Phase I/II trial of weekly cisplatin, etoposide, and irinotecan chemotherapy for metastatic lung cancer: JCOG 9507.

Combinations of cisplatin-irinotecan and cisplatin-etoposide are active and well tolerated in patients with both small-cell lung cancer (SCLC) and nonsmall-cell lung cancer (NSCLC). To define the recommended dose for phase II trials of irinotecan combined with cisplatin and etoposide in chemonaive patients with stage IV disease, 56 patients (11 having SCLC and 45 NSCLC) received cisplatin 25 mg m(-2) weekly for 9 weeks, etoposide 60 mg m(-2) for 3 days on weeks 1, 3, 5, 7 and 9, and irinotecan 20-100 mg m(-2) (levels 1-8) on weeks 2, 4, 6 and 8, together with a prophylactical granulocyte colony-stimulating factor support (50 microg m(-2) on days 4-7 on weeks 1, 3, 5, 7 and 9, and on days 2-7 on weeks 2, 4, 6 and 8). Grade 3-4 leukocytopenia, neutropenia and thrombocytopenia were noted in 20 (36%), 28 (50%) and nine (16%) patients, respectively. Grade 3 diarrhoea, grade 3 cardiac toxicity, and grade 4 transaminase elevation developed in one (1.8%) patient each. Totally, four of 56 patients were removed from the study because of toxicity and recovered, and two other patients died in situations where drug toxicity might contribute to their death. Dose-limiting toxicity was noted in less than one-third of patients at dose levels 1-7, but in all patients at dose level 8. Thus, the recommended dose was determined to be level 7 (irinotecan 90 mg m(-2)). The response rates for SCLC and NSCLC were 91% (10/11) and 38% (17/45), respectively. The median survival time and 1-year survival rate were 11.9 months and 46% for SCLC and 10.1 months and 40% for NSCLC, respectively. This regimen was considered to be feasible and promising for the treatment of stage IV SCLC and NSCLC.

Serum levels of KL-6 are useful biomarkers for severe radiation pneumonitis.

The antigen KL-6, a mucin-like high-molecular-weight glycoprotein, is expressed on type-2 pneumocytes and bronchiolar epithelial cells. Serum levels of KL-6 have been shown to correlate well with the activities of several different kinds of interstitial pneumonia. The purpose of this study was to assess the usefulness of monitoring serum KL-6 levels in patients who had received thoracic radiotherapy (TRT). In particular, the usefulness of such a protocol for the early diagnosis of severe radiation pneumonitis (RP) and the evaluation of its progress and severity was examined. Serum KL-6 levels were retrospectively monitored in 16 patients with lung cancer who had received TRT with or without chemotherapy. Eight of these patients had developed severe RP and eight had developed localized (within the irradiated field) RP. Serum KL-6 levels were measured using a modified sandwich-type enzyme-linked immunosorbent assay. In patients who developed severe RP, serum KL-6 levels showed a consistent tendency to increase after the clinical diagnosis of RP. In four patients, serum KL-6 levels even began to rise before a clinical diagnosis of severe RP had been made. In the patients with localized RP, on the other hand, the serum levels did not show any tendency to increase during or after TRT. Moreover, patients whose serum KL-6 levels rose more than 1.5 times higher than their pre-treatment serum KL-6 level, had a large chance of developing severe RP that was unresponsive to steroid hormones and resulted in death. Serum KL-6 levels, therefore, should be useful indicators for the early diagnosis of severe RP and for estimating its progress and severity in patients treated with TRT.

Japanese experience of telemedicine in oncology.

We started telemedicine projects from 1990 with a telepathology system within Tsukiji Campus of National Cancer Center. In 1994, we connected Tsukiji Campus and Kashiwa Campus by 6 Mbps optical fiber leased line using IP protocol for data transmission, for teleconference, telepathology, and teleradiology projects. We also started connection of regional cancer centers and are now forming a cancer center network of 14 cancer centers. We are at present organizing 130 teleconferences per year with an attendance of more than 16000 people as summary. We have also used a high-resolution image transferring system, such as SHD (2000 pixelsx2000 pixels resolution) system on one side, and an economical telemedicine system using JAVA and a WWW browser (NCC_image) on the other side. We think that providing information is another field of telemedicine. We began the experimental gopher and WWW service in 1993. We are now providing official up-to-date cancer information for patients and healthcare professionals. We are getting more than 400000 hits per month. We are also providing a teleconference video session which is held every week on the Internet using a Real Video system with synchronized slide presentation on the WWW browser. We are also organizing a Cancer Image Reference Database System including DICOM images with viewer software. This paper is a summary of the telemedicine projects performed at the National Cancer Center.

Risk factors of treatment-related death in chemotherapy and thoracic radiotherapy for lung cancer.

We retrospectively analysed the incidence and risk factors of treatment-related death in the treatment of chemotherapy- and thoracic radiotherapy-naïve patients with lung cancer. Between July 1992 and December 1997, 1799 patients were diagnosed as having lung cancer in our hospital and 926 patients received chemotherapy and/or thoracic radiotherapy. 25 patients (2.7%) died from toxicity of the treatment, 10 from pneumonia, 7 from radiation pneumonitis, 6 from sepsis, 1 from perforation of the small intestine and 1 for an unknown reason. 18 patients (2.3%) died from chemotherapy-related toxicity. The incidence of treatment-related death (TRD) from chemotherapy was highly correlated with the performance status (PS), PS 0: 0.7%, PS 1: 2.2%, PS 2: 4.0%, PS 3: 7.7% and PS 4: 25% (P=0.004). 7 patients (1.6%) died from pneumonitis after thoracic radiotherapy. Multivariate analyses demonstrated that poor PS (relative risk (RR): 1.95, 95% confidence interval (CI): 1.05-3.65, P=0.034) and chemotherapy using the cisplatin+vindesine+mitomycin C regimen (RR: 9.36, 95% CI: 1.29-68.0, P=0.027) are associated with treatment-related death from chemotherapy. Pulmonary fibrosis identified on a plain chest X-ray film (RR: 165.7, 95% CI: 8.79-3122, P<0.001), the combination of cisplatin+irinotecan (RR: 120.5, 95% CI: 2.90-4993, P=0.012), advanced age (RR: 1.17, 95% CI: 1.002-1.37, P=0.047), and elevated lactate dehydrogenase (LDH) (RR: 10.4, 95% CI: 1.20-90.2, P=0.033) were also associated with treatment-related death from thoracic radiotherapy. The administration of mitomycin C in addition to cisplatin-based regimens for patients with lung cancer should be carefully considered.

Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue in the thymus of a patient with pulmonary amyloid nodules.

Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-type lymphoma) is a rare thymic tumor, with only seven previous cases described worldwide to date. We describe the only case to have presented with pulmonary amyloid nodules. A 63-year-old Japanese female was found to have an anterior mediastinal tumor and multiple bilateral pulmonary nodules during a medical check-up in 1990 followed by chest radiography and computerized tomography. Because the mediastinal tumor grew larger, she was referred to the National Cancer Center Hospital East and hyperglobulinemia was pointed out. The thymus was resected through median sternotomy and pulmonary nodules were also resected through left thoracotomy. The solid and nodular tumor with several small satellite extensions and cyst formation was completely confined to within the thymus and the resected pulmonary nodules consisted of solid masses with a rough surface. Histologically, monotonous medium-sized centrocyte-like cells occupied the medulla of the thymus and infiltrated Hassall's corpuscles (lymphoepithelial lesions) and the resected pulmonary nodules consisted of eosinophilic amorphous deposits which showed birefringence on Congo Red staining. Immunohistochemically, the tumor cells were positive for CD20 and CD79a. IgG and kappa light chain restrictions were also found in plasmacytoid cells in the tumor. Clonal rearrangement of the immunoglobulin heavy chain gene was demonstrated by polymerase chain reaction. We diagnosed this case as low-grade B-cell MALT-type lymphoma in the thymus and nodular pulmonary amyloidosis. Since the patient had only localized amyloid deposits in the lung far from the thymic malignant lymphoma and had high serum immunoglobulins, the pulmonary amyloid deposits might be derived from a circulating precursor associated with hyperglobulinemia.

Significance of serum pro-gastrin-releasing peptide as a predictor of relapse of small cell lung cancer: comparative evaluation with neuron-specific enolase and carcinoembryonic antigen.

Neuron-specific enolase (NSE) and carcinoembryonic antigen (CEA) have been reported to be useful markers for staging, monitoring treatment, and predicting relapse in patients with small cell lung cancer (SCLC). Recently, pro-gastrin-releasing peptide (Pro-GRP) became available as a sensitive, specific, and reliable tumor marker for patients with SCLC. The aim of this study is to determine the most useful tumor marker to detect the relapse of SCLC. Furthermore, we analyzed the relationship between tumor markers at relapse and survival from relapse or response to salvage chemotherapy. Medical records were reviewed to obtain serum levels of Pro-GRP, NSE, and CEA before and after the initial chemotherapy, and at relapse. Consecutive 66 patients with SCLC, with an objective response and confirmed relapse treated at the National Cancer Center Hospital East, were analyzed in this study. The percentages of patients whose tumor marker level were elevated before treatment, decreased after the treatment, and increased again at relapse were 67% (95% CI, 55-78) for Pro-GRP, 20% (10-29) for NSE, and 38% (26-50) for CEA. Multivariate analysis indicated that poor performance status before initial treatment and elevated serum levels of lactate dehydrogenase at relapse were poor prognostic factors for patients with recurrent SCLC (P<0.005). None of the serum levels of Pro-GRP, NSE, and CEA at relapse was a significant prognostic factor and associated with an objective response to salvage chemotherapy. The present study demonstrated that serum levels of Pro-GRP reflect the disease course of patients with SCLC most accurately.

Effect of nebulized morphine in cancer patients with dyspnea: a pilot study.

BACKGROUND: It is known that opioids may decrease subjective dyspnea. The recent finding that opioid binding sites are present in the peripheral bronchus supports the possibility of a local action of opioids. However, the clinical benefit of nebulized morphine is controversial. The purpose of this study was to confirm the feasibility of nebulized morphine and to evaluate its clinical benefits. PATIENTS AND METHODS: Fifteen cancer patients with dyspnea in the Thoracic Oncology Division and Palliative Care Unit in the National Cancer Center Hospital East were given 20 mg of morphine hydrochloride dissolved in 5 ml of normal saline through an ultranebulizer. The subjective effects were evaluated using a visual analog scale (VAS) immediately before and 60 min after inhalation. Respiratory rate (RR), hemoglobin oxygen saturation (SpO2) and blood pressure also were measured twice at these two time points. A questionnaire about adverse reactions was included. RESULTS: No major adverse reactions such as respiratory depression, sleepiness, nausea or vomiting were observed. VAS was significantly decreased after nebulization (p = 0.005) without any significant change in RR or SpO2. In eight of 15 patients, dyspnea was improved as measured by a decrease in VAS of more than 10%. This correlated with the desire of the patients to continue its use. CONCLUSION: Our preliminary data confirmed the feasibility of nebulized morphine and suggested its possible clinical benefit for dyspneic patients. A randomized controlled study is warranted to exclude a placebo effect and to compare the clinical benefits of nebulized morphine with those of other methods of treatment.

Phase I study of cisplatin and docetaxel plus mitomycin C in patients with metastatic non-small cell lung cancer.

BACKGROUND: Docetaxel, cisplatin and mitomycin C are some of the active drugs used in the treatment of patients with metastatic non-small cell lung cancer (NSCLC). The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose of the three drugs in combination for such patients. METHODS: Chemotherapy-native patients with metastatic NSCLC were enrolled in this study. The doses of docetaxel and cisplatin were fixed at 60 and 80 mg/m2, respectively. It was planned to increase the dose of mitomycin C from 4 to 6 and 8 mg/m2. All drugs were administered on day 1 and repeated every 3-4 weeks. RESULTS: All six patients received 60 mg/m2 of docetaxel and 80 mg/m2 of cisplatin, three of them with 4 mg/m2 of mitomycin C (level 1) and the other three with 6 mg/m2 of mitomycin C (level 2). Two of the three level 2 patients experienced dose-limiting toxicities (DLTs) in first cycle: febrile neutropenia and grade 3 hyponatremia. Based on these data, the MTD was concluded to be 60 mg/m2 for docetaxel, 80 mg/m2 for cisplatin and 6 mg/m2 for mitomycin C. Evaluation of the data from all of the cycles, however, showed that four of the six patients experienced DLTs. CONCLUSIONS: The addition of mitomycin C to docetaxel and cisplatin resulted in relatively high toxicities. It was impossible to use a high enough dose of mitomycin C to improve the survival of NSCLC patients. We therefore concluded that further evaluation of this combination is unwarranted.

Primary unknown cancer in pulmonary hilar lymph node with spontaneous transient regression: report of a case.

A 69-year-old man was referred to our hospital in December 1993 because an abnormal mass had been detected in the right pulmonary hilum. Computed tomography (CT) of the chest revealed a swollen hilar lymph node between the right middle and lower lobe bronchi, and an adherent tumor in the right ventrobasal segment (S8). Chest roentgenogram in February 1994, however, showed no evident tumor in the right lung field. In March 1996, the mass in the right pulmonary hilum reappeared on chest roentgenogram. Chest CT revealed a swollen hilar lymph node between the right middle and lower lobe bronchi, but there was no tumor in right S8. The patient underwent video-assisted thoracoscopy on 17 May 1996. Intraoperative needle biopsy of the node revealed cancer cells. We performed right middle and lower bilobectomy with mediastinal dissection. Histological diagnosis revealed a large cell carcinoma almost completely occupying a hilar lymph node. The resected middle and lower lobes showed no tumors, except for a coagulation necrosis measuring 1.5 cm in diameter in S8b, corresponding to the site where a tumor shadow had been depicted on the CT image in December 1993. We concluded that the coagulation necrosis might have been the primary site of the tumor, which had spontaneously regressed and then appeared in the metastatic interlobar node.

[Comparison of screening-detected and symptomatic lung cancer patients].

Survival rates were studied in 416/27 screening-detected and 1,099/188 symptomatic patients with non-small cell lung cancer (NSCLC)/small cell lung cancer (SCLC). Screening-detected patients with both NSCLC and SCLC had earlier stage disease, showed better PS distribution, and a greater part of the patients underwent standard therapy than the symptomatic cohort with a significant difference. Median survival time, 5- and 10-year survival rates were 1,220 days, 44.4% and 34.9%, respectively, in the screening-detected patients, and 248 days, 11.3% and 7.5%, respectively, in the symptomatic patients with NSCLC. They were 584 days, 21.2% and 15.9%, respectively, in the screening-detected patients, and 257 days, 4.8% and 2.3% in the symptomatic patients with SCLC.

Clinicopathologic characteristics of patients with nonsmall cell lung carcinoma with elevated serum progastrin-releasing peptide levels.

BACKGROUND: Progastrin-releasing peptide (proGRP) is a specific tumor marker in patients with small cell lung carcinoma (SCLC). It has been reported that serum proGRP levels rarely are elevated in patients with nonsmall cell lung carcinoma (NSCLC); the reported frequency is <3%. The purpose of this study was to examine the clinicopathologic features of NSCLC patients with high serum proGRP levels. METHODS: The authors measured serum proGRP levels with a TND-4 kit, a newly developed enzyme-linked immunoadsorbent assay, in 544 NSCLC and 206 SCLC patients. Pathologic features were examined using conventional hematoxylin and eosin staining and histochemical and immunohistochemical staining using polyclonal antibodies to proGRP, chromogranin A, calcitonin, and monoclonal antibody to the neural cell adhesion molecule (NCC-Lu-243). RESULTS: The serum proGRP levels were elevated in 140 SCLC patients (68.0%) and in 23 NSCLC patients (4.2%). Seven of these 23 NSCLC patients had serum proGRP levels > or = 100 pg/mL. They included two patients with renal dysfunction, one patient diagnosed cytologically with adenocarcinoma without undergoing precise pathologic examination, two patients diagnosed histologically with squamous cell carcinoma with foci of small cell elements, and two patients diagnosed with large cell neuroendocrine carcinoma and poorly differentiated adenocarcinoma, respectively, which showed neuroendocrine differentiation on immunohistologic analysis. The remaining 16 NSCLC patients had serum proGRP levels < 70 pg/mL. CONCLUSIONS: Nearly all NSCLC patients had serum proGRP levels < 100 pg/mL. However, if an NSCLC patient presents with a proGRP level > or = 100 pg/mL, the clinicopathologic features must be examined with regard to the small cell component, neuroendocrine differentiation, and renal dysfunction.

Second-line chemotherapy for relapsed small cell lung cancer.

Between January 1985 and August 1991, 159 patients with small cell lung cancer received first-line chemotherapy and 123 (77%) were responders. Of these, 88 relapsed, the remainder having died of other or unknown diseases or being alive without carrying cancer. The relapsed patients were examined to evaluate the outcome of the treatment for relapsed small cell lung cancer and to identify the factors that would contribute to the response rates and the survival durations. Forty-eight of 88 relapsed patients received second-line chemotherapy. Of the 48, 3 were evaluated as showing a complete response, 13 as partial response, 9 as no change, 15 as progressive disease and 8 as not evaluable. The response rate was 33% (95% confidence interval 20.4-48.4%). The median survival time was 146 days. The duration and rate of response in first-line chemotherapy affected the response rates of the second-line chemotherapy, but without statistical significance (P = 0.058 and 0.067 respectively). Increased response duration, time off chemotherapy and previous response to first-line chemotherapy all had a positive effect on the survival times (P < 0.01). Relapsed small cell lung cancer still shows a response to second-line chemotherapy without lessening survival time, and thus clinical trials of new drugs or combination chemotherapeutic regimens for relapsed small cell lung cancer cases would be reasonably justified. Randomized comparative studies are warranted for determining the benefits of second-line chemotherapy for relapsed small cell lung cancer cases.

Phase II study of high-dose dexamethasone-based association in acute and delayed high-dose cisplatin-induced emesis--JCOG study 9413.

Thirty-three patients with lung cancer receiving 80 mg m(-2) cisplatin were treated with high-dose dexamethasone (32 mg m(-2) on days 1-3, 16 mg m(-2) on day 4 and 8 mg m(-2) on day 5) combined with granisetron on day 1 and metoclopramide on days 2-5. Twenty-eight (85%) patients had no nausea or vomiting on day 1, and 16 (48%) achieved total control on days 1-5 with acceptable toxicity. High-dose dexamethasone for cisplatin-induced delayed emesis should be further evaluated in a phase III trial.

Dose-intensive weekly chemotherapy for treatment of relapsed small-cell lung cancer.

PURPOSE: This study was undertaken to determine the activity and toxicity of dose-intensive weekly chemotherapy (cisplatin, vincristine, doxorubicin, and etoposide [CODE] regimen) for previous treated, recurrent small-cell lung cancer (SCLC). PATIENTS AND METHODS: The 17 patients with relapsed SCLC entered onto the study were to receive intensive weekly chemotherapy with the CODE regimen. All 17 patients had been heavily pretreated with some form of cisplatin-based combination chemotherapy. Six patients had received previous chemotherapy with CODE and one patient with cisplatin and etoposide (PE) as induction therapy. Nine patients had been treated with concurrent or sequential PE plus thoracic irradiation (TRT). The median time off chemotherapy was 6.7 months (range, 3.3 to 72). Patients were treated with 9 weeks of the CODE regimen. Response, survival, and toxicity data were noted. RESULTS: All 17 patients were assessable for response, survival, and toxicity. Fifteen of 17 patients (88.2%) had an objective response, with five complete responses (CRs; 29%) and 10 partial responses (PRs; 58.8%). The median durations of response and survival were 156 days and 245 days, respectively. Myelosuppression was significant, with 76% of patients developing grade 4 leukopenia. No treatment-related death was observed. CONCLUSION: The CODE regimen is highly active in the treatment of relapsed SCLC with an encouraging survival outcome.

Late recurrence of small-cell lung cancer: treatment and outcome.

The 2-year survival of patients with small-cell lung cancer (SCLC) with limited disease is about 25% and the survival curve continues to decline after 2 years. We reviewed 34 cases of survivors of SCLC who had been free of disease for 2 years and who constituted 12.2% of the 278 patients with SCLC newly diagnosed at our institution from 1977 to 1991. The cancer had recurred in 13 patients, 10 of whom were treated with chemotherapy and/or radiotherapy, and 1 complete and 1 partial response were obtained. Three patients received only supportive care because of poor performance status. The median survival after recurrence in the 13 patients was 7.4 months (range 0-39 months). A second primary cancer was noted in 5 patients, but 3 of them died from recurrence of SCLC. The prognosis of patients with late recurrence of SCLC was relatively good, and it seems that adequate treatment in such cases may lead to long-term survival.

A randomized cross-over trial of granisetron and dexamethasone versus granisetron alone: the role of dexamethasone on day 1 in the control of cisplatin-induced delayed emesis.

We studied the role of dexamethasone (DEX) administered on day 1 in controlling cisplatin-induced delayed emesis. Forty patients were randomly allocated to receive either granisetron (GRN) and DEX on day 1, or the same dose of GRN alone. On days 2-5, all the patients received metoclopramide and DEX. They were crossed over to the other antiemetic regimen with their second course of chemotherapy. Thirty-one patients were evaluable for efficacy. The mean visual analogue scale scores for nausea on days 1 and 2 were 9.1 and 18.8 mm for GRN and DEX, and 16.3 and 28.5 mm for GRN alone, respectively (P<0.05 on day 2). The mean numbers of emetic episodes on days 1-3 were 0.036, 0.46 and 0.36 for GRN and DEX, and 0.39, 0.89 and 0.57 for GRN alone, respectively (P<0.01 on day 1). Hiccups and restlessness were noted in 38% and 33% of cycles, respectively. Addition of DEX to GRN on day 1 thus enhanced the control of delayed emesis.

[A case report of coronary artery bypass graft surgery and subsequent chemotherapy for the patient with unstable angina and small cell lung cancer].

A 74 year old female with lung cancer had undergone coronary artery bypass graft surgery (CABGS) and survived for 9 months after subsequent chemotherapy. She had been suffering from severe chest pain since 2 years before that time, and deteriorated intractably. At the same time, lung cancer was suggested radiologically, and revealed as small cell lung cancer by bronchial biopsy. Coronary angiogram study was done to verify the coronary artery disease and severe triple artery disease was shown. CABGS was done to relieve her condition to start chemotherapy. Post-operative course was fine and CODE therapy [cisplatin, oncovin (vincristine), doxorubicin (adriamycin), etoposide] was done subsequently to CABGS. Cancer focus and swollen lymph node were vanished in radiographic examination. She had discharged and spent at home for a while. However, multiple metastatic lesions emerged later, and deceased finally 9 mouths after CABGS. We conclude, CABGS done for her was a reasonable therapy to relief her condition and was successful to carry out chemotherapy.

Pharmacokinetics of bronchial artery infusion of mitomycin in patients with non-small cell lung cancer.

The pharmacokinetics of bronchial artery infusion of 20 mg (11.4-14.0 mg/m2) mitomycin was studied in 14 patients with non-small cell lung cancer (NSCLC). The mean elimination half-life was 34.3 min (range 6-72), and the area under the plasma concentration-time curve (AUC) was 166 ng h/ml (39-312). The mean maximum plasma drug concentration (Cmax) was 178 ng/ml (12-540) and back-extrapolated plasma drug concentration was 308 ng/ml (17-1423). The mean volume of distribution in the one-compartment model was 0.183 l/kg (0.010-0.887) and the rate constant for unchanged drug appearing in the urine was 1.91/min (0.57-7.27). There was considerable variation among individuals with respect to the pharmacokinetics of mitomycin, and the mean Cmax and AUC were lower than those reported after intravenous administration.

[A phase II study of UFT in non-small cell lung cancer].

A phase II evaluation of UFT, a mixture of tegafur and uracil, was performed in 13 patients with non-small cell lung cancer (eight patients with adenocarcinoma and five patients with squamous cell carcinoma). UFT at a dose of 600 mg was given per os every day for more than four weeks. Among 12 evaluable patients, one patient with adenocarcinoma of the lung showed partial response. The response rate for UFT was 8.3%. Toxic effects included anorexia (31%), nausea (15%), liver disorder (15%), and pigmentation (8%).