Predictive factors in radiotherapy for non-small cell lung cancer: present status

PURPOSE: To evaluate the predictive factors for radiation response in non-small cell lung cancer (NSCLC) and the role of such factors in guiding high dose radiation therapy. METHODS: The first International Workshop on Prognostic and Predictive Factors in Lung Cancer was organized by the Hellenic Cooperative Oncology Group and held in Athens, Greece under the auspices of the International Association for the Study of Lung Cancer. Presentations at this meeting provided the outline of this report, which has also been supplemented with available data from the current literature. RESULTS: The predictive factors for both the natural history and the therapy outcome of NSCLC are grouped as follows: (1) tumor related factors (anatomic factors); the extent of tumor (tumor stage) is one of most important prognostic factors affecting the therapy outcome. Tumor size (T stage), anatomical structures involved (T4 vs. T3 lesion), and the presence of regional lymph node metastasis have a significant impact on both prognosis and response to appropriate therapy; (2) host-related factors (clinical factors) that are important in therapy response include performance status, weight loss of more than 10% of body weight in the previous 6 months, and associated co-morbidities, i.e. pulmonary and cardiac diseases; (3) technical factors of radiation therapy which play a decisive role in successful outcome. The target volume should be defined accurately using modern imaging studies. The radiation dose fractionation schedule, in terms of the dose intensity and total dose, should be high enough to provide local tumor control in the majority of patients. Three-dimensional (3-D) conformal planning is an essential tool in dose escalation studies to determine the maximum tolerated dose of radiation; (4) biological/radiobiological/metabolic factors. Biologic markers resulting from genetic lesions in lung cancer are grouped as follows: (a) oncogene amplification and overexpression (aberrant gene expression) and mutated tumor suppressor genes -- ras gene, myc gene, HER-2/neu and survivin gene, p53 and mutated beta-tubulin gene; (b) tumor biologic/radiobiologic factors -- tumor cell proliferation kinetics, hypoxia, intrinsic cellular radiosensitivity, gamma factor, and DNA content; (c) enzymes and hormones: neuron-specific enolase, serum lactate dehydrogenase, and enhanced glucose metabolic rate supported by increased glucose transporter protein. The surviving fraction of tumor cells at 2.0 Gy of radiation (SF2) as a measure of intrinsic tumor cell radiosensitivity, potential doubling time (T(Pot)) as a measure of the rate of tumor cell proliferation and gamma factor representing the slope of the survival curve at 50% survival rate are being investigated as potential predictors for therapy response. Enhanced glucose utilization, a hallmark of malignant transformation, is being studied as a potential monitor for therapy response by using PET-FDG. CONCLUSION: Current data indicate that there is a dose-response relationship between radiation dose and local tumor control, and also between local tumor control and survival in stage III NSCLC. Therapeutic factors, i.e. total radiation dose, fractionation schedule and dose intensity, and use of 3-D conformal radiation to secure the optimum therapeutic ratio are important for improved local tumor control and survival. Future research should be directed towards radiation dose escalation using 3-D conformal therapy to determine the maximum tolerated dose (MTD) of radiation in chemo-radiotherapy, and the use of this MTD for improved local tumor control and survival. Radiobiological, molecular, and metabolic markers may have potential for monitoring tumor response and optimizing radiation therapy.     

Dose escalation in locally advanced carcinoma of the prostate

Radiotherapeutic management of advanced prostate cancer is challenging. Several retrospective analyses showed a dose response for local tumor control before the availability of conformal radiation therapy. Attempts to escalate dose without the benefit of modern treatment planning was commonly fraught with high rates of bowel or bladder complications. The advent of image-guided or computed tomography-based treatment planning has allowed safe delivery of high-dose radiation therapy in men with prostate cancer with an acceptable rate of side effects and complications. Several prospective clinical trials have been conducted both at single institutions and in the cooperative group setting. Early evidence suggests that patients with high-risk factors such as advanced clinical stage, high initial prostate-specific antigen, or poorly differentiated tumors may benefit from high-dose 3-dimensional conformal radiation therapy with improved biochemical and local tumor control. A published randomized trial with conformal radiation therapy shows that a modest escalation of radiation dose leads to improved biochemical disease-free survival for a select group of patients. A confirmatory trial within the Radiation Therapy Oncology Group is underway to determine if dose escalation will improve overall survival in men without compromising quality of life. Copyright Elsevier Inc. All rights reserved.     

Strahlentherapie des Prostatakarzinoms

Background

Prostate cancer is the seventh most common cause of death for men in Germany with a mortality rate of 10,1 %. External beam radiotherapy is the alternative primary therapy apart from surgery for patients with locally confined prostate cancer.

Results

The oncological result is linked to the overall dose used. The use of three-dimensional (3-D) conformal radiation therapy allows dose escalation with low side effects. In particular, intensity modulated radiotherapy (IMRT) enables complex dose distributions. As the prostate is a relatively mobile organ, image-guided radiation therapy is the key for a correct dose distribution, which can be achieved with nowadays tools fast and simple.

Conclusions

The new techniques are responsible for a safe dose escalation with low side effects. Patients with intermediate and high risk prostate cancer do profit from the combination of neoadjuvant/simultaneous and adjuvant hormone therapy.     

Radiation dose responses for chemoradiation therapy of pancreatic cancer: An analysis of compiled clinical data using biophysical models

PurposeWe analyzed recent clinical data obtained from chemoradiation of unresectable, locally advanced pancreatic cancer (LAPC) in order to examine possible benefits from radiation therapy dose escalation.Methods and MaterialsA modified linear quadratic model was used to fit clinical tumor response and survival data of chemoradiation treatments for LAPC reported from 20 institutions. Biophysical radiosensitivity parameters were extracted from the fits.ResultsExamination of the clinical data demonstrated an enhancement in tumor response with higher irradiation dose, an important clinical result for palliation and quality of life. Little indication of improvement in 1-year survival with increased radiation dose was observed. Possible dose escalation schemes are proposed based on calculations of the biologically effective dose required for a 50% tumor response rate.ConclusionsBased on the evaluation of tumor response data, the escalation of radiation dose presents potential clinical benefits which when combined with normal tissue complication analyses may result in improved treatment outcome for locally advanced pancreatic cancer patients.     

Breast conservation therapy (BCT): Surgery as the cornerstone of multi-specialty care

Surgical care has been the mainstay of breast cancer diagnosis and treatment. As care has evolved, increased collaborative approaches among surgeons, radiologists, radiation oncologists and medical oncologists have improved the quality of breast cancer treatment for the patient. Breast conservation therapy (BCT) exemplifies how multi-specialty care can increase cancer cure rates at the same time that the disfiguring aspects of breast cancer treatment can be minimized. New questions are being raised within clinical forums about how to do better both for the patient and for her oncologic treatment. The following questions represent three current issues in BCT:

1. What general operative approaches in BCT can minimize morbidity and optimize the cosmetic outcome from surgery?
2. What role does radiation therapy play in BCT for invasive and non-invasive breast cancer to supplement surgical intervention?
3. What role can neoadjuvant chemotherapy play in improving BCT rates?

     

What do we know and what don't we know about tamoxifen in the human uterus

Since its introduction in the early seventies, the list of indications for the use of the antiestrogen tamoxifen has been continuously expanded. Tamoxifen is now used for the treatment of metastatic breast cancer and for long-term and often indefinite administration as an adjuvant therapy. Large clinical trials in three countries are now evaluating the efficacy of tamoxifen as a preventive agent. However, tamoxifen therapy has been associated with an increased incidence of endometrial carcinoma. Laboratory and clinical data available to date on this controversial issue can be summarized as follows:

1. Tamoxifen can have an estrogenic effect on endometrium in the presence of low estrogen levels.
2. Tamoxifen treatment is probably associated with an increased incidence of endometrial cancer; however, this association appears to be linked to higher tamoxifen doses (40mg/d).
3. It is not known whether tamoxifen causes or allows the identification of occult endometrial carcinoma.
4. At the present time there is evidence for a tumor promoting effect of tamoxifen on endometrial cancer at a dose of 20 mg per day.
5. Replacement of tamoxifen by ‘pure’ antiestrogens or coadministration of progestins with tamoxifen do not appear to offer benefit unless clinical trials demonstrate a reduced incidence of endometrial problems.
6. Patientsmust be evaluated for pre-exsisting endometrical carcinoma before starting tamoxifen therapy.
7. Close followup of long-term tamoxifen patients with endometrial biopsies is recommended with individuals who experience symptoms.

     

Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial.

PURPOSE: High-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. MATERIALS AND METHODS: A 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. RESULTS: At 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. CONCLUSION: Dose 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.     

Conformal radiotherapy of prostatic cancer: a general review]

Recent progress in radiotherapeutic management of localized prostate cancer is reviewed. Clinical aspects--including dose-effect beyond 70 Gy, relative role of conformal radiation therapy techniques and of early hormonal treatment--are discussed as well as technical components--including patient immobilization, organ motion, prostate contouring, beam arrangement, 3-D treatment planning and portal imaging. The local control and biological relapse-free survival rates appear to be improved by high dose conformal radiotherapy from 20 to 30% for patients with intermediate and high risk of relapse. A benefit of overall survival is expected but not yet demonstrated. Late reactions, especially the rectal toxicity, remain moderate despite the dose escalation. However, conformal radiotherapy demands a high precision at all steps of the procedure.     

Results of a phase II concurrent chemoradiotherapy study using three-dimensional conformal radiotherapy with cisplatin and oral etoposide in stage III nonsmall-cell lung cancer

This phase II study was designed to utilize conformal radiation therapy with cisplatin and oral etoposide in patients with stage III or locally recurrent non-small-cell lung cancer to determine tolerance and toxicity of therapy. From April 1992-February 1996, 18 patients with pathologically confirmed stage IIIA, IIIB, or locally recurrent non-small-cell lung cancer (NSCLC) were entered on study. Metastatic workup included a CT scan of the thorax and upper abdomen as well as a bone scan. Chemotherapy consisted of IV cisplatin (100 mg/m2) with IV etoposide (25 mg/m2) on day 1; oral etoposide was given (50 mg/m2) days 2-14. Using three-dimensional planning, 40-45 Gy were delivered to the clinical target volume, followed by a boost to the gross tumor volume for a total of 70 Gy. Patients with recurrent disease received 40-50 Gy in total. Eighteen patients were enrolled: 16 patients were treated with curative intent and were evaluable for outcome. Two patients were treated for locally recurrent NSCLC and were not included in the outcome analysis. Stages included IIIA (44%) and stage IIIB (54%). Forty-four percent had T3/4 tumors, and 69% had N2/3 disease. Overall survival at 1 year was 64%, while 2-year overall survival was 50%. Distant metastasis-free survival at 1 year was 67%, and at 2 years 60%. The 1-year chest progression-free survival was 57%, and at 2 years 50%. Sixty-three percent required hospitalization for dehydration or neutropenia. Fifty-six percent developed leukopenia (<1,000 cells/microl) sometime during the therapy. We conclude that concurrent cisplatin and oral etoposide with conformal radiation therapy provide encouraging results in stage III lung cancer. The major toxicities of this therapy included leukopenia, thrombocytopenia, and mucosal esophagitis. Local progression of disease continues to be a problem with the current doses given. Future studies should evaluate dose escalation of radiation therapy with limited volumes, utilizing conformal radiation and chemotherapy to improve local control and potentially impact upon distant metastases.     

Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer

Purpose: Three-dimensional conformal radiation therapy (3D-CRT) is a technique designed to deliver prescribed radiation doses to localized tumors with high precision, while effectively excluding the surrounding normal tissues. It facilitates tumor dose escalation which should overcome the relative resistance of tumor clonogens to conventional radiation dose levels. The present study was undertaken to test this hypothesis in patients with clinically localized prostate cancer.Methods and Materials: A total of 743 patients with clinically localized prostate cancer were treated with 3D-CRT. As part of a phase I study, the tumor target dose was increased from 64.8 to 81 Gy in increments of 5.4 Gy. Tumor response was evaluated by post-treatment decrease of serum prostate-specific antigen (PSA) to levels of ≤1.0 ng/ml and by sextant prostate biopsies performed ≥2.5 years after completion of 3D-CRT. PSA relapse-free survival was used to evaluate long-term outcome. The median follow-up was 3 years (range: 1–7.6 years).Results: Induction of an initial clinical response was dose-dependent, with 90% of patients receiving 75.6 or 81.0 Gy achieving a PSA nadir ≤1.0 ng compared with 76% and 56% for those treated with 70.2 Gy and 64.8 Gy, respectively (p < 0.001). The 5-year actuarial PSA relapse-free survival for patients with favorable prognostic indicators (stage T1-2, pretreatment PSA ≤10.0 ng/ml and Gleason score ≤6) was 85%, compared to 65% for those with intermediate prognosis (one of the prognostic indicators with a higher value) and 35% for the group with unfavorable prognosis (two or more indicators with higher values) (p < 0.001). PSA relapse-free survival was significantly improved in patients with intermediate and unfavorable prognosis receiving ≥75.6 Gy (p < 0.05). A positive biopsy at ≥2.5 years after 3D-CRT was observed in only 1/15 (7%) of patients receiving 81.0 Gy, compared with 12/25 (48%) after 75.6 Gy, 19/42 (45%) after 70.2 Gy, and 13/23 (57%) after 64.8 Gy (p < 0.05).Conclusions: The data provide evidence for a significant effect of dose escalation on the response of human prostate cancer to irradiation and defines new standards for curative radiotherapy in this disease.     

Intensity modulated radiotherapy (IMRT) decreases treatment-related morbidity and potentially enhances tumor control

Intensity modulated radiation therapy (IMRT), a new form of three-dimensional conformal radiation therapy (3DCRT), optimizes the concept of computer-controlled radiation deposition in tumor (target) while sparing adjacent normal structures. A retrospective review was done on the initial 185 patients with tumors in different sites including prostate cancer, head and neck cancer, pediatric tumors, adult brain tumors, and previously irradiated recurrent tumors treated with IMRT.

Preliminary findings indicate that IMRT is a new clinically feasible tool in radiation oncology. Treatment-related morbidity profile was favorable. Tumor response, local control, and the ability to palliate previously irradiated patients are encouraging. Intensity modulated radiation therapy will allow dose escalation, leading to better tumor control.     

Strategy for dose escalation using 3-dimensional conformal radiation therapy for lung cancer

PURPOSE: Local failure is a major obstacle to the cure of locally advancednon-small-cell lung cancer. 3-Dimensional conformal radiationtherapy (3-DCRT) selects optimal treatment parameters to increasedose to tumor and reduce normal tissue dose, potentially permittingdose escalation. There are several ongoing trials of dose escalationusing 3-dimensional conformal radiation therapy for non-small-celllung cancer. We performed this analysis to determine if dataderived from dose volume histograms could be used as the basisfor designing the method of dose escalation in these trials. METHODS AND MATERIALS: Between 1990 and 1993, 31 patients were treated with 3-DCRTand had complete normal tissue dose volume histograms createdas part of the planning process. The stage distribution wasstage I/TI 13%, stage IHa in 45%, and stage Illb in 42%. Themedian radiation dose to gross disease was 70.2 Gy (52.2–;72Gy). Elective mediastinal irradiation (50.4 Gy) was administeredto 52% (16/31) of patients. RESULTS: Thr toxicity encountered in this experience was pulmonary. Dose-volume-histogramdata were used to analyze the predictors of toxicity and showeda correlation between risk of pulmonary toxicity and indicesof dose to lung parenchyma. Grade 3 or higher pulmonary toxicityoccurredin 38% (3/8) of pts with > 30% of lung volume receiving >25 Gy, versus 4% (1/23) of pts. with < 30% lung receiving> 25 Gy (p =0.04). Grade 3 or higher pulmonary toxicity occurredin 29% (4/14) of patients with a predicted pulmonary normaltissue complication probability of 12% or higher versus 0% (0/17)in patients with a predicted probability of less than 12% (p=0.03).The single fatality occurred in a patient with a calculatedpneumonitis probability of 85% and a high percent (49%) lungvolume receiving > = 25 Gy. CONCLUSION: This preliminary experience demonstrates a correlation betweenlung dose-volume-histogram data and the risk of severe pulmonarytoxicity. This provides an opportunity to modify the methodof radiation dose escalan. Dose-volume-histogram data can allowescalation according to the risk to the lung parenchyma (whichis the major organ of concern) rather than escalation accordingto tumor dose levels. Because of the major inter-patient variabilityof intrathoracic tumor bulk and anatomic distribution, thisstrategy is intuitively appropriate. This approach may facilitatecompletion of dose escalation studies and identification ofmaximum tolerable pulmonary dose levels. lung cancer, radiation, 3-dimensional treatment planning     

Novel radiation technologies for malignant gliomas.

Despite the advent of new technologies available for the imaging of brain tumors and the evolution of methods to deliver more focused radiation therapy, most malignant gliomas recur locally. Therapies aimed at increasing local control of gliomas will set the stage for improved survival in a disease with a dismal overall prognosis. This review focuses on several radiotherapeutic approaches to dose escalation that may help improve local control.     

First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy.

PURPOSE: To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy. PATIENTS AND METHODS: The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status or=grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications). RESULTS: Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4. CONCLUSION: Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group.     

Dose-escalated 3D conformal radiotherapy in prostate cancer

3D conformal radiotherapy involves the delivery of radiation to a defined 3D tumor volume while minimizing doses to adjacent critical tissues. The use of sophisticated imaging tools and advanced treatment planning software have allowed for better target definition enabling the oncologist to conform or shape radiation volume more closely around the target while minimizing dose to the rectum and bladder. 3D conformal radiotherapy has resulted in dramatic reductions in acute and late toxicity of radiation treatment in prostate cancer. It has also allowed for safe escalation of radiation dose with improved tumor control compared with conventional dose radiotherapy. Long-term tumor control rates with 3D conformal radiotherapy are comparable with results using radical prostatectomy.     

Dose-escalated 3D conformal radiotherapy in prostate cancer

3D conformal radiotherapy involves the delivery of radiation to a defined 3D tumor volume while minimizing doses to adjacent critical tissues. The use of sophisticated imaging tools and advanced treatment planning software have allowed for better target definition enabling the oncologist to conform or shape radiation volume more closely around the target while minimizing dose to the rectum and bladder. 3D conformal radiotherapy has resulted in dramatic reductions in acute and late toxicity of radiation treatment in prostate cancer. It has also allowed for safe escalation of radiation dose with improved tumor control compared with conventional dose radiotherapy. Long-term tumor control rates with 3D conformal radiotherapy are comparable with results using radical prostatectomy.     

A Phase I Study of Bortezomib in Combination With Standard 5-Fluorouracil and External-Beam Radiation Therapy for the Treatment of Locally Advanced or Metastatic Rectal Cancer

BackgroundStandard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation.Patients and MethodsPatients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m²/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies.ResultsNine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m² dose level. There was no clear evidence of suppression of nuclear factor-κB target gene expression in biopsy samples.ConclusionThe MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.     

Cost-Benefit Analysis of 3D Conformal Radiation Therapy: Treatment of Prostate Cancer as a Model

Three-dimensional conformal radiation therapy (3D-CRT) is a promising new treatment technique based on the principle that improved precision in both tumor definition and dose delivery will enhance outcomes by maximizing dose to the tumor area while minimizing dose to normal tissue. Using a cost-benefit analysis, in terms of outcomes, we first examined the overall risks and benefits of 3D-CRT. We then used the treatment of prostate cancer as a model to compare actual clinical outcomes reported between 3D-CRT and standard radiation therapy (SRT). Our analysis shows that application of 3D-CRT to the clinical setting remains difficult because of the continual difficulties of target definition, and that dose escalation cannot yet be justified on the basis of the lack of benefit found, and suggested increased late toxicity, in most of the dose escalation series compared with SRT.     

Intensity-modulated radiation therapy

Intensity-modulated radiation therapy (IMRT) has found widespread use in the treatment of head and neck cancers. This technology allows for conformal dose distributions around a tumor target while a rapid dose fall-off spares surrounding critical structures. The properties of IMRT are particularly suited for treating head and neck cancers due to the close proximity of dose-limiting normal tissues allowing for potential dose escalation. Further studies are ongoing to investigate long-term clinical outcomes and toxicity.     

The impact of three-dimensional radiation on the treatment of non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) patients with locally advanced unresectable disease have a grim prognosis. Radiotherapeutic strategies are necessary to improve the permanent eradication of thoracic disease. The poor results achieved with conventional external beam radiation therapy reflect in part, the inadequacy of such therapy in achieving its primary objective of achieving local control. The impact of three-dimensional conformal radiation therapy (3-DCRT) on local disease eradication and its potential role in improving survival is assessed. DESIGN: This review addresses aspects of the software and hardware technology of 3-DCRT, the clinical and technical aspects of target volume definition, the use of 3-DCRT to predict radiation pneumonitis, strategies for dose escalation in NSCLC, and analyses the clinical results to date. RESULTS: Initially investigators compared the best treatment techniques devised with conventional planning techniques to those devised with 3-DCRT. These analyses showed that 3-DCRT had the potential to deliver high dose radiation (>70 Gy) with minimal underdosing and with a concomitant relative sparing of normal tissues. This technical demonstration of enhanced therapeutic ratio is the basis for the evolving clinical utilization of 3-DCRT for NSCLC. Software and hardware developments continue to develop and have the potential to solve evolving clinical issues. Dose-volume-histograms have been used to accurately quantify lung dose and derived parameters have the potential to predict the risk of pneumonitis for individual patients before treatment. Initial clinical results have been promising and strategies for further dose escalation are emerging. CONCLUSION: Preliminary experience has resulted in promising survival following three-dimensional conformal radiation therapy alone for locally advanced NSCLC. More follow-up and experience will determine late toxicity, maximum dose, and efficacy of dose escalation with three-dimensional conformal radiation therapy. Strategies should be developed to integrate this modality into the combined treatment of locally advanced non-small cell lung cancer.