Peter H. Wiernik

Cardiac disease after radiation therapy for Hodgkin's disease: Analysis of 48 patients

Occult or overt but delayed cardiac disease after thoracic radiotherapy for Hodgkins disease may be common. Detailed cardiac evaluations were performed in 48 patients with Hodgkins disease at risk a mean of 97 months after radiotherapy. The study protocol included echocardiography, gated radionuclide ventriculography, and cardiac catheterization. Cardiac disease was found in 46 patients (96%) and included constrictive or occult constrictive pericarditis (24 patients), an abnormal hemodynamic response to a fluid challenge (14 patients), coronary artery disease (6 patients), and left ventricular dysfunction (2 patients). Most patients (53%) had normal echocardiograms. Gated blood pool radionuclide angiocardiography was performed in 42 patients. Excluding patients with occlusive coronary artery disease, the left ventricular ejection fraction at rest (mean 59%) and during exercise (mean 69%) was within normal limits. Congestive heart failure occurred in 2 patients. Six patients had pericardiectomy for constrictive pericarditis and 3 patients had coronary artery bypass surgery for coronary artery disease. Thus (1) delayed cardiac disease after radiotherapy is common, (2) chronic pericardial disorders are the most frequent manifestations of this disease, and (3) the prognosis for patients who have radiation-induced cardiac disease is generally favorable.

A combined modality approach to the treatment of Hodgkin's disease. Preliminary results of a prospectively randomized clinical trial

Eighty‐seven previously untreated patients with pathologic Stage IA, II (A or B), or IIIA Hodgkins disease were randomized over a 48‐month period to receive either megavoltage extended field radiotherapy alone or megavoltage radiotherapy limited to involved lymph node sites (including at least an upper mantle field) followed by combination chemotherapy with nitrogen mustard, vincristine, prednisone, and procarbazine (MOPP). Four patients (4.6%) failed to achieve remission with initial radiotherapy. Seventy‐two evaluable patients have currently completed therapy. Ten of 41 patients achieving remission with radiation alone have relapsed, compared to only 1 of 31 receiving radiation plus chemotherapy. Seven patients have died, 3 of whom failed to achieve remission with initial radiotherapy. The other 4 had Stage IIIA disease treated with radiation alone. Severe myelosuppression occurred infrequently during chemotherapy, and neither serious infections nor second neoplasms have been observed. Although these preliminary results are encouraging, longer followup is required to determine the ultimate effects of combined modality therapy on survival and long‐term complications.

A comparative clinical trial of 5‐azacytidine and guanazole in previously treated adults with acute nonlymphocytic leukemia

Adults with previously treated acute nonlymphocytic leukemia received either 5‐azacytidine or guanazole in a randomized study. Eighteen patients were treated with 5‐azacytidine at a dosage of 200–250 mg/m2/day × 5 intravenously (i.v.) and six achieved a remission (five complete). The median duration of complete remission was 100 days. Among the 12 patients who received guanazole, at a dosage of 25–30 g/m2/day × 5 by continuous i.v. infusion, only one partial remission ensued. Patients who responded to 5‐azacytidine had a more profound degree of leukopenia (median 600 WBC/mm3) than nonresponders (median 1700 WBC/mm3). Both the time taken to reach the nadir white blood count (median, 14 days) and the duration of the nadir (median, 17 days) were long after each course of 5‐azacytidine, particularly for those patients who achieved a remission. Principal toxicities seen after 5‐azacytidine administration were gastrointestinal intolerance, fever, and neuromuscular toxicity. Fever was the principal toxicity observed after guanazole therapy; one patient developed erythema nodosum with arthralgias and another, recurrent pulmonary infiltrates. Survival from the start of therapy was clearly longer for the patients receiving 5‐azacytidine (median 140 days) because of the prolongation of survival seen in the responding patients (median 266+ days). 5‐Azacytidine has significant activity as an induction agent in adults with acute nonlymphocytic leukemia, but guanazole does not appear to be of particular value for patients with this disease.

The therapeutic implications of splenic involvement in stage IIIA Hodgkin's disease

In an effort to determine the most appropriate initial therapy for patients with stage IIIA Hodgkins disease, a comparative analysis was undertaken of 13 pathologically staged IIIA Hodgkins disease patients whose abdominal disease was localized to the spleen (III8A); 17 IIIA patients with spleen and abdominal lymph node involvement (III8+n+A) and 44 stage IIA patients. The three groups were treated concurrently with either extended field irradiation alone or limited field irradiation followed by MOPP chemotherapy. Relapse rates after irradiation alone were 17% for the III8A patients; 63% for the III8+n+A patients and 25% for the stage IIA patients. Following therapy with irradiation and chemotherapy no relapses occurred among the III8A and III8+n+A patients while 2/16 (13%) stage IIA patients relapsed. After irradiation alone stage III8+n+A patients had a significantly shorter remission duration and survival than the stage IIA patients (p = 0.03 and 0.002, respectively) but remission duration and survival were similar for the III8A and IIA patients. When therapy was irradiation and chemotherapy no significant differences in remission duration or survival were noted for the three groups. The most common sites of relapse for the III8+n+A patients were extralymphatic (60%) while no extralymphatic relapse have occurred among the IIA patients (p < 0.02). The only relapse among the III8A patients was at an extralymphatic site. These data have shown that patients with III8A Hodgkins disease have a similar prognosis to stage IIA disease but after therapy with irradiation along stage III8+n+A patients have a poorer prognosis. Combined irradiation and chemotherapy should, therefore, be considered for stage III8+n+A Hodgkins disease when abdominal nodal disease cannot be included in the initial radiation port.

Frozen Autologous Platelets in the Supportive Care of Patients with Leukemia

Multiple units of platelet concentrate obtained by intensive plateletpheresis of patients with leukemia in remission were pooled and frozen using 4 to 5 per cent dimethylsulfoxide and retransfused during periods of thrombocytopenia. Plateletpheresis was well tolerated by all donors and an average platelet yield per unit of 0.99 × 1011 (n = 155) was obtained. The results of 107 transfusions to 36 patients are presented. An average of 32.4 per cent of the platelets were lost during the freeze‐thaw process. Freezing loss was lowest at a freezing rate of one degree C per minute, at a lower final concentration of platelets, and when polyolefin bags were used. The mean corrected posttransfusion count increment was 6,400/μl (range 600–19,000 xm2/1011 platelets transfused). In vivo results did not correlate with freezing rate but were statistically significantly better at lower platelet (approximately 0.16 × 1011 platelets/10 ml) concentrations. Eleven patients, including some who were refractory to random donor platelets were supported entirely with autologous platelets during reinduction therapy for leukemia. When administered prophylactically the autologous platelets seemed to prevent hemorrhage during periods of thrombocytopenia although in most patients bleeding times were not corrected posttransfusion. This study demonstrates that frozen autologous platelets can be used in the supportive care of thrombocytopenic patients. Further technical improvements are necessary before platelet freezing becomes practical for widespread use.

A Standardized Technique for Efficient Platelet and Leukocyte Collection Using the Model 30 Blood Processor

The Model 30 Blood Processor is a safe and simple means of harvesting blood cell components. Presently cell collection depends on a visual assessment by the operator of the indistinct boundaries of cell fractions. To determine when each cell component could best be harvested, serial samples were taken from the output port at fixed intervals and the results of counts and differentials were graphed and tabulated. Studies in normal donors were done using acid‐citrate‐dextrose (ACD), 2 per cent sodium citrate in 6 per cent hydroxyethyl starch (HES), or heparin as anticoagulants. There was considerable overlap between the latter part of the platelet band, the leukocyte band and the rising hematocrit with all three anticoagulants. Normally functional lymphocytes could be harvested efficiently (˜ 80%) using ACD or heparin. Platelets could be harvested from ACD very efficiently (˜ 90%). Granulocytes could not be harvested from ACD (< 10%) since they were dispersed in the red blood cell (RBC) layer. Using HES, granulocytes could be harvested efficiently (˜ 70%) by extending collection into the RBC layer. Based on these data, a standard technique for cell collection has been devised. The flow rate is slowed to 20 ml/min and collection is carried 30 ml (90 seconds at a rate of 20 ml/min) for platelets. The RBC loss is approximately 6 to S and 2 to 3 ml/pass respectively. These studies indicate that the Model 30 is a highly efficient apparatus for blood cell separation, but the volume of blood processed is limited by the intermittent blood flow.

Chemotherapy versus chemoimmunotherapy for small-cell undifferentiated carcinoma of the lung

Thirty‐eight patients with small‐cell carcinoma were treated with cyclophosphamide, Adriamycin, and VP16–213 ± MER. Response and survival of the six patients who received radiotherapy prior to entering the study were inferior compared with patients who received chemotherapy alone. Of 32 previously untreated patients, 13 had limited and 19 had extensive disease. Ninety‐seven percent of these 32 responded and 63% achieved complete remission (CR). All patients with limited disease had a response and 77% achieved CR. Patients with extensive and limited disease had 9 ½ months (range 1–26 months) and 14 months (range 3 ½–42+ months) median survival, respectively. The median survival for all complete responders irrespective of extent of disease was 16 months (range 6–42+ months). Three patients with limited disease are disease free more than 34+ months and off all therapy 10 + to 18 + months. Eighteen of 38 patients required antibiotics for fever during neutropenia. Eight patients had MER fevers and nine had serious infections. There were four drug‐related deaths. MER therapy did not influence response rate, drug toxicity, or survival, but did add morbidity. This combination chemotherapy alone is an effective treatment for previously untreated small‐cell lung cancer patients regardless of extent of disease.

Doxorubicin, cyclophosphamide and VP16-213 (ACE) in the treatment of small cell lung cancer

SummarySmall cell lung cancer requires aggressive combination chemotherapy. The three active agents, doxorubicin (A) 45 mg/m2 i.v. day 1, cyclophosphamide (C) 1.0 mg/m2 i.v. day 1 and VP16-213 (E) 50 mg/m2/day i.v. days 1–5 were given together. The combination (ACE) was given every 21 days without chest irradiation. One hundred and seventy-four patients have been stratified for extent of disease and randomized on three sequential studies testing ACE vs ACE + MER immunotherapy (38 patients), or ACE vs ACE alternating with CCNU, methotrexate, vincristine and procarbazine (109 patients), or ACE vs ACE II (ACE with continuous VP16-213-100 mg/m2/dayx5 days-27 patients-ongoing). The immunotherapy and the alternating non-cross resistant combination have not proven beneficial with respect to response or survival. The ACE combination, regardless of additional treatments, has produced greater than 90% response overall. In limited disease the complete response (CR) frequency is 65%. The median survival for limited disease overall is 14 months and 18 months for patients achieving CR. In extensive disease the CR frequency is 40% with a median survival of 9 months overall and 13 months for patients achieving CR. Response frequency and survival are identical in the first two studies and 20–30% of patients with limited disease are long-term survivors with one late relapse (>3 years). Patients who achieved CR had a significantly longer survival regardless of other factors such as performance status or extent of disease. Prophylactic cranial irradiation was demonstrated to be useful in prevention or delaying CNS metastases in patients who achieved CR. The third generation study of high-dose VP16-213 infusion seeks to increase the CR frequency. ACE chemotherapy without chest irradiation is a highly effective treatment for all patients with small cell lung cancer and compares favorably with all other studies with or without adjuvant radiotherapy.

Cyclophosphamide, vinblastine, procarbazine and prednisone with CCNU and vinblastine maintenance for advanced Hodgkin's disease.

Fifty patients with advanced Hodgkins disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) in a 21‐day cyclic regimen. Thirty‐one patients (62%) achieved a pathologically documented complete remission (CR). Of the 23 previously untreated patients, 13 obtained CR. Twenty‐seven patients had been previously treated and 15/19 (79%) of those with prior major radiation therapy and 3/8 (37.5%) of those who had received both irradiation and chemotherapy achieved CR. Sixteen of the patients who attained CR received maintenance therapy with monthly alternating CCNU and vinblastine but as of this report, neither remission duration nor survival is significantly prolonged when compared to the 14 patients followed in remission on no therapy. Patients who received more than six courses of induction therapy (median 9.5, range 8–12) have had significantly fewer relapses and longer remissions than have those patients who received only six courses of therapy. It is concluded that: 1) CVPP is an effective regimen at inducing CR in patients with advanced Hodgkins disease and has less gastrointestinal and neurologic toxicity than MOPP; 2) maintenance therapy with CCNU and vinblastine to date has not been beneficial; and 3) greater than six courses of induction chemotherapy prolongs remission duration and is associated with fewer disease relapses.

Role of 67gallium citrate scanning in the management of non‐hodgkin's lymphoma

67Gallium scans were performed as part of the initial evaluation in 45 patients with non‐Hodgkins lymphoma. Eighteen of these patients underwent staging laparotomy and splenectomy. In addition, scans were performed either shortly after therapy was completed or during subsequent followup in 10 patients. The initial scans were found most useful for patients with histiocytic lymphoma: in detecting sites of involvement above the diaphragm and the high para‐aortic/mesenteric region, and when tumors were greater than 2 cm in diameter. The addition of 67Ga scanning to the pre‐operative clinical evaluation reduced the number of incorrectly staged patients from 8 to 4.