Milan Cancer Institute Research Articles

Management of breast cancer after childhood cancer and Hodgkin’s lymphoma.

1566 Background: The risk of developing a secondary breast cancer (SBC) among women receiving chest radiotherapy (RT) for pediatric cancer and Hodgkin lymphomas (HL) is well established. The present study analyzes the clinical characteristics, pathology, management and prognosis of BC occurring after RT. Methods: From 1980 to 2010, 80 cases of SBC in a series of 76 survivors were diagnosed. These patients were treated from 1965 to 1992 with RT +/- chemotherapy for pediatric cancer or HL at Milan Cancer Institute. The histology, grading, nodal status, hormone receptor status, stage of the SBC, type of chemotherapy and surgery, disease free and overall survival were analyzed. Results: The median age at diagnosis of first neoplasms and of SBC was 18 and 38 years, respectively. The main histological features and the hormone receptor status paralleled the frequency observed in the case series of primary BC treated in the same Institution in the similar period of time. 67% of the tumors had ductal histology, 62% had positive estrogen receptor, 50% presented with pN0 and 68% with pT1 tumors. The incidence of bilateral synchronous SBC was 5%. In 59% of patients (41) adjuvant chemotherapy was administered, including antracyclines in 43% of this subgroup, followed by endocrine therapy in hormone positive receptor tumors only. Conservative surgery was feasible in 43 women (56%) and despite prior chest irradiation, subsequent breast RT was delivered in 33 of them. The five year disease free survival, overall and specific BC survival were 47%, 78% and 79%, respectively. Conclusions: Clinical characteristics, pathology and outcomes of SBC among this series of young women are similar to those observed in primary BC. Conservative surgery and repeat irradiation is also possible, without tissue necrosis. Despite previous therapies for their first malignancy, in a specialized institution patients with SBC can be managed in the same way as primary BC and carries similar chances of cure.

Artificial neural network for the joint modelling of discrete cause-specific hazards

Artificial neural network (ANN) based regression methods have been introduced for modelling censored survival data to account for complex prognostic patterns. In the framework of ANN extensions of generalized linear models for survival data, PLANN is a partial logistic ANN, suitable for smoothed discrete hazard estimation as a function of time and covariates. An extension of PLANN for competing risks analysis (PLANNCR) is now proposed for discrete or grouped survival times, resorting to the multinomial likelihood. PLANNCR is built by assigning input nodes to the explanatory variables with the time interval treated as an ordinal variable. The logistic function is used as activation for the hidden nodes of the network, whereas the softmax, which corresponds to the canonical link of generalized linear models for polytomous regression, is adopted for multiple output nodes, to provide a smoothed estimation of discrete conditional event probabilities for each event. The Kullback-Leibler distance is used as error function for the target vectors, amounting to half of the deviance of a multinomial logistic regression model. PLANNCR can jointly model non-linear, non-proportional and non-additive effects on cause-specific hazards (CSHs). The degree of smoothing is modulated by the number of hidden nodes and penalization of the error function (weight decay). Model optimisation is achieved by quasi-Newton algorithms, while non-linear cross-validation (NCV) and the Network Information Criterion (NIC) were adopted for model selection. PLANNCR was applied to data on 1793 women with primary invasive breast cancer, histologically N-, who underwent surgery at the Milan Cancer Institute between 1981 and 1986. Differential effects of covariates and time on the shape of the CSH for the three main failure causes, namely intra-breast tumor recurrences, distant metastases and contralateral breast cancer, have been enlightened. PLANNCR can be suitably adopted in an exploratory framework for a thorough evaluation of the disease dynamics in the presence of competing risks.

Conservative Treatment of Breast Cancer: Its Evolution

Over recent decades, breast carcinoma surgery has witnessed a considerable evolution. The extent of surgery undertaken has progressively reduced, leading to less disfigurement and a significant improvement in quality of life, thereby offering women considerable motivation to seek early diagnosis. From an oncological perspective, outcome was found to be equally effective, and this key observation provided us with significant impetus to investigate the effects of reducing the radiotherapy field. We present the achievements made so far in the conservative treatment of breast carcinoma, based on experiences at the European Institute of Oncology in Milan and, prior to 1994, at the Milan Cancer Institute. Conservative surgery of breast carcinoma, both in the breast and in the axillary nodes, has yielded very good results in terms of overall survival and impact on quality of life. The reduction of the radiation field, conducted in our Institute by means of electron intraoperative radiotherapy (ELIOT), is currently the subject of evaluation via a randomised trial.

Adjuvant chemotherapy for operable breast cancer: old vs new schema

In 1975 we presented our first report on the efficacy of cyclophosphamide, methotrexate and fluorouracil (CMF) as adjuvant treatment for node-positive breast cancer. Thirty years later, the results of this study demonstrate that the significant advantage in both relapse-free (reduction in relative risk for relapse of 29%) and overall survival (reduction in relative risk for death of 21%) persists over the years and that adjuvant CMF can exert a moderate but worthwhile suppression of micrometastases, regardless of anatomical sites [1]. With the aim of further improving the prognosis of operable breast cancer patients, in the early 1980s many research groups designed and carried out new randomized trials including anthracyclines. Despite the fact that many individual trials failed to observe a true benefit for the tested anthracycline regimen, the arithmetic construction on which the international overview is based (i.e. the summing up of many individual trials to increase the statistical power) allowed it to be estimated that there was a reduction in the risk for disease relapse and death of approximately 10%, corresponding to an absolute difference of approximately 3% [2]. At the Milan Cancer Institute we designed two different studies to test the effectiveness of sequential non-cross-resistant regimens containing anthracyclines. Briefly, in patients with moderate risk for relapse the sequential delivery of CMF followed by adriamycin was compared with CMF alone, whereas in a second study conducted in high-risk patient the inverse sequence (adriamycin followed by CMF) was tested. The rationale behind these studies was that switching to another regimen early in the administration of chemotherapy could overcome drug resistance. The updated 20-year results confirmed that the relative merits of anthracycline-containing adjuvant programs can also depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighted against potential risks [3]. The treatment results observed after sequential adriamycin followed by CMF in a poor risk subset could probably be explained by an increased density of the anthracycline, which was delivered at full dose within the first 9 weeks of treatment. The value of dose density was recently confirmed by the National Cancer Institute's Breast Intergroup INT C9741 trial, in which patients who received the dose-dense regimens had significantly improved early treatment outcome compared with their counterparts who did not receive these regimens. The role of sequential non-cross-resistant regimens was tested in many other trials, both in the adjuvant and neoadjuvant settings. Of note, the 3-year joint efficacy analysis of the National Epirubicin Adjuvant Trial (NEAT) and of the Scottish Cancer Trials Breast Group reported a highly significant benefit in favor of the sequential regimen, supporting the hypothesis that the sequential administration of single-agent anthracyclines given upfront before CMF can indeed improve treatment outcome. Also, the addition of taxanes after delivery of adriamycin and cyclophosphamide contributed to improving therapeutic results over the nontaxane regimen both in the adjuvant and neoadjuvant settings. By contrast, in the INT C9741 trial no difference was detected in treatment outcome between the concurrent or sequential schedules of adriamycin, cyclophosphamide and paclitaxel. Similarly, the MD Anderson randomized study failed to detect superiority of the sequential arm. Thirty years ago, treating patients who were free of identifiable metastatic disease with systemic adjuvant therapy because some of them might eventually develop distant disease was a revolutionary departure from prior treatment approaches [4]. It has been estimated that improvements since the 1970s in the way in which breast cancer is managed must have prevented about 25–30% of the breast cancer deaths in middle-aged women that would otherwise have occurred in the year 2000.

Survival in Hodgkin’s disease patients – Report of 25 years of experience at the Milan Cancer Institute

The aim of this study was to assess the long-term therapeutic outcome and risk of treatment-related complications in Hodgkin’s disease. From May 1973 to September 1990, four randomised studies have been activated at the Milan Cancer Institute using nitrogen mustard, vincristine, procarbazine and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimens, with or without irradiation, involving a total of 811 patients with intermediate and advanced Hodgkin’s disease. Overall, ABVD contributed to significantly reduce the relative risk of lymphoma progression and death compared with the MOPP regimen. With a prolonged follow-up, a total of 106 patients (75 of whom were in continuous complete remission after first-line chemotherapy) developed a variety of cancers, resulting in a total risk of 22.2%. Our 25 years of experience re-emphasises that ABVD can cure a high fraction of patients with Hodgkin’s disease. However, patients in continuous complete remission, are at a high risk of developing second cancers, especially when the treatment strategy includes extensive irradiation. The main focus of future trials should be on reducing treatment sequelae to improve the quality of life of long-term survivors.

A selective history of the therapy of Hodgkin's disease.

A selective history of the therapy of Hodgkin's disease.

Double-peaked time distribution of mortality for breast cancer patients undergoing mastectomy.

To gather information on the natural history of breast cancer from the time-distribution of deaths of patients undergoing mastectomy alone. A total of 1173 patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy without any adjuvant therapy for operable breast cancer, were examined. The risk of death at a given time after surgery was studied utilizing the death-specific hazard rate. The risk distribution was assessed relative to tumor size, axillary lymph node involvement, and menopausal status. The hazard rate for death presented an early peak at about the 3rd-4th year after surgery and a second late peak near the 8th year. The double-peaked pattern was almost completely generated by N+ patients, while N- patients did not show relevant structures. Pre-menopausal patients showed an initial mortality wave covering about 6 years, with maximum height at the 4th year, followed by a peak 8 years after surgery, while post-menopausal patients showed an early high mortality surge peaking at the 3rd year, followed by a modest increase at the 8th year. Detailed analysis revealed that post-menopausal patients with early mortality had significantly larger tumors and higher nodal involvement, while no special trait characterized the corresponding pre-menopausal patients. Moreover, patients of the late mortality peak were more likely to have suffered early local-regional or contra-lateral recurrence or to be pre-menopausal patients recurring anywhere at the second recurrence peak. The double-peaked hazard curve confirmed the occurrence of discontinuous features in the natural history of breast cancer for patients undergoing mastectomy. Indeed, the mortality pattern maintained definite signs of the previous double-peaked structure of recurrences. However, death events did not parallel the corresponding recurrence events and, moreover, pre and post-menopausal patients revealed dissimilar survival after recurrence, at least for early deaths. These findings, showing disconnection of mortality pattern from recurrence pattern for subsets of patients, suggest that parameters other than those influencing the recurrence risk may determine the survival of recurred patients.

Pain experienced by patients hospitalized at the National Cancer Institute of Milan: research project "towards a pain-free hospital".

According to the data of the literature, the prevalence of pain in cancer patients at various stages of the disease and the settings of care range from 38 to 51%, with an increase of up to 74% in the advanced and terminal stages. Despite published World Health Organization (WHO) guidelines for pain management, 42 to 51% of cancer patients receive inadequate analgesia and 30% receive no analgesics at all. A 3-year Research Project "Towards a Pain-free Hospital", which began one year ago, is ongoing at the National Cancer Institute of Milan. The research is organized in three subsequent steps. In the 1st one, a series of patient- and staff-oriented evaluation tools are used to assess the level of appropriateness of pain communication, assessment, management and control of the in-patients. The 2nd step will implement a number of continuing educational interventions aimed at improving patient awareness and staff knowledge of the appropriate pain assessment and management in order to respond to the patient's pain problem. In the 3rd step, all the assessment tools used in step one will be applied again to establish the prevalence of pain, the causes and intensity and patient satisfaction with pain management and to evaluate the impact of the interventions performed during the 2nd step regarding the overall ability of our hospital to tackle pain emergency in the hospitalized cancer population. The results relative to the 1st step are herein reported, in particular as regards the study on prevalence, causes, severity of pain, the interference of pain with sleep, mood and concentration, the use of pain medications and the relief obtained, the structural validity and internal consistency of the assessment tool used. A total of 258 patients hospitalized for at least 24 h were interviewed by 9 physicians using a brief structured questionnaire prepared ad hoc: 51.5% of the patients presented pain during the previous 24 h caused by surgery (49.6%) or by the tumor mass itself (29.3%). Out of the 133 patients with pain, a high degree (much or very much) of pain at rest was present in 27.1% and pain on movement in 30.8%; 31.6% did not take any analgesic treatment, and 14.3% of the latter reported a high degree of pain at rest and 21.4% on movement. Pain interfered with sleep from much to very much in 28.8% and with irritability and nervousness in 15.9% of the patients. In the 91 patients taking analgesics, 57.2% reported a high degree of pain relief. A high degree of pain and interference, however, was associated with low relief levels. The assessment tool used was shown to have a good structural validity and internal consistency (Chrombach alpha index of interference scale = 0.73). Although the Milan Cancer Institute has the longest tradition in Italy of pain assessment by means of validated tools and pain management according to the WHO guidelines and educational efforts in this field, the results of the study clearly show that it is necessary to persevere with continuing educational and informative programs in order to reduce the frequency and severity of pain and thus improve the quality of life of in-patients.

Elevated pretreatment serum levels of Il-10 are associated with a poor prognosis in Hodgkin's disease, the milan cancer institute experience.

Alterated cytokine secretion may play a role in determining Hodgkin's disease-related immunosuppression. The aim of this study was to analyze the clinical significance of interleukin-10 (IL-10) serum levels in 73 chemotherapy-naive patients with Hodgkin's disease. We evaluated the relationship between pretreatment circulating values of IL-10 and both the clinical characteristics of the disease as well as the prognosis in terms of freedom from progression and overall survival. Abnormally high pre-treatment serum levels (mean+/-standard error: 26.79+/-13.24 pg/ml) were detected in 33/73 (45%) patients. The percentage of patients with enhanced IL-10 secretion was significantly higher in the presence of advanced disease (56% vs 32%, P<0.03), systemic symptoms (57% vs 34%, P<0.04) and more than 3 involved sites (61% vs 36%, P<0.03). The high basal levels of IL-10 negatively influenced long-term results: at 8-years freedom from progression (FFP) and overall survival (OS) for patients with IL-10>6 pg/ml vs</=6 pg/ml were 69% and 76% vs 97. 5% and 95%, respectively. The multivariate analysis confirmed the prognostic value of IL-10 basal serum levels (FFP, P=0.0001; OS, P=0. 06). Our study suggests that high pre-treatment circulating levels of IL-10 are associated with a poor prognosis, irrespective of other common prognostic variables.

Anterior craniofacial resection for malignant ethmoid tumors--a series of 91 patients.

Anterior craniofacial resection is now recognized as the best treatment for ethmoid tumors involving the cribriform plate with or without invasion of anterior cranial fossa. Ninety-one patients underwent an anterior craniofacial resection for ethmoid malignant tumors at the Milan Cancer Institute between 1987 and 1994. The patient population was divided into two sections (30 and 61 patients) based upon some important variants (type of craniotomy, antibiotic treatment, postoperative care). The mean age was 53.4 years (range, 24 to 78 years). There were 62 men and 29 women. Forty-nine patients had a recurrence after previous treatments (surgery and/or radiotherapy). The subdivision by histology was as follows: 50 cases of adenocarcinoma, 16 cases of epidermoid and undifferentiated carcinoma, 8 cases of esthesioneuroblastoma, 5 cases of adenoid cystic carcinoma, 5 cases of melanoma, and 6 rare tumors. The stages (according to our new staging) were as follows: 37 cases with T2, 27 cases with T3, and 27 cases with T4. The mean follow-up was 47 months. Seven patients died after surgery (6 in the first series). The survival at 3 and 5 years was, respectively, 52% and 47%, and the disease-free survival (DFS) was 30% and 24%, with a statistically significant difference at multivariate analysis in favor of patients without prior treatment (p = .033) or T2 versus T3 and T4 (p<.007). An anterior craniofacial resection should be performed in cases of ethmoid tumors reaching or eroding the cribriform plate. A scrupulous intra- and postoperative approach is necessary to avoid severe complications. The patients often survive for a long time with recurrence ongoing. Our new staging identifies the critical extensions of ethmoid tumors.

Current and future trends in the multidisciplinary approach for high-risk breast cancer. The experience of the milan cancer institute

Current and future trends in the multidisciplinary approach for high-risk breast cancer. The experience of the milan cancer institute

985 Breast cancer chemoprevention with retinoids and tamoxifen

In March 1987, a breast cancer chemoprevention study with Fenretinide (4-HPR) started at the Milan Cancer Institute with the aim of evaluating the effectiveness of this retinoid in reducing the incidence of contralateral breast primaries in breast cancer patients. Subjects take 4-HPR at the daily dose of 200mg for 5 years vs no treatment. Accrual is closed with 2,972 randomized patients. No difference is shown at present between the two groups but some preliminary data seem to suggest that the agent might be effective in inhibiting the growth of hormone independent tumours. Other aims are to contribute to a better understanding of the pharmacokinetics and mechanisms of action of this drug, as well as to determine its effectiveness in prevention or protection of women against ovarian cancer. Another breast cancer chemoprevention trial using Tamoxifen (TAM) began in September 1992 from an original idea of U. Veronesi and C. Maltoni. Presently, more than 3,500 hysterectomized women aged 35–70 are participating in the study. According to a double blind design, the subjects take either 20mg/day of TAM or placebo for 5 years. The decision to include only hysterectomized women was made to avoid the unjustified risk of endometrial cancer in those taking TAM. The study involves 43 Italian centres and 3 associated centres in South America. The Data Centre and the National Coordinating Centre are in Milan, at the European Institute of Oncology. Most randomized patients (89%) are between 45 and 65 years of age (median age: 51); 56% have had minor side effects (mainly menopausal symptoms).

Combined Modality Approach for High-Risk Breast Cancer: The Milan Cancer Institute Experience

After 20 years of successive clinical trials, the results achieved at the Milan Cancer Institute have helped to establish the effectiveness of adjuvant combination chemotherapy in high-risk women with resectable breast cancer. The most significant findings can be summarized as follows: (1) the clinical benefit in terms of relapse-free and total survival can be prolonged up to 20 years from surgery; (2) the use of anthracyclines (doxorubicin) can contribute to improved treatment outcome; (3) dose intensity and dose size are the leading prognostic variables; and (4) adjuvant treatments are not associated with important iatrogenic morbidity. New modalities that could profoundly change current treatment strategies will involve high-dose sequential chemotherapy and primary chemotherapy. In fact, the use of rhG-CSF-elicited hematopoietic progenitors will grant a substantial reduction in granulocytopenia and related toxicities; this, in turn, will permit the administration of regimens based on high dose size and dose intensity. As far as primary chemotherapy is concerned, the shift from mutilating to breast-conserving operations has led to important advantages in a society concerned for body integrity. In the few studies with sufficient follow-up, objective tumor response to primary chemotherapy has been translated into superior relapse-free survival compared with that of nonresponders. In particular, from the first Milan study the knowledge is clearly emerging that the response rate is inversely related to the initial tumor volume and that the degree of tumor regression (complete pathologic remission versus moderate versus minimal response) appears to represent a marker of outcome. Should this crucial observation be confirmed in other ongoing trials, then the amount of tumor shrinkage could rank among the most important prognostic variables because it is reproducible and inexpensive. As a consequence, the achievement of complete (or near complete) pathologic remission will become the major goal of properly intensified drug regimens to ensure a durable relapse-free survival rate. To make legitimate the wide adoption of the strategy involving primary chemotherapy, most breast cancer specialists correctly advocate that the initial promising results be validated through classic randomized trials. The question to answer appears simple: Will preoperative chemotherapy be superior to postoperative chemotherapy in terms of relapse-free and total survival? In our opinion, the simple attempt to shift from postoperative (adjuvant) to preoperative (primary) chemotherapy may not be enough, although formally correct, to maximize treatment outcome, and thus become the new strategy of choice.(ABSTRACT TRUNCATED AT 250 WORDS)

Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events.

Local disease recurrences are a concern in conservative breast cancer surgery, and many studies have attempted to identify risk factors for these events. It is important to distinguish local recurrences linked to increased risk of distant spread from those due to inadequate local treatment. We evaluated the incidence of local and distant recurrences according to demographic, biological, and pathologic variables in a large series of women who were conservatively and uniformly treated for breast cancer, with the aim of identifying women in whom local failure is predictive for distant metastases and who are therefore candidates for aggressive systemic treatment. Medical records of 2233 women who had been hospitalized at the Milan Cancer Institute from 1970 to 1987 were analyzed. All women received quadrantectomy and axillary lymph node dissection followed by radiotherapy for the breast. Quadrantectomy is breast-conserving removal of most of the affected quadrant by a radial incision that includes part of the skin. The end points considered were local failures (including local recurrences and new ipsilateral carcinomas) and distant metastases. Statistical analysis employed the competing risks and multiple failures approaches. There were 119 local recurrences, 32 new ipsilateral carcinomas, and 414 distant metastases as first events. The timing of local failures and distant metastases differed: The yearly probability for local failures was approximately 1% up to the 10th year and for distant metastases was 5% in the 2nd year and decreased progressively until the 8th year. Young age was an important risk factor, with peritumoral lymphatic invasion also predictive for local and distant recurrences. Tumor size and axillary lymph node involvement were not related to local recurrence but were important predictors of distant metastases. Extensive intraductal component was only a risk factor for local recurrence. Early (< 2 years) local failure predicted for distant metastases compared with later failure. In local failure patients, the 5-year survival rate was 69% from failure. Local recurrences and distant metastases are partially independent events that occur at different times; several predicting factors also differ. However, women with local recurrences have increased risk of distant metastases. In particular, women 35 years old or younger at first diagnosis who had initial peritumoral lymphatic invasion and local recurrence within 2 years are at high risk for distant spread. For recurrence in cases with an extensive intraductal component or where initial local surgery was possibly inadequate, women are at lower risk.

How Should We Manage Breast Cancer in the Breast, or Buddy, Can You Paradigm?

It is easy to define the goals of the best locoregional therapyfor women with invasive or noninvasive breast cancer. Thesegoals are quite obviously the best survival, the least disfigure-ment, and the least likelihood of significant systemic toxicity.What is not so easy to define are the optimal ways of achievingany one of these three goals without compromising any of theothers. The good news is that, within the past decade, a varietyof paradigm-shifting clinical trials have been completed thatprovide a significantly higher degree of confidence in the ef-ficacy of some of the choices that we offer our patients. In part,this improved situation is based on an awareness that theachievement of each of these three goals is more independentthan was previously thought. Unfortunately, not everyone ac-cepts this as proven, given the fact that most invasive breastcancers in the United States are still managed by mastectomy.Nearly a century ago, the Halstedian view of breast cancer(and, in fact, most malignancies) held that their growth was ex-pansile and that dissemination occurred through locally acces-sible lymphatic channels. A direct corollary of this belief wasthat a large enough extirpative circle drawn around the tumorwould totally remove it and the patient. This biologicalconcept, combined with a far more advanced presentation ofmost breast cancers common years ago, achieved local controlat the expense of very substantial disfigurement. Equally un-deniably, many women treated in this way, albeit a minority inaggregate, survived for decades to die of other unrelated causes.The development by Fisher et al. (/) of the notion that thepredominant lethality of breast cancer was due to systemichematogenous spread, which had generally occurred prior tolocal therapy, gave rise to the idea that local management mightnot have a very significant impact on survival. A series of ran-domized trials involving even less surgical treatment of thebreast, with or without additional radiation therapy, have tendedto support this notion; virtually all trials showed no decrementin survival associated with surgery that was limited first to thebreast alone and later to the tumor and immediately surroundingtissue (I-6). What is also clear is that the removal of increasing-ly less breast tissue and the omission of radiation therapy alllead to increasing rates of local treatment failure within thebreast. For example, in the National Surgical Adjuvant Breastand Bowel Project (NSABP) B-06 protocol (/), patients whoreceived radiation therapy following lumpectomy had more thana threefold reduction in breast recurrences. Similarly, the MilanCancer Institute trial (7), which compared quadrantectomy withtumorectomy, showed that the more extensive local surgeryresulted in more than a threefold reduction in breast recurrencesat the expense of greater disfigurement. On the basis of theseand other studies, it is obvious that both increasing the extent oflocal breast surgery and adding adjuvant radiation therapy to thebreast can more effectively cure breast cancer. Clearly, cureof breast cancer does not guarantee avoidance of systemicmetastases and eventual death from breast cancer. On the otherhand, it is certain that adequate local treatment of some breastcancers does result in the of patients who would otherwiseeventually become incurable if left untreated. These argumentsare well summarized in the current American Society of ClinicalOncology Kamofsky Memorial Lecture delivered by Hellman(8). Among many data that could be cited, the unequivocal im-provement in survival produced by screening mammography es-tablishes the fact that some breast cancers behave as localizeddiseases and if left alone long enough (the unscreened popula-tion) will have systemic recurrences (9).The most important question, however, is whether or not anysubset of patients in whom viable invasive or noninvasive breastcancer cells are retained in the breast following incomplete localtherapy develop disseminated disease as a result of the failure toremove them. This issue is probably the single, most importantscientific argument given for mastectomy following a diagnosisof noninvasive duct cell carcinoma of the breast. The articlefrom the Milan Cancer Institute, appearing in this issue of theJournal (10), attempts to address this question. More than 2000women sequentially treated with quadrantectomy and radiationtherapy were assessed for either local or distant treatmentfailure; the prognostic variables predicting either and time totreatment failure were presented. These authors, as well asothers (11-15), noted that some prognostic variables, such as ageunder 40 years and local lymphatic permeation, predicted forboth local treatment failure and distant disease. Other variables,

Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer

Only a few studies have evaluated the long-term effects of adjuvant chemotherapy for breast cancer. Furthermore, neither the relation between the risk of second malignancies and type of adjuvant regimen utilized nor the interaction between chemotherapy and breast irradiation or age of the patients have been described in detail. A total of 2,465 patients entered into prospective studies of CMF-based adjuvant chemotherapy carried out at the Milan Cancer Institute between June 1973 and July 1990 were evaluated. The median follow-up was 12.0 years and detailed information about therapy was available for all patients. At 15 years, the cumulative actuarial risk of second malignancies (excluding contralateral breast cancer and basal skin cancer) was 6.7% +/- 0.8% for the total series. The figures were 8.4% +/- 2.9% after local-regional treatment alone, 6.4% +/- 0.9% following CMF, and 5.1% +/- 1.0% following CMF plus Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy). Compared to the general female population, the relative risk following CMF-based adjuvant chemotherapy was 1.29. Three patients, all of whom had received CMF-based chemotherapy, developed acute non-lymphocytic leukemia (cumulative risk 0.23% +/- 0.15%; relative risk 2.3). No differences were evident when breast irradiation was considered, but the cumulative risk of second tumors was slightly higher in women aged > or = 50 years at surgery (7.7% +/- 1.3%) than in younger patients (6.0% +/- 1.0%). At present, there is no evidence of a significantly increased risk of second malignancies following adjuvant CMF-based chemotherapy such as the one given in this case series. A low risk of acute leukemia was associated with the cumulative total dose of cyclophosphamide administered, and breast irradiation did not enhance this risk. Our findings suggest that there is no reason to omit alkylating agents from short-term effective adjuvant chemotherapy.

Radiation therapy for breast cancer

Prospective randomized studies continue to dominate issues of local regional radiation therapy for breast cancer. The National Surgical Adjuvant Breast and Bowel Project, designed to assess the role of radiation therapy in the management of breast-conserving surgery for duct carcinoma in situ, has published preliminary results. These results indicate that the use of radiation therapy decreases the local recurrence rate in women with this disease, with a short median follow-up for the entire group so far. The Milan Cancer Institute likewise first reported on their trial assessing the role of radiation therapy in early invasive breast cancer, following a quadrantectomy procedure in the breast as well as an axillary node dissection. Again, radiation therapy significantly decreased the local recurrence rate in the treated breast compared with observation alone. Several important retrospective analyses continue to search for prognostic indicators that might effect the outcome of patients treated with breast-conserving surgery and irradiation. The issue of early age, as well as the issue of sequencing needed adjuvant chemotherapy with whole-breast irradiation was the subject of several articles. Other researchers focused on methods of detection of failure in the irradiated breast, including several innovative studies using magnetic resonance imaging. Documentation of radiation-related treatment sequelae is also reviewed, along with a retrospective study assessing the palliative role of strontium-89 isotope treatment of women with widespread metastatic bone lesions.

Combined modality treatment for primary gastrointestinal non-Hodgkin's lymphoma: The Milan Cancer Institute Experience

The study analyzes clinical-pathologic features, treatment and outcome of all patients with primary lymphoma of the gastrointestinal tract (GI-NHL) seen during the past two decades at the Milan Cancer Institute. Clinical and histopathological data from 135 patients presenting with GI-NHL and disease localized within the abdomen were reviewed. Of these, 114 (84%) presented with limited disease (stage I and II), while 21 patients were found to have disease involvement of other abdominal organs (i.e., liver, pancreas, peritoneum) or more than one gastrointestinal site and were therefore classified as stage IV. Seventy-three percent presented with lymphoma in the stomach, 15% in the small intestine and 9% in the large bowel, while in 5 cases multiple localizations of the gastrointestinal tract were documented. Median age was 50 years, with one-fourth of patients older than 60 years. According to the revised Kiel classification for GI-NHL, 61% of patients presented with pure high-grade lymphoma, 9% high-grade NHL associated with residual low-grade lymphoma, and 30% had low-grade NHL. Nine percent presented with bulky disease, 5% with elevated LDH and 21% with a Karnofsky performance status (PS) < or = 80. Laparotomy with radical (108 patients) or palliative (15 patients) intent was performed in all patients who were not deemed at high risk of complication from major surgery. Complete removal of all measurable tumor was feasible in 101 patients, with no difference relative to primary site. Surgical morbidity and mortality were 11% and 2%, respectively. Overall, 83% of patients were treated with chemotherapy. Patients who did not receive systemic chemotherapy included 12 managed with surgery alone and 10 who received only postoperative irradiation mainly because of low-grade lymphoma with superficial disease. Of patients with limited disease, 99% achieved complete tumor remission. After a median follow-up of 73 months, 13 of 113 patients have relapsed, mostly (70%) outside the gastrointestinal tract. The actuarial 10-yr. freedom from progression (FFP) and overall survival (OS) were 84% and 86%, respectively. Aside from age, no other factor revealed a statistically significant impact on outcome. There was only a trend in favor of low-grade histology (FFP 97% vs. 79%), that failed to reach statistical significance. Of patients with advanced abdominal disease, 48% achieved complete remission with chemotherapy with or without prior surgical debulking. Actuarial 10-yr. FFP and OS were 44% and 42%, respectively. In this subset, tumor burden and LDH levels represented the most important prognostic factors affecting outcome. This retrospective study underscores the good results obtained in a wide and unselected population of patients with limited-stage primary GI-NHL following a combined-modality approach that included surgical debulking and systemic chemotherapy for most patients. Surgery alone can be considered adequate treatment for patients with low-grade NHL disease that does not infiltrate beyond the submucosa. Patients with advanced GI-NHL show a long-term outcome similar to that of patients with advanced NHL arising outside the gastrointestinal tract.

Radiation therapy for breast cancer.

Local regional control, despite its lack of impact on survival, continues to be recognized as an important end point in and of itself. In addition to recent updates on conservation studies demonstrating this dichotomy, local regional radiation is now playing an important role in the management of advanced breast cancer postmastectomy. The most extreme example of this importance is its inclusion in autologous bone marrow transplantation programs. Documentation of the long-term outcome of breast or chest wall radiation, in terms of both complications and treatment failures, appears increasingly in this year's literature. With sophisticated biostatistical analysis of all factors predicting for both local failure and late complications, patient selection for these treatments should become easier for both the woman and her physician.

From adjuvant to neo‐adjuvant chemotherapy in high‐risk breast cancer: The experience of the Milan Cancer Institute. Steiner award lecture 1992

From adjuvant to neo‐adjuvant chemotherapy in high‐risk breast cancer: The experience of the Milan Cancer Institute. Steiner award lecture 1992