Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. Aberrant tyrosine kinase activity influences tumor growth and is regulated by phosphorylation. We investigated phosphorylated kinases as target in PDAC. METHODS: Mass spectrometry-based phosphotyrosine proteomic analysis on PDAC cell lines was used to evaluate active kinases. Pathway analysis and inferred kinase activity analysis was performed to identify novel targets. Subsequently, we investigated targeting of focal adhesion kinase (FAK) in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Tyrosine phosphoproteomics upon treatment was performed to evaluate signaling. An orthotopic model of PDAC was used to evaluate the combination of defactinib with nab-paclitaxel. RESULTS: PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases to various degree. The non-receptor kinase, FAK, was identified in all cell lines by our phosphotyrosine proteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo. CONCLUSIONS: Our study shows high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel against this devastating disease.

Co-expression analysis of pancreatic cancer proteome reveals biology and prognostic biomarkers.

PURPOSE: Despite extensive biological and clinical studies, including comprehensive genomic and transcriptomic profiling efforts, pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease, with a poor survival and limited therapeutic options. The goal of this study was to assess co-expressed PDAC proteins and their associations with biological pathways and clinical parameters. METHODS: Correlation network analysis is emerging as a powerful approach to infer tumor biology from omics data and to prioritize candidate genes as biomarkers or drug targets. In this study, we applied a weighted gene co-expression network analysis (WGCNA) to the proteome of 20 surgically resected PDAC specimens (PXD015744) and confirmed its clinical value in 82 independent primary cases. RESULTS: Using WGCNA, we obtained twelve co-expressed clusters with a distinct biology. Notably, we found that one module enriched for metabolic processes and epithelial-mesenchymal-transition (EMT) was significantly associated with overall survival (p = 0.01) and disease-free survival (p = 0.03). The prognostic value of three proteins (SPTBN1, KHSRP and PYGL) belonging to this module was confirmed using immunohistochemistry in a cohort of 82 independent resected patients. Risk score evaluation of the prognostic signature confirmed its association with overall survival in multivariate analyses. Finally, immunofluorescence analysis confirmed co-expression of SPTBN1 and KHSRP in Hs766t PDAC cells. CONCLUSIONS: Our WGCNA analysis revealed a PDAC module enriched for metabolic and EMT-associated processes. In addition, we found that three of the proteins involved were associated with PDAC survival.

Percutaneous radiofrequency ablation using internally cooled wet electrodes for the treatment of patients with lung tumors.

OBJECTIVE: To assess the safety and feasibility of computed tomography-guided radiofrequency ablation (CT-guided RFA) in unresectable lung neoplasms, using a new 15G monopolar internally cooled wet electrode. PATIENTS AND METHODS: 15 consecutive patients with lung neoplasms (< 4 cm), both primary and secondary, unsuitable for or refusing surgery, underwent percutaneous CT-guided RFA using a 15G electrode with a 3-cm exposed tip. The prevalence and grade of adverse events and technical success were evaluated, as well as the extension of the ablation zone, the complete response rates, and the time to progression, determined at CT examination performed 1, 6, and 12 months after the procedure. RESULTS: A total of 22 lung neoplasms were treated (mean diameter: 28 mm; range: 20-39 mm). Technical success was obtained in all patients, without major complications or intraprocedural deaths. Mild or moderate pneumothorax was registered in 46.7% of patients, while a perilesional hemorrhage was observed in 5/15 cases. During the follow-up period, a complete response was obtained in 19 out of 22 lesions (86.4%) with three partial response, two of them successfully retreated with the same technique. CONCLUSIONS: Percutaneous RFA using a 15G internally cooled wet electrode is a safe and feasible treatment for unresectable lung neoplasms, with high complete response rates.

PRODIGE: PRediction models in prOstate cancer for personalized meDIcine challenGE.

AIM: Identifying the best care for a patient can be extremely challenging. To support the creation of multifactorial Decision Support Systems (DSSs), we propose an Umbrella Protocol, focusing on prostate cancer. MATERIALS & METHODS: The PRODIGE project consisted of a workflow for standardizing data, and procedures, to create a consistent dataset useful to elaborate DSSs. Techniques from classical statistics and machine learning will be adopted. The general protocol accepted by our Ethical Committee can be downloaded from cancerdata.org . RESULTS: A standardized knowledge sharing process has been implemented by using a semi-formal ontology for the representation of relevant clinical variables. CONCLUSION: The development of DSSs, based on standardized knowledge, could be a tool to achieve a personalized decision-making.

Concurrent and adjuvant temozolomide-based chemoradiotherapy schedules for glioblastoma. Hypotheses based on two prospective phase II trials.

AIM: To investigate the impact of nonstandard concomitant temozolomide (TMZ) administration in two prospective phase II studies for glioblastoma (GBM). PATIENTS AND METHODS: From October 2000 to June 2008, 104 patients were enrolled in two studies: 25 in RT-TMZ-10.00 and 79 in RT-TMZ-01.04. Adjuvant radiotherapy (RT) was used with a total dose of 59.4 Gy (1.8 Gy/day). Patients received concomitant TMZ (75 mg/m(2)/day) from Monday to Friday during the first and last weeks of RT in the RT-TMZ-10.00 study and from Monday to Friday during all weeks of RT in the RT-TMZ-01.04 trial. Adjuvant TMZ (200 mg/m(2)) was administered for 5 days every 28 days. RESULTS: Median progression-free (PFS) and overall survival (OS) were 9 and 16 months, respectively, with no significant difference between the two groups (p = 0.5 and 0.14, respectively). The 2- and 5-year OS rates were 32 and 3 %, respectively, and similar to those observed with standard treatment regimens. CONCLUSION: Our data support the hypothesis that adjuvant TMZ is more important than concomitant chemotherapy (CH) and that RT is the more important element of the concomitant treatment schedule.

Targeted "bone-seeking" radiopharmaceuticals for palliative treatment of bone metastases: a systematic review and meta-analysis.

AIM: The aim of the study was to assess the state of the art of the use of bone-seeking radiopharmaceuticals for palliation therapy of pain from bone metastases. METHODS: A systematic literature search was conducted about therapy with 89Sr-chloride and 153Sm-EDTMP between 2001-2011. The primary outcomes were efficacy and toxicity. Descriptive and quantitative data were extracted from each study, calculating event rates and odds ratio (OR) with 95% confidence intervals (CI) for pooled analysis. Subgroup analyses were performed. RESULTS: Fifty-seven studies contributed to the systematic review. Forty-six studies used radiopharmaceuticals as a single agent, 15 investigated therapeutic combinations. Most of the studies included patients with prostate cancer. The overall efficacy of bone-seeking radiopharmaceuticals as single agents was 70%, whereas it was 74% when used in combination with other therapies. Complete response was reported in 27% of patients. Efficacy resulted to be 70% for prostate cancer and 79% for breast cancer. The overall toxicity of radiopharmaceuticals was 15%: the toxicity was 11% selecting only studies reporting on the use of radiopharmaceuticals as a single agent. No significant difference was found between bone-seeking radiopharmaceuticals and other oncological treatments regarding efficacy or toxicity. Reports of objective response outcomes suggest that bone-seeking radiopharmaceuticals have some cytotoxic activity, either alone or combination with chemotherapy. CONCLUSION: This literature analysis emphasizes multiple evidences of high efficacy and low toxicity of bone seeking radiopharmaceuticals; moreover, this therapy may have a therapeutic potential beyond simple palliation of bone pain.

Identification of melanoma with a gas sensor array.

BACKGROUND/PURPOSE: The relationship between diseases and alterations of the airborne chemicals emitted from the body has been found in many different pathologies and in particular for various forms of cancer. Metabolism of cancer cells is greatly altered during their lifetime; then, modification of chemicals is supposed to be large around cancer tissues. Positive hints in this direction were provided, as an example, on studying the breath composition of lung cancer-affected subjects. Besides the conventional analytical approaches, in recent years sensor arrays were also applied to these researches considering the chemical composition changes as those occurring in other applications such as for instance, those dealing with food quality measurements. METHODS: In this paper, the first application of sensor arrays to study the differentiation between melanomas and nevi, namely malignant and benign affection of melanocytary cells, respectively, is presented and discussed. The localization of lesions on the skin surface made possible the utilization of differential measurements aimed at capturing the differences between two adjacent skin regions. This approach strongly reduces the influence of skin headspace variability due to the peculiar subjective odour background and the skin odour variability. The measurement campaign involved 40 cases; 10 of these were diagnosed melanomas referred to surgical intervention. Nine of these diagnoses were further confirmed by histological examinations of the removed tissue and one was a false positive. RESULTS: The differences in the chemical composition of headspace were verified with a gas-chromatographic investigation, and the classification of electronic nose data provided an estimated cross-validated accuracy of the same order of magnitude as the currently used diagnostic instruments. CONCLUSION: Electronic nose sensors have been shown to have good sensitivity towards volatile organic compounds emitted by skin lesions, and the method seems to be effective for malign lesions identification. The results presented in this paper encourage a second experimental campaign with a larger number of participants and a systematic use of gas chromatography mass spectrometer technology in order to identify some possible melanoma biomarkers.

Locoregional pain treatment. Troubles and prospectives: antalgic radiotherapy.

Pain control in patients with cancer represents a significant aspect of radiation therapy practice. Radiation therapy is one of the most effective, and often the only, therapeutic option to relieve pain caused by nerve compression or infiltration by malignant tumor, pain from liver and bony metastases and it provides also successful palliation of dysphagia caused by oesophageal carcinoma and of pain due to pancreatic cancer. Various instruments are avaliable for pain evaluation but a valid methodology to assess the pain status in the patient with cronic cancer pain is still an important clinical problem. In this complex and wide scene this contribution wants to confirm the role of radiotherapy in cancer pain control, in paricular in bone metastases, and to involve the patient himself in the survey of radiation treatement response by a subjective evaluation of bone pain, elaborating a reliable and valid unidimensional method by which recording the self-rating of the patient's sensation. Materials and Methods For the subjective evaluation of pain caused by bone metastases we used an application form with which drawing information in the course of time in terms of: response to the treatment, duration of symptom relief and quality of life. Results Considering as cut-off a dose of 30 Gy, which is commonly considered the conventional treatment for bone metastases, the partial and complete response were, respectively, of 54% and 30% in the patients treated with dose higher than or equal to 30 Gy, and 60% and 20% in the ones treated with doses lower than 30 Gy. In the whole, in 84 patients, the global response was of 82%, in accordance with literature. Conclusion In this retrospective study, the analysis of patient's subjective experience confirmed the effectiveness of radiotherapy in reducing pain caused by bone metastases and in improving quality of life of the patient himself. Given the conflicting opinions on low-dose short-course radiotherapy versus prolonged or higher dose schedules on initial pain relief, we are going to define categories of homogenous patients on whom starting treatment schedules with the aim or of palliation of the symptom or of the functional restitutio, on the base of the expectation and the quality of life.

Ten years of preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation in three consecutive studies.

PURPOSE: To compare acute toxicity, tumor response, and sphincter preservation in three schedules of concurrent chemoradiation in resectable transmural and/or node-positive extraperitoneal rectal cancer. PATIENTS AND METHODS: Between 1990 and 1999, 163 consecutive patients were treated according to the following combined modalities: FUMIR: between 1990 and 1995, 83 patients were treated with bolus i.v. mitomycin C (MMC), 10 mg/m(2) day 1, plus 24-h continuous infusion i.v. 5-fluorouracil (5-FU) 1,000 mg/m(2) days 1-4, and concurrent external beam radiotherapy (37.8 Gy). PLAFUR-4: between 1995 and 1998, 40 patients were treated with cisplatin (c-DDP) 60 mg/m(2) given as slow infusion (1-4 h) on days 1 and 29, plus 24-h continuous infusion i.v. 5-FU 1,000 mg/m(2), days 1-4 and 29-32 with concurrent external-beam radiotherapy (50.4 Gy). PLAFUR-5: between 1998 and 1999, 40 patients were treated with c-DDP 60 mg/m(2) given as slow infusion (during 1-4 h) on days 1 and 29, plus 24-h continuous infusion i.v. 5-FU 1,000 mg/m(2), days 1-5 and 29-33 with concurrent external-beam radiotherapy (50.4 Gy). RESULTS: Grade > or = 3 acute toxicity occurred in 14%, 5%, and 17% of patients treated in the FUMIR, PLAFUR-4, and PLAFUR-5 studies, respectively (p = 0.201). In the FUMIR, PLAFUR-4, and PLAFUR-5 studies, clinical response rate was 77%, 70%, and 83%, respectively. Tumor downstaging occurred in 57%, 68%, and 58% of patients, respectively. Pathologic complete response was recorded in 9% (FUMIR), 23% (PLAFUR-4), and 20% (PLAFUR-5) of patients. Sphincter-preserving surgery was feasible in 44% (FUMIR), 40% (PLAFUR-4), and 61% (PLAFUR-5) of patients having a distance between the anal-rectal ring and the lower pole of the tumor of 0-30 mm, and in 95%, 100%, and 100%, respectively, in those having a distance of 31-50 mm. Comparing FUMIR vs. PLAFUR, the clinical response rate was similar in the two series: a partial response was observed in 62/81 (77%) patients with FUMIR treatment, and in 61/80 (76%) patients with PLAFUR treatment. Tumor downstaging was observed in 46/81 (57%) patients and in 50/80 (68%) patients, respectively. The pathologic complete response rate was statistically higher in the PLAFUR series: 7/81 (9%) patients with FUMIR treatment and 17/80 (21%) patients with PLAFUR treatment (p = 0.04). Major downstaging (pT0+ pTmic+ pT1) in the FUMIR group was reported in 12/81 (15%) patients versus 31/80 (39%) patients in the PLAFUR group (p = 0.0006). The anal sphincter was preserved in 63/81 (78%) patients with FUMIR treatment and in 69/80 (86%) patients with PLAFUR treatment. The perioperative morbidity was statistically lower with PLAFUR: a perioperative morbidity was experienced by 20/81 (25%) patients with FUMIR treatment and by 9/80 (11%) patients with PLAFUR treatment (p = 0.042). CONCLUSION: In our experience, higher radiation dose (50.4 Gy vs. 37.8 Gy), a second course of concurrent 5-FU, and the use of c-DDP instead of MMC improved the pathologic response rate without increasing acute toxicity and perioperative morbidity. The use of 5-FU 5-day infusion (PLAFUR-5) resulted in higher toxicity with a similar response rate compared to 4-day infusion (PLAFUR-4).

Ten year experience with induction therapy in locally advanced non-small cell lung cancer (NSCLC): is clinical re-staging predictive of pathological staging?

OBJECTIVE: To verify if in our experience with 'induction therapy' in non-small cell lung cancer (NSCLC) the clinical re-staging is really predictive of pathological staging. MATERIALS AND METHODS: From January 1990 to February 2000, 136 patients with locally advanced NSCLC underwent a protocol of induction therapy according to three different treatment plans: Carboplatin + radiotherapy--study A; Cisplatin + 5-Fluorouracil + radiotherapy--study B; Gemcitabine + radiotherapy--study C. RESULTS: Clinical re-staging showed in the patients enrolled in study A a clinical Complete Response rate (cCR) of 2.3%; a clinical Partial Response rate (cPR) of 50%; a clinical Stable Disease (cSD) rate of 44.3%; a clinical Disease Progression (cDP) rate of 3.4%. In study B, cCR was 0%; cPR: 71.4%; cSD 10.7%; cDP: 17.9%. In study C, cCR was 0%; cPR: 23.5%; cSD: 11.8%; cDP: 64.7%. After clinical re-staging, 76 patients (47 group A; 23 group B; 6 group C) were judged to be resectable and underwent a surgical operation. Pathological staging showed no tumour in eight patients (10.5%; 8/76) (three in study A, four in study B, one in study C) and microscopic neoplastic remnants in seven (9.2%; 7/76). Thirty-nine patients were pN0. Overall downstaging rate in the operated patients was 51%. No precise correlation was found among clinical re-staging and pathological staging. We had two cCRs and eight pCRs, and all of these pCRs had been re-staged as cPR except in one case (cSD). In seven cases, where only microscopic remnants have been found, six had been clinically restaged as cPR and one as cSD. CONCLUSIONS: Our experience confirmed how often the clinical re-staging data are unreal. Accordingly surgery should be indicated in any case where an induction therapy has been administered, if it is reasonably possible.

Quality handbook in radiotherapy: personal experience.

The Quality Handbook includes the description of the activities carried out in Radiotherapy and the methodology used to ensure the Quality Assurance according to the principles indicated in national and international documents of reference and the recommendations of accreditation agencies. The structure of the Quality Handbook, the main aspects of single chapters, the selected quality indicators undergoing inspections are analysed and procedures to be followed for changes and updating of the Quality Handbook are described. The Quality Assurance program is illustrated in another article of this issue.

Quality handbook in radiotherapy. Brachytherapy: personal experience.

Brachytherapy is a conventional method of radiation therapy characterized by peculiar technical, clinical, operational and radioprotection problems. Therefore, the management of a service or department of brachytherapy requires a specific organization aimed at Quality Assurance. In this report, the personal experience with the drawing up of a Quality Handbook of brachytherapy with reference to the method used and the structure of the document, is described.

Quality assurance in radiotherapy: personal experience.

The approach to the implementation of a Quality Assurance Program applied from 1 October 2000 at the Radiotherapy Service of the "Università Cattolica del S. Cuore, Policlinico "A. Gemelli" of Rome, is described. Some major aspects of this program are analyzed.

Radiotherapy versus follow-up in the treatment of pathological stage Ia and Ib non-small cell lung cancer. Early stopped analysis of a randomized controlled study.

OBJECTIVE: This is an analysis of a randomized controlled clinical trial planned to evaluate the effects of adjuvant radiotherapy (AR) on the local recurrence rate in patients with non-small cell lung cancer (NSCLC) with pathological stage (pStage) Ia (pT1N0) and Ib (pT2N0). The effects of AR on the long-term survival have also been marginally evaluated. MATERIALS AND METHODS: This clinical trial was planned with the hypothesis that AR on pStage Ia and Ib, R0 NSCLCs was effective on local recurrence rate. From July 1989 through March 1997, 104 patients with NSCLC who presented with pStage Ia and Ib have been observed and treated and entered the study. Male/female ratio was 91:13; the mean age was 62 years (range 41-75 years). All patients underwent major pulmonary resection and homolateral standard hilar and mediastinal lymph node dissection. pStage was T1N0 in 29 and T2N0 in 75 cases. Patients have been randomized 'by chance' into two groups (G1 and G2). G1 received radiotherapy, G2 did not receive any adjuvant treatment. Fifty-two patients entered G1 and 52 entered G2. RESULTS: Post-operative mortality was nil. Seven patients have been excluded from the study (four in G1 and three in G2), due to incomplete follow-up data. We do not report any radiotherapy-related complication or deterioration of lung function. The treatment effect on the local recurrence rate demonstrated a clearly significant protective effect of the AR. No statistically significant difference was found from the comparison of the 5-year survival rate of the treated (83%) versus untreated (70%) patients. No detrimental effect of the radiotherapy has been assessed. CONCLUSIONS: AR in the treatment of pStage Ia and Ib NSCLC has been well tolerated and had a significant relative effect on the local recurrence rate but did not significantly modify overall survival even if a positive trend in the group of treated patients is reported.

Research trends in the treatment of colorectal cancer.

Colorectal carcinoma ranks second in incidence after lung cancer in males and breast carcinoma in females. Within the clinical research on this tumor, new molecules of antineoplastic agents and new combined modality treatments have been introduced. From the examination of ongoing protocols some trends can be identified: the interest in immunotherapy and genetic therapy, frequently tested in combination with chemotherapy; the effort at the optimization of the administration of antineoplastic agents in the most common sites of metastatic lesions by hepatic or intraperitoneal infusion; the trend to a more aggressive treatment of metastastatic lesions with hyperthermia and cryoablation as well with the combination of systemic therapy and surgery. As far as radiotherapy is concerned, the main goals of clinical research seem represented by the need to optimize combined modality therapy in T3-4 rectal carcinoma both in terms of pre- and postoperative radiotherapy timing as well as of the combination with adjuvant chemotherapy. There is a growing interest in new drugs which in the future may replace the conventional 5-fluorouracil in concurrent chemoradiation.

Advances in the treatment of lung cancer: economic and organizational aspects.

The organizational optimization in radiotherapy tends to a correct balance of quality of service and containment of health care expenditure; this goal is necessarily correlated with the real potentialities available to each center while considering the possible clinical benefits for the patient. In lung cancer, outcomes achieved with radiation therapy are encouraging in terms of local control and survival when treatment is performed with the available modern technology whose costs from an exclusively economic analysis are shown to be still quite high. In an assessment focused on clinical outcomes, better local control, higher survival and improved quality of life represent tangible benefits: this has a positive impact on community costs and may represent a high priority goal for health care providers, yielding a benefit that can be quantified with the most recent analyses of health care economy.

Preoperative chemoradiation with cisplatin and 5-fluorouracil for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, sphincter preservation.

PURPOSE: To evaluate the impact of preoperative external radiation therapy intensified by systemic chemotherapy including bolus cisplatin (c-DDP) and 4-day infusional 5-fluorouracil (PLAFUR-4) on tumor response and sphincter preservation in patients with extraperitoneal T3 rectal cancer with acceptable toxicity, and to compare the results to our previous experience with bolus mitomycin c (MMC) and 4-day infusion 5-FU (FUMIR). METHODS AND MATERIALS: Between October 1995 and March 1998, 40 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: slow infusion i.v. c-DDP, 60 mg/m2, day 1 and 29 plus 24-h continuous infusion i.v. 5-fluorouracil (5-FU) 1000 mg/m2, days 1-4 and 29-32, and concurrent external beam radiotherapy (45 Gy whole pelvis followed by 5.4 Gy boost). All but 3 patients had T3 disease. Surgery was performed 6-8 weeks after the end of chemoradiation. RESULTS: No patient had Grade 4 acute toxicity. Grade 3 hematological toxicity was observed only in 2 (5%) patients. No patient had major gastrointestinal, skin, or urological acute toxicity. All patients had radical surgery. There was no perioperative mortality; perioperative morbidity rate was 12%. Overall, 23% (9 of 40) of patients had a complete pathological response and 10% (4 of 40) of patients had rare isolated residual cancer cells (Tmic). Comparing the stage at the diagnostic workup with the pathological stage, tumor downstaging was observed in 27 (68%) patients; nodal status downstaging was detected in 24 (60%) patients. Thirty-four (85%) patients had a sphincter-saving surgical procedure. In 4 of 10 (40%) patients who were definitive candidates for an abdominoperineal resection (APR), the sphincter was preserved, as it was in 13 of 13 (100%) probable candidates. Lengthening of the distance between the anorectal ring and the lower pole of the tumor > or =20 mm was observed in 9 (23%) patients. None of the patients had soilage after the sphincter-saving procedure. In our previous experience with FUMIR the complete pathological response was 9%, the sphincter-saving surgical procedure was performed in 66% cases, and the Grade 3+ toxicity was observed in 13% of patients. CONCLUSIONS: The addition of c-DDP to 5-FU (PLAFUR-4) in a neoadjuvant radiochemotherapy schedule improved the pathological response rate in comparison with our previous experience. Toxicity was low indeed, thus we commenced another study adding one more day of 5-FU infusion (PLAFUR-5) to further improve our results.

[Indications for elective neck dissection in malignant epithelial parotid tumors]. / Indicazioni allo svuotamento linfonodale latero-cervicale elettivo nelle neoplasie maligne epiteliali della parotide.

The purpose of the present study was to define the indications and extension for the treatment of lymph nodes in clinically NO patients with primary malignant epithelial parotid tumors. A retrospective analysis was performed on 46 cases with such tumor out of 307 parotid neoplasms (246 benign, 61 malignant) consecutively treated from 1985 to 1994. Lymph node metastases were present only in the histotypes with a high degree of malignancy (overall incidence, 24%). Two patients (5%) showed occult metastases. No correlation was found between the size of the neoplasm and the incidence of lymph node metastases. However, the latter were significantly more common in locally highly aggressive neoplasms (class "a"), 8%; class "b" 43%; P = 0.006). Due to the small number of cases, it was not possible to correlate the incidence of occult metastases with neoplasm size or local extension. As regards topographic distribution of lymph node metastases, level II was always involved, level V was never involved, and level i.v was involved only when metastases were found in the upper levels. Occult metastases were found only at level II. Over a follow-up period of 2 to 10 years, no cases were seen with cervical recurrences. Although drawn from a limited series, the results are similar to the data generally reported in the literature, showing that lymph node metastases are rare in neoplasms with a low grade of malignancy whereas there is a significant increase in the incidence of metastatic lymph nodes and occult metastases when the grade of malignancy is high. In conclusion, in clinically NO patients, a suprahomohyoid neck dissection (levels I-II-III) is indicated only when the neoplasm shows a high grade of malignancy or when it is a class "b" malignancy. In the other cases, neck dissection is determined by the clinical evidence of metastasis and can be extended to the lower levels. Neck dissection can be avoided in NO patients whenever ultrasound and fine needle biopsy are both routinely used in the preoperative evaluation of the cervical lymph nodes.

Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation.

PURPOSE: To evaluate whether or not an intermediate dose of preoperative external radiation therapy intensified by systemic chemotherapy could improve the tumor response, sphincter preservation, and tumor control. METHODS AND MATERIALS: Between March 1990 and December 1995, 83 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: bolus i.v. mitomycin C (MMC), 10 mg/m2, Day 1 plus 24-h continuous infusion i.v. 5-fluorouracil (5FU) 1000 mg/m2, Days 1-4, and concurrent external beam radiotherapy (37.8 Gy). All but 2 patients had T3 disease. Surgery was performed 4-6 weeks after the end of chemoradiation. RESULTS: Total Grade 3-4 acute toxicity during chemoradiation was observed in 11 (13%) patients: hematological Grade 3 toxicity was recorded in 8 (10%) patients, and Grade 4 toxicity was recorded in 2 (2%) patients. Grade 3 diarrhea was seen in 2 (2%) patients. No patient had major skin or urological acute toxicity. Two patients had no surgery: 1 died before surgery from septic complications after Grade 4 hematological toxicity; 1 refused surgery and is still alive after 6 years. There was no postoperative mortality and the overall perioperative morbidity rate was 25%. The analysis of tumor response involved 81 patients. Overall, 9% (7) of 81 patients had a complete pathologic response. Comparing the stage at the diagnostic workup with the pathologic stage, tumor downstaging was observed in 46 (57%) patients. We had 7 (9%) pT0, 5 (6%) pT1, 33 (41%) pT2, and 36 (44%) pT3. Nodal status downstaging was detected in 46 patients (57%). No evidence of nodal involvement was observed in 59 patients (73%). The incidence of tumor response was affected significantly by the number of quarters of rectal circumference involved (p = 0.03) and, marginally, by the length of the tumor (p = 0.09). The distance between the lower pole of the tumor and the anorectal ring had no influence. Of the patients, 63 (78%) had a sphincter-saving surgical procedure. In 12 (44%) of 27 patients candidate for an APR, the sphincter was preserved, as it was in 19 (95%) of 20 probable candidates. Lengthening of the distance between the anorectal ring and the lower pole of the tumor > 20 mm was observed in 21 patients (26%). Of 63 patients, 4 (6%) had moderate soilage after the sphincter-saving procedure. CONCLUSION: Preoperative combined modality therapy seems to afford some potential advantages in nonrandomized trials: patients are able to tolerate higher chemotherapy doses and they experience a lower acute toxicity. Tumor downstaging and resectability rates are high; sphincter preservation is feasible. Larger T3 tumors remained less influenced by this treatment; thus, taking into account the low toxicity rate recorded, a more aggressive schedule should be applied in these resectable tumors.

Radiotherapy and local control in rectal cancer.

Recurrence is a stage in the natural history of rectal cancer. Preoperative radiotherapy or postoperative radiochemotherapy lower the rate of recurrence, improving local control. From 1980 to 1997, at the "Divisione di Radioterapia" of the "Università Cattolica del S. Cuore" of Rome 380 patients with rectal cancer of early clinical stage T2-3, candidates for surgery for cure, underwent radiation therapy. 119 patients underwent postoperative radiotherapy (45-50 Gy); 45 patients underwent "sandwich" radiotherapy (45 Gy:27 Gy before and 28 Gy after surgery), of whom 7 were treated with preoperative radiotherapy alone; 145 patients underwent preoperative concomitant radiochemotherapy according to 3 different protocols, radiotherapy (38 Gy) combined with mitomycin C and 5-FU; radiotherapy (50.4 Gy) combined with cisplatin and 5-FU; radiotherapy (45 Gy) combined with 5-FU and folinic acid. 71 patients were treated with preoperative radiotherapy (38 Gy) combined with IORT (10 Gy). Median follow-up was 6 years. Overall local control was 85% at 3 years, 83% at 5 years, 81% at 10 years. The rate of local control at 5 years was: 76% for postoperative radiotherapy, 83% for "sandwich" radiotherapy, 84% for preoperative radiochemotherapy and 93% for preoperative radiotherapy combined with IORT. Local control was shown to be significantly better with preoperative treatment as compared to postoperative treatment (p = 0.02). The incidence of metastases was 35% in the patients with local recurrence and 16% in those with local control. The difference in survival was highly significant in patients with local control as compared to those with local recurrence: at 5 years 87% and 32% respectively. Patients with local control showed a lower incidence of metastasis and a better survival.