Carlo Uslenghi

Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP

This paper reports the preliminary results of a controlled study randomizing MOPP vs. a new four‐drug combination (ABVD) in advanced Hodgkins disease. ABVD consists of 6 cycles of adriamycin, bleomycin, vinblastine, and imidazole carboxamide. The purpose for designing this new combination was two‐fold: to compare the efficacy of ABVD with MOPP, and to demonstrate absence of cross‐resistance between the two regimens. Of 60 patients entered into the study, 45 (MOPP 25, ABVD 20) are presently evaluable for the analysis of remission induction. No patient was previously treated with chemotherapy; 20% had relapsed after primary radiotherapy. Whenever possible, complete remission was defined also through rebiopsy of known organ involvement. Complete remission occurred in 76% of patients treated with MOPP and in 75% of those given ABVD, with no difference between the two regimens as far as stage (IIIB–IIIs and IV), histologic type, and prior irradiation were concerned. Crossover carried out for progressive disease or for relapse after initial remission showed absence of cross‐resistance between MOPP and ABVD. Toxic manifestations after ABVD were in general well tolerated and reversible. The percent of optimal dose for each drug was as follows: adriamycin 87%, vinblastine 87%, bleomycin 96%, and imidazole carboxamide 96%. These preliminary results indicate that in terms of complete remission, ABVD could represent a successful alternative to MOPP to be used either in MOPP failures or in sequential combination with MOPP. However, the lack of long‐term followup limits at the present time an adequate comparison between the two treatments.

Natural history and survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by radical mastectomy.

This retrospective study evaluates the time and site of relapse as well as the median survival of 454 consecutive patients with T3‐T4 Nx Mo breast cancer treated with radiation therapy from 1968 to 1972. Radiotherapy was delivered with kilovoltage to the first 221 patients and with cobalt to 233 patients, respectively. A group of 133 selected patients was subjected to radical mastectomy 6–8 weeks after completion of the irradiation. The incidence of first relapse was 45% within the first 18 months from starting radiotherapy. The incidence of relapse was higher in presence than in absence of regional adenopathy, with no statistical difference between T3 and T4. Inflammatory carcinoma showed the highest percent of relapse during the first 12 months (48%). The relapse rate appeared independent from type of irradiation. The site of first relapse occurred more often (68%) in areas distant from irradiation fields. Sterilization of both primary tumor and regional nodes was obtained only in 10% of patients. The median survival for the whole series was 2.5 years, with no significant difference between roentgen therapy (3 years) and cobalt (2.5 years). Unfavorable survival was directly related to the presence of regional adenopathies (2.3 years), especially in the supraclavicular fossa (1.4 years) and of inflammatory carcinoma (1.2 years). Patients treated with radiotherapy followed by surgery showed a median survival of 3.9 years compared to 2.1 years for those given only irradiation. The importance of sequentially combining chemotherapy with radiotherapy is discussed.

Recent trends in the medical treatment of Hodgkin's disease.

Abstract The results of recent trials with chemotherapy and combined chemotherapy and radiotherapy for advanced Hodgkins disease are reviewed. The results of three, four and five drug combinations designed during the past four years by deletion, substitution or addition of various components of MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) failed to improve both the incidence and the duration of complete response. Therefore, MOPP remains the simplest, most effective and safest drug therapy to be used in clinical practice. At present, there are no sufficient data indicating which is the optimum maintenance regimen. Furthermore, there is not yet sufficient evidence to state that maintenance therapy is really of significant benefit once complete remission has been achieved after 6–8 cycles of intensive combination chemotherapy. The goals for future chemotherapy probably would be in the use in sequence of two effective non-cross resistant combinations which differ in their drug content. The preliminary results of a controlled study randomizing MOPP with adriamycin, bleomycin, vinblastine and imidazole carboxamide (ABVD) are presented. Complete remission was observed in 77% of patients after MOPP and in 83% after ABVD. No cross resistance was observed between the two regimens in a limited number of patients. Another possibility for improving the disease-free survival lies in the appropriate use of combined treatment modalities, where chemotherapy and radiotherapy can become ideal partners to achieve eradication of Hodgkins disease. Although the results of some pilot studies appear encouraging, timing and dosage of chemotherapy and radiotherapy deserve more accurate evaluation.

Endolymphatic radiotherapy in malignant lymphomas. A clinical evaluation of 285 patients

The authors report treatment of inguinal and retroperitoneal lymph nodes of 285 malignant lymphomas (143 Hodgkins disease and 142 lymphoreticular sarcomas) with Lipiodol Fluide 131I (endolymphatic radiotherapy). From 1961 to 1966 the radioactive contrast material was injected in doses ranging from 0.2 to 2.5 mc/cc (10 cc each foot). Adequately opacified nodes responded promptly with marked and progressive reduction in size. When indicated, a second administration of Lipiodol 131I in a dose of 2.5 mc/cc was always feasible. Several factors prevented a homogeneous and satisfactory distribution of radioactive contrast material throughout the iliac and the para‐aortic nodes in one third of the cases. Therefore, in many instances patients had to be treated with external radiation therapy. Histopathologic examination of lymph nodes removed at exploratory laparotomy (four cases) or at autopsy (ten cases) confirmed that Lipiodol 131I did not fill all the iliac and para‐aortic nodes and that destruction of lymphomatous tissue was often incomplete. Recurrences were seen mostly in abnormal adequately filled nodes opacified with high doses of Lipiodol 131I In Hodgkins disease they occurred particularly in the para‐aortic area and in lymphoreticular sarcomas in the inguinal and iliac chains. Side effects were minimal. They included amenorrhea, pulmonary insufficiency, hepatic failure and hemolytic anemia. Clinical and histologic signs of pulmonary and hepatic fibrosis were not seen. The authors conclude that endolymphatic radiotherapy should not be considered as a radical treatment for retroperitoneal adenopathies in malignant lymphomas and that its role as a prophylactic therapeutic tool deserves more extensive long‐term studies.

In vivo study of the complement system during infusion of radiographic contrast media

It has been claimed that activation of the complement system may play a role in reaction to radiographic contrast media (RCM) infusion. In order to clarify the effects of RCM on the complement system, three different parameters (CH50, C3a, and C1 inhibitor) were measured in 20 patients undergoing intravenous pyelography for diagnostic purposes. We found no significant changes in C3a levels, but CH50 and C1 inhibitor fell significantly at the different sampling times; however, the decreases lost significance when the data were corrected for hemodilution with the total protein content of each sample as a reference. We conclude that RCM infusion does not activate the complement system.

Ultrasonography of Proliferative Vascular Lesions of the Skin

High‐resolution ultrasonography with small part probes was performed on 20 proliferative vascular lesions of the skin (3 lymphangiomas, 9 hemangiomas, 8 Kaposi sarcomas). All the lesions were submitted to histological examination. The histological cuts were made in the same planes as the ultrasound scans in order to obtain a direct comparison.

Usefulness of chest and skeletal survey to assess the time of relapse in breast cancer.

The pertinent radiographs of 151 patients treated with radical mastectomy who showed relapse in the chest and/or in the skeleton as first site were reevaluated. Diagnostic accuracy was calculated by comparing the first examination considered as positive with the previous ones reported as negative. For chest lesions the accuracy was 80 % (70 % for parenchymal nodular densities), with no difference between symptomatic and asymptomatic patients. For bone metastases retrospective evaluation confirmed the radiological report (i.e., the time of relapse), in 73.8 %, with a value of 89.7 % in symptomatic and 53.4 % in asymptomatic patients. The site of involvement and morphological characteristics of the lesions did not influence the diagnostic accuracy. Therefore chest examination and, for symptomatic patients, radiographic bone survey still represent a useful modality to assess the diffusion of breast cancer. For asymptomatic patients other modalities, such as bone scan and biochemical tests, should be utilized.

Classification and Treatment of Hodgkin's Disease

A new clinical classification for Hodgkins disease is proposed by the Committee for the Study of Malignant Lymphomas of the National Cancer Institute of Milan in cooperation with the Institute of Radiology of the University of Milan. The method of treatment of Hodgkins disease adopted in these Institutes is also outlined. The histologic classification includes paragranuloma, nodular sclerosis, granuloma and sarcoma. Stage I: disease limited to a single peripheric lymphatic region. Within this stage two groups can be recognized: a) involvement of one single lymph node or few nodes limited to a small area of the region (unifocal lesions); b) involvement of many nodes spread throughout the region (uniregional lesions). Stage II: disease limited to two contiguous lymphatic regions, or to few deep nodes (mediastinal, retroperitoneal). Stage III: disease limited to two non contiguous peripheric lymphatic regions, or to many peripheric and/or deep (mediastinal, retroperitoneal) regions, provided the involvement is either above or below the diaphragm. Stage IV: generalized disease with involvement of lymph nodes above and below the diaphragm, or involvement of one or more lymphatic regions with concomitant involvement of visceral organs, bones, marrow, nervous system and skin. Systemic symptoms and signs, fatigue, fever, night sweats, loss of weight, itching, anemia, lymphocytopenia, high erythrosedimentation rate) must be recorded in each case to evaluate prognosis and proper treatment, bu are not considered in this classification for lymph node staging. Primary visceral, bone, nervous and cutaneous involvement is exceptional; therefore staging for such lesions is not considered in this classification. In all stages endolymphatic radiotherapy with Lipiodol F 131I is indicated (10 ml in each foot with 2.5 mc/ml, corresponding to a tumor-dose of 15 - 20,000 rads). This is considered as a radical as well as a prophylactic treatment for those lymph nodes adequally filled with the contrast material; in case of non filling or incomplete filling of part of the lymph node chain, treatment will be completed with external radiation therapy. Stage I and II are treated with radical and prophylactic radiotherapy. If systemic symptoms and signs are still present after radiotheraphy, a course with anticancer drugs will be administered. Radiation therapy is given with high voltage or Co60 units. In radical treatments tumor doses of at least 3,000 r within 3–4 weeks are administered to all involved lymphatic regions. Prophylactic radiotherapy is indicated for regions clinically free of disease but contiguous to the involved areas, with tumor doses not less than 3,000 r in 3–4 weeks. In stage II radical radiotherapy follows a course with chemotherapy. In stage IV chemotherapy is the treatment of choice; palliative radiotherapy is given to any bulk of tumors, wherever the location, when specific symptoms can be attributed to the masses. The anticancer drug of choice is methyl-bis-(β-chloro-ethyl)-amine HCl(HN2) 0.4 mg/kg i.v., for those patients who did not receive any previous course of chemotherapy. Otherwise, as well as during the course of the disease, other polyfunctional alkylating agents, vinblastine (alone or in combination with chlorambucil), methylhydrazine, and corticosteroids will be administered according to each clinical situation. Radical surgery followed by radical radiotherapy is reserved for primary lymphatic involvement only in specially selected patients in stage I with unifocal lesions. Primary involvement of the stomach, small bowel or colon is treated by surgical extirpation and radiotherapy. Splenectomy is indicated when this viscus is the only site of involvement. During pregnancy radiation therapy is not administered below the diaphragm. Chemotherapy is not given during the first 4 months of pregnancy. The need for one internationally accepted clinical classification of Hodgkins disease is stressed.

Failures (cause and time) of radiotherapy in oral cancer

The results of a retrospective clinical evaluation concerning 434 cases of oral carcinomas treated with radiotherapy from January 1959 to December 1967 are presented. The analysis of the results obtained shows that radiotherapy alone may offer a reasonable possibility of success in limited lesions (68.3% 5-year survival of Stage I patients). In more advanced local cases, and especially those with regional adenopathies, radiotherapy alone cannot consistently control the disease for a long period of time; 5-year survival from the onset of treatment was respectively 36.5% and 24.5% for Stage II and III cases. Moreover, if controlateral or bilateral metastatic adenopathies or fixed lymph nodes are present, the prognosis becomes dramatic (2.6% 5-year survival of Stage IV patients). Among the irradiation techniques currently available, curietherapy (interstitial applications or surface molds) presumably offers the best possibility of success, since the observed failures, both overall and stage by stage, are inferior. Radiotherapy alone may generally be of proven efficacy if the local or locoregional extension is limited. In more advanced cases a combined surgery-chemotherapy treatment method is recommended. The criteria for a combined therapeutic approach for these tumors are also discussed.

Lymphangiographic diagnosis of malignant lymphoma

Abstract Three cases of malignant lymphoma involving retroperitoneal nodes, in which the clinical diagnosis could be clearly established by lymphangiography, are reported. In two cases the left retroperitoneal node chain apparently was the only site of involvement. In one case the right retroperitoneal chain showed recurrence after two years, with roentgenologic findings identical with those described for the left chain. Lymph node biopsy confirmed the roentgenologic diagnosis in the first case, and hepatic biopsy became conclusive only after lymphangiography in the third patient. In the second case it was possible by lymphangiography to detect pathologic lymph nodes in the retroperitoneal space in the absence of positive physical and other roentgenologic and laboratory findings.