days per week for 6 weeks suggest benefit from HFX radiation therapy with 69.6 Gy. Improvement in survival with HFX radiation therapy at 69.6 Gy total dose without increase in normal tissue effects, justifies phase III comparison with standard fractionation alone and combined with systemic chemotherapy in this common presentation of NSCCL.

Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study.

PURPOSE: The present intergroup phase III randomized study compared combined chemotherapy (CT) plus radiotherapy (RT) treatment versus RT only in patients with locally advanced esophageal cancer. MATERIALS AND METHODS: Two courses of chemotherapy during 50 Gy RT followed by additional two courses of the same CT, versus 64 Gy RT alone were investigated. CT consisted of cisplatin 75 mg/m2 on day 1 [corrected] and fluorouracil (5FU) 1,000 mg/m2/d on days 1 to 4 every 4 weeks with RT and every 3 weeks post-RT. The main objective of the study was to compare overall survival between the two randomized treatment groups. Patients were stratified by tumor size, histology, and degree of weight loss. RESULTS: Sixty-two assessable patients were randomized to receive RT alone, and 61 to the combined arm. Patients characteristics were as follows: squamous cell cancer, 90% versus 85%; weight loss greater than 10 lb, 61% versus 69%; and tumor size, > or = 5 cm, 82% versus 80% on the RT and CT-RT arms, respectively. Systemic side effects, which consisted of nausea, vomiting, and renal and myelosuppression, occurred more frequently on the combined arm, while local side effects were similar in both groups. With a minimum follow-up time of 5 years for all patients, the median survival duration was 14.1 months and the 5-year survival rate was 27% in the combined treatment group, while the median survival duration was 9.3 months with no patients alive at 5 years in the RT-alone group (P < .0001). Additional patients (69) were treated with the same combined therapy and were analyzed. The results of the last group confirmed all of the results obtained with combined CT-RT in the randomized trial, with a median survival duration of 17.2 months and 3-year survival rate of 30%. CONCLUSION: We conclude that cisplatin and 5FU infusion given during and post-RT of 50 Gy is statistically superior to standard 64-Gy RT alone in patients with locally advanced esophageal cancer.

Radiation palliation of cervical cancer.

Radiation is a useful modality for palliation of local-regional disease in patients with cervical cancer who require palliation because of distant metastases, extensive local-regional disease, medical consideration, or patient concerns. Two radiation schedules have been reported on for the treatment of advanced pelvic disease including cervical cancer. The large single-dose schedule consisted of 10-Gy fractions repeated at monthly intervals to a maximum of 30 Gy. This schedule has produced good palliative results with symptomatic improvement in approximately 50% of patients and objective response in 35%-80%. However, severe late toxicity was shown to be as high as 42% (actuarial). The second schedule tested by the Radiation Therapy Oncology Group consisted of 3.7-Gy fractions given twice a day for 2 days (14.8 Gy) repeated after 2-4 weeks for a maximum of 44.4 Gy. There were 284 patients accrued, and the subgroup of 61 cervical cancer patients is analyzed in this article. The subjective response (50%-100% complete response) and objective response (53%) were similar to those observed with the large single-fraction schedule. The late toxicity was significantly lower (7%-actuarial). For patients who may survive 6 months or longer, this second schedule is preferable.

Combination of surgery, irradiation, and hyperthermia in treatment of recurrences of malignant tumors.

Management of recurrent tumors after initial treatment by surgery, radiotherapy, and sometimes chemotherapy is a formidable challenge. Proximity of tumor to critical organs (e.g., carotid artery in recurrent head and neck tumors) often makes radical surgery impossible. Prior definitive course of radiation therapy precludes delivering a second radical course of irradiation. In the Division of Radiation Oncology, Washington University, we have used combined postoperative hyperthermia and modest dose radiotherapy to treat 23 patients with recurrent tumors and postoperative residual disease. Generally, 3200 to 4000 cGy was delivered in eight to ten fractions in 4 to 5 weeks, in combination with eight to ten sessions of minimum tumor heating to 42.5 degrees to 43 degrees C for 60 minutes, twice a week as stated in the results. Follow-up period was one to 5+ years. Of the 23 patients treated, only three failed within the treatment volume.

Carcinoma of the extrahepatic biliary system--results of primary and adjuvant radiotherapy.

From 1975-1983, 20 patients with primary carcinomas of the gallbladder (GB) or extrahepatic bile ducts (EHBD) were irradiated with curative intent at the Washington University Medical Center and affiliated hospitals. Of the 17 patients with EHBD cancer, one received adjuvant irradiation after gross resection with positive microscopic margins. All others received primary irradiation for unresectable tumors, or for gross residual tumor after incomplete resection. The 8 patients receiving Ir192 implant in addition to external radiation showed improved (p = 0.06) survival compared to the 9 receiving external only: median 15 months (range 1.5-34 + months) versus 7 months (range 2.5-21 months). Failures were predominantly local-regional, with only one patient showing metastatic spread without known local-regional tumor. Adjuvant radiation therapy was given after cholecystectomy to 3 patients with GB cancers showing tumor extension beyond the serosa or to regional lymphatics. Of these, two survived at 22+ and 27+ months; the third died of local recurrence at 5 1/2 months. Although numbers are small, these results appear to support the use of adjuvant radiotherapy in patients with microscopic residual GB cancer. Aggressive local and regional radiotherapy can add to the quality and length of survival in both patient groups, that is, those with resectable lesions with high likelihood of microscopic residual, and also those with unresectable or gross residual disease after surgery.

Physiological mechanisms in hyperthermia: a review.

In experimental animal systems, hyperthermia at therapeutic temperature (43-45 degrees C) causes a profound increase in blood flow in normal tissues while it induces only meager and temporal increases in blood flow in tumors. A severe vascular occlusion and hemorrhage usually follows the increase in blood flow in the tumors at the above temperatures. Another pronounced physiological change in tumors by heat is a prompt decrease in intratumor pH. The decrease in intratumor pH would accentuate the thermokilling of tumor cells and also possibly inhibit repair of thermodamage and development of thermotolerance in tumors. The temperature in tumors may rise higher than that in normal tissues during heating because of inefficient heat dissipation from the tumor as a result of decrease blood flow or vascular occlusion. Thus, the differential effects of heat on vascular function and pH in tumors and normal tissues may result in a greater damage in tumors than in surrounding normal tissues. Further investigation is urgently needed to find out whether similar physiological changes occur in human tumors and normal tissues by hyperthermia.

Fitting of normal tissue tolerance data to an analytic function.

During external beam radiotherapy, normal tissues are irradiated along with the tumor. Radiation therapists try to minimize the dose of normal tissues while delivering a high dose to the target volume. Often this is difficult and complications arise due to irradiation of normal tissues. These complications depend not only on the dose but also on volume of the organ irradiated. Lyman has suggested a four-parameter empirical model which can be used to represent normal tissue response under conditions of uniform irradiation to whole and partial volumes as a function of the dose and volume irradiated. In this paper, Lyman's model has been applied to a compilation of clinical tolerance data developed by Emami et al. The four parameters to characterize the tissue response have been determined and graphical representations of the derived probability distributions are presented. The model may, therefore, be used to interpolate clinical data to provide estimated normal tissue complication probabilities for any combination of dose and irradiated volume for the normal tissues and end points considered.

Phase I/II study of treatment of locally advanced (T3T4) non-oat cell lung cancer with high dose radiotherapy (rapid fractionation): Radiation Therapy Oncology Group Study.

The Radiation Therapy Oncology Group (RTOG) completed a pilot study to test the feasibility of high dose of radiation therapy and its impact on tumor control and survival. From April 1, 1983 through May 1985, a total of 56 patients were treated on this protocol. All patients had locally advanced disease without distant metastases. The treatment regimen consisted of delivering 7500 cGy in 28 fractions over 5.5 weeks to the tumor, while the nodal bearing areas received 5040 cGy in the same period (daily dose to the mediastinum was 180 cGy; daily dose to gross tumor was 268 cGy). This is a considerably higher dose, with a TDF of 142 compared with a TDF of 92 (conventional fractionation of 6000 cGy in 6 weeks), which is the highest dose used in previous RTOG studies. Doses in this protocol (7500 cGy) was corrected for lung transmission whereas doses in prior RTOG protocols (6000 cGy) were uncorrected. Thus, after correction dose of 6600 cGy was calculated and coded for comparison. All short-term toxicities were acceptable, and the only major toxicity was one third-degree esophagitis in a patient with a follow-up of 12 months. Forty-four out of fifty-six patients received prescribed dose of irradiation. There were 17 complete responders and 15 partial responders, with an overall response rate of 32 out of 44 (72.7%). At the time of this report, there were 9 patients alive (NED); 5 died without tumor; and the remainder died of tumor or unknown.

Characteristics of improved microwave interstitial antennas for local hyperthermia.

The heating potentials of two newly-developed microwave interstitial antennas are reported in this paper. The longitudinal (parallel to the antenna) and transverse (over a plane perpendicular to the antenna) specific absorption rate (SAR) distributions of single and an array of four parallel antennas were measured in a muscle equivalent phantom and their performance characterized at 915 MHz in terms of the following parameters: peak depth (location of the profile peak with respect to the surface), 50% HL (effective heating length over which SAR greater than 50% of the peak normalized SAR), dead length (axial length at the antenna tip with SAR less than 50% of peak normalized SAR), and the variations of the specific absorption rate pattern relative to the depth of insertion. The results are analyzed and discussed in terms of these parameters and other factors important in the clinical use of these antennas for effective interstitial hyperthermia.

Evaluation of a standard breast tangent technique: a dose-volume analysis of tangential irradiation using three-dimensional tools.

PURPOSE: A thorough dose-volume analysis of a standard tangential radiation technique has not been published. We evaluated the adequacy of a tangential radiation technique in delivering dose to the breast and regional lymphatics, as well as dose delivered to underlying critical structures. METHODS AND MATERIALS: Treatment plans of 25 consecutive women with breast cancer undergoing lumpectomy and adjuvant breast radiotherapy were studied. Patients underwent two-dimensional (2D) treatment planning followed by treatment with standard breast tangents. These 2D plans were reconstructed without modification on our three-dimensional treatment planning system and analyzed with regard to dose-volume parameters. RESULTS: Adequate coverage of the breast (defined as 95% of the target receiving at least 95% of the prescribed dose) was achieved in 16 of 25 patients, with all patients having at least 85% of the breast volume treated to 95% of the prescribed dose. Only 1 patient (4%) had adequate coverage of the Level I axilla, and no patient had adequate coverage of the Level II axilla, Level III axilla, or the internal mammary lymph nodes. CONCLUSION: Three-dimensional treatment planning is superior in quantification of the dose received by the breast, regional lymphatics, and critical structures. The standard breast tangent technique delivers an adequate dose to the breast but does not therapeutically treat the regional lymph nodes in the majority of patients. If coverage of the axilla or internal mammary lymph nodes is desired, alternate beam arrangements or treatment fields will be necessary.

A modified method of planning and delivery for dynamic multileaf collimator intensity-modulated radiation therapy.

PURPOSE: To develop a modified planning and delivery technique that reduces dose nonuniformity for tomographic delivery of intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: The NOMOS-CORVUS system delivers IMRT in a tomographic paradigm. This type of delivery is prone to create multiple dose nonuniformity regions at the arc abutment regions. The modified technique was based on the cyclical behavior of arc positions as a function of a target length. With the modified technique, two plans are developed for the same patient, one with the original target and the second with a slightly increased target length and the abutment regions shifted by approximately 5 mm compared to the first plan. Each plan is designed to deliver half of the target prescription dose delivered on alternate days, resulting in periodic shifts of abutment regions. This method was experimentally tested in phantoms with and without intentionally introduced errors in couch indexing. RESULTS: With the modified technique, the degree of dose nonuniformity was reduced. For example, with 1 mm error in couch indexing, the degree of dose nonuniformity changed from approximately 25% to approximately 12%. CONCLUSION: Use of the modified technique reduces dose nonuniformity due to periodic shifts of abutment regions during treatment delivery.

A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: report of Radiation Therapy Oncology Group 84-07.

PURPOSE: A Phase I/II trial was conducted by the Radiation Therapy Oncology Group from 1984 to 1989 for 355 evaluable patients with non-small-cell lung cancer to assess tolerance to and efficacy of accelerated fractionation irradiation via concomitant boost. METHODS AND MATERIALS: "Large" fields (primary tumor and locoregional lymph nodes) received 1.8 Gy followed after 4 to 6 hr by 1.8 Gy two to three times weekly to reduced "boost" fields (primary and involved nodes only). The total doses escalated during the study and started with 63 Gy in 5 weeks (45 Gy "large" field and 18 Gy "boost") for 61 patients. After follow-up for ongoing toxicity assessment, the total dose was increased to 70.2 Gy in 5.5 weeks (50.4 Gy "large" field and 19.8 Gy "boost") for the next 180 patients. The last 114 patients received 70.2 Gy in 5 weeks (45 Gy "large" field and 25.2 Gy "boost"). RESULTS: Pretreatment patient characteristics were well balanced between the three treatment arms. Grade 3 acute toxicity was 7% for the 63 Gy arm; it was 14% and 17% for the two 70 Gy arms. Grade 4 or greater acute toxicities (esophagitis and pneumonitis) were 2 to 3% for all three arms. Late toxicities ranged between 5 and 9% (> or = Grade 3) and 0 to 2% (> or = Grade 4), not statistically different among the three arms. There was no difference between the three regimens in median survival (9 months) or 1-year survival (39 to 44%). However, the 2-year survivals ranged from 16% (63 Gy) to 21% ("shortened" 70.2 Gy). Among 176 patients who had the same criteria as Cancer and Leukemia Group B protocol 84-33 (American Joint Committee on Cancer Staging, 1984, Stage III; Karnofsky performance status 70 to 100; < 6% weight loss), the 2-year survival rates ranged from 18 to 22%. CONCLUSION: Concomitant boost accelerated fractionation irradiation regimens for non-small cell lung cancer may offer improved long-term survival without enhanced late toxicity. While acute toxicity is somewhat increased, further refinement of the relationship of "large" to "boost" field doses may improve the therapeutic ratio. Further Phase I/II testing seems justified and necessary, before concomitant boost accelerated fractionation irradiation is tested in Phase III trials for NSCLC.

Radiation therapy alone for stage I non-small cell lung cancer.

PURPOSE: This paper is a retrospective analysis of patients with clinical Stage I non-small cell carcinoma of the lung treated with definitive radiation therapy alone. The results of therapy, patterns of failure and the relationship of technical aspects of the delivery of radiotherapy to outcome are presented. MATERIALS AND METHODS: From 1980 through 1990, 53 patients with Stage I non-small cell lung cancer were treated with definitive radiation therapy alone at the Radiation Oncology Center of the Mallinckrodt Institute of Radiology and its affiliated hospitals. All patients had a pathologic diagnosis of non-small cell lung cancer and were not candidates for surgical resection because of either patient refusal (10 patients), poor performance status (5 patients), or premorbid medical problems (38 patients). The median age was 73 years. Histologic cell type included squamous (32), adenocarcinoma (11), large cell (4), and unclassified non-small cell (6). Initial tumor size was < or = 3 cm in 23 patients, between 3 and 5 cm in 13 patients and > or = 5 cm in 17 patients. Diagnostic staging varied during the study period. All patients had chest X-rays and computed tomography scans of the chest. A majority had liver and bone scans, but only four underwent mediastinoscopy. The radiation therapy was of megavoltage energy in all patients, with a median primary prescription tumor dose of 63.2 Gy. Survival was measured from the date radiation therapy was initiated. RESULTS: The actuarial overall survival rate for the entire group was 19% at 3 years and 6% at 5 years, with a median survival time of 20.9 months. Of the 49 deaths, 35 died of lung cancer; 13 died of intercurrent illness, and one died of pancreatic cancer, which made the actuarial cause-specific survival 33% at 3 years and 13% at 5 years. The actuarial 3-year disease-free survival was 33%. Local primary tumor progression occurred in 22 patients, resulting in a 51% 3-year actuarial freedom from local progression. An additional four patients failed in regional lymph nodes that were included in the original treatment portals. Multivariate analysis found only T stage to be associated with overall survival (p = .02). However multivariate analysis showed age as a prognostic factor to be approaching statistical significance (p = .07). Patients under 70 years of age showed an increased survival rate compared to patients over 70 years. Radiation therapy doses > or = 65 Gy appeared to result in a decreased proportion of patients dying of lung cancer with no apparent increase in either acute or long-term complication rates. CONCLUSION: Results of definitive radiation therapy for inoperable Stage I non-small cell lung remain inferior to surgical therapy. Potential methods to improve local control with radiotherapy are discussed.

The influence of field size and other treatment factors on pulmonary toxicity following hyperfractionated irradiation for inoperable non-small cell lung cancer (NSCLC)--analysis of a Radiation Therapy Oncology Group (RTOG) protocol.

PURPOSE: The risk of pulmonary toxicity, observed in an Radiation Therapy Oncology Group Phase I/II randomized dose escalation trial of hyperfractionated irradiation for nonsmall cell lung cancer, was analyzed with regard to custom vs. hand blocking and compliance to protocol specified treatment field parameters. MATERIALS AND METHODS: There were 832 evaluable cases analyzed. The protocol required field margins 2 cm beyond primary tumor and involved nodes. In 674, the field margins were considered "per protocol" or as having minor protocol variations. In 94, margins exceeded protocol specification ("excessive margin" group). In this group, the area (cm2) of the effective (blocked) field and the portion including lung was measured from simulator films with a computer scanning device. Based on size and location of the primary and nodal disease, "per protocol" fields were constructed and the area (cm2) of lung included beyond these margins was estimated. Patients from both groups who received less than 30 Gy to normal lung were excluded from analysis of pulmonary toxicity. RESULTS: Grade 1 acute lung toxicity was higher (p = .009) in the "excessive margin" group compared to the "per protocol" group, whereas late lung toxicity was not significantly different (p = .94). The risk of Grade 2 or greater acute toxicity increased as area of excess irradiated lung increased. Overall lung toxicity, defined as the greater of either acute or late toxicity, was evaluated by multivariate analysis, in relation to assigned dose, effective treated field area, and type of shielding. Overall maximum lung toxicity (> or = Grade 2) was significantly greater in the "excessive margin" group, when lung treated beyond protocol margins exceeded an area of 35 cm2, than in the "per protocol" group, but only when the effective treated field size was > or = 180 cm2 (68% vs. 37%; p = .02). This effect was independent of assigned total dose or type of shielding. CONCLUSION: For nonsmall cell lung cancer treated with hyperfractionated irradiation, the risk of overall pulmonary toxicity was increased for patients treated with field sizes in excess of protocol specified margins of tumor coverage in comparison to patients treated with protocol specified margins. This effect was seen only when the area of lung treated beyond protocol margins exceeded 35 cm2 and when the overall field size was below 180 cm2.