Ralph E. Johnson

Nonlymphomatous malignant tumors complicating Hodgkin's disease. Possible association with intensive therapy.

Abstract Case records of 425 patients with Hodgkins disease treated at the NIH were reviewed. Note of all biopsy-proved malignant tumors other than Hodgkins disease was made. Cases were divided into subgroups on the basis of treatment received, and expected incidences of malignant tumors were calculated for each subgroup on the basis of age, sex, and mean follow-up period from the time of diagnosis of Hodgkins disease. Significantly increased risks of development of second malignant tumors were found in the entire 425 patients (ratio of observed to expected, 3.5) and in the subgroups treated with both radiotherapy and chemotherapy (ratio, 3.3) and with intensive radiotherapy without intensive chemotherapy (ratio, 3.8). The greatest increase in risk was observed in 35 patients who received both intensive radiotherapy and intensive chemotherapy (ratio, 29).

Sequential nonsurgical and surgical staging of non-Hodgkin's lymphoma.

The yield of specific diagnostic procedures in the staging of non-Hodgkins lymphoma was assessed in 170 consecutive patients who were evaluated with a sequence of diagnostic procedures. Stage III or Stage IV disease was established in 141 of 170 patients (80%) by nonsurgical procedures, including lymphangiography (positive in 78%), bone-marrow biopsy (positive in 39%), percutaneous liver biopsy (positive in 21%), and peritoneoscopy-directed liver biopsy (positive in 29% of those tested). Staging laparotomy showed disease outside conventional nodal irradiation fields in 21 of 26 patients with a positive lymphangiogram, but in only three of 17 patients with a negative lymphangiogram. The yield of staging procedures was highest in patients with nodular lymphomas, only 6% of whom were Stage I or Stage II after staging, but was lowest in patients with histiocytic lymphoma, 30% of whom had localized disease. This study shows that the presence of disseminated disease can be detected in the majority of patients with non-Hodgkins lymphoma without the use of staging laparotomy.

Adriamycin and Enhanced Radiation Reaction in Normal Esophagus and Skin

Clinical evaluation of 10 patients with small cell carcinoma of the lung treated with radiotherapy and periodic cycles of combination chemotherapy with cyclophosphamide, vincristine, and adriamycin showed frequent and occasionally severe esophageal and skin reactions. Eight of the 10 patients had esophagitis, four required supportive intravenous fluids, and two subsequently developed esophageal narrowing and stricture formation. Recurrent esophagitis with augmentation of injury in the recently irradiated esophagus was observed 11 times in eight of the 10 patients after cycles of chemotherapy, and contributed to the sustained toxicity seen in two patients. Dermatitis in the form of moist desquamation was observed in five of the patients at very low doses of supervoltage radiation therapy. Acute pulmonary reactions was notably absent. This combination of chemotherapy, particularly adriamycin, potentiates the effect of radiotherapy on the normal esophagus and skin, and further implicates the radiosensitizing property of adriamycin.

Risk of new cancers in patients with Hodgkin's disease.

An assessment of the risk of new cancers in patients with Hodgkins disease (HD) requires consideration of potential intrinsic and extrinsic factors. Because series of untreated patients with HD do not exist, the true intrinsic risk of development of new cancers cannot be assessed, although the immunologic abnormalities associated with active HD are a potential contributory factor. In recent years, reports of new cancers occurring in patients with HD have considered the role of extrinsic factors in the form of therapeutic intervention. Exposure to ionizing radiation, a known carcinogen in humans, has been suggested as a possible explanation of increasing reports of cases of acute nonlymphocytic leukemia (ANLL) complicating HD. Studies from the National Cancer Institute have shown a highly significant increase in incidence of new cancers (including ANLL) in intensively treated HD patients, and suggested the possibility of a synergistic carcinogenic effect of combined exposure to ionizing radiation and cytotoxic drugs. While the mechanism of induction of second malignant tumors in patients with HD is not clear, it is probably complex, and may relate to interactions between immunosuppressive factors associated with the disease and further immunosuppression and direct cellular damage produced by radiation, cytotoxic drugs, or combinations of both. Further efforts to investigate long term complications of cancer therapy and to design therapeutic programs that will minimize these complications are most important, in view of the improved survival in a number of malignant diseases, which may be anticipated with modern multimodal anticancer therapy.

Combined modality therapy of Ewing's sarcoma

Since 1964, 66 consecutive patients with Ewings sarcoma have been treated at the National Cancer Institute with local irradiation of the primary site combined with adjuvant regimens of progressively more intensive systemic chemotherapy. Actuarial survival rates for the total series show a 56% 2‐year and 35% 5‐year survival. The 43 patients without clinically detectable metastases at diagnosis have 64% 2‐year and 52% 5‐year survival rates. The current protocol, alternating high‐dose pulses of adriamycin and cyclophosphamide‐vincristine, is providing improved disease‐free survival as compared to previous protocols, and indicates further progress toward the ultimate goal of complete tumor eradication. In addition to the problems of diagnostic accuracy in evaluating treatment results, other major factors influencing prognosis include initial metastatic disease, site of the primary tumor, age at diagnosis, and presence of systemic symptoms. At least these, and probably others, must be taken into account in developing randomized prospective trials for determination of optimal adjuvant therapy.

Determination of prognostic factors and their influence on therapeutic results in patients with Ewing's sarcoma

We have analyzed the results of treatment of 117 patients with Ewings sarcoma admitted to the National Cancer Institute since 1964. All patients received local irradiation to the primary site and a series of progressively more intensive systemic chemotherapy regimens using drugs known to be active as single agents in this disease. Four protocols were employed with varying numbers of patients in each treatment group. Initially, there appeared to be a difference among treatment groups with regard to disease‐free survival (overall P =.06), with the later regimens having more favorable outcomes. We then undertook a statistical analysis of the influence of five pretreatment variables—age, sex, site of primary disease, serum lactic acid dehydrogenase (LDH), and metastatic status—on disease‐free survival. Of these five factors, important indicators of favorable prognosis for the entire group (and for each of the treatment subgroups) were a distal site of primary disease, normal serum lactic acid dehydrogenase (LDH) level at presentation, and the absence of metastatic disease at the time of presentation. When we examined treatment results with respect to these prognostic factors, we found that the subgroups treated with the more aggressive regimens contained higher proportions of patients with favorable prognostic factors. After adjustment for differences in composition of treatment groups with respect to prognostic factors, the apparent difference in disease‐free survival vanished (P =.62). These results indicate that in the case of Ewings sarcoma, prognostic factors must be carefully considered in the design of treatment protocols and the subsequent analysis of end results.

Mixed anaplastic small-cell and squamous-cell carcinoma of the lung.

Excerpt The pleomorphism of lung cancer is well known and the appearance of histologically well and poorly differentiated areas within a tissue specimen, or even the coexistence of multiple discree...

Radiation Therapy of Midline Granuloma

During a 15-year period, 10 patients with well-documented midline granuloma were treated with high-dose, deep local irradiation and followed for extended periods of time. Long-term remissions were achieved in 7 patients, with a mean (+/- SEM) survival postirradiation of 7.4 (+/- 1.4) years in the 6 patients still alive. True midline granuloma, which is a localized, destructive, inflammatory process of the upper airways, can be distinguished from Wegeners granulomatosis and neoplasms of the upper respiratory tract by several clinicopathologic criteria. The cause of midline granuloma is unknown, but it most likely represents an abnormal accelerated hypersensitivity reaction to an unknown antigen(s). Although serious complications of high-dose local irradiation to the upper airways can occur, the risk is warranted because of the high, long-term remission rate in this previously uniformly fatal disease.

Preliminary Experience with Total Nodal Irradiation in Hodgkin's Disease

Total nodal irradiation (TNI) of all major lymph-node areas was evaluated in 163 consecutive previously untreated patients with Hodgkins disease and compared to extended-field therapy in Stages I and II. The decreased relapse rate following TNI is reflected in improved survival rates. TNI has also been effective for Stage III-A, less satisfactory for Stage III-B. Extension of disease to extranodal sites has correlated with clinical staging and histopathology, defining certain groups as especially suitable for adjuvant chemotherapy.

“Total” Therapy for Small Cell Carcinoma of the Lung

Seventy-one consecutive patients with small cell carcinoma of the lung were treated with an integrated approach between November, 1974, and May, 1977. The regimen included radiotherapy to the primary site, relatively brief (6 to 12 weeks) although intensive chemotherapy, and prophylactic cranial irradiation. Complete responses were achieved in 75% and 40% of patients with limited and extensive disease, respectively. Modest prolongation of survival (median, 10 months) was realized by patients with extensive disease, but prolonged relapse-free survival was not observed. In contrast, one-half of the patients with limited disease who achieved a complete response have remained clinically free of disease without further treatment for a mean of 18 months (range, 6 to 33 months). Since all relapses to date have been noted within the first year following cessation of treatment, this experience suggests there may be a potential for cure in those survivors who are now relapse free for intervals exceeding two years.