Francis S. Morrison

Low-Dose Involved Field Radiation after Chemotherapy in Advanced Hodgkin Disease: A Southwest Oncology Group Randomized Study

Up to 40% of patients with stage III or IV Hodgkin disease relapse within 5 years of entering complete remission with current chemotherapy regimens [1-4]. Only 20% of patients who relapse enter a prolonged second complete remission after receiving chemotherapy, radiation, or bone marrow transplantation [5-14]. Thus, prevention of relapse remains an important issue. Factors associated with relapse after a complete response has occurred with chemotherapy include the following: nodular sclerosis histology, bulky disease, more than three cycles of chemotherapy required to achieve complete response, decreased chemotherapy doses, and B symptoms [15-22]. Eighty percent of relapses in patients with Hodgkin disease occur in sites of initial clinical involvement [22, 23]. Because Hodgkin disease is a radiosensitive tumor, a logical step is to use radiation in an attempt to eradicate subclinical disease after remission induction with chemotherapy. Kaplan [24] and others have shown that a radiation dose of 2000 to 2500 cGy is effective in preventing recurrence in all but 25% to 30% of patients with clinical disease when radiation is used as the sole treatment modality [24]. This relatively low dose of radiation might be even more effective if only subclinical disease was being treated. Further, using low-dose radiation after chemotherapy might decrease some of the morbidity associated with the combined use of both modalities at full doses. Early nonrandomized studies by Prosnitz and colleagues [25], in which the MVPP regimen (nitrogen mustard, vincristine, prednisone, and procarbazine) was administered with low-dose involved field radiation, showed only a 10% relapse rate when stage III or IV patients had achieved complete response with chemotherapy before receiving radiation. In 1978, we initiated a randomized trial for patients with stage III or IV Hodgkin disease that was designed to test the efficacy of low-dose involved field radiation after complete remission induction with chemotherapy. The MOP-BAP (nitrogen mustard, vincristine, procarbazine, bleomycin, doxorubicin, and prednisone) chemotherapy regimen was used as induction treatment because this regimen had been associated with a complete response rate of 77% [2]. Complete responders to six cycles of MOP-BAP were randomly assigned to a radiation dose of 2000 cGy to initially involved sites or to no further treatment. We determined the remission duration and relapse-free and overall survival rates for the entire group of patients with advanced Hodgkin disease as well as for several major subsets of patients. Methods Previously untreated patients (n = 564) with clinical or pathologic evidence (or both) of stage III or IV Hodgkin disease were registered for induction with MOP-BAP chemotherapy between June 1978 and September 1988. Pathology slides were reviewed by the Southwest Oncology Group Pathology Review Committee. A final review was made by the Lymphoma Central Repository. Patients who were known to be positive for human immunodeficiency virus or who had a clinical diagnosis of the acquired immunodeficiency syndrome were excluded from analysis. The pathology review is now complete for 95% of the patients who entered this study. Thirty-four patients (6%) were ineligible, primarily because they had non-Hodgkin lymphoma after pathology review. The Ann Arbor Staging Classification was used [26]. Staging requirements included bone marrow aspiration and biopsy; renal, heart, and lung function studies; and staging laparotomy or radiographic evaluation of the abdomen with either computerized tomography or lymphangiography or both. Patients with any mass 6 cm or more in size were designated as having bulky disease. Flow sheets, prestudy forms, and radiographic reports were reviewed on all patients who achieved complete response to make the assessment of bulky disease. Liver biopsy was required in patients with stage IIIB or IV disease unless the patient had clinical liver involvement or it was medically contraindicated. Clinical liver involvement was defined as an enlarged liver on physical examination or computed tomography together with increased levels of at least one liver enzyme other than alkaline phosphatase or lactate dehydrogenase. Clinical spleen involvement was defined as a palpable spleen on physical examination or an enlarged spleen on computed tomography with or without filling defects. Response Definitions A partial response was defined as a 50% or greater decrease in the sum of the products of the largest diameter and its perpendicular for 4 weeks or more. Patients with questionable residual disease were classified as partial responders. For patients with minimal residual disease detected by computerized tomography scanning after six cycles of chemotherapy, designation of partial or complete remission was left to the discretion of the individual investigator. In general, however, patients with minimal residual disease were classified as partial responders. If the residual mediastinal mass on the computerized tomographic scan was less than 3 cm or the residual peripheral nodal mass was 1.5 cm or less, partial responders were classified as having minimal residual disease. Complete response was defined as disappearance of all clinical evidence of disease for 4 or more weeks. Treatment Chemotherapy The MOP-BAP chemotherapeutic regimen consisted of nitrogen mustard (6 mg/m2) on day 1, bleomycin (2 mg/m2) and vincristine (1 mg/m2; maximum dose, 2 mg) on days 1 and 8, doxorubicin (30 mg/m2) on day 8, and prednisone (100 mg) and procarbazine (100 mg/m2) on days 2 to 7 and 9 to 12. Courses were repeated every 28 days if the absolute granulocyte count was 1500 cells/mm3 or more. A total of 6 cycles was administered. Prednisone was given only during the first and fourth cycles. Initial doses of MOP-BAP were 50% of those listed above if the patient was older than 65 years or had bone marrow involvement with leukopenia. Dose escalation in subsequent courses was encouraged. Initial doxorubicin doses were also decreased by 50% to 75% for serum bilirubin levels greater than 1.5 mg/dL or increases in liver enzyme levels of more than threefold the normal level or both. Subsequent drug doses were reduced for severe myelosuppression or delayed hematopoietic recovery as in previous Southwest Oncology Group studies [2] using this regimen. The ratio of actual/planned full-dose chemotherapy for each of the 5 drugs (nitrogen mustard, bleomycin, procarbazine, vincristine, and doxorubicin) was calculated for the 530 eligible patients. The average percentage was used to describe the amount of chemotherapy given. The average for the 5 drugs was 85%. The average number of courses was 5.6. The average actual/planned ratio for each drug was 86% for nitrogen mustard, 84% for doxorubicin, 82% for procarbazine, 91% for bleomycin, and 81% for vincristine. Sixty-six percent of patients achieving complete response received more than 85% of the planned induction chemotherapy. Radiation Therapy for Complete Responders All patients were seen in consultation by a radiation oncologist before induction chemotherapy was started, and all clinical and pathologic sites of disease were mapped. If the patient was later given radiation, all initially involved areas were included in the treatment ports with the exception of bone marrow. Patients with previously involved nodal sites received 2000 cGy in 150-cGy fractions, those with previously involved liver sites received 1500 cGy in 150-cGy fractions, those with previously involved spleen sites received 1500 cGy in 125-cGy fractions, and those with previously involved lung sites received 1000 cGy in 100-cGy fractions. Kidney blocks were used when necessary, and a spinal cord block was used when the dose to the cord had reached 2000 cGy. Patients only received radiation to those areas identified as being clinically or pathologically involved with Hodgkin disease. Radiation was started, 6 weeks after day 1 of the sixth MOP-BAP cycle, if the leukocyte count was more than 3000 cells/mm3 and if the platelet count was more than 100 000/mm3. A 3-week rest was recommended between radiation of large volumes or major lymph node areas. Supervoltage radiation of at least 2 MV or cobalt-60 was required. Port films, dose calculations, and treatment records were reviewed by the Quality Assurance Center, the Radiologic Physics Center, and the Medical and Radiation Oncology Coordinators. Failure to give any radiation to a previously involved site or concomitant administration of radiation and chemotherapy was considered a major radiation violation. Dose infractions and failure to complete radiation for any reason were considered minor radiation violations. Ninety-six percent of patients receiving radiation have had their records evaluated by the Radiologic Physics Center in Houston, Texas, and the Radiation and Medical Oncology Study Coordinators. All eligible patients who achieved complete response and were randomized were included in comparisons of remission duration, relapse-free survival, and survival regardless of whether a major or minor radiation violation had occurred. Patients randomized to no further treatment received no radiation or chemotherapy after six cycles of MOP-BAP until they relapsed. Planned follow-up intervals in patients randomized to receive low-dose radiation were identical to those for patients randomized to no further treatment. Treatment at the time of relapse was at the discretion of the individual investigator. Study Design When the study was initially opened, patients in complete response were randomized after six cycles of MOP-BAP and restaging to one of three possible groups: no further therapy, levamisole for 2 years, or low-dose radiation to previously involved sites of disease. The study design was changed in 1982 because of lower-than-anticipated patient accrual. The levamisole arm was eliminated, and patients were randomized before

Superiority of adriamycin‐containing combination chemotherapy in the treatment of diffuse lymphoma. A southwest oncology group study

As a part of an ongoing prospective controlled trial, the Southwest Oncology Group compared the results of treatment of advanced non‐Hodgkins lymphoma with two CHOP regimens (cyclophosphamide, adriamycin, vincristine and prednisone with either low‐dose bleomycin or BCG by scarification) to a COP regimen (cyclophosphamide, vincristine and prednisone) with low‐dose bleomycin (COP‐Bleo). The study design emphasized histopathology review and systematic restaging to define complete remission (CR). Confirmed rates of CR for 443 evaluable patients were 59% for 286 patients receiving the CHOP regimens and 59% for 157 patients receiving COP‐Bleo. Rates of CR were higher for patients with nodular lymphoma (69%) compared to those with diffuse lymphoma (54%) (p = 0.005). For patients with nodular lymphoma there was no difference in CR rates according to treatment. For patients with diffuse lymphomas the CR rate was higher with the CHOP programs (58%) than with COP‐Bleo (44%) (p = 0.10). Overall duration of CR and survival was significantly longer for patients with nodular lymphoma compared to diffuse lymphoma (p < 0.01). At this time, remission duration and survival were similar regardless of induction regimen used in patients with nodular lymphoma. However, in patients with diffuse lymphoma, the duration of CR and overall survival were improved by treatment with the CHOP regimens compared to COP‐Bleo (p = 0.02). Thus, in this controlled study we have demonstrated that initial combination chemotherapy employing the CHOP regimen was a superior remission induction therapy for patients with diffuse lymphoma. Cancer 43:417–425, 1979.

The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: a phase-III intergroup study

One hundred and forty one patients were treated in a combined Eastern Cooperative Oncology Group and Southwest Oncology Group phase-III study evaluating low-dose cytarabine (LDAC) versus supportive therapy for the treatment of myelodysplastic syndrome (MDS). Patients were randomized to either cytarabine 10 mg/m2 subcutaneously BID or supportive therapy. Central pathology review was required. All patients were classified according to the FAB criteria for MDS. The overall concordance rate for the MDS subtype was 52%, and 25 patients were pathology exclusions, including 20 with AML. The overall response rate to a single cycle of LDAC was 32%, with 11% complete and 21% partial responses. The median duration of response was 5.9 months, with a range of 1.4–33.5 months. Responses were seen in all subtypes. Infections were more common in the LDAC arm. There was no difference in the time to progression or the overall survival for patients treated with LDAC or supportive therapy. The incidence of leukemic transformation was similar in both arms at 15%, but it differed according to the MDS subtype. Patients receiving LDAC had a decreased transfusion requirement after 3 months. There was a significant correlation between the degree of cytoreduction after receiving a single cycle of LDAC and survival. This survival difference was most marked in patients with the RAEB and RAEB-T subtypes. Although LDAC produced responses in all subtypes of the MDS, there was no effect on overall survival or transformation to AML. However, selected patients benefited from a single cycle of LDAC with durable responses. A cytoreductive effect appears to be required for a durable response. Future studies should include pathology review and must address the clinical and biological heterogeneity of MDS.

Phase III comparison of the treatment of advanced gastrointestinal cancer with bolus weekly 5‐FU vs. methyl‐CCNU plus bolus weekly 5‐FU. A southwest oncology group study

In a randomized and stratified study, 294 patients with advanced gastrointestinal cancer were treated either with 5‐fluorouracil (5‐FU) 400 mg/m2 weekly intravenously (i.v.) or 5‐FU 400 mg/m2 i.v. weekly plus methyl‐CCNU 175 mg/m2 orally (p.o.) every 6 weeks. The response rate in colorectal cancer with 5‐FU was 9.5% while the two‐drug treatment produced a response of 31.8% (p = .009). The response in all gastrointestinal cancers to 5‐FU was 10.6% as compared with 29.3% for the combination (p = .012). All responses were partial. The two‐drug regimen is more effective and more toxic than weekly 5‐FU therapy.

Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone alone or with levamisole or with levamisole plus BCG for malignant lymphoma: a Southwest Oncology Group Study.

Between 1977 and 1983 the Southwest Oncology Group (SWOG) evaluated chemotherapy alone (cyclophosphamide, doxorubicin, vincristine, prednisone; CHOP) or chemoimmunotherapy (CHOP-levamisole or CHOP-levamisole-BCG) in a randomized prospective clinical trial involving 715 eligible patients with all types of malignant lymphoma (ML). Of 281 evaluable patients with favorable histologic types of ML, 171 (61%) achieved complete remission (CR) and there was no difference in CR rate, CR duration, or survival according to the type of initial treatment. Of 388 evaluable patients with unfavorable histologic types of ML, 194 (50%) achieved CR. Levamisole appeared to adversely affect CR rates in nodular mixed and nodular large-cell lymphoma and CR duration in patients with unfavorable histology ML. Chemoimmunotherapy with levamisole or levamisole-BCG offers no advantage in terms of CR rates, CR duration, or survival compared to CHOP chemotherapy alone, and levamisole may have had an adverse impact on outcome in certain subtypes of ML.

The effect of provider education on blood utilization practices

OBJECTIVE Our aim was to determine prospectively if a process of provider education and subsequent audit of transfusion criteria can reduce inappropriate blood product infusion. STUDY DESIGN Beginning in December 1990, a year-long process of provider education and quality assurance audit, with the use of guidelines based on National Institutes of Health blood product consensus conferences, was instituted. After this orientation and education period, the medical records were reviewed for patients on the obstetrics and gynecology service from Dec. 1, 1990, through Sept. 30, 1991, who received blood products (packed red blood cells, fresh-frozen plasma, cryoprecipitate). This group was compared with patients cared for by our service over a similar period before the institution of these guidelines. The incidence of cesarean birth and operative intervention for gynecologic malignancies, as well as the number of major operative gynecologic procedures, was found to be unchanged during the total study period (Dec. 1, 1988, through Sept. 30, 1991). RESULTS In 1989 there were 1236 units of blood products transfused; in contrast, in 1991 428 units of blood were transfused. In 1989, 107.9 +/- 59.9 units of packed cells per month were used in 33.6 +/- 16.8 patients (3.2 units per patient). In contrast, in 1991, 14.4 +/- 5.8 patients per month received transfusions (2.82 units per patient) with 40.7 +/- 17.2 units of packed cells (p < 0.0001). This represents a 75% decrease in the total number of packed cells and a 60% decrease in the number of patients undergoing transfusion per month. Similar reductions in the usage of cryoprecipitate and fresh-frozen plasma were noted (p = 0.024 and 0.002, respectively). Acute operative blood loss was the most common indication for transfusion. Abdominal hysterectomy was the most common procedure followed by exploratory laparotomy and cesarean section. No patients in whom blood was not used had untoward effects. CONCLUSION Education as to appropriate blood utilization and concurrent quality assurance audit techniques can safely reduce blood usage on a busy obstetrics and gynecology service in a tertiary care center.

Improved complete remission rates and survival for patients with large cell lymphoma treated with chemoimmunotherapy: A southwest oncology group study

Between 1974 and 1977, 652 patients with non‐Hodgkins lymphoma without prior chemotherapy were randomized to 1 of 3 combination chemotherapy programs designed to induce complete remission (CR): COP‐bleomycin (180 patients), CHOP‐bleomycin (232 patients) or CHOP plus immunotherapy with Bacillus Calmette Guerin (BCG) (240 patients). With mature follow‐up, the major effect of BCG immunotherapy was observed in patients with large cell lymphomas (diffuse or nodular “histiocytic”) and not in other common lymphoma subtypes. CR rate for 65 patients with large cell lymphoma treated with CHOP‐BCG was 68% compared to 48% in 61 patients treated with CHOP‐bleomycin (P = 0.02) (two‐tailed test) or 44% for 45 patients treated with COP‐bleomycin (P = 0.02). CR duration for both CHOP‐based regimens was similar and superior to that produced by COP‐bleomycin (P = 0.03). Survival of patients with large cell lymphoma treated with CHOP‐BCG was better than that observed with CHOP‐bleomycin (P = 0.02) or COP‐Bleomycin (P = 0.002). Although the explanation for the favorable effect of BCG remains unclear, further clinical trials to evaluate the combination of chemotherapy and other “biologic response modifiers” is warranted for patients with lymphoma.

Comparison of lymphangiography and computed tomography scanning in evaluating abdominal disease in stages III and IV Hodgkin's disease: A southwest oncology group study

The authors reviewed the records of 139 patients who had laparotomy plus computed tomography (CT) and/or lymphangiograms (LAG) as part of a their staging workup for Hodgkins disease, in accordance with Southwest Oncology Group (SWOG) protocol 7808. They evaluated the relative ability of CT and LAG to detect disease in the abdomen. Two regions of the abdomen were designated, the upper and the lower, to further examine the capabilities of CT and LAG in the lower abdomen and CT in the upper abdomen. A LAG was more sensitive (P < 0.05) than CT in detecting positive lower abdominal nodes. in the upper abdomen, CT scan had low sensitivity for detecting positive nodes, liver, or spleen. This study suggests that LAG of the lower abdomen provided more information than CT, and therefore should not be abandoned as a valid method for detecting nodal disease.

Automated erythrocyte exchange in fulminant falciparum malaria.

Excerpt With increasing travel to endemic areas and negligent prophylaxis, the number of gravely ill patients with malaria in this country is increasing (1). Prompt, effective treatment is essentia...

Thrombotic thrombocytopenic purpura : Evolution across 15 years

Thrombotic thrombocytopenic purpura (TTP) was originally described 70 years ago. It is considered an uncommon disorder with a reported occurrence rate of one case per 1 million patients. Mortality has decreased from almost 100% early on to 30–50% with the advent of newer treatment methods. We reviewed 41 patients with a diagnosis of TTP spanning the years 1980 to mid 1994. We found a much higher case rate, one per 6000 hosptial admissions, and an overall death rate of 40%. However, isolating 5 year periods we noted a marked fall in mortality from 54% (1980–1984), 44% (1985–1989), to 18% (1990–1994). Previous reports describe relapsing TTP and report an incidence of 7–15% although very recent data suggests a higher incidence. In our study, we found an overall relapse rate of 25% and by 5 year periods 23% (1980–1984), 13% (1985–1989), and 46% (1990–1994). We suggest that the improvement in survival and the increase in relapse rate are related and reflect more effective therapy for this once almost always fatal disease. Patients now survive their initial episode and thus are at risk for recurrence. Identification of risk factors for relapse will require further study.