Ellis J. Van Slyck

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

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.

Essential thrombocythemia with transition into acute leukemia.

A 57-year-old black man with sustained platelet count of 2 million/mm3 and evidence of intermittent gastrointestinal bleeding was diagnosed as having essential thrombocythemia. Studies of bone marrow morphology, platelet aggregation, and other variables were confirmatory of the disease. The patient was treated briefly with low doses of Myleran for less than three weeks. He was then lost to follow-up study. Approximately 16 months later he reappeared complaining of recurrent nose bleeds. He was found to be pancytopenic and diagnosis of acute leukemia was made on the basis of bone marrow aspiration.

Case Report: Marked Mature Neutrophilic Leukocytosis: A Leukemoid Variant Associated with Malignancy

Abstract Two cases of extreme granulocytosis are reported, emphasizing the clinical implications and differential diagnosis. Leukemoid reactions to malignancy, not chronic neutrophilic leukemia, will comprise the majority of such cases when the granulocytic response contains largely mature cells, whereas confusion with chronic granulocytic leukemia may result when peripheral immaturity is more manifest. Distinguishing features are discussed.

The sézary syndrome with rapid pulmonary dissemination

The authors report the case of a patient with long‐standing Sézary syndrome who developed the acute onset of bilateral pulmonary infiltration, severe hypoxemia, and hypotension. Initial diagnostic considerations centered around infection, but an open‐lung biopsy revealed “mycosis fungoides” without evidence of an infectious process. The patient showed striking improvement when given vincristine and cyclophosphamide, but ultimately died 3 months later of a nonpulmonary catheter‐related infection. This rare clinical association stresses the value of open lung biopsy as a diagnostic measure even in desperately ill individuals.

Case Report: Nonsecretory Multiple Myeloma with Osteoporosis: Immunocytologic and Bone Resorptive Studies

Two patients, ultimately found to have advanced nonsecretory multiple myeloma, presented with skeletal pain, diffuse skeletal demineralization, and fractures. The correct diagnosis was initially obscured by the absence of typical hematologic findings and discrete lytic bone lesions. Bone marrow examination was diagnostic. Intracytoplasmic IgA or IgD kappa was demonstrated in the myeloma cells of each case. Decreased quantitative polyclonal serum immunoglobulins and hypercalcemia were important clinical clues. The demonstration of increased osteoclast activating factor (OAF) derived from the cultured myeloma cells from each case suggests that the secretion of OAF and immunoglobulin are unrelated.

Colchicine in refractory chronic lymphocytic leukemia. A Southwest Oncology Group study.

SummaryFourteen patients with active chronic lymphocytic leukemia who had failed prior therapy were treated with progressive doses of weekly intravenous colchicine beginning at 2 mg and escalating as high as 7 mg in a single injection. Responses were seen in two of 14, with a lessening of adenopathy and splenomegaly. Toxicity was characterized by gastrointestinal intolerance in eight and thrombocytopenia in 12. There is activity of the drug in chronic lymphocytic leukemia but, as administered in this study, high dose therapy is not ideal and it may be more beneficial if the drug were given as low dose daily or weekly therapy.

Mitoxantrone (dihydroxyanthracenedione) in acute leukemia: An evaluation of two treatment schedules by the Southwest Oncology Group

Fifty-eight evaluable patients with acute leukemia were treated with Mitoxantrone (DHAD) according to two schedules: 14 mg/M2 as a single I.V. pulse dose administered three-week intervals, and 4 mg/M2/day for five days every three weeks. Six of 58 patients achieved a complete remission. One complete remission and 1 partial remission were observed among 26 patients treated with the single pulse schedule. Five (16%) complete remissions were attained among 32 patients treated on the daily × 5 schedule. Responses were observed only in patients with non-lymphoblastic leukemia. DHAD was very well tolerated with myelosuppression as the major toxicity. Nausea and vomiting were minimal. Subclinical cardiac toxicity occurred in two patients. This was identified by serial reductions in cardiac ejection fractions. DHAD appears to have significant activity in acute non-lymphoblastic leukemia with minimal toxicity.