Adjuvant treatment of stage I lung cancer with high-dose vitamin A.

PURPOSE: Vitamin A and retinoids are strong inhibitors of epithelial cancer promotion and progression in experimental carcinogenesis. This study examined whether they may prevent the occurrence of upper aerodigestive cancer in subjects heavily exposed to tobacco smoking, such as patients already cured of an early-stage lung cancer. PATIENTS AND METHODS: The adjuvant effect of high-dose vitamin A was tested on 307 patients with stage I non-small-cell lung cancer. After curative surgery, patients were randomly assigned to either a group prescribed retinol palmitate administration (orally 300,000 IU daily for 12 months) or a control group prescribed no treatment. RESULTS: After a median follow-up of 46 months, the number of patients with either recurrence or new primary tumors was 56 (37%) in the treated arm and 75 (48%) in the control arm. Eighteen patients in the treated group developed a second primary tumor, and 29 patients in the control group developed 33 second primary tumors. A statistically significant difference in favor of treatment was observed concerning time to new primary tumors in the field of prevention (P = .045, log-rank test). The treatment difference in terms of disease-free interval was close to statistical significance (P = .054, log-rank test) and just significant when adjusted for primary tumor classification (P = .038, Cox regression model). CONCLUSION: Daily oral administration of high-dose vitamin A is effective in reducing the number of new primary tumors related to tobacco consumption and may improve the disease-free interval in patients curatively resected for stage I lung cancer. The impact of such a treatment on survival needs to be further explored.

Somatostatin receptor imaging of small cell lung cancer (SCLC) by means of 111In-DTPA octreotide scintigraphy.

Somatostatin receptors have been described on the membrane of neoplastic cells derived from the APUD system and their expression has also been demonstrated on small cell lung cancer (SCLC) in vitro and in vivo. 21 patients with SCLC were studied using 111In-octreotide (111In-OCT) scintigraphy. Scintigraphic examinations were performed following intravenous (i.v.) injection of 111 MBq 111In-OCT with whole-body scintigraphy and planar scintigraphy of the thorax as well as the SPET technique. No short-term side effects were described following 111In-OCT administration. We studied the 111In-OCT biodistribution in 3 patients with serial scintigraphies at 1, 5 and 24 h. We used the 5 h as standard scanning time for the following 18 patients. The scintigraphic results were compared with those of other conventional diagnostic procedures. 111In-OCT detected 86% (48/56) of the lesions already known at the time of scintigraphy. It was positive in all 20 SCLC patients and negative in one lung adenocarcinoma. 111In-OCT showed high sensitivity for mediastinal metastases (94%) and good sensitivity for bone metastases (75%) and abdominal lymph node metastases (71%). 111In-OCT did not detect two liver metastases. 111In-OCT detected five unknown lesions which were confirmed by other diagnostic examinations. 111In-OCT was also effective in cancer patients with low levels of NSE. Our study shows that 111In-OCT scintigraphy is a reliable, non-invasive technique to detect primary SLCL and its locoregional or distant metastases. The clinical utility of receptor status characterisation obtained with 111In-OCT scintigraphy should be evaluated by means of an appropriate prospective study.

A randomized clinical trial comparing radiation therapy v radiation therapy plus cis-dichlorodiammine platinum (II) in the treatment of locally advanced non-small cell lung cancer.

Cis-Dichlorodiammine platinum (II) (cis-DDP) was demonstrated to be a potentiator of radiation therapy (RT) in experimental tumor models and in cultured cells. To assess the effectiveness of a combined modality treatment including RT and a weekly low-dose administration of cis-DDP, from January 1986 to June 1987, 95 patients with unresectable locally advanced non-small cell carcinoma of the lung (stage IIIa, b) were randomized for study. Fifty patients received RT alone at doses of 50 Gy; 45 patients received the same RT plus cis-DDP 15 mg/m2 IV weekly. An overall response rate of 50% and 64% was observed in the RT and RT + cis-DDP group, respectively. No statistically significant differences were detected with regard to median survival time (11 months for RT v 16 months for RT + cis-DDP) and progression-free interval (7 months in the RT arm v 9 months in the RT + cis-DDP arm), but the patterns of the first failure appeared to be affected by treatment. In fact, a lower number of intrathoracic relapses was observed in the RT + cis-DDP arm (12 in the RT + cis-DDP v 23 in the RT arm). Toxicity was mild and the feasibility of this schedule must be remarked. A better local control of disease can be obtained using cis-DDP as a radiation potentiator, but the true influence of this combined modality treatment on the length of survival, and the optimal cis-DDP timing and dosage are still to be evaluated in further clinical trials.

Synchronous brain metastasis from lung cancer. Result of surgical treatment in combined resection.

The results of combined surgical resection of brain metastasis and primary lung cancer from January 1976 to April 1986 were evaluated. In all cases the brain metastasis was single and synchronous and was resected first. There were 20 men and one woman, with an average age of 53 years. All patients initially had neurologic symptoms related to an intracranial mass. In 19 patients the primary lung cancer was roentgenologically visible, but in two the lesion was recognizable only by bronchoscopy. There were no operative deaths. Nine of 21 patients had a poor postoperative course and died during the first 6 months. The combined surgical approach improved the short-term survival rate in four patients, who died 11, 12, 18, and 21 months after the thoracic operation. In six patients (28.5%) survival for more than 2 years was obtained (three died after 27, 30, and 40 months, three are alive after 25, 28, and 48 months). Two others patients are alive and well 4 and 16 months after the thoracic operation. Synchronous onset of brain metastasis from lung cancer does not necessarily contraindicate combined operations, which can provide long-term survival in selected patients. The absence of mediastinal node metastasis is a favorable prognostic factor. Computed tomographic screening of the brain improves patient selection.

Intensification of 111In-DTPA-octreotide scintigraphy by means of pretreatment with cold octreotide in small cell lung cancer.

Small cell lung cancer (SCLC) expresses somatostatin receptors that can be traced with 111In-DTPA-octreotide scintigraphy. Although this technique is currently employed for staging and follow-up of neuroendocrine tumors of the gastrointestinal tract, its role in the clinical work-up of SCLC is at present under discussion. A better imaging contrast is desirable and recent reports suggest that this aim could be achieved by pretreatment with cold octreotide. Here we report on the results of 111In-DTPA-octreotide scintigraphy in 12 SCLC patients carried out before and after octreotide treatment. The patients were treated for 7 days with octreotide 200 micrograms three times a day s.c. Uptake was studied at 5 h with whole body planar and SPET imagings. In all cases studied, pretreatment with octreotide was followed by enhancement of tumor imaging. In one patient a better contrast of the lesions was found at the parenchymal and mediastinal levels as well as at brain level, allowing a clear definition of otherwise questionable metastases. After octreotide treatment, a decrease in background uptake in the subdiaphragmatic area was observed in most cases, allowing a better imaging of liver metastases. The enhancement effect was confirmed by semiquantitative analysis of scintigraphic uptake. Taken together, our results seem to indicate that cold octreotide enhancement can improve 111In-DTPA-octreotide imaging and optimize its clinical role in SCLC.

Influence of glutathione administration on the disposition of free and total platinum in patients after administration of cisplatin.

The kinetics of platinum (Pt) was studied in 12 patients suffering from non-small-cell lung cancer or pleural mesothelioma. Each subject received an infusion of cisplatin (CDDP, 80 mg/m2), and six patients were pretreated with glutathione (GSH, 2.5 g given i.v.) at 15 min prior to the cisplatin infusion. After a 3- to 4-week interval, all patients were given a second course of treatment on the same schedule. A biexponential model was fitted to plasma concentrations of total and ultrafilterable Pt. The excretion of Pt in urine was evaluated during the first 48 h after the CDDP infusion. Following the administration of CDDP alone or with GSH pretreatment, the pharmacokinetic parameters of Pt did not significantly differ between the treatments. Also, the unbound fraction determined at each sampling time did not vary significantly between the treatments. However, it is noteworthy that the mean values obtained for the terminal half-life, the volume of distribution, the renal clearance, the percentage of the dose excreted in the urine, and the mean residence time of total Pt were higher in patients who had been pretreated with GSH, suggesting that GSH might increase both the rate of Pt elimination and the extent of Pt distribution and, as a consequence of the latter, might prolong the residence time of Pt in the body. In addition, the unbound fraction of Pt from the 4th to the 48th was higher following the first dose of CDDP+GSH than after treatment with CDDP alone. Because of the rather high variability in the values of the parameters obtained, further work is planned using a larger number of patients.

Combination chemotherapy and interferon alpha 2b in the treatment of advanced non-small-cell lung cancer. The Italian Lung Cancer Task Force (FONICAP).

Thirty-four patients with previously untreated advanced non-small-cell lung cancer were treated with a combination of polychemotherapy and recombinant interferon. Chemotherapy consisted of cyclophosphamide, 400 mg/m2, epidoxorubicin, 50 mg/m2, and cisplatin, 40 mg/m2 (CAP) i.v. on day 4; recombinant alpha 2b interferon (r alpha 2b IFN) was given i.m. daily at the dose of 3-5 MU from days 1 to 7. The treatment was repeated every 4 weeks. In the 32 eligible patients the overall response rate was 19.3% (95% C.L. 7.4-37.4%). Non-hematologic toxicity consisted formerly in flulike symptoms and fatigue complained of by 37.5% and 31.2% of patients, respectively, and vomiting reported in 68.7% of patients; grade III-IV myelotoxicity was observed in 12.5% of cases. In no case was the toxicity life threatening. The median overall actuarial survival and progression-free survival were 37 and 20 weeks, respectively. This study indicates that the combination of CAP chemotherapy and r alpha IFN is feasible and active in the treatment of advanced non-small-cell lung cancer.

Cis-platin and radiotherapy in the treatment of unresectable lung cancer.

The goal of this pilot study was to verify the efficacy of the association of cisplatin plus radiotherapy in the treatment of lung cancer. Thirty-seven consecutive patients entered the study. They were treated with radiotherapy (four weekly doses of 2.5 Gy for a total of 50 Gy) and cis-platin once weekly (12 mg/m2). Partial remission was obtained in 15 patients, and 1 patient had a complete remission. Three patients previously inoperable underwent surgical treatment. The actuarial survival curve of the 29 evaluable patients showed a mean survival of 8.5 months. The mean survival of the latter is not evaluable because half of the patients are still alive after 12 to 30 months. No hematologic or renal toxicity was observed with the above schedule.

Radiotherapy versus radiotherapy plus cisplatin treatment for locally advanced non small cell lung cancer: preliminary results of a randomized study.

Preliminary results of a randomized study (radiotherapy versus radiotherapy plus weekly low-dose cisplatin) are reported. Fifty-four patients (43 evaluable) with stage IIIa-b non small cell lung cancer were randomized. Objective responses (CR + PR) were seen in 62% of the radiotherapy-treated group and in 63% of the group treated with radiotherapy plus cisplatin. No major toxicity was seen. Patient compliance for both treatments was satisfactory.

Indium-111-DTPA-octreotide scintigraphy modulation by treatment with unlabelled somatostatin analogue in small-cell lung cancer.

AIMS AND BACKGROUND: Small-cell lung cancer (SCLC) tissue expresses somatostatin receptors and can be visualized by means of the indium-111-labelled somatostatin analogue DTPA-D-Pheoctreotide. The aim of the study was to investigate whether treatment with a cold somatostatin analogue can affect the imaging of somatostatin receptor scintigraphy. METHODS: Three patients with SCLC were treated with 200 micrograms of cold octreotide three times a day subcutaneously for 7 days. Whole body and planar scintigraphy was performed before and after the treatment. RESULTS: 111In-DTPA-octreotide uptake was increased in cancer lesions, whereas fixation in normal tissues (liver, spleen, kidneys) decreased. CONCLUSIONS: This is the first demonstration of an enhancement of SCLC imaging following unlabelled somatostatin analogue administration. Similar results have been described by other authors in a limited number of carcinoid tumors.

Effect of octreotide on neuroenolase levels in patients with small cell lung cancer.

AIMS AND BACKGROUND: The somatostatin analog octreotide has an antiproliferative effect on small cell lung cancer lines in vitro and in experimental xenograft transplantation systems in vivo. Thus it is worth investigating octreotide activity in the clinical setting. METHODS: We studied the effect of octreotide (200 micrograms three times a day subcutaneously for seven days) on serum levels of the tumor marker neuroenolase in 13 patients with small cell lung cancer. RESULTS: A decrease in neuroenolase levels was observed at day 7 during octreotide treatment, with a mean +/- SD of 32.6 +/- 42.0 ng/ml compared to basal values of 44.4 +/- 57.7 ng/ml and to washout values of 50.3 +/- 65.7 ng/ml (P < 0.03). CONCLUSIONS: Our results indicate that octreotide is effective in reducing neuroenolase levels in small cell lung cancer patients. These data suggest a possible role for octreotide in the treatment of this kind of tumor.

Carbon monoxide, cigarettes and family doctors.

AIMS AND BACKGROUND: General practitioners could play a key role in preventive programs against tobacco-related diseases. However, they seldom take action in the office even with minimal advice counselling. Such behaviour might reflect the lack of academic teaching and the lack of practice with motivational and dependence questionnaires, considered basic tools to help smokers to quit successfully. The study was aimed to investigate the awareness of a sample of Italian family doctors as regards tobacco epidemiology and smoking cessation strategies. METHODS: A total of 428 family doctors were administered a questionnaire with a set of questions on their personal smoking habits and on personal initiatives in the office towards smokers. Another set of questions regarded their knowledge on tobacco issues, with special attention to carbon monoxide, which is widely perceived as a very dangerous poison and works as a motivational tool on smokers and adolescents. Carbon monoxide measurement was carried out on all participants to obtain objective data on smoking and to show the feasibility of the test. RESULTS: The percentage of self-reported current smokers among general practitioners was 24%, with a high prevalence of ex-smokers (46%), and 29% of never smokers. Family doctors were more keen to counsel adolescents than adults about tobacco, and they were very interested in continuing medical education on the issue. The doctors who took part in our study showed a surprising limited knowledge of all the issues associated with smoking cessation and prevention such as epidemiology, cigarette characteristics, success rate of smoking cessation programs, Fagerström's tolerance questionnaire, safety of nicotine replacement therapy and the knowledge of carbon monoxide as a product of cigarette smoke. CONCLUSIONS: The scenario depicted by our survey underscores the necessity to improve the knowledge and performance of primary care physicians on tobacco-related issues in order to implement primary and secondary prevention in clinical practice.

In vivo and in vitro growth of SCLC cells derived from biopsies.

In order to increase the availability of SCLC cells derived from biopsies, in vivo and in vitro growth methods were investigated. The cells grown in both conditions were periodically monitored for reactivity with 2 monoclonal antibodies (MAbs): MLuC1 directed against SCLC cells and IM1 which recognizes the class II antigen on activated lymphocytes and macrophages. About 50% of the 28 analyzed SCLC specimens were found to proliferate in one or both systems. The in vitro-grown cells exhibited the same heterogeneity found in the original cell suspensions and moreover, in some cases only normal cells were recovered after several in vitro passages. From the subcutaneous transplanted tumors a large number of MLuC1-positive tumor cells could easily be recovered, thus indicating the validity of the in vivo methodology. The MBr1 MAb, directed against an epithelial antigen, was found to react with about 50% of the 26 tested tumors, mainly those which demonstrated in vivo and/or in vitro growth capacity. These data suggest that only some tumors, presumably with peculiar biological characteristics, can efficiently grow in these artificial systems.

Disseminated tuberculosis of the central nervous system responsive to rifabutin.

Multiple cerebral tuberculomas are now very rare. We report the case of a young man with an 8-month history of headache, febricula and abscess of the left tibiotarsal joint, which was found to contain mycobacterium tuberculosis. Chest X-rays revealed miliariform dissemination to both lungs while CT and MR brain scans revealed numerous small nodules, especially in the posterior cranial fossa. Despite anti-tuberculosis therapy the patient developed a right pyramidal hemisyndrome and intracranial hypertension. The inclusion of rifabutin in the treatment schedule was followed by rapid improvement and a year later the patient was in good health and free from cerebral and pulmonary lesions. The interest of the case lies in the multiplicity of sites of the TB process in a non immunodepressed patient, the dissemination to the CNS without meningeal involvement, the resistance to standard antimycobacterials and the swift response to rifabutin.

Evaluation of neuron-specific enolase, tissue polypeptide antigen, and carcinoembryonic antigen as markers for staging and monitoring response to therapy of lung cancer.

Serum neuron-specific enolase (NSE), tissue polypeptide antigen (TPA), and carcinoembryonic antigen (CEA) were measured in 60 patients with small-cell lung carcinoma (SCLC) and in 94 patients with advanced non-small-cell lung carcinoma (NSCLC) at diagnosis, during induction chemotherapy, and at restaging. At diagnosis, the positivity rates of NSE, TPA, and CEA were 88, 52, and 43% in SCLC, and 20, 62, and 53% in NSCLC, respectively. Serum NSE and TPA levels were significantly higher in extensive than in limited SCLC. TPA and CEA levels were significantly correlated with the extent of NSCLC. NSE and TPA were significantly concordant with the clinical response to initial combination chemotherapy, the former in SCLC, the latter in both SCLC and NSCLC. By discriminant analysis, the presentation levels of the markers were not predictive of response to induction chemotherapy, whereas changes in NSE and TPA levels after the first cycle of chemotherapy were.

111In-octreotide uptake in granulomatous and tumor lesions in a patient with small-cell lung cancer.

A case of a patient with small cell lung cancer and right submandibular node enlargement due to granulomatous lymphadenitis is presented. Diagnostic procedures included: biopsy of the cervical node, transmission computed tomography of the chest, bronchoscopic examination and biopsy of the pulmonary lesion. The patient underwent 111In-octreotide scintigraphy (whole body and single photon emission tomography) which revealed both lesions. We conclude that granulomatous lesions are to be considered as a possible cause of false positive results, when octreotide scintigraphy is used to evaluate distant metastases in patients with known cancer.

Salmon calcitonin in cancer pain: comparison between two different treatment schedules.

The analgesic effect of salmon calcitonin (Calcitonina-Sandoz) was evaluated in an open study of thirty-four patients with bone metastases of a lung cancer. Two different administration protocols were used: eighteen subjects received sCT 400 IU/day for three consecutive days, while the remaining sixteen were given sCT 200 IU/day for six consecutive days. In both protocols salmon calcitonin was diluted in saline and infused intravenously in one hour. Bone, visceral and neuritic pain were evaluated by means of Huskisson's visual analog scale and Keele's pain scale. The analgesic efficacy of salmon calcitonin was also evaluated on the basis of daily consumption of analgesic drugs. Salmon calcitonin proved of extreme efficacy in the treatment of intractable pain from advanced malignancy. A higher and earlier analgesic activity was observed with sCT at the 400 IU daily dosage.

111In-DTPA-D-Phe-1-octreotide scintigraphy of small cell lung cancer.

Twenty-one patients with small cell lung cancer (SCLC) were investigated with 111in-octreotide (111-In-OCT) scintigraphs, 5 hours after the i.v. injection of 111 MBq of the radiotracer. Whole-body and planar scintigraphy as well as SPECT of the thorax were required. The scintigraphic results were compared to those of other conventional diagnostic procedures used for the staging and follow-up of SCLC patients. 111In-OCT detected 86% (48/56) of the lesions already known at the time of scintigraphy, being positive for all 20 SCLC lesions and negative for one lung adenocarcinoma. 111In-OCT showed a high sensitivity for mediastinal metastases (94%) and good sensitivity for bone (75%) and abdominal lymph node metastases (71%). It did not detect 2 liver metastases but revealed 5 unknown lesions which were then confirmed by other diagnostic examinations. 111In-OCT was also effective in patients with low levels of NSE. Three patients received cold octreotide for seven days to investigate whether this treatment might affect SCLC imaging. Scans were performed before and after treatment. The 111In-OCT uptake increased in the cancer lesions while the fixation in normal tissues decreased, demonstrating enhancement of SCLC imaging following cold octreotide administration.