Radiotherapy Division Research Articles

Relationship of time dose factors to tumor control and complications in the treatment of Cushing's disease by irradiation

The records of the Radiotherapy Division of the Radiology Department of Vanderbilt University Hospital were reviewed for the period 1952–1970. During those 19 years 45 patients with a well-documented diagnosis of Cushing's disease were treated initially by external irradiation of the pituitary. All of the patients were treated with megavoltage equipment using photons. When the results of irradiation are compared against total doses of radiation, it is evident that the control rate is unsatisfactory at doses less than 4000 rad and the maximum benefits of irradiation are evident in the 4500–5000 rad dose range. It is also clear that the complication rate increases as the dose exceeds 4800 rad. If the various treatment regimens of irradiation are converted to “equivalent” doses by the Nominal Standard Dose (NSD) or Time-Dose-Fractionation (TDF) methods, the relationship between “dose” and efficacy of therapy and complications is demonstrated. In order to reduce the possibility of treatment-related morbidity, the use of three or more small (4 × 4 cm) treatment portals or rotational techniques is recommended to a pituitary dose of 4600–5000 rad treating 5 days a week for 5–6 weeks.

Non-Hodgkin's lymphomas of stage III extent.Is total lymphoid irradiation appropriate treatment?

Many investigators have regarded Stage III lymphomas as a generalized form of disease and have accordingly recommended systemic treatment programs. Between 1961 and 1973, 68 patients with clinical or pathologic Stage III non-Hodgkin's lymphomas were seen in the Division of Radiation Therapy at Stanford University Medical Center and were treated by high dose (3500 rads or more) total lymphoid radiation therapy only. Of the 17 patients who had a diffuse histologic pattern, the actuarial survival at 5 years was 39%, but only three patients have remained free of disease. In contrast, for the 51 patients who had a nodular histologic pattern, the actuarial survivals at 5 and 10 years were 75% and 65%, respectively. Corresponding relapse-free survivals for patients with nodular lymphomas were 43% and 33%, respectively. Of 28 patients who relapsed with nodular lymphomas, 18 (64%) had relapses confined to lymph nodes; six of these were extensions to previously unirradiated epitrochlear-brachial nodes. Seven of the 18 patients were treated only with further conventional external radiation therapy at the time of their relapses and remain free of disease for additional periods of 2 to 5 years. Hence, 30 of 51 (59%) patients with nodular lymphomas have thus far been controlled by high dose total lymphoid irradiation only. Over 90% of relapses among patients with nodular lymphomas were seen within the first 5 years. The data suggest that high dose conventional radiation therapy to incorporate not only the routine total lymphoid fields but also the epitrochlear, mesenteric, and Waldeyer's ring region has curative potential even in Stage III non-Hodgkin's lymphomas, especially in the nodular group.

Initial relapses in previously treated Hodgkin's disease. I. Results of second treatment.

Two hundred forty-three consecutive patients with Hodgkin's disease who relapsed after an initial course of treatment at the Stanford University Division of Radiation Therapy underwent subsequent systematic evaluation and retreatment. An analysis of the influence of numerous parameters, including sex, histopathology, original stage, relapse site, and original and second therapy, on actuarial survival and on relapse-free survival was undertaken. Most relapses (87%) occurred within 3 years of the initial treatment course. The 5-year relapse-free survival measured from the time of second treatment increased from 14% before to 39% after the introduction of multiple agent chemotherapy (MOPP) for relapsing disease. Patients treated with MOPP chemotherapy for nodal relapses showed increased subsequent relapse-free survival (61%) when compared with patients treated only with radiotherapy for nodal relapses. Based on the combined findings of this analysis, recommendations are made regarding the management of patients with Hodgkin's disease who have suffered a relapse.

Treatment of primary adenocarcinoma of the cervix.

Between 1956 and 1971, a total of 74 cases of adenocarcinoma of the cervix was treatedin the Division of Radiation Therapy of the University of Maryland Hospital. Radical radiation therapy was followed by routine surgery early in the study;after 1967, surgery was used only for radiation failure. The likelihood of local control and 5-year survival was not improved by the routine addition of surgery to radical radiation, although the incidence of serious complications was markedly elevated. The results of treatment of adenocarcinoma of the cervix by radiation therapy alone are not significantly different from those achieved with squamous cell carcinoma. Surgery should be used as a salvage procedure in case of failure, rather than on a routine basis.

Non-Hodgkin's lymphomas. VI. Results of treatment in childhood.

A retrospective study was undertaken reviewing records of all children seen in the Division of Radiation Therapy at Stanford University Hospital between 1961 and 1971 with a diagnosis of non-Hodgkin's lymphoma. Of 41 patients who had been originally diagnosed as having a non-Hodgkin's lymphoma, a diagnosis was confirmed in only 32. Two cases were interpreted as malignant histiocytosis, and 7 other patients were diagnosed as having Hodgkin's disease. Of the 32 patients with a non-Hodgkin's lymphoma, all but 1 had lymphoma of the diffuse type, with diffuse histiocytic lymphoma being the most common histologic diagnosis. Lymphangiography was attempted in all but 1 patient. Fifty-five percent of Stage I patients and 38% of Stage II patients are alive and free of disease more than 2 years after the completion of radiation therapy alone. There were no relapses seen after 12 months. Bone marrow involvement was seen in 5 patients at presentation and developed in an additional 8 patients following the initiation of radiation therapy.

Patterns of spread of distant metastases in head and neck cancer.

Ninety-six (12.3%) of a total of 779 patients with head and neck cancer were found (clinically or at autopsy) to have distant metastases in the period from 1955 to 1967, in a study at the Division of Radiation Therapy, Stanford University School of Medicine. The study was confined to adults with epithelial tumors. All areas in the head and neck region were reviewed, except the paranasal sinuses, eye, ear, and thyroid gland. Metastases to the lungs, bone, and liver were the most common, but unexpected metastases to the heart, spleen, and gastrointestinal tract were frequently found. The most advanced primary tumors (T4) were most likely to have metastases. More than 50% of patients in whom the primary site was effectively controlled developed metastases. Forty patients of the 96 with metastases had an autopsy; further metastatic sites, not apparent clinically, were found in most of these patients.

Patterns of Spread of Distant Metastases in Head and Neck Cancer

Ninety-six (12.3%) of a total of 779 patients with head and neck cancer were found (clinically or at autopsy) to have distant metastases in the period from 1955 to 1967, in a study at the Division of Radiation Therapy, Stanford University School of Medicine. The study was confined to adults with epithelial tumors. All areas in the head and neck region were reviewed, except the paranasal sinuses, eye, ear, and thyroid gland. Metastases to the lungs, bone, and liver were the most common, but unexpected metastases to the heart, spleen, and gastrointestinal tract were frequently found. The most advanced primary tumors (T4) were most likely to have metastases. More than 50% of patients in whom the primary site was effectively controlled developed metastases. Forty patients of the 96 with metastases had an autopsy; further metastatic sites, not apparent clinically, were found in most of these patients.

Choroid metastasis.

Carcinoma metastatic to the choroid is a grave prognostic sign. Seven cases were seen in the Division of Radiation Therapy at the University of California at Los Angeles, from 1961 to 1970. All the patients were women. Three cases were from breast primaries, 3 from lung primaries, and one primary remained occult. The average survival after the onset of ocular symptoms was 9.3 months. The longest survival was only 16 months. All were treated with radiation therapy. Three showed marked improvement, 3 showed slight improvement, and only one received no benefit. The pertinent literature is reviewed.

Presumptive palliative irradiation in metastatic carcinoma of the breast.

Sixty per cent of the 550 patients with breast cancer referred to the Division of Radiation Therapy, Stanford University, during the past 10 years have been referred for the treatment of metastatic sites. Although the sites of involvement and the treatment regimens used were too variable for meaningful statistical analysis, a review of the techniques employed revealed the evolution of a pattern of treatment which might be termed presumptive palliation. In this approach, it is advocated that individual sites of metastatic involvement be treated aggressively with the best equipment and therapeutic technology available with the goal of sterilizing the metastatic focus at the time of its earliest detection. By using this approach, troublesome or even catastrophic foci of disease may be eliminated permitting more effective palliation of the individual sites than may be accomplished by waiting until the metastases cause severe pain, loss of structural integrity, or severe malfunction.

Radiation therapy in carcinoma of the false cord.

It is widely recognized that radiation therapy offers an excellent chance of cure to patients with early vocal-cord cancer. Fairly reliable correlation of clinical staging with prognosis permits a meaningful selection of either surgery or radiation therapy as the treatment of choice. Carcinoma of the false cord, being relatively uncommon, is seldom referred to in the literature as a distinct entity, and the value of radiotherapy in its treatment is not well established. Reports dealing with vocalcord tumors employ precise anatomical terms and some form of staging, while false-cord tumors are either not staged or are grouped with tumors of distinctly different anatomic site and clinical behavior. In some versions of the “extrinsic-intrinsic” classification, false-cord tumors are grouped with cancers of the pyriform sinus and hypopharynx and share the poor prognosis of the latter group (1). In current nomenclature, these tumors appear under the more restricted category of “supraglottic laryngeal” tumors together with a reasonable attempt at staging. This improvement, however, is vitiated by the almost automatic implication that supraglottic cancers are, by that group designation, surgical problems (2, 3). It must be admitted that clinical reports tend to support this conclusion by demonstrating that persistent local disease and metastatic lymphadenopathy are frequent sequelae to radiation therapy, but the value of these reports is somewhat clouded by a consistent failure to relate results to precise locations and stages of disease. Too often, failure which should be related to stage is erroneously related to site, and the fine distinctions which are considered essential to proper management of vocal-cord cancer are not drawn. This report deals with radiation therapy as the sole treatment of a small group of patients presenting at McPherson Eye, Ear, Nose and Throat Hospital and Duke University Medical Center. Most of these patients have been followed five years or more. Incidence Over a four-year period beginning in 1961, approximately 2,500 new cancer cases were seen and treated in the Radiation Therapy Division of Duke University Medical Center. Of this group, 59 presented with early endolaryngeal cancers, divided into 53 true-cord and 6 false-cord cases (Fig. 1), an incidence of 11 per cent among early endolaryngeal tumors. This figure agrees quite well with the 10 per cent reported by Coutard and Valat in their classic monograph on false-cord tumors (4). Clinical Staging The staging used is a modification of that suggested by the American Joint Committee for Cancer Staging and End Results Reporting in 1962 (5). As it applies to vocal-cord cancer, the single category T-2 of the original staging system includes both mobile and fixed cords. We recommended preoperative treatment and delivered 4,800 R in twenty-nine days, beyond which he refused further irradiation or surgery.

Megavoltage radiation therapy and lymphangiography in ovarian cancer.

Cancer of the ovary has been treated postoperatively at Stanford with uniform megavoltage radiotherapy technics since 1956. This study was undertaken to evaluate the efficacy of this therapy and to introduce the use of lymphangiography as an aid in staging and treatment planning. Patients and Staging One hundred twenty-nine patients with cancer of the ovary were referred by private gynecologists or the Stanford University Department of Gynecology to the Division of Radiation Therapy for evaluation between January 1956 and December 1965 (table I). All patients were followed either in the Radiation Therapy-Gynecology Tumor Clinic or in collaboration with their private physicians; none was lost. The dual classification staging system proposed by Rubin was used (13). In his system each tumor is classified according to both its anatomic extent and histologic appearance (table II). One hundred three of the patients were untreated at the time of referral and had tumors limited to the abdomen. See Figure 1 and ta...

Paravertebral "round cell" tumors in children.

Arecent review of the records of the Division of Radiotherapy, Children's Hospital Medical Center, and of the Children's Cancer Research Foundation of Boston has disclosed 5 patients who had a malignant neoplasm which appeared to be unusual because of its histologic characteristics and its clinical course in relation to the site of origin at diagnosis. In each child, the epidural space of a portion of spinal cord was involved and the adjacent paravertebral soft tissues were infiltrated to varying degrees. Symptoms of cord compression were due to extradural pressure. Except for a congenital abnormality of a vertebral body, one patient exhibited no radiographic evidence of bone alteration at the local site. The other patients were found to have radiographic changes in the neural arch of a vertebral body at the site of tumor involvement. These changes were due to pressure by extrinsic tumor and secondary bone reaction. Case Reports CASE I: M. K., a girl, was born with a lumbar hemivertebra at L-2 and resulta...

Linear Accelerator Supervoltage Radiation Therapy: Testicular Tumors

Since the late 1950's a number of reports have appeared, relating higher survival rates for patients with testicular tumors. While some improvement was possible for seminoma rates, more could be done for carcinoma simply because previous rates were so low. The larger, early reports (15) were by surgeons and necessarily reflected the surgical approach. As series accumulated after the advent of megavoltage equipment and more vigorous treatment philosophy (6, 7), radiotherapy was emphasized more, coincident with an improvement in results. Primarily in Britain, several groups began to feel that surgery had no role to play in the treatment of these tumors (16, 17). Most recently, George et al. (10, 11) and Kurohara et al. (12) emphasized the role of combined radiotherapy and surgery. We felt our treatment technics and results should be analyzed in detail so that they might be compared with others in an effort to select the most optimal treatment policies. Materials and Methods Pathology: All slides have been reviewed by one of three Stanford pathologists, and nearly half have been recalled and confirmed in connection with a separate study (4). For the purpose of this review, the pathology as outlined by Dixon and Moore (3) has been adhered to with the exception that teratocarcinomas and embryonal carcinomas have been combined into the “carcinoma group” as was done by Ekman et al. (5) and Kurohara et al. We felt this was advisable since staging is more important than histology within this group, and further subdivision makes our results statistically not significant. Staging: Table I presents our clinical staging system which is modified from that of Boden and Gibb (1). The major problem in comparing studies which employ various treatment methods has been the impossibility of correlating clinical with surgical staging. Prior to lymphangiography, as many as two-thirds of clinical Stage I carcinomas were found to be Stage II at surgery (6, 7, 15). With the acceptance of the lymphangiogram in staging, the clinical staging much more closely approximates that of surgery. Table II presents an evaluation of the correlation between the lymphangiographic and surgical staging in 9 carcinoma patients. These will be discussed later. As can be seen in this result, it is likely that the lymphangiogram will be as accurate here as with the lymphomas (18). Lymphangiography has produced a serious problem in that clinical staging in most series has been changing during the last five to ten years as a greater percentage of patients was routinely staged with the lymphangiogram. Table III is the distribution by stage of the two largest histologic groups. Patients: All patients seen in the Division of Radiation Therapy have been reviewed for this study. Table IV gives the histologic distribution of the 146 patients seen from March 1956 to November 1967.

SHUNTING FOLLOWING TRUMA

From the Department of Medicine and Radiology (Division of Radiation Therapy and Nuclear Medicine), Hahnemann Medical College, Philadelphia, Pennsylvania

Radiation therapy for rhabdomyosarcoma.

The treatment of rhabdomyosarcoma has been the subject of considerable discussion (4). Radical surgical extirpation of the primary tumor is usually attempted, occasionally followed by irradiation. Unfortunately, widespread metastases usually appear early in the course of the disease and lead to a rapid death; this makes accurate evaluation of any therapeutic regime difficult. Rhabdomyosarcoma of the orbit, the most common primary orbital malignant tumor of childhood (8), offers a unique opportunity to study the role of surgery, radiotherapy, and chemotherapy in treatment of this tumor because disease in this site tends to remain localized, often for periods of months (1). Despite an absence of time-dose data, surgeons have dismissed irradiation in attempts at curative treatment (3, 8, 9). Lederman claims the disease is radiosensitive, but not radiocurable, owing to its prompt local recurrence (7). Present Material We have reviewed the records of 17 patients with a diagnosis of orbital rhabdomyosarcoma referred to the Division of Radiotherapy of the Columbia-Presbyterian Medical Center from January 1952 to December 1966. Fourteen were classified as embryonal in type, two were called undifferentiated, and one was an alveolar rhabdomyosarcoma. The sex ratio was 8 females to 9 males. Age at presentation has ranged from six months to thirteen years (Table I). The most common initial sign of disease was a mass appearing in 16 patients; proptosis as present in 10. The initial site of the orbital tumor was specified in 14 cases, 7 in each eye. The inner aspect of the upper lid was involved 9 times, the lower inner aspect twice. One lesion arose in each of the following sites: mid-upper lid, mid-lower lid, and upper outer lid. In no patient was bilateral orbital involvement either a presenting symptom or a later development. To better assess the effect of local treatment, the cases have been divided into three groups according to the stage of disease at the time of initiation of radiotherapy. These groups are: (a) generalized disease; (b) locally recurrent disease after surgery; (c) localized disease treated with primary, definitive radiotherapy after biopsy. Three patients presented with signs and symptoms of generalized disease, and all succumbed. Two received only palliative treatment. Local orbital tumor control was achieved in one patient until death two years after the administration of 5,500 R in thirty-six days (Fig. 1). In 14 patients, only localized disease was demonstrable. Biopsy was followed by immediate exenteration in 9. In only 1 of the 9 was exenteration followed by “prophylactic” irradiation (3,600 R/twenty days) and chemotherapy (actinomycin D); he remains free of disease forty-eight months later. Exenteration was deemed incomplete in 2 patients. One of these 2 died during subsequent treatment as a result of chemotherapy complication; the other was treated with radiation and is alive without disease four years later (Fig. 2).

Radiation Therapy for Lymphoma of the Spinal Canal

There is a paucity of reports concerning lymphomatous involvement of the spinal canal. Review of the literature leaves one confused as to the incidence of primary central nervous system involvement by lymphoma, its best management, and the results to be expected from it. In an attempt to clarify these points, we have reviewed the experience of the Division of Radiotherapy of the Columbia-Presbyterian Medical Center and New York Neurological Institute with 53 histologically proved cases of spinal canal lymphoma. This discussion is limited to involvement of the spinal canal; intracranial and peripheral nerve involvement is excluded. By the term lymphoma, we include Hodgkin's disease, lymphosarcoma, and reticulumcell sarcoma, but exclude leukemia and myeloma. Fifty-eight patients with lymphoma of the spinal canal were registered between January 1935 and December 1964. The hospital charts were not available for review in 5 cases, leaving 53 for analysis. Histologic proof of epidural disease was obtained in 48. In 5 the histologic diagnosis was made from biopsy of another site. In addition, the clinical course, roentgenographic and laboratory data, and treatment response were consistent with spinal canal lymphoma. The sex ratio was 34 males to 19 females, and the age at presentation ranged from nine to seventy-one years, the mean age being forty-three and a half years (Fig. 1). Local or radiating pain was experienced by all patients and was the most frequent initial symptom. Other initial symptoms were : paraparesis (6 cases) , bowel disturbance (1 case), nonspecific respiratory symptoms (6 cases), and pruritus (1 case). Forty-seven patients had a sensory deficit on admission; 42 had motor weakness or paralysis. Sphincteric disturbance was present in 26. The duration of symptoms prior to hospitalization averaged six weeks, with 7 patients noting symptoms for less than two weeks and 5 for more than one year. In contrast with other series, spinal canal involvement was the first manifestation of lymphoma in 45 patients (7). No histological type demonstrated a predilection for a particular area of the spinal canal (Fig. 2). Roentgenographic studies showed adjacent bony involvement in 29 patients. A paravertebral soft-tissue mass was noted radiographically or at the time of surgery in 30 cases. In 32 patients myelography was performed; in all the findings were abnormal and showed an extradural mass constricting the intradural space. Laboratory studies proved of little diagnostic aid except that the cerebrospinal fluid protein value was elevated in all 47 patients in whom the test was performed. The mode of treatment, clinical response, and survival in 51 cases are shown in Figure 3. Thirty-nine patients (77 per cent) benefited from therapy. Although the therapeutic result was generally inversely proportional to delay between onset of symptoms and institution of treatment, several patients made an excellent recovery despite sphincteric disturbance for periods of several days.

Radiation therapy for intracranial lymphoma.

Although lymphoma is seen frequently in an active radiotherapy department, intracranial manifestations attributed to the disorder are rare (2). Histologic proof of such involvement is reported even less frequently. In one-third of the patients with clinical symptoms of intracranial lymphoma, no histologic evidence of involvement could be demonstrated at surgical exploration or postmortem examination (6, 7). In the absence of histologic confirmation, it is difficult to judge the effect of treatment or the course of the disease. Long-term survival in intracranial lymphoma has been considered nonexistent (5, 7). Recent evidence to the contrary led us to review the experience in the Division of Radiotherapy of the Columbia-Presbyterian Medical Center and New York Neurological Institute in an attempt to determine the course of disease more accurately. Present Experience Twenty-four histologically verified cases of intracranial lymphoma (lymphosarcoma, reticulum-cell sarcoma, mixed lympho-reticulum-cell sarcoma...

Has prophylactic irradiation proved itself in the treatment of localized Hodgkin's disease?

The question of whether prophylactic irradiation of surrounding uninvolved sites will yield better results than localized irradiation alone in the management of Hodgkin's disease is presently unsettled. Peters (13) in 1950 and later, in 1958, Peters and Middlemiss (15) reported that prophylactic irradiation of all proximal lymph node chains in addition to the sites of clinical involvement increased the longevity of patients with localized Hodgkin's disease when they were compared to those who were given local irradiation only. This concept of prophylactic irradiation was based on the clinical impression that, before they became generalized, recurrences were more frequent in contiguous lymph node chains than at distant sites. In 1962, Kaplan (9) confirmed the belief that radical irradiation (local plus prophylactic) yielded a result superior to that of palliative local irradiation in respect to freedom from recurrences. The report which challenged this approach of prophylactic irradiation was that of Easson and Russell (4) in 1963. Their experience of a 40 per cent fifteen-year survival rate in a large series of patients treated by adequate dosage to localized fields resulted in figures comparable to those of Peters (13) with extended-field irradiation. Scheer, in 1963, felt that the prompt treatment of proximal recurrences in patients with Stage I Hodgkin's disease was sufficient to produce long-term survivors and that the seemingly random distribution of the subsequent sites of involvement provided little basis for the selection of fruitful areas to treat prophylactically. An analysis of our experience in which the two technics of treatment (localized vs. extended fields) were employed, indicates that the problem remains unsolved. Present Clinical Series The total group of patients with Hodgkin's disease treated at the University of Rochester Medical Center's Division of Radiotherapy between 1930 and April 1964 consists of 113. All cases were histologically verified. The present study is limited to 39 cases of localized Hodgkin's disease, Stages I and IIA, treated by two different therapeutic policies (Fig. 1). A. Local Irradiation Group Before 1958, 18 patients with Stages I and IIA Hodgkin's disease were treated by local irradiation to the entire involved lymph node region, employing generous single- or multiple-field arrangements. The major aim of treatment was to assure local tumor regression; once this was achieved, irradiation was terminated. The tumor doses ranged from 600 to 3,400 R with half the patients receiving 1,500 R or less and the majority less than 2,000 R. The quality of radiation varied from 220 kV to 1 MeV. B. Prophylactic (Extended-Field) Group From 1958 to 1963, 21 patients with similar staging were treated by a technic based on the principles of Vera Peters (13) in which the surrounding clinically uninvolved lymph-node-bearing sites were treated.

Lymphatico-venous communications and lymph reflux after thoracic duct obstruction. An experimental study in the dog.

1From the Department of Radiology, Division of Radiation Therapy, State University of New York, Downstate Medical Center, and Kings County Hospital Center. Brooklyn N. Y. *Research Associate in Radiology, Present address: Department of Radiology, Kanazawa University School of Medicine. Kanazawa, Japan †Director, Radiation Therapy and Associate Professor of Radiology

Clinical Radiology of the Biliary TractClinical Radiology of The Biliary Tract. By ShehadiWilliam H., M.D., F.A.C.R., Director, Department of Radiology, The United Hospital, Port Chester, N. Y.; Formerly Professor and Director, Department of Radiology, the New York Polyclinic Medical School and Hospital, New York, N. Y. With a chapter on Radiation Therapy by JacoxHarold W., B.S., M.D., Professor of Radiology,

Clinical Radiology of the Biliary TractClinical Radiology of The Biliary Tract. By ShehadiWilliam H., M.D., F.A.C.R., Director, Department of Radiology, The United Hospital, Port Chester, N. Y.; Formerly Professor and Director, Department of Radiology, the New York Polyclinic Medical School and Hospital, New York, N. Y. With a chapter on Radiation Therapy by JacoxHarold W., B.S., M.D., Professor of Radiology,