Lawrence R. Coia

Tolerance of normal tissue to therapeutic irradiation

The importance of knowledge on tolerance of normal tissue organs to irradiation by radiation oncologists cannot be overemphasized. Unfortunately, current knowledge is less than adequate. With the increasing use of 3-D treatment planning and dose delivery, this issue, particularly volumetric information, will become even more critical. As a part of the NCI contract N01 CM-47316, a task force, chaired by the primary author, was formed and an extensive literature search was carried out to address this issue. In this issue. In this manuscript we present the updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, with a special emphasis on partial volume effects. Due to a lack of precise and comprehensive data base, opinions and experience of the clinicians from four universities involved in the contract have also been contributory. Obviously, this is not and cannot be a comprehensive work, which is beyond the scope of this contract.

Three-dimensional treatment planning for lung cancer

The experience of four institutions involved in a three-dimensional treatment planning contract (NCI) for lung cancer is described. It was found that three-dimensional treatment planning has a significant potential for optimization of treatment plans for radiotherapy of lung cancer both for tumor coverage and sparing of critical normal tissues within the complex anatomy of the human thorax. Evaluation tools, such as dose-volume histograms, and three-dimensional isodose displays, such as multiple plane views, surface dose displays, etc., were found to be extremely valuable in evaluation and comparison of these complex plans. It is anticipated that with further developments in three-dimensional simulation and treatment delivery systems, major progress towards uncomplicated local regional control of lung cancer may be forthcoming.

Complications from large field intermediate dose infradiaphragmatic radiation: An analysis of the patterns of care outcome studies for Hodgkin's disease and seminoma☆

There are only infrequent complications from intermediate dose infradiaphragmatic radiation to the para-aortics or para-aortic and iliac nodal regions as given in Hodgkins disease or seminoma. Nonetheless, such complications can cause significant debility and may be lifelong. Treatment related factors associated with such complications should be identified and where possible, avoided. We have analyzed the records of 1,026 patients treated nationwide in the Patterns of Care Outcome. Studies including the Hodgkins national practice survey (387 patients), Hodgkins large facility survey (253 patients), and Seminoma national practice survey (386 patients). There were 883 patients who received infradiaphragmatic radiation to the para-aortics or para-aortic and iliac regions. Complications which occurred in these patients included gastrointestinal injury, hepatitis, nephritis, gonadal injury, hematopoietic injury, second malignancy, and miscellaneous others. There were 139 complications of any severity and 35 major complications requiring hospitalization for management. The 3-year actuarial complication rates were 14% and 4% for any and major complications, respectively. There was a statistically significant increase in both any complications and major complications with dose (p less than .01). The most frequent complications were those related to gastrointestinal injury such as peptic ulceration, hemorrhage, chronic diarrhea, and intestinal obstruction. Major bowel complications comprised 60% (21/35) of major complications and increased with dose from 1% for doses less than 3,500 cGy to 3% for doses greater than or equal to 3,500 cGy (p = .03). This study indicates that total dose is an important factor in determining complications, particularly gastrointestinal injury, in patients receiving infradiaphragmatic radiation in Hodgkins disease and seminoma and that prior G.I. disease is associated with an increased risk of radiation related bowel complication. The radiotherapist should seek to optimize the therapeutic ratio in these diseases where gross disease can be controlled with 3500 cGy or less with few exceptions.

Numerical scoring of treatment plans

This is a report on numerical scoring techniques developed for the evaluation of treatment plans as part of a four-institution study of the role of 3-D planning in high energy external beam photon therapy. A formal evaluation process was developed in which plans were assessed by a clinician who displayed dose distributions in transverse, sagittal, coronal, and arbitrary oblique planes, viewed dose-volume histograms which summarized dose distributions to target volumes and the normal tissues of interest, and reviewed dose statistics which characterized the volume dose distribution for each plan. In addition, tumor control probabilities were calculated for each biological target volume and normal tissue complication probabilities were calculated for each normal tissue defined in the agreed-upon protocols. To score a plan, the physician assigned a score for each normal tissue to reflect possible complications; for each target volume two separate scores were assigned, one representing the adequacy of tumor coverage, the second the likelihood of a complication. After scoring each target and normal tissue individually, two summary scores were given, one for target coverage, the second reflecting the impact on all normal tissues. Finally, each plan was given an overall rating (which could include a downgrading of the plan if the treatment was judged to be overly complex).

Conservative management of extensive low-lying rectal carcinomas with transanal local excision and combined preoperative and postoperative radiation therapy. A report of a phase I-II trial.

Between 1986 and 1990, 16 patients were enrolled in a prospective Phase I/II study of transanal local excision and combined preoperative and postoperative radiation therapy (RT). All patients had biopsy‐proven adenocarcinoma extending to within 6 cm of the anal verge and involvement of at least one third of the rectal circumference with tumor. Five of 16 patients (32%) had T3 tumors, and only two patients had T1 tumors. Patients received a single 500 cGy fraction of RT to the pelvis within 24 hours before surgery and underwent transanal excision followed by postoperative RT (median dose, 5040 cGy). With a median follow‐up of 33 months, overall 3‐year actuarial survival was 94%. Two patients had isolated local recurrences (both successfully salvaged), and four had distant metastases but maintained local control. The 3‐year actuarial rates of continuous freedom from any relapse, continuous local control, and no evidence of disease at last follow‐up were 53%, 80%, and 71 %, respectively. Only three of 16 patients required colostomy, resulting in a 3‐year actuarial colostomy‐free rate of 77%. There was a trend toward a higher rate of relapse (P = 0.066) in patients with T3 tumors than those with T1 and T2 tumors. Sphincter‐preserving therapy for low‐lying rectal carcinomas using local excision and combined preoperative and postoperative RT is feasible, although improved local and adjuvant therapy is needed for patients with T3 lesions.

Three-dimensional photon treatment planning for carcinoma of the nasopharynx

The role of 3-D treatment planning for carcinoma of the nasopharynx was assessed in a four institution study. Two patients were worked up and had an extensive number of CT scans on which target volumes and normal tissues were defined. Treatment planning was then performed using state of the art dose planning systems for these patients to assess the value of the new technology. In general, it was demonstrated that multi-field conformal plans could achieve good tumor dose coverage, while at the same time reducing normal tissue doses, compared to standard treatment planning techniques. The role of inhomogeneity corrections, beam energy, and the use of CT vs. simulation films for defining target volumes were also discussed. In addition, techniques to evaluate 3-D plans for the nasopharynx were considered, and some analysis of this problem is presented in this paper.

Adenocarcinoma of the esophagus and esophago-gastric junction: the effects of single and combined modalities on the survival and patterns of failure following treatment.

One hundred sixty-five patients with localized adenocarcinomas of the esophagus or esophago-gastric (EG) junction were treated with surgery alone, radiation therapy alone, chemotherapy alone, surgery followed by post-operative radiation therapy, chemotherapy, or chemosensitized radiation therapy, and chemosensitized radiation therapy alone. Patients were retrospectively evaluated for survival, control of tumor within the mediastinum, post-operative swallowing function, patterns of failure, and treatment-related morbidity. Follow-up of survivors ranges from 9-88 months (median 23 months). Chemotherapy and radiation therapy as single modalities were associated with a recurrence rate of 100%. Combined modality therapy significantly reduced the risk of local recurrence in all patient groups. Chemosensitized radiation therapy alone reduced the local recurrence rate to 48%, and surgery followed by radiation therapy reduced the local failure rate to 24%. When chemotherapy or chemosensitization was added to surgery plus radiation, the risk was further reduced to 15%. The use of combined modality therapy was also found to extend the survival of patients without excessive toxicity. Median survival was shortest among the group treated with radiation alone (5 months) and intermediate among patients following chemosensitized radiation alone (10 months) or complete surgical resection alone (15 months). Patients treated with all three modalities had the longest median survival (21 months). Based on this experience, the optimum treatment of these patients appears to include aggressive attempts at surgical resection with chemosensitized radiation therapy. Excellent palliation can also be achieved in unresectable patients with chemosensitized radiation therapy with a smaller chance for long term survival.

Three-dimensional photon treatment planning in carcinoma of the larynx

The role of three-dimensional (3-D) treatment planning in the definitive treatment of carcinoma of the larynx with radiation was evaluated at four institutions as part of an NCI contract. A total of 30 different treatment approaches were devised for two patients with larynx cancer. CT scans were obtained for both patients and various treatment planning tools were employed to optimize beam arrangements and to evaluate the resulting dose distribution. The effect on dose distribution of a number of factors was also examined: 1) the use of dose calculation algorithms which correct for tissue inhomogeneities, 2) the variation of the CT numbers used for inhomogeneity corrections to simulate inaccuracies in the knowledge of the CT numbers, and 3) the modification of beam energy. A multitude of data was used in plan evaluation and a numerical score was given to each plan to estimate the tumor control probability and the normal tissue complication probability. We found 3-D treatment planning to be of potential value in optimizing treatment plans in larynx cancer. Improved target coverage was achieved when complete information describing 3-D geometry of the anatomy was utilized. In some cases, the treatment planning tools employed, such as the beams eye view, helped devise novel beam arrangements which were useful alternatives to standard techniques. We found little effect of change in CT number on dose distributions. A comparison between dose distributions calculated with tissue inhomogeneity corrections to those calculated without this correction showed little difference. We did find some improvement in the dose to the primary tumor volume at lower beam energies, but with an increased larynx volume potentially receiving doses above tolerance.

Significance of prone positioning in planning treatment for esophageal cancer

The treatment of esophageal cancer is made difficult by the close proximity of the esophagus to the spinal cord and the requirement to treat the esophageal target volume to doses greater than or equal to 60 Gy while limiting the spinal cord dose to less than or equal to 46 Gy. By placing the patient in the prone position, the esophagus can be displaced away from the spinal cord. We explored the results of this commonly used technique on 16 patients who have undergone simulation in both supine and prone positions. Both AP and lateral orthogonal radiographs were obtained in both positions. The distance between contrast material in the esophagus and spinal cord was noted in at least four transverse planes through the thoracic esophagus on each of the 16 patients. These four transverse planes were located at 3 cm above the carina, at the carina, 3 cm below the carina and 6 cm below the carina. The mean displacement (+/- 1 SD) of the esophagus away from the spinal cord when the patient was in the prone position compared to supine at each of these levels was 1.3 (+/- 0.8) cm, 1.8 (+/- 0.9) cm, 1.8 (+/- 1.0) cm, and 1.9 (+/- 1.1) cm. The range of displacement for all 64 displacement determinations was 0 to 4.2 cm with a mean of 1.7 cm. To evaluate further the consequences of prone positioning on treatment planning and doses received to target volumes and critical structures, we performed 3-dimensional treatment planning with a patient in both prone and supine positions. The requirements were to achieve a tumor volume dose of 60 Gy while keeping the spinal cord dose below 46 Gy. Two types of conventional treatment plans were examined in prone and supine positions. A 6-field plan consisted of delivery of 40 Gy through a large 3-field beam arrangement followed by delivery of 20 Gy through a similar 3-field cone down. An 8-field plan involved the delivery of 30 Gy through AP/PA beams followed by a 3-field beam arrangement to 40 Gy and a subsequent 3-field cone-down for the final 20 Gy. Comparison of dose volume histograms revealed that the 6-field plan spared relatively more heart whereas the 8-field plan spared relatively more lung. Regarding the primary consideration of coverage of target volume with avoidance of spinal cord, prone positioning was superior to supine positioning whether 6- or 8-field arrangements were used.

The Use of Mitomycin in Esophageal Cancer

Concurrent administration of chemotherapeutic agents and radiation with or without surgery has yielded better local disease control and more prolonged survival than has standard radiation therapy or surgery alone in patients with esophageal cancer. Combinations of 5-fluorouracil (5-FU) and either cisplatin or mitomycin have proven most effective in this setting. As a single agent, mitomycin has generated response rates of 14-42% in patients with squamous cell carcinoma of the esophagus. The response of patients with esophageal adenocarcinoma to single-agent mitomycin is unknown. The clinical use of mitomycin concurrent with 5-FU and radiation is well established in esophageal cancer. There is some experimental evidence to suggest that synergy may occur between 5-FU and mitomycin. Mitomycin is preferentially cytotoxic to hypoxic cells, which are relatively radioresistant. It is not clear whether use of mitomycin with radiation is additive or supra-additive as experimental evidence exists to support both types of interaction. Nonrandomized clinical trials suggest that using either cisplatin or mitomycin concurrently with 5-FU and relatively low-dose radiation (30 Gy) prior to esophagectomy can result in comparable rates of pathologic complete response (20-30%) and median survival (12-19 months). Hematologic toxicity is frequently severe if all 3 drugs are used concurrently in combination with radiation. In patients with advanced disease (stage III or IV), combination chemotherapy/radiation therapy can result in significant palliation with tolerable morbidity. The use of concurrent chemotherapy and radiation has changed the pattern of failure in esophageal cancer from one dominated by inability to control local disease to one where systemic failure predominates. Current and proposed trials in esophageal cancer have changed their focus accordingly to meet this new treatment challenge.