Istituto Nazionale Tumori Research Articles

MRI in the Early Detection of Breast Cancer in Women with High Genetic Risk

Women with BRCA1 or BRCA2 germline mutations have an elevated risk of developing breast and/or ovarian cancer. Because of the early onset of the disease, screening of this group of women should start at an earlier age than in the general population. The association of breast magnetic resonance imaging (BMRI) and ultrasonography (US) with mammography (MX) and clinical breast examination (CBE) in the regular surveillance of these individuals has been proposed and seems to improve the early detection of breast cancer. Within a multicenter study started by the Istituto Superiore di Sanità (Rome), at the Istituto Nazionale Tumori of Milan (INT) we enrolled 116 women at high genetic risk for breast cancer; they were either BRCA1 or BRCA2 mutation carriers or had a strong family history of breast cancer. They underwent CBE, MX, US and BMRI once a year. Between June 2000 and April 2005, at INT 12 cancers were detected among the 116 screened individuals (10%). In this subgroup, 1 patient refused BMRI and in 2 cases US was not performed. With BMRI we found 11 cancers and 6 of them were detectable only by this technique. In these 6 cases, the size of the disease was less than 1 cm and MX was false negative due to irregularly nodular parenchyma in 4 cases and scar tissue or prosthesis in the other 2. US was not performed in 2 cases and was false negative in 4 cases. Three false positive results were found with BMRI: 1 case was considered suspect but related to hormonal influences; 1 case with the same pattern was sent for second-look US, which gave a negative result and BMRI review after 6 months showed normalization of the parenchyma; in the third case histology revealed the presence of adenosis. No false positive results were registered for MX. The aim of secondary prevention is the detection of cancer at its earliest stage. BMRI screening in women with BRCA1 or BRCA2 mutations or at high familiar risk appears to be highly sensitive and may detect mammographically occult disease. The accuracy of MR imaging is higher than that of conventional imaging but the technique is flawed by a lower specificity. In order to avoid unnecessary biopsies we believe that the combination of BMRI and conventional imaging can be very useful in screening women with a high genetic risk of breast cancer, especially with second-look evaluation by means of US when BMRI yields the only positive diagnostic result. Second-look US has been demonstrated to be of critical importance both in recognizing false positive BMRI results and in guiding biopsies, when necessary.

Refining the postmenopausal breast cancer treatment paradigm: the FACE trial

It is clear that letrozole and anastrozole provide significant benefits for patients with breast cancer. However, possible differences in efficacy have been suggested by varying degrees of aromatase inhibition and effectiveness in the neoadjuvant and first-line settings. Analyses of aromatase inhibitor-treated patient subgroups within the Arimidex, Tamoxifen, Alone or in Combination trial and Breast International Group 1–98 trial, and the National Cancer Institute of Canada Clinical Trials Group’s MA.17 study, have also suggested some differences in efficacy. The question is how best to maximize these differences to benefit specific patient subgroups, such as postmenopausal women with node-positive disease. Nodal status is one of the strongest prognostic factors for breast cancer recurrence and several studies have shown that patients with node-positive disease are at higher risk for early relapse. It is thought that patients at increased risk for early relapse may be better treated with an aromatase inhibitor upfront, but the guidelines are unclear as to which aromatase inhibitor should be used. To answer this important question quickly, the Femara Anastrozole Clinical Evaluation (FACE) trial is recruiting node-positive patients and randomizing them to receive either early adjuvant letrozole or early adjuvant anastrozole. The trial has been designed to differentiate between the two drugs in the shortest possible time frame by using patients at increased risk of early recurrence of breast cancer, so that the required number of events to initiate analysis will be obtained more quickly. In total, 4000 patients who have recently undergone surgery for node-positive primary breast cancer (and who have no clinical or radiological evidence of recurrent disease or metastasis) are being enrolled around the world. The FACE trial will not only provide an efficacy evaluation between these two aromatase inhibitors but also provide a valuable head-to-head comparison of the safety profiles of adjuvant letrozole and anastrozole. The data will be transferred to an independent academic organization, the Istituto Nazionale Tumori (Michelangelo Foundation, Milan, Italy), which will verify and analyze the data, removing any perception of bias. An Independent Data Monitoring Committee will then decide when and how the trial data are to be released. The results are expected to further refine the treatment paradigm for breast cancer in postmenopausal patients with node-positive disease.

Colorectal carcinoma in children: The experience of the Istituto Nazionale Tumori of Milan, Italy

Colorectal carcinoma in children: The experience of the Istituto Nazionale Tumori of Milan, Italy

Extremity soft tissue sarcoma: The need for a differential surgical approach to primary tumor and local recurrence?

9565 Background: To explore the prognostic implications of local recurrence in extremity adult soft tissue sarcoma (eSTS). Methods: From January 1983 to December 2002, 1,017 patients with localized eSTS were treated at Istituto Nazionale Tumori, Milan, Italy. First local recurrence, re-operated with a curative intent, was investigated as a predictor of further recurrence, distant metastasis and cause specific mortality. Such a task was carried out considering recurrent patients earlier operated for primary disease at our institution (Group A, N=88) or elsewhere (Group B, N=150). The follow up of the above patients after recurrence was compared to that of the overall group of 738 patients operated for primary disease at our institution. Analyses were performed by multiple Cox models, in which local recurrence was entered as a time dependent factor, and tumour size, depth, histotype, grade, margins, RT and CT as covariates for the purpose of adjustment. Event-times were computed from the date of diagnosis, with “left censoring” on the time when patients entered our cohort (date of surgery). Results: The hazard ratio estimates of second recurrence, distant metastases and disease-specific mortality in groups A and B were 5.39 vs 2.95 (p<0.001), 3.96 vs 1.54 (p<0.001), and 2.93 vs 1.43 (p<0.001), respectively. The prognostic effect of the covariates on mortality turned out to be not significantly affected by disease local relapse, but a trend for surgical margins in group A could be observed (HR 1.71). Conclusions: Local recurrence correlates with a worse prognosis, in terms of further local recurrence, distant metastases, and death. Such an effect is stronger following surgery at a referral center for eSTS if compared to local recurrence following surgery done elsewhere, i.e. at institutions less likely to perform adequate local treatment for this rare group of tumors. Possibly, this means that “true” local recurrences, not simply due to inappropriateness, single out pts carrying an inherently more aggressive disease. Consistently, these data cannot confirm, but neither rule out that more aggressive surgery (ie, at the cost of a higher amputation rate, in order to avoid contaminated surgical margins) may be needed in pts locally recurring after initial adequate surgery. No significant financial relationships to disclose.

Patterns of tumor response to trabectedin (ET743) in myxoid liposarcomas

9511 Background: Trabectedin (T) is a marine-derived agent found to be active in ovarian cancer and sarcomas. Among sarcomas, activity has been notable in leiomyosarcomas and liposarcomas. Since liposarcomas are a heterogeneous group, including well/de-differentiated, pleomorphic, and myxoid/round cell subtypes, we have noted particularly interesting patterns of responsiveness to T in myxoid liposarcomas, which are associated with t(12;16)(q13;p11) or t(12;22)(q13;q12) chromosomal translocations, resulting in CHOP-TLS or CHOP-EWS fusion products. Methods: 15 cases of myxoid liposarcomas treated with T at the Istituto Nazionale Tumori, Milan, were retrospectively reviewed. In most cases, T was given as a 24-hr continuous infusion every 21 days, at dose levels from 1.0 to 1.5 mg/sqm. 108 courses were delivered, with a median of 5 courses per patient (range 2–20). Observations made in this series were shared with five other institutions having treated myxoid liposarcoma cases with T, all of which also report a significant response rate, for a total of 44 pts. A centralized radiological review of all pts is ongoing. Results: In the Milan series, early tissue alterations in tumors were observed in 14 patients, mainly with a decrease in tumor density on CT scan and/or decrease in contrast enhancement on MRI. These changes were followed by tumor shrinkage amounting to a conventional PR/CR in 8 (pending final review), while 3 others have responses which continue to evolve. Progression followed treatment interruption in one patient, with a minor response occurring at treatment restart. Treatment is continuing in 12 pts (median duration of therapy in excess of 5 months). Further results of the central radiological review from all centres will be reported. Conclusions: Tumor response to T seen in myxoid liposarcoma appears to be marked by early radiological alterations in tumor tissue, often preceding tumor shrinkage, which may be delayed. A selective mechanism of action for this chromosomal translocation-related sarcoma is suggested, and is being actively investigated at the moment. [Table: see text]

Transitory, spontaneously recovering, peripheral facial nerve palsy after vinorelbine administration

Childhood intrinsic brain-stem gliomas have a dismal prognosis. Different treatment strategies have been adopted over the years without changing the final outcome of this ominous disease. Due to this grim prognosis, experimental therapeutic designs are worthwhile. Vinorelbine is a semi-synthetic vinca alkaloid that has demonstrated a broad spectrum of activity both in in vitro and in vivo experimental systems. By adopting vinorelbine during and after focal radiotherapy in the last two years, we have tried to evocate its known synergistic effect in brain-stem tumour control. Vinorelbine was administered intravenously before, during and after radiotherapy on tumour bed for a total duration of 10 months. All the consecutive patients whose clinical and radiological features corresponded to the diagnosis of an intrinsic brain-stem tumour, i.e., diffuse pontine glioma, have been accrued to this treatment protocol since July 2002. A histological assessment was not required. All patients were treated during hospital stay or in the outpatient clinic at the Istituto Nazionale Tumori of Milan (n=12) and at the Pediatric Clinic of Policlinico in Catania (n=1). Two of the thirteen patients so far treated have developed multiple subsequent, and transitory, episodes of monolateral peripheral facial nerve palsy during vinorelbine administration. The palsy always completely and spontaneously resolved at a short interval-around 30 min-after the end of the drug infusion. Obvious tumour progression was excluded by means of MRI; therefore the drug was administered as scheduled until the end of the treatment. We describe possible neurological and oncological implications of this unusual side effect, until now not reported in any other series dealing with vinorelbine as adjuvant treatment.

Craniofacial resection for malignant tumours involving the anterior skull base

Ethmoid malignant tumours are rare, but nearly all at least approach or involve the lamina cribrosa. An anterior craniofacial resection is almost always mandatory for a radical resection. While almost everything has been written about technical details, few studies reported meaningful analysis about prognostic factors and long-term results, for a series of reasons: the infrequency of these tumours, the variety of histologies, small patients cohorts presented by each author, a medley of untreated and pre-treated patients, the lack of a universally accepted classification. We perform a review of the literature in the light of our experience of 330 anterior craniofacial resections for ethmoid malignant tumours. We present our classification of ethmoid malignant tumours (called INT, Istituto Nazionale Tumori). It turned out to be more prognostic than AJCC-UICC classification.

Salivary gland neoplasms in children: The experience of the Istituto Nazionale Tumori of Milan

Epithelial salivary gland tumors are very uncommon in pediatric age. We report a series of 52 cases treated at the Istituto Nazionale Tumori of Milan, Italy, over a 30-year period. These results are presented in conjunction with a literature review of salivary tumors with a view to providing an up-to-date overview of the clinical course, prognosis, and treatment options for this rare tumor. Fifty-two cases of epithelial salivary tumors were reviewed and the clinical-pathological information concerning tumor characteristics, therapy, and follow-up were collected. Patients' age ranged between 4 and 18 years. The major salivary glands were the main site of tumor occurrence (79% of cases arose in parotid glands); 37 patients had benign tumors (pleomorphic adenoma), 15 had malignant tumors (12 mucoepidermoid carcinoma, 9 low grade). All the patients were treated by surgery; local relapses after parotidectomy were 4% and 25%, in benign and malignant tumors, respectively. When tumor enucleation was performed, recurrences occurred in 50% of benign neoplasms. At the time of the report, all patients with benign tumors were alive, 35(95%) without evidence of disease; only one patient with malignant tumor died of disease. Epithelial salivary glands tumor in children had different characteristics compared with their adult counterpart with respect to the frequency of histotypes and site of occurrence, but their prognosis seems to be similar. Parotidectomy (total or superficial) is the best choice for achieving good cure rates in both benign and malignant tumors.

Rhabdomyosarcoma of the Head and Neck Region: Experience at the Pediatric Unit of the Istituto Nazionale Tumori, Milan

This study aims to describe the clinical features and outcome of pediatric patients with head and neck rhabdomyosarcoma (RMS), which can be divided into parameningeal, orbital, or nonorbital, nonparameningeal. This is a retrospective single-institution analysis. The study was performed at the Istituto Nazionale Tumori, Milan, Italy. The study considered 142 consecutive patients < 21 years treated from 1973 to 2003. Patients were treated using a multimodality approach: complete conservative surgery was performed at diagnosis in only two patients, all patients received chemotherapy, and most (91%) also had radiotherapy. Disease-free survival and overall survival were estimated according to the Kaplan-Meier method. For the series as a whole, the 5-year disease-free and overall surival rates were 49% and 57%, respectively. The 5-year overall survival rate improved over the years from 38% before 1980 to 78% after 1990; it was 44% for parameningeal, 79% for orbital, and 77% for nonorbital, nonparameningeal RMS. The treatment of head and neck RMS is complex and necessarily multidisciplinary. Complete surgery is rarely feasible in the head and neck region. This study confirms that orbital RMS has a favourable outcome, whereas therapeutic results are generally unsatisfactory in parameningeal cases, although recent progress in radiotherapeutic techniques and in the efficacy of chemotherapy would suggest clear improvements in survival.

Peripheral blood stem cell collection in pediatric patients: Feasibility of leukapheresis under anesthesia in uncompliant small children with solid tumors

Leukapheresis demands patient's compliance and adequate vascular accesses, which can require invasive methods in very small children whose treatment protocol includes hemopoietic stem cell collection for myeloablative chemotherapy and stem cell rescue. Since 1998, at the Istituto Nazionale Tumori of Milan, in selected uncompliant small children, the placement of peripheral vascular accesses and leukapheresis have been performed at the same time under general anesthesia. Peripheral venous cannulas were positioned for blood collection, while blood was returned through either peripheral cannulas or mono-lumen central catheters previously installed for chemotherapy. A continuous-flow cell separator was used for leukapheresis. Between 1998 and 2003, 47 children with solid tumors underwent anesthesia for a total of 54 leukaphereses. The patients' age ranged from 12.7 to 93 months (median 30.3) and their weight ranged from 7 to 20 kg (median 14.1). Neither metabolic nor anesthesiological complications were recorded. In 89% of cases, the CD 34(+) cell target was achieved at a single harvest; the median number of CD 34(+) cells was 10.8 x 10(6)/kg/leukapheresis (range 1-117) and the median collection efficiency was 63.4% (range 25-100.6). Leukapheresis under anesthesia is feasible and safe in very low-weight children whose compliance is lacking due to age and disease.

Subtotal versus total gastrectomy for cancer of the lower two-thirds of the stomach: a new approach to an old problem.

Many surgeons favour total gastrectomy (TG) 'de principe' in the treatment of gastric cancer, but final demonstration of its advantage over subtotal gastrectomy (SG) is still lacking. We analysed survival after curative TG or SG within groups of patients stratified according to the main prognostic variables as found in multivariate analysis, i.e., nodal status, degree of invasion of the gastric wall, patient age and sex. Our series consisted of 361 patients treated by curative SG and 41 by curative TG, admitted to the Istituto Nazionale Tumori of Milan between 1965 and 1979. In patients with lymph node involvement survival appeared to be significantly better (P = 0.0005) after SG. However, stratifying for age it was found that the benefit was limited to patients over 60 years old. No significant difference in survival was found in the group without nodal involvement (N -) and invasion of the wall to the serosa or beyond. No statistical comparison was possible in N - groups with invasion confined to mucosa, submucosa or muscularis propria because of the small number of such patients who underwent TG. We conclude that SG still represents the standard reference operation for gastric carcinoma provided that a safe proximal margin of resection is guaranteed.

Repeated hepatic resection for recurrent metastases from colorectal cancer.

Since 1980 120 patients with hepatic metastases from colorectal cancer underwent surgery at the Istituto Nazionale Tumori of Milan. Of these, 34 developed recurrence in the liver only and 11 underwent repeat surgery. The median interval between the two resections was 10 months and operative morbidity and mortality rates were 40 per cent and 9 per cent respectively. Nine patients with adequate follow-up were evaluated and after a median follow-up of 17 months four were alive and disease-free, two were alive with lung metastases and hepatic relapse and three had died. The overall median survival of these patients was 23 months.

Early and late results of extended surgery for cancer of the stomach

The experience of the Istituto Nazionale Tumori of Milan of 143 patients who underwent extended surgery for cancer of the stomach from 1965 to 1980 is reviewed. They represent 16.3 per cent of the patients who underwent curative surgery. The operative mortality rate was 15.4 per cent but this significantly decreased in recent years to 8 per cent and the morbidity rate to 17.5 per cent. The overall 5-year survival rate was 19 per cent. Survival was analysed according to tumour penetration (pT) and nodal status (N). It was found that patients without tumour penetration of adjacent structures and nodal involvement (pT3N-) had a better 5-year survival rate (21 per cent) than patients with nodal involvement (pT3N+) (2 per cent). Patients with tumour penetration of adjacent structures and without nodal involvement (pT4N-) had a better 5-year survival rate (29 per cent) than patients with nodal involvement (pT4N+) (5 per cent). These differences were significant on log rank test (P less than 0.000001 and P less than 0.001 respectively) and suggest that nodal status is a stronger prognostic variable than pT level. The role of extended surgery is discussed from the viewpoint of the oncological surgeon who has to weigh up the difficulty of a preoperative diagnosis of tumour infiltration of adjacent structures (predictive positive value 0.39), with the operative mortality rate of at least 8 per cent and long-term results which are strongly affected by the nodal status.

Proposal of a Novel System for the Staging of Thymic Epithelial Tumors

We designed and assessed a new TNM staging system (herein called the INT [Istituto Nazionale Tumori] system) for thymic epithelial tumors in order to overcome the perceived drawbacks of Masaoka's system, which represents the current standard. In all, 123 cases were evaluated. The histologic types according to the World Health Organization (WHO) classification were as follows: subtype A: 5 cases; AB: 40; B1: 16; B2: 29; B3: 16; and C: 17 cases. There were 45 Masaoka's stage I, 33 stage II, 26 stage III, and 19 stage IV cases. A total of 11 INT definitions were grouped into three stages: locally restricted disease (75 cases), which included Masaoka's stage I and selected stage II cases (no pleural invasion); locally advanced disease (37 cases), which included Masaoka's stage III cases plus those staged II owing to pleural invasion and those staged IV owing to intrathoracic nodal or limited pleuropericardial involvement; and systemic disease (11 cases), which included the remaining Masaoka's stage IV cases. Completeness of resection, WHO types, and both staging systems were significant prognostic factors (p < 0.0001) on univariate analysis. The 95-month progression-free survival rates according to Masaoka's system were stage I: 100%; II: 93.6%; III: 46.3%; and IV: 23.2%. The INT system corresponding figures were as follows: locally restricted disease: 98.6%; locally advanced disease: 46.9%; and systemic disease: 11.7%. The INT system was the prognostic factor with the greatest impact (p = 0.0218) on multivariate analysis (Masaoka's system: p = 0.2012; completeness of resection: p = 0.6855; histology: p = 0.9386). The INT system allows finer disease descriptions than Masaoka's system, resulting in a stage grouping with higher prognostic distinctiveness.

Papillary thyroid carcinoma of childhood and adolescence: A 30‐year experience at the istituto nazionale tumori in Milan

Survival rates are reportedly excellent for papillary thyroid carcinomas (PTCs) in childhood/adolescence, despite their strong tendency to spread. The aim of this study was to verify this assumption in a single-institution series spanning a 30-year period with a very long follow-up. From 1968 to 2001, 74 cases of thyroid carcinoma were collected. The papillary histological type was confirmed in 42 cases with available slides; we recorded the sex, age at diagnosis, age of menarche, tumor side and size, TNM/pTNM classification, multicentricity, vascular invasion, type of surgery, post-operative complications, post-surgical therapies and outcome up to May 31, 2004. The female/male ratio was 2.2; pT4, pN1 and M1 cases were 52%, 95%, and 12% (four in lungs and one in bone), respectively. Total thyroidectomy was performed in 33 patients, hemithyroidectomy in 8, and a biopsy in 1 inoperable case. Nine patients (21%) relapsed, six in the cervical lymph nodes and three in the lungs. After a median follow-up of 189 months, all patients were alive, two of them with evidence of disease. Overall and progression-free survival curves were independent of sex, age, TNM/pTNM classification, or type of surgery. Overall survival was also independent of recurrence. Unlike its adult counterpart, PTC of childhood and adolescence is a cancer with a high frequency of spread, but an excellent outcome irrespective of sex, age at diagnosis, TNM/pTNM classification, type of surgery, recurrence. Since pediatric PTCs proved highly responsive to hormone manipulation, it is worth considering a different therapeutic approach from adult cases.

Surgery of residual disease following imatinib mesylate in advanced gastrointestinal stromal tumors (GIST)

9038 Background: To retrospectively analyze the outcome of advanced GIST patients undergoing surgery of residual disease after a period of Imatinib mesylate therapy. Methods: We reviewed patients with advanced GIST who received Imatinib mesylate within a EORTC-STBSG led intergroup trial, or within a Southern European Phase II study, or as a standard of care, and were subsequently operated on at the Istituto Nazionale Tumori, Milano, Italy, between July 2002 and September 2004. Group A patients were operated on while in response; Group B patients after primary or secondary progression. A total of 25 patients were identified, with a median follow-up of 18 months. Median duration of Imatinib therapy before surgery was 17 months. Mutational status is presently available for 14 patients (48%). Results: In Group A patients (n = 19), all were found to have remnants in the abdominal cavity/liver, with a variable proportion of viable cells at pathologic examination, irrespective of radiologic PR or CR. All biomolecularly assessed patients carried an exon 11 mutation (1 patient along with a coexisting acquired exon 13 mutation), except one wild-type. After a median follow up of 19.9 months, all patients are alive, 16 patients (84%) with no evidence of progression (all continued Imatinib after surgery), while 3 patients failed at 16–18 months (2 of them had discontinuated Imatinib). In Group B (n = 6), all patients had viable disease at pathologic examination. Amongst assessed patients, 25% showed an exon 9 mutation, and 75% an exon 11 mutation (1 patient with an acquired concomitant exon 14 mutation). All patients failed after a median of 6 months, 4 are alive and 2 died of disease at 3 and 10 months after surgery. Conclusions: Also this series suggests not to discontinuate Imatinib therapy after surgery of residual disease, even if complete. The prognostic advantage from surgery of residual disease in response is left to elucidate by combining available series. On the other hand, patients with progressive disease are candidates for second-line molecular-targeted therapies, surgery being likely of minimal benefit. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis

Imatinib mesylate in 18 advanced chordoma patients

9012 Background: We reported (Cancer 2004;101:2086) the antitumor activity of Imatinib mesylate in 6 patients with advanced chordoma treated on an individual basis at the Istituto Nazionale Tumori, Milan, Italy, on biomolecular evidence of potential sensitivity to this agent. Other 12 patients were put on treatment thereafter, up to July 2004, before a currently ongoing Phase II study could be opened. We update/report herein efficacy data on the whole series of these 18 patients. Methods: Eighteen patients with a histological diagnosis of chordoma (originating from sacrum in 13, skull base in 3, and vertebrae in 2) started Imatinib mesylate from August 2002 to July 2004, at the daily dose of 800 mg in 14, and 400 mg in 4. M:F ratio was 9:9. Age was 14–77 (median: 56). Extent of disease was locally advanced in 12, local and metastatic in 6. Median interval from diagnosis was 5 yrs (range: 0–12). KPS was = 0–2 in 9, and = 3 in the remaining patients. Results: Two patients (11%) had a “dimensional response”, with a <50% tumor regression in bidimensional size, while other 11 patients (61%) had radiological signs of “tissue response”, with decreased contrast uptake/enhancement and/or decreased tumor density at CT/MRI, following patterns which in GIST are usually indicative of a tumor response. One patient had only a “functional response”, i.e. a decreased glucose uptake at PET scan against an unchanged radiological aspect. Some degree of subjective improvement was reported in 10 out of 14 symptomatic patients. The actuarial progression-free interval at 1 year was 88%, but 2 patients died with no evidence of tumor progression at 41 and 68 weeks, due to complications of a mostly liquefied, enormous tumor mass. Other two patients died and one stopped therapy early, in the absence of tumor progression. Thus, 11 patients are currently on therapy, after 14–70 weeks from treatment start. Conclusions: On a larger number of patients, we confirm that Imatinib mesylate has antitumor “activity” in chordoma. The potential of major clinical “efficacy” is suggested by the progression-free interval (up to 70+ weeks) seen in surviving patients with a long follow-up. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis

Fertility in young patients treated with chemotherapy for Hodgkin’s disease (HD): Long-term results

6578 Background: Due to improved lymphoma cure rates, long-term toxicity, including iathrogenic sterility, is of great concern. We thus evaluated the fertility of patients (pts) treated for HD at the Istituto Nazionale Tumori of Milan from 1990 to 2001 with three different chemotherapy (CT) regimens +/- radiotherapy excluding pelvic nodes. Material and Methods: The case series included 191 pts (73 males,118 females), median age 27 years (range 18–45), in long-lasting complete remission after three different CT regimens: 119 pts received 4–6 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine); 48 pts were given 6–8 cycles of VEBEP (VP16, epirubicin, bleomycin, cyclophosphamide, prednisone) and 25 pts were treated with sequential CT including intermediate-high doses of epirubicin, vincristine, prednisone, cyclophosphamide and etoposide for a 3 months period. Fertility was evaluated by semen analysis and conceptions in males and by history of menstrual cycles and pregnancies in females. WHO criteria were used to classify normospermia, azoospermia, abnormal semen (all sperm abnormalities but azoospermia), amenorrhea and normorrhea. Results: Males: after ABVD we observed permanent azoospermia in 6%, abnormal semen in 70% and normal semen in 24%; 30% of pts fathered. After VEBEP we documented permanent azoospermia in 35%, abnormal semen in 46% and normal semen in 19%; 27% of pts fathered. After sequential CT permanent azoospermia occurred in 33% and abnormal semen in 67%; 11% of pts fathered. Females: definitive amenorrhea was documented in 2% after ABVD, 17% after VEBEP and 6% after sequential CT; all pts who became amenorrheic were aged > 30 years at treatment. Pregnancies occurred in 38%, 21% and 25% in each treatment group respectively. Conclusions: Long-term results confirm that ABVD spares fertility in the majority of cases. Regimens containing alkylating agents, like VEBEP or sequential CT, induce sterility in less than 20% of women, but in a large fraction of male pts. Therefore pretreatment cryopreservation of semen should be offered to all males. No significant financial relationships to disclose.

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment

The aim of the present study was to evaluate the effectiveness of two consecutive nonrandomised treatment programs applied between 1989 and 1999 at the Istituto Nazionale Tumori of Milan in an unselected cohort of 59 children over the age of one with stage 4 neuroblastoma. Both treatment programs consisted of two phases, the induction of the remission phase and the consolidation phase. The induction of the remission phase consisted of intensive chemotherapy, and remained the same throughout the study period. The consolidation phase consisted of sequential hemi-body irradiation (HBI) (10 Gy per session, 6 weeks apart) in the first period (1988–June 1994) and sequential high-dose cyclophosphamide, etoposide, mitoxantrone+L-PAM and autologous haemopoietic stem cell transplantation in the second (July 1994–1999). Intention-to-treat analysis revealed a significantly better outcome for patients treated with the second program, the 5-year event-free survival probability being 0.12 for program 1 and 0.31 for program 2 (P=0.03). This finding led us to conclude that sequential HBI is useless as consolidation treatment. The high-dose chemotherapy adopted in the second program enabled a proportion of patients to obtain long-term survival but, since the clinical results remain unsatisfactory, new treatment strategies are warranted.

Medical and Pediatric Oncology, Not Adult and Pediatric Oncology

There are at least three good reasons to study patients with sarcomas; sarcomas can serve as a model of other more common human cancers, important clinically relevant genetic discoveries have been made disproportionately more often in sarcoma than in other tumors (p53, RB, c-kit, pdgfr, etc), and sarcomas affect patients of all ages from the newborn to the elderly. Despite many newly gained laboratory insights, as with many other cancers, progress in sarcoma is often too slow. Unlike other epithelial cancers, sarcomas are quite uncommon in our population. For every 100,000 Americans, 5,000 will have cancer. Of those 5,000 people, fewer than 30 will have any one of the 70 or more types of sarcomas. Progress is partly slowed in sarcomas because of competition for patient accrual into important clinical trials. Pediatric oncologists have been highly successful in accruing patients to clinical trials. Recently, however, there has been a decline in accrual to pediatric studies, perhaps because of new competition or insufficient funding for clinical trial participation. Pediatric oncologists have made important strides in patients with the Ewing’s family of cancers, osteosarcoma, and rhabdomyosarcoma, achieving cure rates from 65% to 75% in patients without metastasis. Many medical oncologists are in awe of the up to 25% cure rate of these diseases, even in the face of metastatic disease. But what about other soft tissue sarcomas? Pediatric oncologists have become comfortable with the phrase “nonrhabdomyosarcoma soft tissue sarcomas.” Medical oncologists giggle snidely at the phrase. Paul Meyers (pediatric oncologist at Memorial Sloan-Kettering Cancer Center, New York, NY) has said it is not adult and pediatric oncologists, but rather medical and pediatric oncologists. The following two articles in this issue are relevant to this point: “Phase II Trial of Neoadjuvant Vincristine, Ifosfamide, and Doxorubicin With Granulocyte ColonyStimulating Factor Support in Children and Adolescents With Advanced-Stage Nonrhabdomyosarcomatous Soft Tissue Sarcomas: A Pediatric Oncology Group Study” by Pappo et al and “Adult-Type Soft Tissue Sarcomas in Pediatric Age: Experience at the Istituto Nazionale Tumori in Milan” by Ferrari et al. I must confess that I like the sound of the second title much more than the first, but the fact is that both titles are accurate. The histologies studied do not include the rhabdomyosarcomas; rather, the histologies studied more often occur in the adult age group. Both articles describe sizeable patient populations. The Children’s Oncology Group article describes 39 patients in a prospective trial. Patients were accrued over less than a 3-year period; 26 institutions contributed patients to the study, of which 24 enrolled one patient. The Milan study reported retrospectively on a group of 182 patients treated at a single institution over a 25-year period. Both studies agree that this population represents 3% to 4% of pediatric cancers and that these cancers are quite heterogeneous in biology and natural history. Both studies agree that synovial sarcoma is the most common histology among the pediatric nonrhabdo soft tissue sarcomas. The Italian group indicates that “most of the experience gained in the treatment of pediatric NRSTS [nonrhabdomyosarcoma soft tissue sarcomas] either derives from managing soft tissue sarcomas in adults or relies on the principles deriving from the management of RMS [rhabdomyosarcomas].” Evidence for the managing principles being derived from rhabdomyosarcoma includes pretreatment evaluation of these patients with bone scans and bone marrow biopsies. Neither of these diagnostic studies is routinely used by medical oncologists who treat soft tissue sarcoma patients. Similar to medical oncologists, many pediatric oncologists choose to treat patients with anthracyclineand ifosfamide-based chemotherapy regimens. However, sometimes the experiences of medical oncologists are not considered by pediatric oncologists. Both studies included JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 18 JUNE 2