Raymond S. Bush

The significance of anemia in clinical radiation therapy

The time is appropriate for the publication of the excellent review by David G. Hirst of the experimental and clinical evidence for an association between anemia and an increased local relapse rate following radiation therapy.6 The subject needs to be discussed because there is a continuing uncertainty amongst physicians as to whether RBC transfusions, to correct a chronic anemia, indeed decrease the risk of local relapse following a radical course of radiation therapy. Although acute blood loss can be demonstrated experimentally to be detrimental to the oxygenation of tumors, this is not so for chronic anemia. Thus, as Hirst points out, we do not know the mechanism which underlies the clinical association of a chronically low Hb level with an increased risk of relapse after an established protocol for radiation therapy. The systems used in experimental animals do not provide an adequate explanatory model for the complexity of the clinical situation. Hi&s review provides references to the clinical reports which document the prognostic significance of Hb level for the control of malignancies in patients undergoing radiation therapy. The patient groups in these reports are restricted to those with cancer of the cervix or of the head and neck. Note, criteria for defining a low Hb varies with the report. Some Hb levels at which an increased rate of local relapse has been noted lie in what otherwise might have been classed as the normal range. Nevertheless, there is a heavy weight of clinical evidence, particularly for those patients with cancer of the cervix, which indicates that, given a patient population with a range of Hb levels during treatment, the largest proportion of patients with local relapses will be in those with a Hb level in the low end of that range. 1 will illustrate the point with data from the Princess Margaret Hospital (PMH). Together with my associates at the PMH I have previously reported that for patients with locally advanced cancer of the cervix the average Hb level during radiation therapy is a significant prognostic factor.2*3 How powerful a prognostic factor is that Hb level? To show the relative power I have ranked the Hb level using a Cox regression analysis.4 Used in the analysis are all those patients with Stage IIB or III cancer of the cervix seen and treated with radiation therapy between the years 1965 and 1975 at the PMH. Patients who did not receive both intracavitary 13’Cs and external radiation therapy have been excluded. By keeping the analysis to the years 19651975 all patients will have been followed 10 years or longer. Also, the treatment protocols varied little over that period. The prognostic factors ranked in the Cox regression analysis were Stage (IIB v. III), age (~50 v. r50), central dose (~7000 v. 27000 mixed rads), lateral pelvic dose (~4500 v. 24500 mixed rads), and average Hb level during treatment (~10 v. 10-l 1.9 v. 12-13.9 v. rl4gm%). For both local relapse and overall relapse, stage is ranked first and Hb level second with both having a p value of less than 0.000 1. Age was just significant at a p value of 0.046. With the exclusion of patients with incomplete treatment as noted above, central and peripheral doses were not significant in this particular analysis. Clearly, then, the Hb level is a significant and independent prognostic factor for patients with cancer of the cervix, Stages IIB and III. The question to be answered is whether a low Hb level is just a marker of disease which has an inherently poor prognosis or whether it predicts a poor prognosis because of the relative inefficacy of radiation therapy when a low Hb is present during treatment. To provide information which might help to answer the question just posed, I carried out a log-rank analysis of the same patient data described above, adjusting for stage, central dose, side wall dose and age, and determined the relative control rates at different Hb levels.* Shown in Table 1 are the relative rates for local relapse (LRR), distant relapse (DRR), and total relapse (RR). As can be seen for these patients with Stage IIB and III cancer of the cervix, the major influence of the Hb level during treatment is on the LRR and RR and not the DRR. The LRR decreases from a high of 46% for Hb levels less than lOgm% to 20% for those with a Hb level greater than 12gm%. Note that the effect of bulk of disease as defined

Chordoma: The results of megavoltage radiation therapy

Twenty-four patients with chordoma who received one or more courses of megavoltage radiation therapy following biopsy or incomplete resection were reviewed. The uncorrected survival rate at five years was 62%, and at 10 years was 28%, but most patients had clinically detectable residual chordoma present at the time of death or last follow-up. The duration of symptomatic improvement following irradiation ranged from a few months to 18 years, median 3.5 years. Detailed dose-time and symptomatic response data for 56 patients from this series and from the literature who were treated by conventional daily fractionated megavoltage irradiation show no convincing evidence that symptomatic relief is more likely after high doses than after total doses of only 4000 to 5500 cGy. Patients are rarely cured of chordoma by partial tumor resection and conventional radiation. Four patients received multiple fractions of 100 cGy each day either as retreatment for recurrence, or as initial treatment. Symptomatic responses, and decreases in the size of tumor masses, were seen following total doses ranging from 2000 cGy/20 fractions/5 days/4 X 3 hourly fractions each day to 4000 cGy/40 fractions/12 days/4 X 3 hourly fractions each day. The short duration of follow-up in these patients prevents comparison with conventional fractionation. However, this technique presents one possible new approach for the treatment of chordoma.

Prognostic factors in nodular lymphomas: A multivariate analysis based on the Princess Margaret Hospital experience

A total of 1,394 patients with non-Hodgkins lymphoma were treated at the Princess Margaret Hospital between January 1, 1967 and December 31, 1978. Overall actuarial survival of 525 patients with nodular lymphomas was 40% at 12 years; survival of patients with localized (Stage I & III) nodular lymphomas treated with radical radiation therapy was 58%. Significant prognostic factors defined by multivariate analysis included patients age, stage, histology, tumor bulk, and presence of B symptoms. By combining prognostic factors we have identified distinct prognostic groups within the overall population. Patients with Stage I & II disease, small or medium bulk, less than 70 years of age achieved 92% 12 year actuarial survival and a 73% relapse-free rate in 12 years of follow-up. These patients represent groups highly curable with irradiation.

Role of radiation therapy in localized non-Hodgkin's lymphoma*

Relapse occurs in 50% of patients receiving radiation for clinical stage (C.S.) I and II nodal and extranodal non-Hodgkins lymphoma (N.H.L.). Prior to the introduction of intensive chemotherapy those failing primary control with irradiation and most of those who relapsed died of their disease with a resultant overall mortality of 50%. An analysis of Princess Margaret Hospital results with radiation for C.S. I and II N.H.L. between January 1967 and December 1978 revealed that tumour bulk, age, stage and histology were of independent prognostic significance. It was possible to group patients using combinations of these attributes so that each group encompassed only patients with similar outcomes. Such prognostic groups were identified separately within the low grade and the intermediate plus high grade categories of the Working Formulation. Patients with a high probability of cure with radiation were so defined. Also those patients in whom chemotherapy would be optimal initial therapy were also defined. Such patients were in the intermediate plus high grade histology groups. Thirty percent of all patients with low grade histology lymphoma had an actuarial survival of 83%, and relapse-free rate of 63% at 10 years. By implication, approximately 20% of all patients with these histologies seen at the Princess Margaret Hospital for the same time period achieved prolonged relapse-free survival by localized therapy. This is at variance with the implications of staging from studies where laparotomy and multiple bone marrow biopsies have been used. Such aggressive staging procedures suggest truly localised disease in only 5-6% of patients with low grade lymphoma. A significant relationship between radiation dose and disease control was demonstrated only for patients with intermediate and high grade lymphoma of medium or large bulk. A minimum tumour dose of 30 Gy was required for optimal local control with radiation.

The importance of the pre-irradiation breathing times of oxygen and carbogen (5% CO2: 95% O2) on the in vivo radiation response of a murine sarcoma.

Abstract The effect of localized radiation on the transplantable KHT sarcoma in unanesthetized C3H mice was investigated while the mice breathed either oxygen (O 2 ) or 5% CO 2 : 95% O 2 (carbogen) for times ranging from 0.5 to 120 min prior to irradiation. Tumors were irradiated with a single dose of 2000 rad at a dose rate of 1140 rad/min and tumor cell survival was determined using a lung colony assay. The results for O 2 breathing indicate that survival varies as a function of pre-irradiation breathing time (PIBT). Whereas 10 and 30 min give survival values three times lower than air survival, 15–20 min and very long times (1–2 hr) yield results which are similar to those obtained under air breathing conditions. In animals breathing carbogen there is a minimum in the survival level (factor of three lower than air survival) after 10 min of gas exposure followed by a slow rise in survival over the next 90 min at which time there is no sensitization by this gas mixture relative to air. During a course of seven 500 rad fractions given daily with carbogen, a 5 min PIBT was found to give significantly greater sensitization than a 0.5 min PIBT. These findings give a clear indication that the PIBT of O 2 and carbogen has a strong influence on the effectiveness of the radiation treatment and suggest the need to control this factor carefully in the clinic.

Concurrent radiation, mitomycin C and 5-fluorouracil in poor prognosis carcinoma of cervix: Preliminary results of a phase I-II study

Between July 1981 and June 1983, 27 patients with advanced primary squamous cell carcinoma (SCC) of cervix (FIGO Stages IIIB, IVA or extensive nodal involvement) and 8 with recurrent disease were treated using a pilot regimen of combination chemotherapy (CT): Mitomycin C (MIT), 5 Fluorouracil (5 FU), and radiation therapy (RT). CT and RT doses on this Phase I-II Study were escalated to the current regimen. A split course of RT was used, either pelvic RT alone (4560 Gy in 28 fractions) or the same pelvic RT plus para-aortic RT (3600 Gy in 24 fractions). CT was given: MIT 6 mg/M2 IV push day 1, and 5 FU 1.0 g/M2 (maximum daily 1.5 g) by continuous IV infusion days 1 through 4 of each half-course of RT. This was followed by one application of intrauterine 137Cs when possible. Three of the 8 patients with recurrence in the pelvis or para-aortic nodes had a complete response (CR) to CT-RT and are alive without disease at 19, 19 and 22 months after treatment, respectively. Twenty of the 27 (74%) primary patients had a CR. With a median duration of follow-up of 6 months 4/20 have relapsed, 1 in RT field, 2 at distant sites, and 1 in both. Pelvic disease remains controlled in 19/27 (70%) including one patient salvaged with surgery. The acute toxicity of this regimen was tolerable: 2/35 developed transient leukopenia with one febrile episode, 9/35 developed transient thrombocytopenia without bleeding. Symptomatic sigmoid strictures developed in two patients, one requiring surgical intervention. Sigmoid perforation occurred in one patient and contributed to death. Typically, near complete regression of tumor is noted on completion of the external RT, reproducing the dramatic responses that have been observed in SCC of the anal canal, esophagus and head and neck, with this CT-RT regimen. A Phase III Study is required to establish whether the enhanced response rates to CT-RT will result in increased pelvic control and cure rates compared to those after RT alone.

Choice of postoperative therapy based on prognostic factors

Several patient-tumor related characteristics have been recognized to predict the prognosis of patients with invasive epithelial carcinoma of the ovary. Among the commonly cited variables are stage, residuum, grade, histologic subtype and the age of the patient at diagnosis.3,x The relative importance of each of these variables has not been clarified in the literature. Treatment decisions are often made on the basis of one variable (stage) and treatment outcome is often reported in terms of one or two variables (stage and residuum). If the other factors mentioned are also independent prognostic factors, then it is reasonable to expect that their incorporation into the processes of treatment decision-making and reporting of results would have the effect of refining both. To accomplish this, techniques of multivariate analysis are required. We have recently performed a systematic study of these prognostic factors with a view, firstly, to determine their relative independence and importance, and secondly, to devise a classification which uses information from each of the significant variables for purposes of treatment decision making.’ The clinical data used for this study were taken from the first 430 postoperative patients with all stages studied on prospective treatment protocols at The Princess Margaret Hospital (PMH). Patients were entered on study between April 197 1 and September 1976.’ The age range at diagnosis was 21 to 79, median 54 years. Grading and pathologic subtyping were performed by a review of the material on every case by Dr. T. C. Brown, pathologistin-chief, PMH. Patients were excluded if stromal invasion was not identified. Moderately differentiated lesions were grouped with poorly differentiated ones. Unclassified (=undifferentiated) lesions were all too poorly differentiated to permit recognition of the original pathologic subtype. Meticulous intra-operative staging was not performed routinely. Patients were considered to have no macroscopic residuum if this was clearly implied in the surgical note. In some patients it was uncertain whether all identified disease had been removed. This category is referred to as “?-residuum” or “uncertain residuum.” Small residuum refers to macroscopic disease not removed when bilateral salpingo-oophorectomy and hysterectomy (BSOH) had been completely performed. The large residuum group was so defined if residual disease was present when a complete BSOH was not performed. Large residual masses were invariably larger than 2 cm.

Treatment of epithelial carcinoma of the ovary: Operation, irradiation, and chemotherapy

This paper presents an interim analysis of 279 patients with epithelial carcinoma of the ovary who were entered into a prospective study started in April, 1971. One hundred and three patients were available for analysis three years after diagnosis. Apart from the survival differences by stage and treatment method, this study has shown that the completeness of the initial pelvic operation, in Stages II and III, is of greater prognostic importance than the stage. The importance of the features of the pelvic disease which interfere with the removal of all pelvic organs led the authors to conclude that factors other than stage should be considered in prescribing postoperative treatment. To date, the disease-free survival trends in Stages IB, II, and asymptomatic Stage III show that physicians should place much greater emphasis on the initial operative features when they are seeking the most effective combination of irradiation and chemotherapy. Analysis of failures shows that upper abdominal irradiation is more effective than daily chlorambucil in preventing progression of disease to that area. However, early evidence indicates that chlorambucil added to pelvic irradiation improves the control of pelvic disease. Improved methods of treatment have not yet been identified for early Stage I (IA) and advanced presentations (symptomatic Stages III and IV).

Curability of gastrointestinal lymphoma with combined surgery and radiation

Abstract Of a total of 1394 patients with non-Hodgkins lymphomas seen at the Princess Margaret Hospital between January 1, 1967 and December 31, 1978, 150 presented with gastrointestinal involvement. One hundred-thirteen of those patients had localized (Stage I & II) disease. Prognostic factors affecting outcome included hulk of residual disease after initial surgery and presence of B-symptoms. Patients with Stage IA and IIA with gross residual lysphoma less than 212 em in diameter treated with post-operative abdominal irradiation achieved 85% 10 years failure-free rate and 88% 10 year actuarial cause specific survival. The above group is considered curable with surgery and low dose adjuvant radiation.

Analysis of complications in patients treated with abdominopelvic radiation therapy for ovarian carcinoma

Between 1971 and 1985, 598 patients with ovarian carcinoma were treated with abdomino-pelvic radiation therapy. Acute complications included nausea and vomiting in 364 patients (61%) which were severe in 36, and diarrhea in 407 patients (68%), severe in 35. Leukopenia (less than 2.0 x 10(9) cells/liter) and thrombocytopenia (less than 100 x 10(9) cells/liter) occurred in 64 patients (11%) each. Treatment interruptions occurred in 136 patients (23%), and 62 patients (10%) did not complete treatment. In both situations the most common cause was myelosuppression. Late complications included chronic diarrhea in 85 patients (14%), transient hepatic enzyme elevation in 224 (44%), and symptomatic basal pneumonitis in 23 (4%). Serious late bowel complications were infrequent: 25 patients (4.2%) developed bowel obstruction and 16 required operation. Multivariate analysis was unable to determine any significant prognostic factors for bowel obstruction; however, the moving-strip technique of radiation therapy was associated with a significantly greater risk of developing chronic diarrhea, pneumonitis, and hepatic enzyme elevation than was the open beam technique. We conclude that abdomino-pelvic radiation therapy as used in these patients is associated with modest acute complications and a low risk of serious late toxicity.