A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy.

BACKGROUND: This pivotal phase III trial evaluated the efficacy and safety of palonosetron in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: Patients were randomized to a single intravenous dose of palonosetron 0.25 mg or 0.75 mg, or ondansetron 32 mg prior to HEC. Dexamethasone pre-treatment (with stratification) was used at investigator discretion. The primary efficacy endpoint was the proportion of patients with complete response (CR) during the first 24 h post-chemotherapy (acute phase). RESULTS: In the intent-to-treat analysis (n = 667), palonosetron 0.25 mg and 0.75 mg were at least as effective as ondansetron in preventing acute CINV (59.2%, 65.5%, and 57.0% CR rates, respectively); CR rates were slightly higher with palonosetron than ondansetron during the delayed (24-120 h) and overall (0-120 h) phases. Two thirds of patients (n = 447) received concomitant dexamethasone. Patients pre-treated with palonosetron 0.25 mg plus dexamethasone had significantly higher CR rates than those receiving ondansetron plus dexamethasone during the delayed (42.0% versus 28.6%) and overall (40.7% versus 25.2%) phases. Palonosetron and ondansetron were well tolerated. CONCLUSIONS: Single-dose palonosetron was as effective as ondansetron in preventing acute CINV following HEC, and with dexamethasone pre-treatment, its effectiveness was significantly increased over ondansetron throughout the 5-day post-chemotherapy period.

Biweekly oxaliplatin, raltitrexed, 5-fluorouracil and folinic acid combination chemotherapy during preoperative radiation therapy for locally advanced rectal cancer: a phase I-II study.

Oxaliplatin (OXA), raltitrexed (RTX), 5-fluorouracil (FU) and folinic acid (FA) have shown activity in metastatic colorectal cancer, radioenhancing effect and synergism when combined. We evaluated a chemotherapy (CT) combination of OXA, RTX and FU/FA during preoperative radiotherapy (RT) in locally advanced rectal cancer (LARC) patients. Fifty-one patients with LARC at high risk of recurrence (T4, N+ or T3N0 < or =5 cm from anal verge and/or circumferential resection margin < or =5 mm) received three biweekly courses of CT during pelvic RT (45 Gy). Surgery was planned 8 weeks after CT-RT. Recommended doses (RDs) determined during phase I were utilised in the subsequent phase II trial, where the rate of tumour regression grade (TRG) 1 or 2 was the main end point. No toxic deaths occurred, and severe toxicity was easily managed. In phase II, RDs delivered in 31 patients were OXA 100 mg m(-2) and RTX 2.5 mg m(-2) on day 1, and FU 900 mg m(-2) and LFA 250 mg m(-2) on day 2. Main severe toxicities by patients were grade 4 neutropenia (23%) and grade 3 diarrhoea (19%). In 71% (95% confidence limits, 52-86%) of patients, TRG1 (13) or TRG2 (9) was obtained. All patients are alive and recurrence-free after a median follow-up of 29 months. Combination of OXA, RTX and FU/FA with pelvic RT has an acceptable toxicity and a high clinical activity in LARC and should be studied further in patients at high risk of recurrence.

[Early evaluation using PET-FDG of the efficiency of neoadjuvant radiochemotherapy treatment in locally advanced neoplasia of the lower rectum]. / Valutazione precoce con PET-FDG della efficacia del trattamento radiochemioterapico neoadiuvante nelle neoplasie del retto inferiore localmente avanzate.

BACKGROUND AND PURPOSE: Preoperative chemoradiation allows downstaging of locally advanced rectal cancer and in selected patients also a sufficient downsizing to ensure sphincter preservation. Selection of patients warranting a preoperative approach is improved by magnetic resonance imaging (MRI) which is able to define the involvement of mesorectal circumferential margin. Similarly it would be crucial to define the response to chemoradiation during the treatment but traditional morphologic imaging techniques may fail in differentiating neoplastic tissue from scarring. PET-FDG has been successfully used in the detection of metastatic colorectal cancer allowing imaging of deposits as small as 0.5 cm and may have a role in evaluating early response to chemoradiation. METHODS: In the present study, in patients with T3-T4 rectal cancer undergoing preoperative chemoradiation PET-FDG and flow cytometry analysis on endoscopic biopsy specimen have been performed before, during and after preoperative chemoradiation. RESULTS: Chemoradiation treatment has been successful in terms of downsizing and downstaging of the tumor. PET-FDG was able to demonstrate local response at only ten-fifteen days after the beginning of neoadjuvant therapy, also identifying non responding patients. CONCLUSIONS: FDG-PET may have a role in defining the response to chemoradiation and modulate the treatments strategy in patients with advanced rectal cancer.

Assay of prick test inoculum volume. I. Use and reliability of a gamma camera-based method.

INTRODUCTION: In dermatology and allergy there are clinical research circumstances where very small amounts of substances introduced into the skin have to be measured "in vivo." An example is the assay of reagents injected by prick test. As injected volumes are very small, it is necessary to use indicators that can be measured at very low concentrations. In in vitro studies, gamma-emitting radioisotopes have been shown suitable for use as the indicators. In in vivo studies, except for instruments devised for specific research requirements, the measurement of small sources is taken with a common gamma camera. OBJECTIVE: The purpose of the present study is to evaluate the experimental reliability of a gamma camera-based method to measure microvolumes labeled with radioisotopes and its suitable application in vivo studies. METHODS: Using a solution of 99m Tc-pertechnetate, we prepared, with precision pipettes, some sets of scalar volumes ranging from 1 micro to 200 picoliters, which correspond to activities between some micros and some hundreds of picocuries. The volumes were measured with a gamma camera both with and without a collimator. The overall reliability of the method under different experimental conditions was evaluated for sensitivity, precision, and accuracy. Last, a blind measurement was taken as a final check on the overall reliability of the method. RESULTS: The volume-activity correlation appeared to be linear, with a Spearman coefficient higher than 0.99. The correlation straight lines of the measurements taken with and without a collimator proved that, in both cases, the linearity of the system did not change. The method showed a high degree of precision and accuracy. The maximum variation coefficient never exceeded 1.5% and the standard error 2%. The sampling error of the measured volumes was less than 8% in all the sets: up to 7% was due to the manual operations and to the technical characteristics of the micropipettes. The gamma camera measurement error ranged from 1% to 3%. The blind tests experimentally confirmed the overall reliability of the method. CONCLUSIONS: The method we studied proved highly reliable and inexpensive. Measurement errors are almost exclusively due to sampling errors. The gamma camera is a device any nuclear medicine department is equipped with, and a solution of 99m Tc-pertechnetate is readily available.

Assay of prick test inoculum volume. II. Average values and individual variability.

INTRODUCTION: The amount of reagent introduced into the skin by a prick test is critical in studies on the reproducibility and standardization of the method. OBJECTIVE: The purpose of the present study was to measure the average volume and the individual variability of the inoculum performed with a prick test standardized technique. METHODS: Two hundred forty prick tests--16 inoculations per subject--were performed on the volar sides of arms of 15 healthy volunteers. The tests were performed by a skilled tester whose technical performance complied with the criteria of good reproducibility described in international guidelines. A 1-mm tip standard device and a 50% glycerosaline solution labeled with Tc99m were used for the test. The inoculum size was calculated using a direct assay method based on the gamma camera. RESULTS: The average volume of the prick test inoculum was equal to 0.016 microliters, with a remarkable dispersion of the values around the mean (median, 15906: range, 418 to 82253 picoliters). Further, we observed great variability from one subject to another and great variability in the same subject from one skin site to another. A statistical analysis of the data shows that this variability depends on the individual characteristics of the subjects examined. A skilled tester using a standardized technique is not responsible for significant variability. CONCLUSIONS: Even when performed by a skilled operator and with standardized techniques, the prick test shows great limits of reproducibility, at least as far as the size of the inoculum volume is concerned. The variability of the inoculum depends, in a statistically significant way, on the subject's individual characteristics and therefore can be reduced only within certain limits by the standardization and perfectibility of the technique.

Influence of neoadjuvant chemotherapy on serum tumor markers CA 15-3, MCA, CEA, TPS and TPA in breast cancer patients with operable disease.

Serum levels of CA 15-3, mucinous-like cancer antigen, carcinoembryonic antigen, tissue polypeptide antigen and tissue polypeptide-specific antigen (TPS) have been determined in 99 patients with T2-4 N0-1 M0 breast cancer (BC) before and after primary (neoadjuvant) chemotherapy and after surgery. As a whole, no difference in marker levels was apparent according to tumor and patient characteristics, with the only exception of TPS values, which showed an inverse relationship with the histologic grade. Serum marker levels did not substantially change with respect to baseline either after chemotherapy, despite the high response rate obtained, or after surgery. These data indicate a limited contribution of the primary tumor to the serum marker levels and are consistent for the scarce usefulness of marker evaluation in BC patients with an early stage of disease. Interestingly, pretreatment elevated CA 15-3 levels were correlated with a higher recurrence rate, further supporting the prognostic significance of this tumor marker.

Hyperfractionated radiotherapy and concomitant cisplatin in stage III non-small cell lung cancer: a phase II study by the AIRO-Lombardia Cooperative Group.

A multicenter Phase II study was performed by the AIRO-Lombardia Cooperative Group on 36 patients with Stage III non-small cell lung cancer. The treatment schedule included hyperfractionated radiotherapy, 1.2 Gy twice daily (5 days/week) up to a total dose of 69.6 Gy, and concomitant cisplatin by continuous infusion using a portable pump, 16 mg/m2/week for 6 weeks. Overall, adequate treatment (defined as a total dose > 66 Gy in < 46 days and 6 weeks of infusional cisplatin) was received by 56% of accrued patients. Response was complete in 6% and partial in 56% of patients; median survival was 8 months and 1-year survival rate was 37%. Site of first failure was local in 43%, distant in 43%, local and distant in 10% and unknown in 3% of failing patients. Grade 3 esophagitis was recorded in 14% of patients and a fatal case of late pulmonary toxicity was reported. On the basis of feasibility, toxicity and survival results, the planned extension to Phase III was abandoned by the Group.

[Assessment of the tumor bed dose in the conservative treatment of breast carcinoma]. / Valutazione della dose al letto tumorale nel trattamento conservativo del carcinoma mammario.

We investigated the variations in the total dose given to primary tumor sites in breast irradiation after conservative surgery. Fifty patients consecutively submitted to CT for radiotherapy treatment planning were entered into this study. Treatment was planned with Varian Cadplan 2.61 for both whole breast irradiation (2 Gy/fraction, up to 50 Gy) and boost (2 Gy/fraction, up to 10 Gy) according to the ICRU 50 report. The doses were calculated localizing the tumor site with preoperative mammography or breast US, surgery description, the possible presence of clips and treatment planning CT. The doses to tumor volumes ranged 46.5 to 53.4 Gy [average: 50.7, standard deviation (SD): 1.47] with the tangential fields. The relative biological effects (RBE) ranged 55.2 to 64.9 Gy (average: 61.05, SD: 2.06). The total doses to tumor beds ranged 57.8 to 65.2 Gy (average: 61.6, SD: 1.63) and the relative RBE from 67.8 Gy to 79.4 Gy (average: 74.3, SD: 2.30). In conclusion, in our opinion, the assessment of radiotherapy efficacy in breast irradiation should be related also to tumor bed dose and not only to the prescribed dose. Indeed, its wide range (and, consequently, the marked differences seen in RBE) might be misleading, especially when the relationship between local relapse and boost usefulness is considered.

[Stage 1 glottic laryngeal carcinoma: observations on 76 cases treated with transcutaneous radiotherapy]. / Il carcinoma della laringe--piano glottico--nel primo stadio: osservazioni su 76 casi trattati con radioterapia transcutanea.

In this paper the authors retrospectively review various parameters which influenced local control and survival in a series of 76 patients with Tis or T1 glottic carcinoma. All the patients (89% smokers) received radical irradiation with two oblique anterior isocentric fields (45-315 degrees), with a Cobalt unit, 5 x 5 or 6 x 6, using compensator wedges; 2 Gy were given per fraction, up to 60-66 Gy at the minimum reference isodose. The mean total dose to ICRU reference point was 68 Gy (range: 63-72 Gy). All patients achieved complete remission. Four patients only had a local recurrence and none had regional relapses. Few late side-effects were observed and among them only two grade I and one grade II, the latter requiring tracheotomy. Eight patients died of cardiovascular diseases and nine of secondary cancer. Two patients are alive with a secondary malignancy. The five-year overall survival rate is 77.5%, while NED survival is 93%; no differences in survival rates were found according to T stage, grading, field size, treatment time and total dose delivered. With reference to the current literature, the authors conclude that: a) radiotherapy permits very good local control; b) lymph nodes should not be irradiated; c) very high doses do not improve local control, but only increase late side-effects; d) the role of biologic dose inhomogeneity and overall treatment time remain to be investigated.

[Conservative treatment of stage I-II breast carcinoma. Side-effects and esthetic results]. / Trattamento conservativo del carcinoma mammario negli stadi I-II. Effetti collaterali e risultato estetico.

A good cosmetic result is one of the main goals in conservative breast cancer treatment (quadrantectomy plus radiotherapy and, sometimes, adjuvant chemotherapy). In a retrospective study on 302 patients treated at Cremona Hospital Radiotherapy Department, a group of 68 patients was selected because of its homogeneity: all these patients had been operated by the same surgeon and irradiated according to the same technical rules. Acute reactions, late side-effects and cosmetic results are analyzed in this group. Acute postoperative complications were seen in 15% of the cases and late or persistent changes in 54%. Radiotherapy caused acute reactions in 73.5% of the cases and late side-effects in 47%. An acceptable cosmetic result was obtained in 95.5% of the patients: an excellent result in 31%, a good result in 41% and a sufficient one in 23.5%. The dose to whole breast, the dose to the quadrant and the kind of boost have no influence on the cosmetic results, while concomitant chemotherapy (p = 0.028) and high inhomogeneity in dose distribution (p = 0.04) caused a worse outcoming. The authors believe that better results may be obtained by improving treatment planning (to reduce inhomogeneity) and by optimizing chemotherapy and radiotherapy combination.

Post-radiation angiosarcoma of the breast: a clinical case.

After conservative treatment of breast carcinoma (quadrantectomy and axillary dissection, plus radiotherapy), the growth of an angiosarcoma in the irradiated skin is a very rare event. We report a case, developed in the breast skin 62 months after the irradiation, and discuss the therapeutic possibilities and the role of follow-up in these patients.

[Prenatal screening for Down's syndrome: a simplified method]. / Screening prenatale per la sindrome di Down: un metodo semplificato.

Prenatal screening for Down's syndrome (DS) can be achieved by combining maternal age risks and maternal serum additional parameters (AFP, HCG, uE3) by computer assisted statistical analysis. Nevertheless this measure of risk is far from broad and practical application in Italy, due to cultural and organization difficulties. So we suggest a different technical approach, the age specific risk being multiplied by the HCG/AFP likelihood ratio. HCG and AFP can be tested by an automated Elisa assay, and calculations performed by a simple method, excluding computer and software package use. About 100 pregnancies were evaluated both by a modified version of the Wald test and the method described hereafter. Using the automated HCG and AFP Elisa Testing and Crossley statistical calculation a higher False Positive Rate was observed. On the other hand no different Detection Rate was observed for the two tests. On a retrospective study we found that 5 sera from affected pregnancies were correctly identified both by the modified Wald test and the other method. It is concluded that, despite different False Positive Rates, the choice of which test to use depends on evaluation of local resources, one test being easier-to-perform and more sensitive, the other one probably being more specific but more difficult to perform.

[Chemo-radiotherapy in advanced head and neck tumors. Personal experience]. / La chemio-radioterapia nei tumori avanzati del capo-collo. Esperienza personale.

From January 1981 through December 1983, 49 untreated patients with locally advanced head and neck cancers were randomized in two groups to receive different radiochemotherapy regimens. Group A, including 29 cases, received 4 cycles of induction chemotherapy with Bleomycin, Methotrexate and Hydroxyurea before definitive external radiotherapy (60 Gy); group B, including 20 patients, received the same total dose of radiotherapy but the 4 cycles of chemotherapy, as described above, were administered between the 20- and the 40-Gy doses. Both groups were compared with a control group treated in the same period with radiotherapy (60 Gy) alone. The response to treatment was evaluated at the end of chemotherapy or radiotherapy alone and at the end of combined regimens. Long-term survival rates were analyzed for all groups relative to complete tumor response, disease-free interval and time to disease progression. In our experience the radio-chemotherapy combination, according to the described schedules, failed to improve both local control and overall survival; the comparison with the control group does not suggest that induction or intercalated chemotherapy can increase long-term survival even if initial complete and partial response rates are high.

[Breast carcinoma. Technical problems of radiotherapy. Proposal of an algorithm as an alternative to the lack of scintigraphic visualization of the internal mammary lymph nodes]. / Carcinoma mammario. Problemi di tecnica radioterapica. Proposta di un algoritmo in alternativa alla non visualizzazione scintigrafica delle catene mammarie interne.

In early breast cancer, radiation therapy following conservative surgery needs a topographic evaluation of internal mammary lymph nodes. Three-dimensional lymphoscintigraphy (IML3D) is an useful method for this purpose. The average depth of the lymph nodes is closely correlated with the square root of the body weight/height ratio. We calculated the individual maximum depth of the lymph nodes from this function; the parameter was then verified with the experimental data from our series of cases (53 patients). Although the suggested algorithm needs to be verified on a larger number of patients, we believe the empirical maximum depth measurement to be useful when IML3D is unfeasible or the internal mammary lymph nodes are not demonstrated on scintigraphic scans.

[Proposal for a therapeutic protocol in Crosti lymphoma]. / Proposta di protocollo terapeutico nel linfoma di Crosti.

Three patients with Crosti's lymphoma were treated with radiotherapy using electron accelerators. The energy radiations ranged from 5 to 9 Mev. with large fields. The total dose was 40 Gy, delivered in 2 Gy fractions daily. The treatment lasted four weeks. No side effects were reported and no recurrence was remarked after 24 months.

Bladder cancer prognostic indices: analysis of 286 patients treated with radical radiation therapy.

From 1974 through 1982, 286 patients with histologically proven bladder cancer (Tis 8, T1 62, T2 109, T3 86, T4 21 NXMO) were treated with external irradiation after transurethral resection. Irradiation was given with 260 degrees arc technique photon beam from a Cobalt Unit; the tumor doses ranged from 52.5 to 65 Gy in 21-50 days, with a TDF between 75 and 110. The analysis was conducted with the log rank test on the cumulative percent survival (CPS) at 5 years. The study pointed out the importance of risk factors other than clinical stage on cumulative survival in bladder cancer. Prognostic factors associated with a relatively successful outcome (p less than 0.001) were the Karnofsky performance status (100 vs others) (CPS 75% vs 30%), the absence of ureteral obstruction on the initial intravenous pyelogram (CPS 50% vs 35%), a negative urine culture (CPS 60% vs 30%), normal bladder capacity (CPS 50% vs 35%), low-grade histology (CPS 65% vs 35%), and grossly complete resection (55% vs 40%). The data from this analysis should be taken into consideration when radical radiotherapy is considered in new clinical trials.

[Technics for irradiation of the neck in the treatment of lymph node metastases from solid tumors of the head and neck region]. / Le tecniche di irradiazione del collo per la cura di metastasi linfonodali da tumori solidi del distretto cervico-cefalico.

Some common irradiation techniques for nodal metastasis of head and neck solid tumors are described and analyzed, that can be performed by means of a cobalt unit or by high energy electron beams. Limits and indications of each technique are evaluated particularly referring to dose distribution in the target volume and to isoeffect levels (TDF, CRE) that can be expected in normal tissues, at the end of treatment for different regimes.

[Technic, indications and radiobiological limits of the moving strip treatment of patients with stage III ovarian carcinoma already treated with surgery and chemotherapy]. / Tecnica, indicazioni e limiti radiobiologici del trattamento "moving strip" in pazienti portatrici di carcinoma ovarico al III stadio già trattate con chirurgia e chemioterapia.

Until a few years ago, for patients with ovarian cancer at III stage FIGO, the radiotherapy with moving strip technique followed surgery. The introduction of new chemotherapy agents, Cisplatinum and Adriamycin, has recently changed the course of therapy in the attempt to improve the ovarian cancer prognosis at advanced stages. The authors present a "moving strip" technique which has been revisited to satisfy new request of the therapeutic radio-chemotherapy and surgery method, and moreover they study the real differences between some moving strip technique already published and they describe their characteristics and radiobiologic limits.