Long-term Follow-up and Post-relapse Outcome of Patients with Localized Retroperitoneal Sarcoma Treated in the Italian Sarcoma Group-Soft Tissue Sarcoma (ISG-STS) Protocol 0303.

BACKGROUND: This study was designed to assess patterns of recurrence and long-term outcomes of patients undergoing surgery for localized retroperitoneal sarcoma (RPS) after neoadjuvant high dose long-infusion ifosfamide (HLI) and radiotherapy (RT). METHODS: Patients received three cycles of HLI (14 g/m2). RT was started in combination with II cycle up to a total dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the end of RT. The primary endpoint was relapse-free survival (RFS) after surgery. Secondary endpoints were overall survival (OS), crude cumulative incidence of local recurrence (CCI-LR), and distant metastases (CCI-DM). For patients who relapsed, progression-free survival (PFS) and post-relapse OS were estimated. The trial was registered with ITASARC_*II_2004_003. RESULTS: Between 2003 and 2010, 83 patients were recruited. At a median follow-up of 91.7 months, 42 (56%) of 75 operated patients developed LR (n = 27) or DM (n = 10) or both LR and DM (n = 5) relapse. Seven-year RFS was 46.6% [95% confidence interval (CI) 29.6-52.4]. Thirty-two patients died. Seven-year OS rate was 63.2% (95% CI 42.7-66.0). The corresponding CCI of LR and DM were 37.4% [standard error (SE) 5.5%] and 20.0% (SE 12.6%), respectively. The only factor significantly associated with LR was FNCLCC grading, whereas histological subtype resulted associated with DM. At recurrence, 24 patients (57%) underwent surgery. Two-year post-relapse PFS and OS rates for patients developing LR or DM were 14.8, 41.0, 27.3, and 63.6%, respectively. CONCLUSIONS: LR after neoadjuvant CT-RT for RPS were predominantly infield. While almost one half of relapsed patients underwent further surgery, prognosis was poor.

Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.

BACKGROUND: To report on long-term results of a phase 3 trial comparing three versus five cycles of adjuvant chemotherapy (CT) with full-dose epirubicin+ifosfamide in high-risk soft tissue sarcomas (STS). METHODS: Patients (pts) were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (Arm A) or to receive the same three preoperative cycles plus two postoperative cycles (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary end point, OS, was assessed by the confidence interval of the hazard ratio (HR; Arm A/Arm B) derived from Cox model. RESULTS: Between January 2002 and April 2007, 164 pts were assigned to arm A and 164 to arm B. At a median follow-up (FU) of 117 months (IQ range 103-135 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that three cycles were not inferior to five cycles (one-sided 95% upper confidence limit was 1.24). A per protocol analysis was consistent with these results. Pts with leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) had the lowest, and the highest response rates, respectively. Consistently, Leiomyosarcoma and UPS had the worse and the best prognosis, respectively. CONCLUSIONS: At a longer FU, the non-inferiority of three cycles of a full-dose conventional CT in comparison to five is confirmed. Response to therapy is also confirmed to be associated with better survival. This regimen is currently tested within an ongoing international trial against three cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176).

Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall.

BACKGROUND: To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. PATIENTS AND METHODS: In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. RESULTS: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0. CONCLUSIONS: In this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure.

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients - A GIRCG study.

BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinical-pathological characteristics and prognosis. METHODS: DNA was extracted from paraffin-embedded sections from 221 gastric GIST patients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinical-pathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. RESULTS: KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions were associated with increased risk of relapse or death (p < 0.001; p = 0.0389 and p = 0.002, respectively). After adjusting for Miettinen risk score, KIT deletions remained an independent prognostic factor (HRadj = 2.65, 95% CI [1.15-6.13], p = 0.023). Moreover, KIT deletions in exon 11 codons 557, 558 or 559 were associated with a higher risk of relapse or death than wt tumors (HRadj = 3.29 95% CI [1.64-6.64], p = 0.001). CONCLUSIONS: KIT deletions in exon 11, especially those involving codons 557, 558 or 559, were correlated with a more aggressive gastric GIST phenotype and increased risk of relapse or death.

Extended lymphadenectomy in elderly and/or highly co-morbid gastric cancer patients: A retrospective multicenter study.

BACKGROUND: Gastrectomy with extended lymphadenectomy is considered the gold standard treatment for advanced gastric cancer, with no age- or comorbidity-related limitations. We evaluated the safety and efficacy of curative gastrectomy with extended nodal dissection, verifying survival in elderly and highly co-morbid patients. METHODS: In a retrospective multicenter study, we examined 1322 non-metastatic gastric-cancer patients that underwent curative gastrectomy with D2 versus D1 lymphadenectomy from January 2000 to December 2009. Postoperative complications, overall survival (OS), and disease-specific survival (DSS) according to age and the Charlson Comorbidity Score were analyzed in relation to the extent of lymphadenectomy. RESULTS: Postoperative morbidity was 30.4%. Complications were more frequent in highly co-morbid elderly patients, and, although general morbidity rates after D2 and D1 lymphadenectomy were similar (29.9% and 33.2%, respectively), they increased following D2 in highly co-morbid elderly patients (39.6%). D2-lymphadenectomy significantly improved 5-year OS and DSS (48.0% vs. 37.6% in D1, p < 0.001 and 72.6% vs. 58.1% in D1, p < 0.001, respectively) in all patients. In elderly patients, this benefit was present only in 5-year DSS. D2 nodal dissection induced better 5-year OS and DSS rates in elderly patients with positive nodes (29.7% vs. 21.2% in D1, p = 0.008 and 47.5% vs. 30.6% in D1, p = 0.001, respectively), although it was present only in DSS when highly co-morbid elderly patients were considered. CONCLUSION: Extended lymphadenectomy confirmed better survival rates in gastric cancer patients. Due to high postoperative complication rate and no significant improvement of the OS, D1 lymphadenectomy should be considered in elderly and/or highly co-morbid gastric cancer patients.

Peritonectomy and hyperthermic intraperitoneal chemotherapy: cost analysis and sustainability.

BACKGROUND: Malignancies of the peritoneum remain a challenge in any hospital that accepts to manage them, due not only to difficulties associated with the complexity of the procedures involved but also the costs, which - in Italy and other countries that use a diagnosis-related group (DRG) system - are not adequately reimbursed. MATERIAL AND METHODS: We analyzed data relative to 24 patients operated on between September 2010 and May 2013 with special regard to operating room expenditure, ICU stay, duration of hospitalization, and DRG reimbursement. The total costs per patient included clinical, operating room, procedure, pathology, imaging, ward care, allied healthcare, pharmaceutical, and ICU costs. RESULTS: Postoperative hospital stay, drugs and materials, and operating room occupancy were the main factors affecting the expenditure for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. We had a median hospitalization of 14 days, median ICU stay of 2.4 days, and median operating room occupancy of 585 min. The median expenditure for each case was € 21,744; the median reimbursement by the national health system € 8,375. CONCLUSIONS: In a DRG reimbursement system, the economic effort in the management of patients undergoing peritonectomy procedures may not be counterbalanced by adequate reimbursement. Joint efforts between medical and administration parties are mandatory to develop appropriate treatment protocols and keep down the costs.

Preoperative doxorubicin plus ifosfamide in primary soft-tissue sarcomas of the extremities.

A total of 51 patients with large, primary, high-grade soft-tissue sarcomas of the extremities were treated at our institute with two preoperative and three postoperative cycles of doxorubicin plus ifosfamide/mesna. Preoperative doxorubicin was given intra-arterially for lesions of the lower extremities. Of 47 evaluable patients, 22 (47%) showed clinical responses and 21 (45%), pathologic responses. Clinical and pathologic responses, however, were not necessarily coincident in the same patient. Conservative limb-sparing surgery was performed in 41 cases (87%), and in 4 cases amputation was avoided as a result of the local improvement induced by chemotherapy. Local recurrence occurred in 12 cases (25%), 3 of which required further amputation. Although the follow-up period was only 28 months, the 4-year actuarial survival was 91% and the 4-year metastasis-free value was 69%. An evident difference existed between patients who showed a documented clinical response to chemotherapy and those who did not, the 4-year metastasis-free value being 85% and 59% (P = 0.1), respectively. Adjuvant preoperative chemotherapy may allow for limb-salvage surgical procedures in selected cases.

Unusual types of chondrosarcoma: chondrosarcoma arising in soft tissue and in non-skeletal cartilage.

Five cases of unusual chondrosarcomas of the soft tissue and of the skeletal cartilage are reported. A retrospective clinical study has been evaluated on ways to improve our knowledge of these rare neoplasms.

Carcinoid somatostatinoma of the duodenum.

Carcinoid somatostatinoma is a rare neuroendocrine malignant tumour and the duodenal location is an atypical site of presentation of which only few cases have been reported in the literature. A case of duodenal carcinoid somatostatinoma metastatic to lymph nodes in a 66-year-old patient is presented with an update of the literature. No relevant signs or symptoms were associated to the retrogastric lymph-node mass, which deformed but did not infiltrate the stomach wall. At the first and third portion of the duodenum, two polipoid endoluminal nodules (size 1 cm) were found with adjacent adenopathy partially adherent to the head of the pancreas and with thickening of the antropyloric wall. The patient underwent antrectomy duodenum mobilization and lymphadenectomy in the hepatic artery region. The treatment was successful and, over 3 years after diagnosis, there has been no clinical or radiological evidence of relapse. Duodenal somatostatinoma is rare and its diagnosis is often incidental. Surgery would be the appropriate treatment in the early stage of the disease with good chances of cure.

Chondrosarcoma--55 unreported cases: epidemiology, surgical treatment and prognostic factors.

Fifty-five cases of chondrosarcoma, seen at the Istituto Nazionale Tumori of Milan, were reviewed to collect epidemiological data in order to verify therapeutic effects and the validity of possible prognostic factors. Epidemiological data according to sex and age distribution and skeletal location were in accordance with the literature (male:female ratio, 1.8; mean age, 37 years, 62% of lesions located in the pelvic or scapular girdle). Of 52 cases operated on with the intent of radicality, 5 were intralesional operations, 20 marginal and 27 radical. The local recurrence rate was dependent upon the degree of surgical radicality (60%, 35% and 11% respectively for intralesional, marginal and radical surgery). Age, site, type of first symptom and pathological grading were significant as prognostic factors. The type of the first symptom was directly correlated to the site of the tumour. Sex, tumour size and degree of surgical radicality were not relevant.

A posterior approach for the excision of sacral chordoma.

We report eight cases of sacrococcygeal chordoma treated by high sacral resection through S2 by a posterior approach, with the intention of achieving radical removal. The technique we describe is easier than the combined abdominosacral approach, and there have been no serious intra-operative or postoperative complications. The major technical problems were the margins of excision in the sacrum itself (one recurred) and in the perirectal soft tissues (four recurred), and the preservation of sacral nerve roots. When both S2 roots were preserved, sphincter problems were mild and reversible. One patient died from recurrence 32 months after operation and one was lost to follow-up at eight months. Six patients are alive with a median survival of three years; three of them are free of disease after 22, 36 and 80 months respectively. These results indicate the possibility of surgical cure of this malignant tumour.

A case of pancreatoduodenectomy as resolutive treatment for a solitary metastasis of breast cancer.

A 49-year-old woman was hospitalized for obstructive jaundice 4 years after extended mastectomy for lobular infiltrating carcinoma. After routine investigations that detected a malignant lesion of the pancreas head, the patient underwent pancreatoduodenectomy. The surgical specimen revealed unexpected breast carcinoma metastatic to the pancreas and duodenum wall. The woman is alive and free of disease at 10 years from the mastectomy and 6 years from the pancreatoduodenectomy. This experience confirms the validity of a surgical radical treatment for metastatic lesions in selected cases.

Sebaceous carcinoma arising from the eyelid and from extra-ocular sites.

Sebaceous carcinoma is slow growing, locally aggressive and capable of metastatic spread. The natural history of sebaceous carcinoma arising from the eyelid is well known, but less than 100 cases arising from other cutaneous sites have been reported. Five cases of sebaceous carcinoma, 3 of which originated from the eyelid and 2 from extraocular sites are here reported. The patients (3 men and 2 women; median age, 69 years) were treated at the Istituto Nazionale Tumori of Milan between 1974 and 1984. Pathologic features, complete follow-up and natural history are reported.

Accuracy of breast cancer diagnosis by physical, radiologic and cytologic combined examinations.

Physical examination, mammography and fine-needle aspiration cytology were performed in 1498 consecutive cases with a solitary solid lump of the female breast. The intent was to verify the validity of this diagnostic triplet in the accuracy of the preoperative diagnosis of breast cancer. Clinically sure cancers were excluded from the study. The collected data were evaluated in terms of sensitivity, specificity and predictivity of any procedure alone or in combination. In 1138 cases confirmed by histology (514 carcinomas and 669 benign or non-neoplastic lesions), the physical examination and mammography were very sensitive (respectively 96% and 84%) but with a high rate of false-positive reports (respectively 20% and 18%). The cytologic diagnosis was less sensitive (65%), mostly due to many inadequate smears, but highly specific (93%) and predictive for malignancy (99%) when the cytologic report was frankly positive. Any single procedure improved the overall sensitivity, and taken together this triplet appears to be the most effective noninvasive diagnostic combination that provides in a short time with minimal cost and discomfort, a diagnosis of certain malignancy in about 50% of carcinomas with a predictivity close to 100%, when cytology detected malignancy.

[Locoregional chemotherapy in neoplasms]. / La chemioterapia locoregionale nelle neoplasie.

Intra-arterial chemotherapy of carcinoma increases drug concentration at the level of the tumour and reduces systemic toxicity. It is being used in the treatment of solid tumours in various parts of the body with increasingly encouraging results. It can also be carried out in an outpatient setting owing to the use of particularly advanced techniques.