Placenta-like alkaline phosphatase in gynecological cancers.

In 302 patients with tumors of the cervix, corpus uteri, and ovaries, assessment by clinical staging (tumors-nodules-metastasis system) (4) and histopathology has been related to the presence of serum heat-stable, placenta-lide alkaline phosphatase (PLAP) activity. Early stages of cervical tumors show the highest incidence of this isoenzyme. In advanced stages of this disease, a decrease in frequency was observed that might be interpreted as the result of gradual dedifferentiation of the tumor cells to a point where synthesis of PLAP became undetectable. The same observation was made in adenocarcinomas of the corpus uteri, i.e., patients with advanced disease tended to have the lowest incidence of serum PLAP. Only in cancers of the ovaries did we find a positive correlation between this enzyme marker and the extent of the disease. In more than one-third of the patients examined, PLAP levels were an index of the tumor burden.

The separation of pyruvate-ferredoxin oxidoreductase from Clostridium pasteurianum into two enzymes catalyzing different reactions.

The ferredoxin requiring cleavage of pyruvate to acetyl-CoA and CO2 is catalyzed by pyruvate ferredoxin oxidoreductase (pyruvate:ferredoxin oxidoreductase (CoA-acetylating):, EC 1.2.7.1). The same enzyme is thought to catalyze the reversal of this reaction, i.e. the synthesis of pyruvate from acetyl-CoA and CO2 in the presence of reduced ferredoxin. Evidence is presented that the forward and reverse reactions are catalyzed not by one, but by two proteins that are clearly separable by Sephadex G-200 gel filtration.

Patterns of disease in localized extranodal lymphomas.

The site of origin of lymphoid tissue is an important determinant of lymphocyte migration patterns. The association of gastrointestinal (GI) and Waldeyer's ring lymphoma and the unique lymphocyte migration pattern of gut-associated lymphoid tissue (GALT) have been previously described. To establish whether predictive clinical patterns of disease occur in localized Non-Hodgkin's lymphoma, survival and relapse patterns for 496 patients with stage I and II non-Hodgkin's lymphoma (NHL) treated with loco-regional irradiation (XRT) alone were examined. We identified 139 patients with GALT lymphoma (defined as arising from primitive gut and including Waldeyers' ring, thyroid, and GI lymphomas) and 87 patients with extranodal non-gut-associated lymphoma (ENL). Survival and relapse data were assessed in multifactorial analysis to correct for previously identified other prognostic variables. GALT lymphomas (GALT-L) have a survival advantage compared with other ENL (P = .017) independent of stage and histology. A difference in distant relapse (DR) rate between GALT-L and other ENL (P = .0002) was also identified. The presentation site of localized extranodal NHL is predictive of clinical behavior and is an independent determinant of outcome. This may be an expression of lymphocytic origin and determinants of migration patterns.

Prognostic groups for management of localized Hodgkin's disease.

Two hundred fifty-two patients receiving radical irradiation for clinical stages I and II Hodgkin's disease between 1968 to 1977 had an actuarial ten-year survival rate of 78% and a relapse-free rate of 61%. Sixty-seven patients receiving chemotherapy followed by radiation had a 78% survival rate and a 63% relapse-free rate. Independent prognostic factors for survival and relapse were age, stage, and histology. Disease bulk was predictive only of relapse. Neither site of presentation above or below the diaphragm nor presence of mediastinal involvement was predictive for survival or relapse; however, patients with large mediastinal masses (greater than or equal to 10 cm absolute diameter) had a significantly higher intrathoracic failure rate with conventional mantle irradiation. Analysis of failure, according to age, clinical stage, and histologic type, showed three groups of patients defined according to the risk of relapse with radiation therapy: those with isolated upper cervical stage IA disease (group 1, relapse rate 8%), younger patients with localized stages I and II disease of favorable histologic type (group 2, relapse rate 35%), and older patients with extensive or symptomatic stages I and II disease of less favorable histologic type (group 3, relapse rate 70%). Subsequent analysis of radiation treatment volume indicates that the use of upper abdominal irradiation for patients in group No. 2 could yield results equivalent to those achieved with radiation therapy for surgically staged patients.

Quality assurance in radiation therapy: clinical and physical aspects. Quality assurance: past and present in Canada.

Quality assurance in any clinical field must involve the three components of clinical care: (a) diagnosis and evaluation of patients; (b) medical decision making and treatment; and (c) outcome analysis. Nationally, there have been five annual reviews of outcome from all cancer centers following radiation therapy for cancer at various sites. These reviews are voluntary and organized through the Canadian Association of Radiologists. The objective is to determine if there are any major differences in outcome across the country, and if so, can such differences be related to the population treated or technique used. So far no major differences have been noted, although the reviews have led to improved communication between centers and constructive discussions of dose and technique. There is a National Tumour Reference Centre funded by the National Cancer Institute of Canada (NCIC) to provide assistance in establishing diagnostic criteria in pathology. Ontario has been active through the Ontario Cancer Treatment & Research Foundation and the Ontario Cancer Institute in establishing UICC TNM staging and reporting, together with an evaluative program for this staging system. All other quality assurance programs take place at the level of local centers.

Quality assurance in radiation therapy: clinical and physical aspects. Future plans: clinical.

On a national scale in Canada, the members of the Canadian Association of Radiologists, Section of Radiation Oncology, plan to continue their outcome analyses. Nevertheless, there is considerable activity within many of the cancer centers in establishing quality assurance for all aspects of clinical practice, not just related to the technique of radiation therapy. Studies from the Princess Margaret Hospital will be used as examples to illustrate the need for quality assurance in: (a) diagnosis and evaluation of patients; (b) decision making with respect to treatment; (c) technical components of radiation therapy; and (d) outcome analysis, particularly an analysis of failures. For the future, there are two major objectives related to quality assurance. One is related to those patients with cancers who have a high probability of being cured. In this situation, achieving optimal treatment must be the objective and quality assurance must be directed at determining what is optimal treatment. For those patients in whom cure is still not commonly reached, the objective will be to determine why failures are occurring and whether radiation therapy technique can decrease the relapse rate.

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

A total of 1,394 patients with non-Hodgkin's 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 patient's 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.

Internal mammary lymphoscintigraphy in the assessment of patients with ovarian carcinoma.

Radiocolloid internal mammary lymphoscintigraphy (IML) was evaluated in 364 patients with ovarian carcinoma to determine the frequency of abnormalities in post-operative patients, the association between the results of the lymphoscintigram and known clinical prognostic variables, and to establish whether IML yielded predictive information independent of these variables. Results of IML showed a correlation with established clinical prognostic features and yielded independent prognostic information. The sensitivity and specificity of IML in predicting relapse are 51% and 71% respectively, indicating that a single post-operative IML does not predict relapse or freedom from relapse with sufficient accuracy to make it a clinically useful test even though it provides an independent prediction of relapse.

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.

Neurotoxic radiosensitizers and head and neck cancer patients--how many will benefit?

The causes for the exclusion of patients from a Phase I dose tolerance study of metronidazole as a hypoxic cell sensitizing agent in patients receiving radiation therapy for head and neck cancer have been reviewed. One hundred and fifty nine consecutive patients were assessed between October 1979 and December 1980 according to eligibility criteria decided upon prior to the study. Only 26 (23%) of 111 patients treated with radical radiation therapy entered the Phase I study. The major reasons for exclusion were a history of prior nervous system abnormality, age over 70, and refusal by some patients to participate in the study. The criteria used for patient selection for studies of hypoxic cell sensitizers (and other investigational agents) must be known so that data from each study can be assessed appropriately before being extrapolated to the general patient population. Clinical trials should be designed to take into account factors that might influence patient entry.

Outcome analysis of localized gastrointestinal lymphoma treated with surgery and postoperative irradiation.

One hundred thirteen patients with localized gastrointestinal lymphoma treated by surgery and postoperative irradiation between 1967 and 1985 were reviewed. At 15 years, actuarial survival of this group was 40.6%, with a cause-specific survival of 69.2% and a relapse-free rate of 64%. Two-thirds of relapses occurred at distant sites. In Stage IA and IIA patients with no residuum or with positive resection margins, (N = 90) only site of involvement and stage predicted for relapse. Age, histologic subtype group, and depth of bowel wall invasion did not affect relapse risk. In the very favorable group (Stage IA, IIA, no residuum or microscopic residuum), 8.4% of patients with stomach lymphoma relapsed compared to 25% of patients with small bowel lymphoma. The risk of early relapse was higher in those with Stage IIA small bowel lymphoma than those with Stage IA small bowel lymphoma. We continue to recommend adjuvant abdominal irradiation for patients with Stage IA, IIA completely resected stomach lymphoma and Stage IA completely resected small bowel lymphoma. We recommend combined modality therapy for patients with completely resected Stage IIA small bowel lymphoma and all other localized gastrointestinal lymphoma where visible residual disease is present.

Complications of whole abdominal and pelvic radiotherapy following chemotherapy for advanced ovarian cancer.

We examined the records of 105 patients with advanced ovarian cancer who had been treated with cisplatin combination chemotherapy followed by abdominopelvic radiotherapy. The purpose was to define the morbidity of this approach, and identify those factors predictive of toxicity. Acute toxicity resulting in delay or failure to complete treatment was most commonly due to myelosuppression. Nine of 105 patients (8.6%) required surgery for bowel obstruction that was not due to recurrent disease, 3 had an episode of bowel obstruction that settled conservatively, and a further 5 underwent surgery for obstruction due to recurrent tumor. The presence of both a dose of abdominopelvic radiotherapy over 2250 cGy, as well as a second-look laparotomy prior to radiotherapy, was associated with an increased risk of serious bowel complications. The increased frequency of late bowel morbidity seen in the combined modality group is likely explained by the presence of these two factors, rather than the exposure to chemotherapeutic agents per se. These observations are supported by the published literature.

Analysis of complications in patients treated with abdomino-pelvic 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.

Radiotherapy alone in breast cancer. Analysis of tumor and lymph node radiation doses and treatment-related complications. The experience of the Gustave-Roussy Institute and the Princess Margaret Hospital.

This retrospective analysis was conducted on breast cancer patients treated by radiotherapy alone at The Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients had either operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Previous results showed that a radiation dose increase of 15 Gy can decrease the relative risk of tumor or lymph node recurrence twofold. In this third report, the same data were analyzed to determine the treatment-related complication rates and to correlate these to the radiation dose levels. Overall results were analyzed on 453 patients, but detailed analyses on complications were conducted on 372 patients not developing local recurrence in the first 6 months of follow-up. Each complication was graded on a 3-level previously defined scale. Most frequent complications were skin changes of different degrees, which were usually asymptomatic. More disabling complications were arm edema, impaired shoulder mobility, rib fractures and brachial plexopathy. The incidence of disabling complications was low. The only factor significantly increasing the risk of complications was the radiation dose level to the tumor and axilla. Technical factors such as overlapping fields should also be taken into account. As the more effective control of tumor and lymph nodes obtained in patients treated with higher radiation doses is counterbalanced by an increase in the complication rate, the dose to be delivered for each patient should be carefully chosen according to individual risk factors.

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-Hodgkin's 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.

Radiation injuries to the bowel associated with the treatment of carcinoma of the cervix.

Advances in radiation techniques and increased dosage have improved the cure rate of patients with cancer of the cervix to 65 percent. Associated with this increased dosage (betatron, 5,250 r and intracavitary 137-cesium, 4,000 r at point A) has been a serious complication incidence of 10 percent. Major intestinal complications usually become manifest within an 8 to 24 month period following radiation. Few are associated with tumor and the majority are amenable to surgical correction. Rectosigmoid stenosis is a common and frequently unrecognized complication. The 8 to 12 cm. segment of rectosigmoid, with its rigid wall and narrowed lumen, can be recognized on barium examination. The symptoms are those on incomplete obstruction and deterioration, frequently confused with tumor progression. Thirty-one patients have been treated by resection and low anterior anastomosis with relief of symptoms. Rectosigmoid stenosis progressing to necrosis, perforation, or fistula (an additional 29 patients) is treated best by the Hartmann operation as a first stage. This procedure has been less complicated than either colostomy alone or resection and anastomosis. Fifteen patients with low level rectovaginal fistula or stenosis were treated by defunctioning sigmoid colostomy. A loop transverse colostomy was unsatisfactory. Ileorectovaginal fistulas occurred in an additional six patients. Preoperative investigation should establish the presence or absence of an ileal component in all fistulas. Radiation ileitis is rare as an isolated finding but frequently is associated with severe rectosigmoid damage. Surgical treatment is seldom necessary but, if indicated (ten patients), resection appears to be preferable to bypass.

Prognostic factors in patients with stage I epithelial ovarian cancer.

We analyzed factors predictive of relapse risk in patients with stage I invasive epithelial ovarian cancer: 252 patients from the Princess Margaret Hospital provided a data base for hypothesis generation, and data on 267 patients from the Norwegian Radium Hospital were used for hypothesis testing. The outcomes in most analyses in the two series were very similar, validating the following conclusions. Differentiation (grade) was the most powerful predictor of relapse, followed by dense adherence (which resulted in outcomes equivalent to those in stage II) and, finally, large-volume ascites. When the effects of these three factors were accounted for, then none of the following were prognostic: bilaterality (stage Ib), cyst rupture (stage Ic), capsular penetration (stage Ic), tumor size, histologic subtype, patient age, year of diagnosis, and postoperative therapy. These results allow simplification of stage I substaging, as only differentiation, dense adherence, and large-volume ascites (? peritoneal cytology) need be considered. The 5-year relapse-free rate was 98% in patients with grade 1 tumors in whom both dense adherence and large-volume ascites were absent. These patients are adequately treated by operation alone. Although the relapse risk was high enough in the remaining patients to warrant postoperative treatment, a significant benefit could be shown only for a small subset of patients, namely those with densely adherent tumors treated with abdominopelvic radiotherapy. In grades 2 and 3, none of the therapies used in either series was superior to pelvic radiotherapy or operation alone.

Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast.

Following surgery and regional radiotherapy for operable carcinoma of the breast in premenopausal women, ovarian irradiation (2000 rad in five daily fractions) plus prednisone (7.5 mg per day) results in delayed recurrence and prolonged survival.

Testing the validity of a prognostic classification in patients with surgically optimal ovarian carcinoma: a 15-year review.

A retrospectively designed classification using stage, residuum and a variable which combines prognostic information from both grade and histology (histology-grade variable) has been used at our institution to predict prognosis, and choose therapy in patients with ovarian carcinoma, stages I-III having no or small residuum. In this study, multivariate analysis of prognostic factors were performed over two time periods: Group 1 (1971-1978), contains the patients from which the original classification was derived, and Group 2 (1979-1985), contains a different cohort of patients who are used to test the validity and reproducibility of the original classification. Multivariate analysis showed that the prognostic significance of two variables changed over the two study periods: tumor grade, and residuum. It was found that in the ideal combination of grade and histologic type, when used in conjunction with stage and residuum in a prognostic classification, was unique to each patient cohort. Because of these changes, new and more accurate prognostic classifications were derived for Group 2. However, when all classifications were examined, (including the original), the differences in their ability to stratify patients into risk categories was negligible, and there was no major advantage to using one classification over another for clinical applications. Thus, the retrospectively derived prognostic classification using grade, instead of a combined histology-grade variable, in conjunction with the other significant prognostic factors (stage and residuum), is preferred for prospective application, and for its simplicity.

The effect of chronic reductions in the arterial partial pressure of oxygen on the radiation response of an experimental tumour.

A previous study by the same authors has reported the effect of acute reductions in the arterial partial pressure of oxygen (PaO2) on tumour response to radiation. The results have been extended in the present paper to investigate tumour response to radiation in animals in which the PaO2 is chronically reduced. The purpose of these experiments was to simulate the condition of cancer patients undergoing radiotherapy in the presence of chronically low PaO2 values as might be expected in patients with chronic respiratory disease. Mice bearing transplantable KHT sarcomas were kept in a 12% O2 environment prior to (10--16 days), during and following the radiation treatment of their tumours. During the period of low PaO2 (about 50 mm Hg) exposure, the mice were found to increase their haemoglobin (Hg) levels by approximately 50%. Because of this increase, the response, determined using a growth delay assay of the tumours irradiated at reduced PaO2 was found to be the same as that observed for tumours in mice breathing air throughout the experiment. In mice with reduced PaO2 levels maintained at normal Hb concentrations by periodic bleeding, tumour response was found to be similar to that of mice with acute PaO2 reductions. These results indicate that chronic PaO2 reductions in the absence of Hb compensation may have a detrimental effect on the success of a radiation treatment.