ardani G

Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy

EORTC protocol 22791 compared once daily fractionation (CF) of 70 Gy in 35-40 fractions in 7-8 weeks, to pure hyperfractionation (HF) of 80.5 Gy in 70 fractions in 7 weeks using 2 fractions of 1.15 Gy per day, in T2-T3 oropharyngeal carcinoma (excluding base of tongue), N0,N1 of less than 3 cm. From 1980 to 1987, 356 patients were entered. In the final analysis (June 1990), the local control was significantly higher (p = 0.02 log-rank) after HF compared with CF. At 5 years, 59% of patients are local disease-free in the HF arm compared to 40% in the CF arm. The superiority of HF was demonstrated in patients staged T3N0,T3N1 but not in T2. The Cox model confirmed that the treatment regimen was an independent significant prognostic factor for locoregional control (p = 0.007 log-rank). This improvement of locoregional control was responsible for a trend to an improved survival (p = 0.08 log-rank). There was no difference in late normal tissue damage between the two treatment modalities.

Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors.

The evidence of lymphocytopenia has been demonstrated to predict a poor prognosis in terms of survival in advanced cancer patients. This finding is not surprising because of the fundamental role of lymphocytes in mediating tumor cell destruction. Despite the importance of lymphocytes in the pathogenesis of cancer, there are only few data about the profile and the function of lymphocytes during the various antitumor therapies, and in particular the relation between lymphocyte pretreatment number and response to chemotherapy remains to be established. The present study was performed to evaluate whether the evidence of lymphocytopenia before the onset of treatment may influence the efficacy of chemotherapy in metastatic cancer patients affected by the most frequent tumor types. The study included 183 patients (lung cancer: 89; colorectal cancer: 63; breast cancer: 31), 95 of whom had been previously treated with chemotherapy. The chemotherapeutic regimens consisted of oxaliplatin plus 5-fluorouracil and folates in untreated colorectal cancer, weekly irinotecan in pretreated colorectal cancer, cisplatin plus gemcitabine or etoposide in untreated lung cancer, weekly vinorelbine in pretreated lung cancer, and taxotere in breast cancer patients who had been previously treated with anthracyclines. Lymphocyte count was considered to be abnormally low for values below 1500/mm3. Lymphocytopenia was found in 79/183 (43%) patients, without any significant differences in relation to tumor histology. A complete response (CR) was achieved in 6/104 patients with a normal lymphocyte count and in none of the 79 lymphocytopenic patients. A partial response (PR) was obtained in 39 patients with a normal lymphocyte count and in only eight patients with a low lymphocyte count prior to therapy. Therefore, irrespective of the type of chemotherapy, the objective tumor response rate (CR + PR) in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (8/79 vs 45/104; p<0. 001). This study shows that the evidence of lymphocytopenia prior to chemotherapy is associated with a lower efficacy of treatment in terms of objective tumor regression rates in patients with metastatic solid tumors, and suggests that the action of chemotherapy may depend at least in part on an interaction with the antitumor immunity. Pretreatment lymphocyte count may represent a new, simple biological marker to be taken into consideration by oncologists in the chemotherapeutic treatment of metastatic cancer.

Chemotherapy and angiogenesis in advanced cancer : Vascular endothelial growth factor (VEGF) decline as predictor of disease control during taxol therapy in metastatic breast cancer

Angiogenesis is essential for tumor growth. Since vascular endothelial growth factor (VEGF) represents the main angiogenic factor, the control of VEGF secretion could constitute the most important mechanism to achieve the inhibition of angiogenesis-related processes. High blood concentrations have been proven to correlate with poor prognosis in advanced cancer. In experimental conditions, chemotherapeutic agents such as taxol appeared to inhibit VEGF-induced angiogenesis, while at present there are no data about the influence of chemotherapy on VEGF secretion in cancer patients. This preliminary study was performed to evaluate the effect of taxol therapy on VEGF secretion in advanced cancer patients in relation to the clinical response. The study included 14 patients with metastatic breast cancer who were treated with taxol monochemotherapy (175 mg/m2 i.v. every 21 days for three cycles). Serum levels of VEGF were measured by ELISA in blood samples collected before therapy and at 21-day intervals. The clinical response consisted of partial response (PR) in three and stable disease (SD) in six patients, whereas the other five patients had progressive disease (PD). Abnormally high pre-treatment levels of VEGF were seen in 8/14 patients. VEGF mean values significantly decreased during taxol therapy in patients with PR or SD, whereas no decline was observed in patients with PD. Moreover, the percent of normalization or decline greater than 50% in VEGF levels was significantly higher in patients with PR or SD than in those with PD (5/9 vs. 0/5). This preliminary study would suggest that the efficacy of taxol therapy in metastatic breast cancer - at least in terms of disease stabilization - may be associated with a decrease in VEGF blood levels followed by potential inhibition of cancer-related neovascularization.

Changes in circulating VEGF levels in relation to clinical response during chemotherapy for metastatic cancer

Abnormally high blood levels of vascular endothelial growth factor (VEGF) appear to be associated with a poor prognosis in advanced cancer, probably as a consequence of its angiogenic and immunosuppressive effects. The prognostic significance of changes in VEGF secretion during cancer chemotherapy is still unknown. This study aimed to investigate the relation between VEGF variations and therapeutic results during chemotherapy in advanced malignancies. The study included 90 metastatic cancer patients, 59 with non-small cell lung cancer and 31 with colorectal carcinoma. Chemotherapy consisted of cisplatin plus etoposide for NSCLC and camptothecin for colorectal cancer. Abnormally high (> 2 SD with respect to values in healthy controls) pretreatment VEGF levels were found in 38/90 (42%) patients. The percentage of non-progressive disease in response to chemotherapy was significantly higher in patients with normal levels of VEGF prior to therapy than in those with elevated pretreatment values of VEGF (10/32 vs 4/27; p < 0.05). Moreover, the percentage of VEGF level normalization during chemotherapy was significantly higher in patients with objective tumor response or stable disease than in progressing patients (10/18 vs 0/20; p < 0.001). Finally, among patients with tumor response or disease stabilization, the one-year survival rate was significantly higher in patients with chemotherapy-induced normalization of VEGF than in those with persistently high VEGF blood levels (9/10 vs 3/8; p < 0.05). These results suggest that changes in VEGF levels during chemotherapy may represent a useful biomarker to predict the effect of chemotherapy in terms of tumor response and survival in patients with metastatic solid neoplasms.

Short-term variation in labeling index as a predictor of radiotherapy response in human oral cavity carcinoma.

In vitro determination of [3H]thymidine labeling index (LI) was carried out on squamous cell carcinomas of the oral cavity from 52 patients before and during radiotherapy. Pretreatment LI values ranged from 0.01% to 50%. After administration of the first 10 Gy in five consecutive daily fractions, a decrease in LI was observed in 39 cases and an enhancement in 13 cases, with an overall median 70% decrease in the initial value. The type of variation induced by radiotherapy was not related to pretreatment LI except for tumors with a very low proliferative activity (LI less than or equal to 1.9%), which all showed a marked increase in LI. Pretreatment LI was not indicative of short- or long-term response to radiotherapy, whereas the variation induced on LI after 10 Gy was related to the clinical outcome. A variation in LI of more or less than 70% was not significantly associated (p = 0.077) with clinical objective response (respectively, 85 and 53%). However, all 8 patients who reached a complete regression, notwithstanding an enhancement or a slight decrease in LI, had a local recurrence within 19 months. Conversely, the probability of disease-free survival was 82% for the 11 patients whose tumors had a significant decrease in LI (greater than or equal to 70%) after the first 10 Gy.

Analysis of risk factors for mandibular bone radionecrosis after exclusive low dose-rate brachytherapy for oral cancer.

BACKGROUND Brachytherapy is widely adopted as an exclusive treatment of T1/T2 oral cancer with a high probability of definitive cure. Therefore, any major complication, like mandibular bone necrosis, should be avoided. Many risk factors, either clinical or technical, have been considered in the literature. MATERIALS AND METHODS One hundred consecutive interstitial iridium LDR treatments for early cancers of the tongue and floor of the mouth performed from January 1989 to November 1993 were reviewed. An analysis of some simple technical parameters (total dose, dose-rate, reference volume, linear activity, total reference kerma) was performed in order to identify the main physical risk factors. Moreover, total dose was recalculated as extrapolated responsive dose for normal tissue complications. RESULTS Bone necrosis was observed in 10 out of 100 patients with a median follow-up of 38 months. No significant incidence of this complication was observed when tumor site (mobile tongue versus floor of the mouth), dental status or total physical dose were considered. A significant correlation between the incidence of bone necrosis and two main parameters was found, i.e. dose-rate (P < 0.02) and reference volume (P < 0.05). CONCLUSIONS A threshold value may be suggested both for dose-rate (50 cGy/h) and reference volume (25,000 mm3). Bone necrosis is clearly related to both these parameters since most cases (i.e. 80%) were observed in the subgroup over the volume and dose-rate threshold.

Interventional radiology and radiotherapy for inoperable cholangiocarcinoma of the extrahepatic bile ducts

AIMS AND BACKGROUND To evaluate the effectiveness of external radiation therapy (ERT), alone or combined with endoluminal brachytherapy (BRT), following percutaneous transhepatic biliary drainage (PTBD) in the treatment of patients affected by inoperable cholangiocarcinoma. METHODS & STUDY DESIGN From September 1980 to June 1996, 130 jaundiced patients affected by inoperable cholangiocarcinoma were submitted to PTBD at the Division of Radiology C of the National Cancer Institute of Milan. Nineteen were excluded from the present analysis due to the short survival after PTBD (< 30 days). The other 111 patients were divided into three groups according to the following therapy: no further treatment after palliative PTBD in 89 patients (80%, group 1); ERT in 10 patients (9%, group 2); ERT plus BRT in 12 patients (11%, group 3). All the ERT + BRT patients were enrolled after 1990 and were treated with high-energy photon beams followed by endobiliary insertion of one or two iridium-192 wires. RESULTS Median overall survival among the 111 assessable patients was 126 days; for groups 1, 2 and 3 it was 108, 345 and 428 days, respectively. The patients submitted to radiotherapy (ERT alone or ERT + BRT) were evaluated by radiologic examinations after the end of radiation. In group 2, a partial remission in 3 cases, a progression of disease in 1 case, and no change in 6 cases were observed. Among the patients of group 3, complete remission in 5 and partial remission in 7 patients were achieved. In all the patients achieving complete remission, the PTBD could be removed. CONCLUSIONS The combination of ERT plus BRT improves survival and quality of life of the patients submitted to PTBD for cholangiocarcinoma. Under the technical point of view, radiation treatment is easy to perform, but much caution is required in defining clinical and planning target volumes. Moreover, drainage during the radiation treatment has to be submitted to a very meticulous surveillance.

Adjuvant Postoperative Radiotherapy in Locally Advanced Rectal and Rectosigmoidal Cancer

A pelvic recurrence is the cause of death in about 1/3 of radically operated patients for rectal and rectosigmoidal cancer without clinical evidence of distant metastases. Preoperative and postoperative radiotherapy are largely used to reduce the incidence of locoregional relapses and to improve disease-free and overall survival and quality of life. Benefits from radiotherapy have been widely demonstrated, and adjuvant postoperative radiotherapy is at present strongly recommended. Twenty-one patients with locally advanced (stage B2, B3, C) rectal (11 cases) and rectosigmoidal cancer (10 cases) were treated with postoperative radiotherapy at the National Cancer Institute of Milan from 1975 to 1978. The pelvis received a median dose of 4500 rad (range, 4000–5200 rad) in 5 to 7 weeks through AP, PA opposed fields; 6 patients received a boost of 1000 rad on the perineum. Median follow-up after surgery is 83 months (range, 24–63 months). Only 1 case (« 5%) had a pelvic recurrence, at the perineum. The expected recurrence rate after surgery alone is 40 %, and our favorable results after postoperative radiotherapy are comparable with recent data from other institutions. Radiotherapy side effects were moderate and transient; no late damages to small bowel were observed.

Possible involvement of prolactin in endocrine-resistant metastatic prostate cancer

The hormone resistance of prostate cancer has been proved to depend at least in part on enhanced neuroendocrine activity and the resultant increase in blood concentrations of chromogranin A. Other experimental observations have suggested the involvement of prolactin (PRL), which appears to be a potential growth factor for prostate cancer. Abnormally high levels of PRL have been detected in metastatic prostate cancer, but the clinical significance of this finding has still to be clarified. In an attempt to explain the prognostic significance of serum PRL levels in prostate cancer, in this preliminary study we have analyzed the PRL levels in a group of metastatic prostate cancer patients with hormone-dependent or hormone-resistant cancer. The study included 50 patients with metastatic prostate cancer, 15 of whom had hormone-resistant tumors. The serum levels of PRL were measured by the RIA method. Abnormally high concentrations of PRL were found in 11/50 (22%) patients. Moreover, the percent of patients with cancer-related hyperprolactinemia was significantly higher in the hormone-resistant group than in the hormone-dependent group (8/15 vs 3/35, p<0.01). This study confirms the possible existence of a hyperprolactinemic state in metastatic prostate cancer, as previously reported by other authors. Moreover, it appears to demonstrate that the occurrence of hyperprolactinemia is more frequent in hormone-resistant neoplasms, suggesting the possible involvement of PRL in hormone independence. Further studies concomitantly evaluating PRL and chromogranin A blood concentrations will be necessary to establish whether the hyperprolactinemia precedes and promotes the onset of hormone resistance in prostate cancer, or whether it is simply a consequence of the hormone independence. (Int J Biol Markers 2005; 20: 123-5).The hormone resistance of prostate cancer has been proved to depend at least in part on enhanced neuroendocrine activity and the resultant increase in blood concentrations of chromogranin A. Other experimental observations have suggested the involvement of prolactin (PRL), which appears to be a potential growth factor for prostate cancer. Abnormally high levels of PRL have been detected in metastatic prostate cancer, but the clinical significance of this finding has still to be clarified. In an attempt to explain the prognostic significance of serum PRL levels in prostate cancer, in this preliminary study we have analyzed the PRL levels in a group of metastatic prostate cancer patients with hormone-dependent or hormone-resistant cancer. The study included 50 patients with metastatic prostate cancer, 15 of whom had hormone-resistant tumors. The serum levels of PRL were measured by the RIA method. Abnormally high concentrations of PRL were found in 11/50 (22%) patients. Moreover, the percent of patients with cancer-related hyperprolactinemia was significantly higher in the hormone-resistant group than in the hormone-dependent group (8/15 vs 3/35, p < 0.01). This study confirms the possible existence of a hyperprolactinemic state in metastatic prostate cancer, as previously reported by other authors. Moreover, it appears to demonstrate that the occurrence of hyperprolactinemia is more frequent in hormone-resistant neoplasms, suggesting the possible involvement of PRL in hormone independence. Further studies concomitantly evaluating PRL and chromogranin A blood concentrations will be necessary to establish whether the hyperprolactinemia precedes and promotes the onset of hormone resistance in prostate cancer, or whether it is simply a consequence of the hormone independence.

Nipple discharge as a sign of preneoplastic lesions and occult carcinoma of the breast: clinical and galactographic study in 103 consecutive patients.

A clinical and galactographic investigation was carried out on 103 patients with hematic, serous-hematic, and serous nipple discharge. The age of the patients ranged from 18 to 72 years. A single papilloma was found in 20 cases, diffuse papillomatosis in 2 cases, atypical ductal hyperplasia in 8 cases, and ductal carcinoma in 4 cases (3 of these were infiltrating and 1 was noninfiltrating associated with a diffuse papillomatosis). Mammography gave no indications of carcinoma in any of the 4 cases. In the remaining 49 patients, pictures of ductal hyperplasia, periductal mastitis or sclerosis, sclerosing adenosis, or ductal ectasia were observed. The various types of lesions were often associated. Lacunae, stenosis, or occlusion of the ducts, evidenced by galactography, correlated well with the histologic findings of proliferative lesions of the ductal epithelium. Nevertheless, in practice, it should be the type of discharge that indicates surgery rather than galactographic or cytologic data, which appeared to have little diagnostic value. The frequency with which preneoplastic (or limit) lesions, and also nonsuspect carcinomas were found in patients with a significant nipple discharge confirm the importance of this symptom for a secondary prevention or early diagnosis of mammary neoplastic lesions originating from galactophorous ducts. Finally, complete resection of the galactophorous ducts must be considered as the best treatment in all patients with a suspicious nipple discharge that requires surgery.