U. Veronesi

Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients

Breast conservation has become well-established in the treatment of early mammary carcinoma. However, a standardised treatment modality has not emerged. We have analysed the data from 1,973 patients treated in three consecutive randomised trials by four different radiosurgical procedures: Halsted mastectomy, quadrantectomy plus radiotherapy, lumpectomy plus radiotherapy, and quadrantectomy without radiotherapy, to compare the outcomes of these procedures in terms of local recurrence rate and overall survival. Eligibility criteria were similar in the three trials, and comparability between the four subgroups was excellent. Median follow-up for all patients was 82 months. The annual rates of local recurrence varied markedly according to the treatment. Patients treated with Halsted mastectomy and quadrantectomy plus radiotherapy had low annual rates of local recurrence (0.20 and 0.46, respectively) while both lumpectomy plus radiotherapy and quadrantectomy without radiotherapy had significantly higher rates (2.45 and 3.28, respectively). Patients under 45 years of age had a much higher incidence of local recurrences, while in women over 55 years local recurrences were much less frequent. Overall survival curves were identical in the four groups of patients, so that the three breast conserving radiosurgical procedures had the same survival rates as Halsted mastectomy. However, local recurrence rates were markedly influenced by the treatment method, patient age and specific histological features.

Sentinel lymph node biopsy as an indicator for axillary dissection in early breast cancer

Sentinel node biopsy (SNB) is a new component of the surgical treatment of breast cancer that accurately predicts axillary status. Although the procedure is still mainly investigational, many patients are requesting SNB to avoid axillary dissection if the sentinel node (SN) is negative. From March 1996 to December 1999, 373 patients with breast carcinoma and clinically negative axillary nodes underwent breast surgery, mainly conservative, and SNB. If the SN was histologically uninvolved no further surgical treatment was given. All patients were informed in detail and signed a consent form. SNB involved injection of labelled albumin particles close to the primary tumour, lymphoscintigraphy and location of the sentinel node with a gamma probe during surgery. 379 SNBs were performed on 373 patients (6 were bilateral). In 94, the SN was positive and complete axillary dissection was performed. In 285 cases (280 patients) the SN was negative and no dissection was performed: these were carefully followed with quarterly clinical examination of the axilla. A total of 343 years at risk were available for evaluation from which seven cases of axillary metastases were expected. No cases of clinically evident axillary node metastasis have occurred. These findings provide further confirmation of the validity of SNB and prompt us to suggest that it should become the method of choice for axillary staging in small-sized breast cancer.

Intraoperative radiation therapy with electrons (ELIOT) in early-stage breast cancer.

Local recurrences after breast-conserving surgery occur mostly in the quadrant harbouring primary carcinoma. The main objective of postoperative radiotherapy should be the sterilisation of residual cancer cells in the operative area while irradiation of the whole breast may be avoided. We have developed a new technique of intraoperative radiotherapy of a breast quadrant after the removal of the primary carcinoma (ELIOT). A mobile linear accelerator with a robotic arm is utilised delivering electron beams able to produce energies from 3 to 9 MeV. Different dose levels were tested from 10 to 21 Gy without important side effects. A randomized trial is currently ongoing in order to compare conventional irradiation and ELIOT. More than 400 patients have been enrolled. In addition a new approach for nipple and areola complex conservation, including ELIOT, is under investigation.

Mammographic patterns in breast cancer chemoprevention with fenretinide (4-HPR)

In 1987 a chemoprevention trial was started at the Istituto Nazionale Tumori of Milan to evaluate the efficacy of fenretinide or 4-HPR (an effective agent against carcinogen-induced epithelial tumours in experimental animals) in reducing the incidence of contralateral breast cancer in women previously treated for an early breast cancer (pT1, pT2, N-). Patients were randomised into two groups: 4-HPR 200 mg/day vs. no treatment. We reviewed the mammograms of 149 patients who received 4-HPR for at least 4 years to examine whether changes seen in the mammary glands of rats could also be seen in women. For each patient, at least five mammograms (one at baseline and four annual controls) of the contralateral breast were classified according to Wolfes parenchymal patterns (N1, P1, P2, DY). With the daily dosage of 200 mg and after follow-up, no changes in mammographic patterns were observed.

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.

Clinical Staging and Treatment of Lymphosarcoma and Reticulum Cell Sarcoma.

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 Hodgkins 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 I131 is 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 Co60 units. 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 (Co60 unit) which includes in the whole Waldeyers ring. Prophylactic radiotherapy (Co60 unit with doses not less than 3,000 rads in 3–4 weeks) is given in N0 to the ipsilateral and in N1 to the contralateral submental and cervical lymphatic regions. In N1 and N2 the lymph node bearing areas are given radical radiation therapy. In N3 are irradiated prophylactically also the contralateral submental, cervical and supraclavicular lymphatic regions if clinically free of disease. Endolymphatic radiotherapy is performed only in T1 T2 T3 T4, N3 N4, 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 N2 cases only if radical treatment has not been accomplished, while is always administered in combination with radical radiotherapy in N3 cases, and is considered the treatment of choice with palliative radiation therapy in N4 and 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.

Oncoplastic and reconstructive breast surgery

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Results of Chemotherapy in Breast Cancer. Study Group for Therapy of Breast Cancer, Cancer Chemotherapy Committee, Italian Society of Cancerology

A summary of the results obtained by the Italian Breast Cancer Group in 122 patients with advanced breast cancer randomized over four different treatments: testosterone propionate, given i.m. 3 times a week at the dose of 100 mg per injection; cyclophosphamide, administered i.m. 25 times a month at the dose of 100 mg/day; testosterone + cyclophosphamide i.m. at the above doses; HMNT (4-hydroxy-17 methyl-19-nortestosterone) given i.m. 3 times a week at the dose of 100 mg/day. The criteria for patient selection and methods of evaluation were, with some modifications, these used by the American Breast Cancer Group. Objective improvements were observed in 26.9% of patients treated with testosterone propionate, in 15.6% of patients treated with cyclophosphamide, in 23.5% of those treated with testosterone + cyclophosphamide and in 20% of patients treated with HMNT. The most interesting result, worth of further evaluation, is that observed with the combined testosterone + cyclophosphamide therapy, which yielded the highest number of objective improvements in patients in menopause for less than one year.

Thyroid function in patients with cancer of the breast

In 47 patients with operable cancer of the breast the thyroid activity has been studied with the following tests: a) radioactive iodine uptake, 3 and 24 hours after the administration of 50 μc of I131; b) conversion rate; c) hormonal index, i. e. the quantity of protein bound radioiodine in 1 liter of plasma, evaluated as a percentage of the administered dose. The thyroid function was studied immediately before Halstead operation as well as one, three, and twelve months later. From the data obtained it appears that a) breast cancer patients show a thyroid radioiodine uptake higher than the controls, either at the 3rd or at the 24th hour, b) after the removal of the breast, the uptake decreases, reaching normal values 12 months after the operation, c) the conversion rate does not show any difference from the controls either before or after the operation, d) the hormonal index is considerably higher than normal values before operation, and in spite of a lowering after radical mastectomy, it is still higher one year later. The data seem to show that breast cancer patients have a higher metabolic activity of the thyroid gland, without clinical signs of hyperthyroidism. After removal of the carcerous breast the thyroid activity slowly decreases. However, the conversion rate is not modified as compared to the control patients. Further confirmation of the present preliminary results should be obtained by a comparative evaluation of the results either in patients with other types of tumors, or in patients subjected to surgical procedures for non-tumorous lesions.

Local Recurrence and New Primary Ipsilateral Carcinomas After Conservative Treatment of Breast Carcinoma

One of the greatest concerns in conservative treatment of breast cancer is the increased risk of local recurrence of the disease. In fact, local recurrence not only represents treatment failure and creates serious psychological distress to the patient [4], but ultimately leads, in most cases, to mastectomy, defeating the object of the original project, i.e., avoidance of mutilation. Moreover, it is not unlikely that an increased rate of local recurrence may negatively influence survival and obscure the prognosis [2]. For all these reasons, it appears that the avoidance of local recurrence must be regarded as a major objective in breast-conservation programs.