Interobserver variability of clinical target volume delineation in soft-tissue sarcomas.

PURPOSE: The present observational study reports the results of a multi-institutional dummy-run designed to estimate the consistency of interobserver variability in clinical target volume delineation in two different cases of soft-tissue sarcomas in which postoperative and preoperative radiotherapy were prescribed, respectively. The purpose of this work was to quantify interobserver variability in routine clinical practice. PATIENTS AND METHODS: Two different cases of soft-tissues sarcomas were chosen: a case of postoperative and a case of preoperative radiation therapy. Participating centres were requested to delineate clinical target volumes according to their experience in both cases. Descriptive statistic was calculated for each variable (volume, diameters) separately for two cases. Box-whiskers plots were used for presentation of clinical target volume. A Shapiro-Wilk's test was performed to evaluate the departures from normality distribution for each variable. The comparison between relative variations of diameters was evaluated using the Student's t test. RESULTS: Several variations affecting both volumes and diameters were observed. Main variations were observed in the craniocaudal and laterolateral diameters. Each case showed similar dispersion, indicating a lack of reproducibility in volumes definition. CONCLUSIONS: This observational study highlighted that, in the absence of specific instructions or guidelines, the interobserver variability can be significant both in postoperative and preoperative radiotherapy of soft-tissue sarcomas.

Tumor stage, human papillomavirus and smoking status affect the survival of patients with oropharyngeal cancer: an Italian validation study.

BACKGROUND: Tumor human papillomavirus (HPV) status strongly affects overall survival (OS) of oropharyngeal cancer (OPC) patients. Recently, three groups with different outcomes were identified based on HPV status, smoking history and tumor stage. Our objective was to validate this model using a single-institutional retrospective database. PATIENTS AND METHODS: Patients (n=120) diagnosed with OPC at our institution, treated with concomitant cisplatin plus radiotherapy (RT) (n=64), induction chemotherapy followed by concomitant chemoradiation (n=39) or RT alone (n=17), were stratified in three groups with respect to the risk of death (low 26, intermediate 46 and high 49 patients) according to tumor p16 expression as surrogate of HPV status, pack-years of tobacco smoking and nodal/tumor stage. Group-stratified Kaplan-Meier OS curves were estimated and compared using the log-rank test. RESULTS: The 2-year OS estimates were 100%, 86% and 70%, respectively. The difference between the survival curves was statistically significant (P=0.009). The Harrell's concordance index was 0.70. The calibration plot showed a good concordance between our results and those observed in the original study. CONCLUSIONS: This study validates the risk grouping previously identified. Risk-driven clinical decision making and trial designs will help in better defining the most appropriate treatment in OPC patients.

Docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer.

BACKGROUND: This monocentric study evaluates the activity and tolerability of docetaxel (Taxotere), cisplatin and 5-fluorouracil (5-FU) (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) concurrent with high-dose cisplatin in Epstein-Barr virus -related locally advanced undifferentiated nasopharyngeal cancer. PATIENTS AND METHODS: We retrospectively reviewed the records of patients who received induction docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, and 5-FU 750 mg/m(2)/day (96-h continuous infusion). Following induction, patients received full doses of IMRT concurrently with cisplatin 100 mg/m(2) every 21 days for three cycles. RESULTS: Thirty patients received three TPF cycles (median). Induction was well tolerated; the main toxicity was neutropenia (33%, grade 3-4). During chemoradiotherapy, neutropenia (40%) and mucositis (43%) were the most frequent grade 3-4 adverse events. Mean dose of IMRT was 68.8 Gy. Worst late toxicity was xerostomia. Complete response rate was 93%. At 35 months, two patients had locoregional recurrence, three had distant metastases, and one had both. Three-year progression-free survival and overall survival were 79% [95% confidence interval (CI) 64% to 94%] and 87% (95% CI 74%- to 100%), respectively. CONCLUSIONS: In this high-stage nonendemic cancer population, TPF followed by high-dose cisplatin IMRT was promising; this treatment approach deserves evaluation in randomized trials.

Primary extremity soft tissue sarcomas: outcome improvement over time at a single institution.

BACKGROUND: To assess changes in survival over time of extremity soft tissue sarcoma (ESTS) patients treated at a single reference institution. PATIENTS AND METHODS: Patients with primary localized adult-type ESTS surgically treated at our institution between 1987 and 2007 were retrospectively reviewed. Patients were categorized into four 5-year groups according to the timing of their first operation. Crude cumulative incidence (CCI) of sarcoma-specific mortality (SSM), local recurrence (LR), and distant metastases (DMs) were calculated for each time period. RESULTS: A total of 1094 patients were identified. Median follow-up was 81 months. CCI of SSM and LR were significantly better in period 4 in comparison to periods 1-3 (P < 0.001 for both end points), dropping, respectively, from 15% to 6% and from 23% to 9%. An overall improvement of DMs-free survival at 5 years could be detected in the latter period, as well as a better postmetastasis survival. CONCLUSIONS: Reference institutions for sarcomas may have improved their outcome in the last years. Although biases of retrospective analyses as well as the effect of institutional learning curves need to be discounted, it is possible that optimal exploitation of a series of subtle improvements in sarcoma treatment may make a difference in results currently achievable.

Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution.

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 (

Prediction of TP53 status for primary cisplatin, fluorouracil, and leucovorin chemotherapy in ethmoid sinus intestinal-type adenocarcinoma.

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.

Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution.

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.

The role of radiotherapy in the management of elderly cancer patients in light of the GROG experience.

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.

Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial.

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.

Continuous quality improvement in radiotherapy: implementation methodology and comparison of experiences.

The Quality System (QS) was applied in the Italian Health Service in the late nineties with the identification of a methodology whose focus is also on nonspecific subjects which however are involved in health promotion. The quality handbook represents an instrument of QS, where the documentation and procedures which can make the policy and goals of a center accurately and extensively known, are collected. Continuous quality improvement is characterized by the adoption of the assessment culture according to dynamic processes. Since several years, in Italy, documents indicating the requirements, resources and goals radiotherapy centers should aim at, are being prepared together with the identification of means suitable for quality assurance in radiotherapy.

[Supportive therapy in oncology]. / Le terapie di supporto in oncologia.

The current trend towards a more intensive cancer treatment is possible thanks to the availability of a really important and effective supportive care. It is our opinion that it would be essential for the junior staff in oncology, for the practitioners, but also for the knowledge of anyone contributing in different ways to give the cancer treatment, to have reference points to give also the best supportive care. With this aim we thought to start a study, in Italy, to investigate, first, which is the supportive care used in the most common acute toxicities during or immediately after cancer therapy. We decided to begin with a survey addressed to hematologists, medical oncologists, radiotherapists; 105 centers were contacted. In order to have a high number of people able to answer to different clinical questions we decided to use Internet to communicate with participating centers without moving people. The final goal of the project is to formulate guidelines in supportive care, but also to promote the use of Internet as much as possible in the medical world with the aim to make easier every kind of communication and exchange of information.

Randomized trials on altered fractionation in head and neck cancer radiotherapy with conventional fractionation as control arm: another lap to go.

The Authors present a review of randomized trials on non conventional fractionation in head and neck cancer radiotherapy with conventional fractionation as control arm. Hyperfractionation was studied in 5 trials, accelerated hyperfractionation in 4 trials and accelerated fractionation in 3 trials. Furthermore, the reviews of eminent Authors dealing with the above mentioned trials are summarized. In spite of improved local control rate reported with hyperfractionation, non conventional radiotherapy schedules are not yet recommended as routine clinical practice, but all the radiation oncologists are Invited to join trials on this subject.

[Supportive care in oncology]. / Le terapie di supporto in oncologia.

It is extremely important to deliver treatments, both in medical oncology and in radiation oncology, in compliance with the due dose intensity, in order to achieve the best results in terms of clinical response and local control and, often, also in terms of survival. Supportive care is one of the tools for the achievement of this goal, permitting the delivery of aggressive therapies and the improvement of Quality of Life. It is the aim of the Tsonc study to evaluate what the main therapeutic trend is, on the ground of a survey performed in 105 medical oncology, radiation oncology, and haematology centres. For this assessment the WHO/INH and RTOG common toxicity criteria were adopted, even knowing that these score systems had been developed for reporting acute/subacute toxicity and not to choose the therapeutic approach. However, these scales give us the possibility to refer to highly validated systems and provide participants with a common language. Thirty-two items of toxicity were listed, and each item included 2 to 4 degrees of severity so to report supportive care accordingly. The present paper reports the criteria of choice of the scales and symptoms and the schedule of the queries.

Hyperfractionated and accelerated radiation therapy in central nervous system tumors (malignant gliomas, pediatric tumors, and brain metastases).

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.

Nonstandard fractionation schedules in radiation therapy of head and neck cancer: a review.

The authors present an updated review of the clinical trials on hyperfractionated and accelerated fractionation schedules in radiotherapy of head and neck cancer. The available results in terms of survival and local control, and acute and late toxicity data are summarized in order to show the current status of this research field. The new breed of fractionation schedules that are on study, designed on the ground of new rationales, are presented as well. Finally, an introductory overview of combination therapy including non standard fractionation radiotherapy associated with chemotherapy is reported.

Radiotherapy in the aged.

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.

Radiotherapy in the elderly with lung carcinoma: the experience of the Italian "Geriatric Radiation Oncology Group".

One hundred ninety-six patients aged > or = 70 years, with non small-cell lung carcinoma and no evidence of metastasis on staging, observed over a 6-month period in 20 Italian Radiotherapy Centers, were analyzed in order to assess indications for treatment, tolerance of radiotherapy (assessed in terms of completion of planned doses and toxicity), and quality of life using the Performance Status and a concise activity of life test. Of the 196 patients studied in 20 Italian Centers, 182 (98%) underwent radiotherapy, 109(60%) of whom with radical intent and 73 (40%) with palliative intent. Of 179 assessable patients undergoing radiation treatment, 163 (91%) completed the treatment as originally planned. Of the 64 assessable patients who completed palliative radiotherapy, relief of symptoms was observed in a percentage ranging from 78% to 86%. Analysis of parameters assessing the quality of life, showed no significant differences in general and functional conditions, as assessed before and upon completion of radiotherapy.

Radiotherapy in the elderly: a multicentric prospective study on 2060 patients referred to 37 Italian radiation therapy centers.

60-70% of all cancers will develop in the year 2000 in persons aged 65 and over. Radiation therapy will play a major role in the treatment of cancer, especially in the elderly. The Italian "Geriatric Radiation Oncology Group" (GROG) performed in 1994 a prospective study, in order to assess the characteristics of any old cancer patient referred to radiation oncology centers (age, gender performance status, comorbidity, activities of daily living, family status) and the main features of the tumor in that patient. In about 6 months 2060 patients aged 70 and over entered the study, of whom 1809 were treated with radiotherapy alone, with curative intent in 563 patients, in combination with surgery and/or chemotherapy in 476 and with palliative intent in 769 patients. Most patients had grade 0-1 acute toxicity.