Search

Results obtained by radiotherapy in 314 cases of rhinopharyngeal neoplasms treated from 1928 to 1963 at the Institute of Radiology of the Medical School and at the National Cancer Institute are presented. The series of cases includes 61 epithelial neoplasms, 117 rhinopharyngiomas, 112 connective neoplasms and 24 cases non histologically proved. In 41.7 % of the cases regional lymph node invasion was the first sign of the disease. Regional lymph node involvement was present at the beginning of radiotherapy in 72.5 % of the cases. Sixty-eight cases, hospitalized from 1928 to 1945, were prevailingly treated with endocavitary radiumtherapy and by roentgentherapy. One hundred and sixty cases, hospitalized from 1946 to 1958, were treated by various procedures and, in the last years, almost exclusively by multiple small fields roentgentherapy and by convergent roentgentherapy. Most of the 80 cases treated from 1959 to 1963 were submitted to telecobalt therapy. In the connective neoplasms (lympho- and reticulosarcomas) the overall 3-year and 5-year survival rate has been 34.2 % and 28.5 % respectively. In particular, cases without regional lymph node invasion at the beginning of the treatment had a 5-year survival rate of 61.5 %, opposite to 15.4 % in patients with lymph node metastases. In the other histological forms (rhinopharyngiomas, epitheliomas and non ascertained cases) the overall 3-year survival was 28 %, and the 5-year survival 19.6 %. In patients showing no lymph node involvement at the beginning of the treatment the 5-year survival rate was 37.8 %, in those with unilateral invasion 15.8 %, and in those with bilateral lymph node metastases 5.8 %. In epithelial neoplasms, the 5-year survival was 12.5 % in patients who had, at the beginning of the treatment, neurological or radiological signs of metastases to the base of the skull, and 21.9 % in patients, without involvement of the base of the skull. A statistical analysis of the results obtained in the various periods showed a more favourable outcome in patients treated by telecobalt therapy, as demonstrated both by average life and 3-year and 5-year survival rates.

A new clinical classification for Hodgkin's 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 Hodgkin's 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 Co60units. 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 Hodgkin's disease is stressed.

The preferential sites and mode of spread in 500 consecutive untreated patients with malignant lymphomas (200 Hodgkin's diseases, 150 lymphosarcomas and 150 reticulum cell sarcomas) have been studied. After a detailed diagnosis all patients with primary involvement of lymph nodes and spleen were staged according to the international four-stage clinical classification proposed at Rye in 1965. The lymphoreticular sarcomas with primary onset in Waldeyer's ring were staged according to the T.N.M. classification as modified in Milano by the National Cancer Institute in 1965. Patients with involvement of viscera or tissues without apparent disease in the lymph nodes, spleen or pharynx were listed separately. Primary involvement in Hodgkin's disease was confined in 99.5 % to lymph nodes and spleen. In lymphosarcoma and in reticulum cell sarcoma there was a high primary involvement of Waldeyer's ring (20 % and 53 % respectively) and in other extranodal sites (11–12%). Besides the cervical regions the distribution of lymph node involvement in Hodgkin's disease was predominantly in the mediastinum (20%) and in the paraaortic area (20%), while in lymphoreticular sarcomas mainly in the axillary (16%), iliac (23%) and inguinal (17%) regions. In the lymphoreticular sarcomas with primary onset in Waldeyer's ring the disease on first admission was limited to the pharynx and to the neek nodes in 73 % of cases. Study of the mode of spread showed that in untreated Hodgkin's disease the number of cases with contiguous involvement was 66 % while in lymphoreticular sarcomas it was only 35 %. Further, after localized radiation therapy Hodgkin's disease has a higher (72%) tendency to recur in adjacent lymphoid regions than lymphoreticular sarcomas with primary involvement in nodes and spleen (45%). The therapeutic implications of this study are discussed. The most important conclusion is that prophylactic irradiation should be given to localized Hodgkin's disease and not to lymphoreticular sarcomas with the exception of those arising in Waldeyer's ring.

The Committee for the Study of Malignant Lymphomas of the National Cancer Institute of Milano in cooperation with the Institute of Radiology, University of Milano presents a new clinical classification for lymphosarcoma and reticulum cell sarcoma as well as the method of treatment adopted in these Institutes. For primary lymph node lesions the staging is identical to that already proposed for Hodgkin's disease. Stage I: disease limited to a single peripheric lymphatic region. Within this stage two groups can he distinguished: 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 peripheric 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. For primary pharyngeal lesions the T.N.M. nomenclature has been adopted. T1: unifocal lesion (e.g. nasopharynx, tonsil, uvula); T2: multifocal lesions (e. g. nasopharynx and tonsil, tonsils, tonsil and base of the tongue); T3: unifocal lesion with extension beyond the anatomical confine of the site of origin (e. g. base of the skull, paranasal sinuses, jaw, orbit); T4: multifocal lesions with extension beyond the anatomical confine of the site of origin. N0: no adenopathy; N1: ipsilateral contiguous adenopathy (submental and/or cervical); N2: bilateral contiguous adenopathy; N3: bilateral contiguous and/or supravicular adenopathy (unilateral or bilateral); N4: distant adenopathy. M–-: absence of metastases; M+: presence of metastases (visceral, osseous, nervous, cutaneous). The remaining primary extranodal lesions (visceral, osseous, cutaneous, etc.) are classified as local, regional and diffuse. Systemic symptoms and signs (fatigue, fever, night sweats, more than 10% weight loss, itching, anemia, leukocytosis, lymphocytopenia, high erythrosedimentation rate) must be recorded in each case to evaluate prognosis and proper treatment but are not important for staging the disease. In all stages with primary lymph node lesions endolymphatic radiotherapy with Lipiodol F I131is indicated (10 ml in each foot with 2–5 mc/ml giving a tissue-dose of 15-20,000 rads). This is considered as radical as well as prophylactic treatment for those lymph nodes adequatelly filled with the contrast medium. In case of non filling or incomplete filling of part of the lymph node chains, treatment will be completed with external radiation therapy. Stage I and II are treated with radical radiation therapy. No prophylactic radiotherapy is given. If systemic symptoms and signs are still present after radiotherapy a course with anticancer drugs will be administered. Radiation therapy is given with high voltage or Co60units. In radical treatments tumor doses of at least 3,000 rads within 3–4 weeks are administered to all involved lymphatic regions. In stage III radical radiotherapy follows a course of 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. For primary pharyngeal lesions the primary focus (T1, T2, T3, T4) is always treated with radical radiation therapy (Co60unit) which includes in the whole Waldeyer's ring. Prophylactic radiotherapy (Co60unit with doses not less than 3,000 rads in 3–4 weeks) is given in N0to the ipsilateral and in N1to the contralateral submental and cervical lymphatic regions. In N1and N2the lymph node bearing areas are given radical radiation therapy. In N3are irradiated prophylactically also the contralateral submental, cervical and supraclavicular lymphatic regions if clinically free of disease. Endolymphatic radiotherapy is performed only in T1T2T3T4, N3N4, M–- or M+ cases; otherwise diagnostic lymphangiography is performed and when pathologic nodes are present or suspected they are irradiated with Co60. Chemotherapy is given after the course of radiotherapy in N2cases only if radical treatment has not been accomplished, while is always administered in combination with radical radiotherapy in N3cases, and is considered the treatment of choice with palliative radiation therapy in N4and M+ cases. The drug of choice is methyl-bis-(β-chloro-ethyl)-amine HCl (HN2) 0.4 mg/kg i.v. (single dose) for those patients who did not receive any previous course of chemotherapy. Otherwise, as well as during the course of the disease and in maintenance therapy, other polyfunctional alkylating agents, but chiefly chlorambucil (0.1–0.2 mg/kg/die, p. o.), vinblastine (0.10–0.15 mg/kg/week, i.v.), alone or every two weeks in combination with small daily doses of chlorambucil (5 mg/die, p. o.), methylhydrazine, hydroxyurea, and corticosteroids will be administered according to each clinical situation. Relapses in oropharynx can be treated with intraarterial infusions of amethopterine, vinblastine and cyclophosphamide. Radical surgery followed by a course of radiotherapy is reserved for primary lymphatic involvement only in specially selected patients in Stage I with unifocal lesions. Primary involvement of stomach, small bowel and colon is treated by surgical extirpation and radiotherapy. Splenectomy, lobectomy or pneumonectomy is indicated when these viscus are the only site of involvement. During pregnancy radiation therapy is not administered below the diaphragm and chemotherapy is not given during the first 4 months. The need for one internationally accepted clinical classification for lymphosarcoma and reticulum cell sarcoma is stressed.

A report of the results obtained in 194 cases of epithelial tumors of the oral cavity subjected to telecobalt therapy between June 1958 and December 1964 at the Institute of Radiology, University of Milan, and the Radiology Division of the National Cancer Institute. The criteria for establishing whether the treatment was indicated and the principles of selection of cases are specified. In the majority of cases the tumors were no longer circumscribed (T3-T4) and in over half the cases regional lymph node metastases were present when treatment commenced. Thirty-six patients had previously been subjected to radiotherapy or surgery. Telecobalt therapy was given almost exclusively to stationary fields using one or two portals of entry. Tumors of the floor of the mouth were often irradiated through wedges of lead. In 80% of the cases a tumor-dose of between 5000 and 6000 r was given over 6–8 weeks. At the end of treatment the tumor had completely disappeared in 22.7% of the patients, regressed to some extent in 40.6% and was unchanged or had deteriorated in 36.7%. The survival curves show that 2/3 of the patients died within two years of starting treatment; the five-year survival rate was 10.9%. This case-series confirmed that the prognosis is poorer in cases with regional lymph node metastases at the start of treatment and in patients subjected to telecobalt therapy for relapse after radiotherapy or surgery. The results obtained with telecobalt therapy proved to be considerably inferior to those obtained with curietherapy and so the latter is recommended in cancers of the oral cavity whenever it is feasible. Telecobalt therapy may be indicated, mainly as a symptomatic palliative, in very extensive infiltrating tumors adhering to the bone structures and in patients with inoperable lymph node metastases.

Some diazoacetyl derivatives of glycine known as antitumor and immunosuppressive agents have been found to be powerful mutagens of the base substitution type.

INVESTIGATIONS of the relationships between the anti-tussive activity and other pharmacological properties of many known drugs1led us to conclude that local anæsthetic effect was very important in order to predict the antitussive activity of new compounds, especially if this action is accompanied by other pharmacological effects such as the antispasmodic and antihistaminic ones. A systematic investigation was then carried out on new synthetic derivatives possessing local anæsthetic properties in different degrees. The compound N (2-benzoyloxy-methyl-2-phenylbutyl)-N,N dimethylamine (benzobut-amine)2was found to have the most interesting anti-tussive activity among a series of many other related compounds. Benzobutamine displays local anæsthetic properties and, at the same time, shows antispasmodic, anticonvulsant and antihistaminic effects. In this communication a description of the pharmacological properties of this drug is given.

MOST of the known antitussive agents also possess, in varying degree, other pharmacological properties, such as the analgesic, antihistaminic, local anaesthetic and spasmolytic ones (Silvestrini and Maffii1). These activities are often responsible for, or directly connected with, specific clinical side effects that may limit the effect. In particular, the antitussives that show analgesic effect produce depression of respiration and possibly tolerance, while antihistaminic antitussives often lead to drowsiness, and the local anaesthetic ones usually have a high toxicity.