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PURPOSE: To explore the prognostic effect of microscopic marginal status after surgery for extremity soft tissue sarcomas. PATIENTS AND METHODS: We analyzed 911 consecutive patients surgically treated throughout a 20-year span at a single referral center. Six hundred forty-two were first seen with a primary tumor, and 269, with a locally recurrent tumor. All patients underwent macroscopically complete resection. Microscopic marginal status was negative (tumor size > 1 mm) in 748 patients and positive (</= 1 mm) in 163 patients. Median follow-up was 107 months. RESULTS: Patients with primary disease had a lower disease-specific mortality in comparison to those first examined for recurrence (25% v 37%, respectively, at 10 years). Size, malignancy grade, depth, histotype, and local recurrence had a statistically significant prognostic effect at multivariable analysis, while microscopically positive surgical margins had not, though a trend in favor of negative margins was observed. However, an extra risk was observed for patients with positive margins after 3 to 5 years (hazard ratio, 1.8 after 5 years v 0.8 before 5 years). In patients treated for a local recurrence, the prognostic impact of positive margins was higher (hazard ratio, 1.6). CONCLUSION: Positive surgical margins had a weak adverse prognostic effect, which was more pronounced for those patients escaping an early relapse. This would seem to justify a policy of surgical adequacy in adult soft tissue sarcomas, though clinical decision making in borderline presentations for conservative surgery might be reasonably flexible and shared with the patient. Once a local relapse has occurred, the impact of local treatments seems more critical.
PURPOSE: To assess the role of TP53 status in predicting pathologic complete remission after primary chemotherapy in patients with ethmoidal intestinal-type adenocarcinoma (ITAC). PATIENTS AND METHODS: Thirty patients with ethmoidal ITAC enrolled onto a phase II study received chemotherapy with cisplatin, fluorouracil, and leucovorin (PFL) followed by surgery and radiation. On surgical specimens, absence of viable tumor cells was defined as pathologic complete remission (pCR). TP53 status/p53 function, analyzed on pretreatment biopsies, were retrospectively correlated with pathologic results and patient outcome. RESULTS: Twelve patients achieved a pCR; 18 patients did not (overall response rate, 40%). In patients with wild-type (wt) TP53 or functional p53 protein, the pCRs were 83% and 80%, respectively; in patients with mutated TP53 or impaired p53 protein, pCRs were 11% and 0%, respectively (P < or = .0001). At a median 55-month follow-up, all pCR patients were disease-free; 44% of nonresponding patients experienced relapse (P = .0061). CONCLUSION: The results indicate the existence of two genetic ITAC subgroups, defined by differences in TP53 mutational status or protein functionality, that strongly influence pathologic response to primary chemotherapy and, ultimately, prognosis. PFL seems to be highly effective in terms of pCR and disease-free survival in the presence of a wt or a still-efficient p53 protein, even when encoded by a mutated TP53 gene (eg, early-stop codon mutation), but ineffective in ITACs carrying a disabled p53 protein. Whether this model is extensible to other head and neck cancers needs appropriate investigation.
PURPOSE: To explore prognostic factors in surgically treated aggressive fibromatosis (extra-abdominal desmoid tumor). PATIENTS AND METHODS: A total of 203 consecutive patients treated with surgery over a 35-year period at a single referral center were retrospectively reviewed. One hundred twenty-eight were first seen at our institution with primary disease, whereas 75 had a recurrent tumor. All patients underwent macroscopically complete resection. Margins were rated as negative in 146 (97 with primary tumors, 49 with recurrences) and positive in 57 (31 in primary, 26 in recurrences) patients. Median follow-up was 135 months. RESULTS: Patients with primary disease had a better disease-free survival rate than those with recurrence (76% v 59% at 10 years). Presenting with a recurrence was also the strongest predictor of local failure in the multivariate analysis. In patients first treated for primary disease, size and site had prognostic significance, whereas microscopically positive surgical margins did not. In contrast, in patients with recurrence, there was a trend toward better prognosis if margins were negative (although this was not significant at multivariate analysis). CONCLUSION: Presence of microscopic disease does not necessarily affect long-term disease-free survival in patients with primary presentation of extra-abdominal desmoid tumors. Thus, function-sparing surgery may be a reasonable choice when feasible without leaving macroscopic residual disease. In patients with recurrences, positive margins may more clearly affect prognosis, potentially necessitating adjuvant radiation in selected cases.
PURPOSE: Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results. The present study was designed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents. PATIENTS AND METHODS: Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas (primary diameter > or = 5 cm or any size recurrent tumor) in extremities or girdles were eligible. Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm. One hundred four patients were randomized, 51 to the control group and 53 to the treatment group (five cycles of 4'-epidoxorubicin 60 mg/m(2) days 1 and 2 and ifosfamide 1.8 g/m(2) days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor). RESULTS: After a median follow-up of 59 months, 60 patients had relapsed and 48 died (28 and 20 in the treatment arm and 32 and 28 in the control arm, respectively). The median disease-free survival (DFS) was 48 months in the treatment group and 16 months in the control group (P =.04); and the median overall survival (OS) was 75 months for treated and 46 months for untreated patients (P =.03). For OS, the absolute benefit deriving from chemotherapy was 13% at 2 years and increased to 19% at 4 years (P =.04). CONCLUSION: Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months. Therefore, our data favor an intensified treatment in similar cases. Although cure is still difficult to achieve, a significant delay in death is worthwhile, also considering the short duration of treatment and the absence of toxic deaths.
60-70% of all cancers will develop in individuals aged 65 and over during this century. Radiation therapy will play a major role in the treatment of cancer, especially in the elderly. The Italian Geriatric Oncology Group (GROG) in 1994 started a number of prospective studies to assess the characteristics of each elderly cancer patient referred to the radiotherapy centers (age, gender, performance status, comorbidity, ADL, family status) and the main features of the tumor in that patient. Based on the obtained results, the role of radiotherapy is underlined and future perspectives are identified.
The authors review the main contributions of the international literature concerning the role of hyperfractionation (HF), accelerated fractionation (AF), and accelerated hyperfractionation (AHF) of the dose in radiation therapy (RT) of central nervous system tumors. Basic rationales, clinical results, acute/late toxicity, and current prospectives are summarized in three sections focusing on malignant gliomas, pediatric brainstem tumors, and brain metastases. In supratentorial malignant gliomas the superiority of AHF (0.89 Gy x 3 fractions/day; total dose 61.4 Gy) over conventional fractionation ((CF) total dose 58 Gy) was demonstrated by a randomized trial. However, the gain in median survival time was less than 6 months. No other randomized trials support the preferential choice of non-CF schedules outside clinical trials. Ongoing trials are exploring the role of AHF in combination with chemotherapy, hypoxic cell and radiosensitizing agents. As for pediatric brainstem tumors, there are no data to support the routine use of HF that should be preferably used in an investigative setting. As late sequelae have been reported in the few long-term survivors, patients should be carefully selected. Regarding brain metastases AF RT and AHF RT, with their faster treatment course, may represent a convenient alternative to CF RT for the palliation of brain metastases. In carefully selected patients with solitary brain metastases non-CF RT may be part of aggressive treatment approaches.
Radiation therapy fulfills all the requirements to be used with curative or palliative intent in nearly every case of cancer in the elderly. Radiotherapy is not associated with acute mortality in older persons and can permit organ and tissue preservation. The modern modalities to deliver radiotherapy treatment permit a large sparing of normal tissues. We need major information on proliferative activity of normal tissues and cancer in the elderly, on results according to stage of tumors, and on acute and late sequelae according to performance status of the patient. It is mandatory to perform prospective studies in order to work out protocols for oncologic treatments and specifically for radiotherapy, to treat adequately an increasing part of population.
PURPOSE: To compare computerized tomography (CT) and magnetic resonance (MR) in relation to their accuracy in the staging of nasopharyngeal carcinoma (NPC); to compare CT and MR in postirradiation follow-up of NPC. METHODS AND MATERIALS: Staging: From 1985 to 1993, 53 patients affected with NPC were studied with MR and CT. All cases were biopsy-proved epithelial carcinoma. Plain and contrast-enhanced CT scans were performed with third-generation scanners. Magnetic resonance were obtained with 0.5 and 1.5 Tesla units in sagittal, axial, and coronal planes. Computerized tomography was chosen as reference method and findings obtained with MR were compared to those obtained with CT. FOLLOW-UP: From 1985 to 1993, 53 patients irradiated with radical intent were followed up with both CT and MR; 71 examinations were performed in all. The baseline follow-up scan was performed, in general, no sooner than 2 months after the end of radiotherapy. All patients were submitted to unlimited clinical follow-up. RESULTS: Staging: Magnetic resonance showed retropharyngeal adenopathies in 6 of 14 cases in which oropharyngeal involvement had been reported after CT; in 3 other patients, adenopathies were recognized on MR, while primary extent to parapharyngeal space had been diagnosed on CT initially. Infiltration of long muscles of the neck was revealed with MR in 14 cases. On the other hand, CT showed bone invasion in 12 patients vs. 8 on MR. Upstaging to T4 occurred in four cases on the basis of CT; no upstaging occurred after MR. FOLLOW-UP: Findings on CT were uncertain in 10 out of 53 patients, disease recurrence was excluded by MR in nine cases, whereas progressive disease was confirmed in one patient. CONCLUSION: Staging: Our series shows that either CT and MR can provide essential information in the staging of NPC. Magnetic resonance, however, seems to provide the most detailed imaging of soft tissue invasion outside the nasopharynx and of retropharyngeal node involvement. Nonetheless, its limitations in evaluating bone details suggest that CT should be always performed when the status of base of skull is uncertain on MR. General reasons and our data indicate that CT can still be considered a valuable tool in routine NPC staging. Follow up: Magnetic resonance may be the modality of choice because it seems to solve, more often than CT, the problems of differentiation between postradiation changes and recurring tumor, apart from those cases showing subtle bone erosions on initial CT scan.
The serum tissue polypeptide antigen (TPA) was determined before and at the end of radiotherapy in a group of patients with head and neck epidermoid carcinoma. The baseline values were significantly higher than those in healthy control subjects. They did not depend on the site of the neoplasia but increased with clinical stage. A cut-off value of 85 U/l discriminated two groups of patients according to survival: patients whose values were lower than the cut-off had a disease-free 6-year survival rate of 61%, compared to only 22% in patients with higher TPA levels. Until the second year of follow-up, patients with complete response had baseline values significantly lower than relapsed patients. However, at 5 years the pretreatment values were similar for patients being disease-free, patients with recurrence and patients deceased within the 2-5 year period.
The authors review the main contributions of international literature to show the current status in clinical trials on unconventional fractionations of the dose in radiotherapy of head and neck cancers. Several clinical (but only a few randomized) trials have been conducted over the last 15 years using hyperfractionated (HF), accelerated (AF) or mixed (HF-AF) schedules. HF schedules have obtained promising results in terms of local control in comparison with conventional fractionation (CF) of the dose. Improvement in survival was also obtained by the random trials of Pinto and Sanchiz, whereas in EORTC trial no. 22791, the improvement in survival rate was only marginal. A significant increase in local control and, less frequently, in survival has been claimed in several studies using HF-AF. Such data still need to be confirmed by a random study, since EORTC trial 22811 showed superimposable results in comparison with CF. Selection of the most suitable cases for altered fractionation schemes is also being studied in ongoing trials of the EORTC (22851) and RTOG (90-03). As regards acute reactions during and after altered fractionation, they are more severe than after CF. Only pure HF with a dose intensity approximately comparable to CF seems to produce similar acute reactions. Several factors have been found to influence the severity of acute mucosal reactions: interfraction interval, overall treatment time, total dose, and field size. As regards late damage, genuine HF schemes seem to cause roughly equivalent late damage in comparison to CF, whereas high-dose intensity schedules have a higher rate of complications. Interfraction interval, overall treatment time, total dose, fraction size and field size can influence the risk of late sequelae. Before altered fractionations can be considered standard therapy, more data are needed, which should be provided by multicentric randomized trials, some of which are already in progress.
Forty-eight patients with soft tissue sarcomas were treated with Iridium implant after wide local excision between 1980 and 1990 at our institution. External irradiation was also given postoperatively in 33 patients with initially resectable tumours (treatment A) and preoperatively in 3 with initially unresectable tumours (treatment C); brachytherapy was the only treatment in 12 patients presenting small superficial tumours or recurring after previous irradiation (treatment B). Median follow up was 51 months (range 6-148). Fifteen patients (31%) failed; local recurrence was present in 9 (18.8%) and distant metastases in 11 (22.9%). Local failures were 3/33 (9%) after the treatment A, 4/12 after the treatment B, 3/2 after the treatment C. The incidence of local failures was affected by the tumor size, the presence of positive histology at the resection margins, and the total radiation dose. There was no impairment of wound healing and no necrosis; a severe sclerosis was observed only in the 3 patients receiving preoperative irradiation probably because large size fractions were used. We concluded that brachytherapy should be included in the radiation program for soft tissue sarcomas when a satisfactory geometry may be achieved and in particular when the tumor is located in sites where external irradiation only has a higher probability of producing major side effects.
The basal endocrine status of 29 patients treated with curative radiation therapy for nasopharyngeal carcinoma was assessed; they were disease-free for a minimum of 4 years from the end of treatment. None showed clinical evidence of endocrine disease, and most of them had a substantially normal hormonal blood pattern. A slightly elevated TSH value, suggesting subclinical primary hypothyroidism, was found only in two male patients, which could be ascribed to the radiotherapeutic treatment of the neck. Although we cannot exclude more subtle alterations of hypothalamic-pituitary function, the percentage incidence of endocrine impairment in our patients seems lower than previously reported by other authors.
Forty-five consecutive biopsy specimens of nasopharyngeal carcinoma (NPC) and 10 biopsies of healthy nasopharyngeal mucosa obtained from non-cancer patients were investigated by immunohistochemical methods. Monoclonal (B2, T1) and policlonal antibodies (against S-100 protein and lysozyme) with reference to infiltrating lymphocytes and accessory cells (monocytic/macrophagic and dendritic cells) were used. Variable population densities of dendritic cells (S100+) were demonstrated in 22 out of the 45 cases (49%) of NPC; the distribution of these cells was typically within the cancer nests. Monocytic/macrophagic cells (Lys+) were found along the tumor margins and interspersed among the tumor cells in 14 out of 45 (31%) cases. No significant statistical correlation between density of accessory cells and histological type of NPC (classified according to Micheau criteria) was found. Cases with a moderate to marked density of dendritic and monocytic/macrophagic cells survived longer than those with a slight one (mean survival of 63%, 67% and 29%, 27% respectively). In NPC tissues T-lymphocyte infiltration was prevalent. In contrast, B cells were numerous and T cells rare in normal control tissues. The intensity of T-cell infiltration was significantly high in cases with a marked density of S-100+ cells, according to the ability of these cells to present antigens to sensitized T-cells. This study suggests a prognostic significance for reactive cells infiltrating NPC, which means longer survival for cases associated with marked infiltration density of accessory cells.
Ninety-seven patients affected with nasopharyngeal carcinoma (NPC) were examined with both conventional and Computed Tomography (CT) to evaluate the involved sites with both methods. CT staging was more accurate, showing involvement in more locations than conventional tomography, so that staging was modified in 23 of 97 patients. Two hundred and seventeen patients treated from 1970 to 1985 were subdivided into group A (111 patients who underwent conventional tomography only) and group B (106 patients examined with CT, from 1978 on). A trend toward more advanced stages at presentation was observed in group B; nevertheless, local control at 5 years was higher in group B (59%) than in group A (42%). The role of Magnetic Resonance (MR) imaging in NPC staging was also evaluated in 30 patients: there was disagreement in 2 cases. Involvement of different structures was shown in 10 of 28 cases with the same CT and MR staging. MR imaging proved a valuable tool in the follow-up as well: in fact, it clarified 12 questionable opacities on CT in a group of 35 followed patients as inflammatory lesions in 10 patients and tumors in 2.
The results were analyzed of 175 patients with glottic squamous cell carcinomas who were treated with curative purposes (1970-1986). One hundred and sixteen of them underwent surgery at the Otolaryngology Department of the University of Florence, and 59 were treated by radiation therapy at the Florence University and Hospital Departments of Radiotherapy. In the surgical series 78 cases were treated with radical surgery and 38 with conservative surgery. All patients were staged according to TNM system (UICC 1978) as T2. Overall 10-year local control rates were 74% for the surgical series and 69% for the cases treated by radiation therapy. After salvage therapy 10-year survival rates were 83% and 76%, respectively. The analysis of the results showed no statistically significant difference. In the group treated by radical surgery 80% local control was observed, versus 66% in the cases treated with conservative surgery. 10-year survival rate was higher in the latter group (89% versus 81%) because of better results of salvage therapy: 7 of 10 recurrences were salvaged with the second treatment. Several prognostic factors were evaluated, i.e., T extent, anterior commissure involvement, subglottic invasion, vocal cord mobility impairment, and ventricular involvement. Anterior commissure involvement was the main factor affecting outcome in the surgical series: in the presence of this factor, 64% 10-year local control was observed versus 85% in the patients without commissure involvement. This factor proved more important in the patients treated with conservative surgery (10-year control: 42% versus 88%) than in those undergoing radical surgery (78% versus 85%). Anterior commissure involvement and the number of involved subsites were found to worsen prognosis in the series treated by radiation therapy: cases with anterior commissure involvement had 59% 10-year local control versus 83%. The cases with a deeper spread had 60% local control versus 75%. Vocal cord mobility impairment was a less important prognostic factor in both series. Our results suggest radiation therapy as a valuable method in the treatment of the small T2 laryngeal cancers which are not suitable for conservative surgery.
From 1975 to 1985, 161 patients affected by head and neck cancer (58 oropharynx, 67 oral cavity, 36 paranasal sinuses) were treated with radiotherapy using an accelerated fractionation (AF) schedule at the University and Hospital Radiotherapy Departments of Florence. Most cases, classified with U.I.C.C. and A.J.C. TNM (1978) were advanced (137/161 = 85%). Five-year actuarial local control and survival was 38% for the oropharynx, 18% and 20% for the oral cavity, and 38% and 31% for the paranasal sinuses. Results were analysed according to T and N stage as well. Severe late sequelae were evaluated in 53 patients without local disease and with a minimum follow-up of one year: 8 patients developed osteonecrosis; there were 3 cases of trismus, 2 cases of laryngeal oedema, one case of blindness and one case of ophthalmitis.
A retrospective analysis of the results obtained with curative radiation therapy in a series of 205 patients affected by early glottic cancer treated from 1970 to 1985 at the Florence University and Hospital Departments of Radiotherapy is presented. All patients were staged according to TNM System (UICC 1978) as T1-T2 NO. The overall 5-year local control rates were 88% for T1a, 75% for T1b, and 64 for T2. The main cause of failure was progression or recurrence in T (41/48); five failures were observed in T and N at the same time and two in N. Of these 48 patients, 21 (44%) were salvaged with surgery. After surgical salvage of radiation failures, the 5-year survival rates were 95%, 91%, and 73%, respectively, for T1a, T1b, and T2. The extent of T and the number of subsites involved significantly affected local control. Vocal cord mobility was less important. The incidence of failures and damages was analyzed according to the radiation beam, the size of the irradiated volume, fractionation, and total tumor dose.