Margaret Edison

Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer

PURPOSE We performed a prospective randomized clinical trial to determine whether higher doses of etoposide and cisplatin (EP) yield more complete responses or longer survival in small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS Ninety patients with previously untreated extensive-stage SCLC fulfilled criteria for randomization to standard-dose versus high-dose EP. Another 25 patients at risk of excessive toxicity from high-dose treatment were given standard-dose therapy. During cycles 1 and 2 of EP, patients on standard-dose treatment received intravenous etoposide 80 mg/m2 on days 1 to 3 and cisplatin 80 mg/m2 on day 1 every 3 weeks; high-dose treatment consisted of etoposide 80 mg/m2 on days 1 to 5 and cisplatin 27 mg/m2 on days 1 to 5 every 3 weeks. All patients received standard-dose EP in cycles 3 and 4. In cycles 5 through 8, completely responding patients continued standard-dose EP; all other patients received either cyclophosphamide, doxorubicin, and vincristine, or (if possible) a combination drug program based on in vitro drug sensitivity testing of tumor-cell lines established from individual patients. RESULTS Despite 68% higher doses and a 46% higher dose-rate intensity actually given to patients randomized to receive high-dose relative to those randomized to receive standard-dose EP, complete response rates (23% v 22%; P = .99) and median survival durations (10.7 and 11.4 months, respectively; P = .68) were virtually identical. Complete responses occurred in 4% of patients and the median survival duration was 5.8 months in nonrandomized patients. Leukopenia (P < .0001), thrombocytopenia (P < .0001), febrile neutropenia (P = .01), and weight loss (P = .02) were significantly more common in patients randomized to receive high-dose compared with standard-dose EP. CONCLUSION No therapeutic benefits resulted from increasing planned doses by 67% for the first two cycles of EP in patients with extensive-stage SCLC. Higher doses were associated with substantially worse toxicities.

Smoking Cessation after Successful Treatment of Small-Cell Lung Cancer Is Associated with Fewer Smoking-related Second Primary Cancers

Combination chemotherapy for small-cell lung cancer results in objective responses in 80% to 90% of patients and in 3% to 13% of 2-year cancer-free survivors [1-7]. Relapses 2 years after initiation of therapy occur in approximately one third of 2-year survivors [1, 6, 7]. In addition, deaths from second malignancies, particularly of the lung, and from nonmalignant smoking-related medical problems have been reported in patients with small-cell lung cancer who survive free of cancer for more than 2 years [3, 5, 7-10]. Consequently, the overall 5-year survival rate for all patients with small-cell lung cancer is low, reported as 2.4% to 6% [1, 5, 7-9, 11, 12]. To estimate the risk for second primary cancers in survivors of small-cell lung cancer, we evaluated all patients with this malignancy who remained disease free for 2 years after the initiation of therapy at the National Cancer Institute. The potential change in the risk for a second cancer during follow-up was studied to determine whether the risk increases or decreases with time. In addition, the influence of smoking cessation on the development of subsequent primary smoking-related cancers is undefined [13-20]. Smoking history in our patient population was therefore carefully assessed, and the effect of smoking cessation was evaluated. Methods Patients From April 1973 to December 1989, 540 consecutive patients with histologically confirmed, previously untreated small-cell lung cancer were treated in National Cancer Institute intramural therapeutic trials. All had primary small-cell carcinoma of the lung with evaluable tumor lesions; none were treated in an adjuvant setting after surgical resection. The majority of patients were assigned a performance status, metastatic sites identified, and they were classified as having either limited- or extensive-stage disease as previously defined [21, 22]. The patients began treatment with combination chemotherapy with or without radiotherapy using various regimens that have been reported previously [11, 21-29]. The current status of all patients was determined. The locations of the initial small-cell lung cancers were identified by reviewing reports of chest roentgenograms, thoracic computed tomography, fiberoptic bronchoscopies, mediastinoscopies, and thoracotomies in all patients who were free of cancer for 2 or more years after the initiation of chemotherapy. The sites of subsequent intrathoracic cancer were localized by reviewing reports of chest roentgenograms, thoracic computed tomography, fiberoptic bronchoscopies, thoracotomies, and autopsies. Chest roentgenograms and computed tomographic scans from patients with second primary non-small-cell lung cancers were compared with pretreatment radiotherapy chest roentgenograms showing treatment ports. All initial and subsequent pathologic material was reviewed by one of two pathologists from our institution. The diagnosis of small-cell lung cancer was made and confirmed using the previously defined histologic criteria [30, 31]. Smoking history in all 55 2-year cancer-free survivors was repeatedly determined by a combination of patient follow-up visits, chart and protocol database review, and contact of either patients alive at the time of manuscript preparation or relatives of deceased patients. Smoking cessation was defined as completely stopping smoking by the end of treatment, which was usually of 6 months duration. Definitions The upper aerodigestive tract includes the epithelial regions of the head and neck, lung, and esophagus [13, 32-34]. Smoking-related cancers include cancers of the lung, head and neck, esophagus, bladder, pancreas, kidney, and possibly the stomach [35]. A second primary non-small-cell lung cancer after an initial small-cell lung cancer occurs when 1) tumor histologic findings show non-small-cell lung cancer without small-cell elements; 2) no evidence suggests local or distant recurrence of small-cell lung cancer; and 3) the second cancer is identified more than 2 years after diagnosis of the original small-cell lung cancer [3, 36, 37]. Statistical Analysis For estimation of the expected values of second cancer development, the period of risk began 2 years after diagnosis of the small-cell lung cancer and ended with the date of death, date of last follow-up, or date of diagnosis of a second cancer, whichever occurred first. Person-years of observation were accumulated using the computer program of Monson [38]. Age, sex, and time-specific rates for mortality obtained from the National Mortality Statistics and for cancer incidence obtained from the Surveillance, Epidemiology, and End Results (SEER) program were applied to the appropriate person-years of observation, had this population experienced the same rates prevailing in the national or SEER populations, respectively. Statistical methods for risk estimation were based on the assumption that the observed number of second cancers followed a Poisson distribution [39]. Test of significance and confidence intervals (CIs) for the relative risk (observed and expected) were calculated by using exact Poisson probabilities. To determine the absolute risk, or excess cases of cancer per 1000 persons per year, the number of expected cases was subtracted from the number observed; the difference was divided by the number of person-years of observation and multiplied by 104. Trends and homogeneity were tested as described by Breslow and colleagues [39]. Results Patient characteristics at time of initiation of treatment for both the entire patient population and for the 2-year cancer-free survivors are summarized in Table 1. Of the 540 patients, 55 (10%) were alive and free of cancer 2 or more years after the initiation of treatment protocols Figure 1, corresponding to 22% of 204 patients with limited-stage and 3% of 336 patients with extensive-stage disease. Eighty-six of the patients did not have a performance status assigned or metastatic sites identified prospectively. Compared with the entire patient population, the 2-year cancer-free survivors had a higher percentage of women, of patients with limited-stage disease, and of fully ambulatory patients (Eastern Cooperative Oncology Group performance status, 0-1). These favorable prognostic factors are thoroughly described in the literature [40-43]. The other 485 patients died or had relapsed with small-cell lung cancer within 2 years. The median follow-up from initiation of therapy was 6.1 years (range, 2.1 to 15.1 years) for the 55 patients. Ten patients have remained free of cancer since initial treatment. Five other patients remain alive; three developed second primary cancers that were successfully treated; and two relapsed with small-cell lung cancer, one achieving a prolonged second complete response (>3 years) after recurrence and the other currently receiving salvage chemotherapy. Of the 55 patients, 40 have died: 16 from recurrent small-cell lung cancer, 13 from second primary cancers, 1 from a suspected second primary lung cancer (lung mass without histologic confirmation), and 10 from other causes. Table 1. Patient Characteristics Figure 1. Flow diagram of the outcome of 540 patients with small-cell lung cancer treated at the National Cancer Institute from 1973 to 1989. Eighteen of the 55 patients developed recurrent small-cell lung cancer 2.1 to 12.2 years (median, 3.2 years) after beginning chemotherapy (see Figure 1). The histopathologic features of 4 of the 18 (22%) recurrent small-cell lung cancer tumors included subpopulations of cells with prominent nucleoli but were still in the histologic spectrum of small-cell lung cancer [30]. Eighteen of the 55 2-year cancer-free survivors developed one or more second primary cancers 3.5 to 13.3 years (median, 7.5 years) after beginning therapy for small-cell lung cancer. One of the 18 patients with a second primary cancer had invasive squamous cell carcinoma of the lip, which metastasized to the regional lymph nodes. Another patient died of a central nervous system disorder but had an incidental esophageal cancer discovered at postmortem examination. These cancers were not included in the calculations of the relative risk because incidence data are not available from SEER on nonmelanoma skin cancer and on incidental cancers discovered at postmortem examination (Table 2). The sarcoma was included with other lung cancers because the SEER incidence rates are based on the classification of cancers by site of origin, not by histologic findings. Table 2. Incidence of Second Primary Cancers after at Least 2 Years of Survival with Small-Cell Lung Cancer* The risk for development of a second cancer more than 2 years after the diagnosis of small-cell lung cancer increased by approximately four times, mostly due to the 16-fold increase in second non-small-cell lung cancers (nine squamous; one adenocarcinoma, one large cell carcinoma, and one sarcoma; and one suspected second primary cancer without histologic confirmation) (Table 2). A patient who developed an adenocarcinoma of the lung 12 years after the initial diagnosis of small-cell lung cancer had an initial biopsy specimen with predominant small-cell lung cancer histologic features and an adenocarcinoma component. The patient who developed a squamous cell cancer of the head and neck 8.9 years after the initiation of treatment for small-cell lung cancer had mixed small-cell/large-cell histologic features. The other 53 patients had only small-cell lung cancer in their biopsy specimens at presentation. Seven cancers developed in the lung contralateral to the original small-cell lung cancer, two in a different lobe of the ipsilateral lung, three in the same lobe, and one site could not be accurately determined because of the presence of massive bilateral pleural effusions. The relative risk for a second primary non-small-cell lung cancer compared with that in the general population increased significantly over time from 6 times at 2 to 4 years to 36 t

Female patients with small cell lung cancer live longer than male patients

PURPOSE The incidence of lung cancer is rising in women in the United States, and recent reports have suggested that female patients treated for small cell lung cancer have an improved survival compared with their male counterparts. In view of these findings, we decided to determine if, in our patient population, women live longer than men and if a higher proportion of female patients are entering our trials. PATIENTS AND METHODS The survival of women entering therapeutic clinical trials for small cell lung cancer from 1973 through 1986 at the National Cancer Institute-Navy Medical Oncology Branch was evaluated and compared with the survival of similarly treated men during the same time period. RESULTS The survival of female patients was longer than that of male patients (median of 13 months versus 10 months). Cox proportional hazards modeling incorporating multiple prognostic factors indicated that women survived significantly longer than men (p = 0.002) when adjustment for other significant factors was made. This survival advantage for women was consistent in both early and late time periods analyzed. In addition, women constituted a larger proportion of patients entering clinical trials in the later time period, as is consistent with the rising incidence of lung cancer in women nationwide. CONCLUSION We believe it will be important that comparisons of current clinical trials with older trials that enrolled fewer women control for the favorable prognostic factor of the female sex.

Pulmonary toxicity with combined modality therapy for limited stage small-cell lung cancer.

To assess the pulmonary toxicity of radiation therapy combined with chemotherapy v chemotherapy alone, we reviewed the clinical course of 80 patients with limited stage small-cell lung cancer treated in a randomized prospective trial. Life-threatening pulmonary toxicity, defined as bilateral pulmonary infiltrates extending beyond radiation ports with symptoms requiring hospital admission, developed in 11 patients (28%) receiving combined modality therapy and in two (5%) receiving chemotherapy alone. Eight of these 13 patients died from pulmonary complications with no clinical evidence of tumor in five. Pulmonary toxicity initially presented at a median of 63 days (range, 21 to 150 days) after the start of combined modality therapy and at a median of 217 days after chemotherapy alone. Biopsies obtained in 11 patients with severe toxicity revealed only interstitial fibrosis with no evidence of an infectious agent. Review of pretreatment parameters such as age, performance status, and radiation portal area failed to reveal any significant differences between patients with or without pulmonary complications. However, initial pulmonary function tests (PFTs) revealed a significantly lower vital capacity (P = .03) and forced expiratory volume (FEV/1.0 second) (P = .04) in patients with subsequent pulmonary complications. Pulmonary toxicity was significantly more common with combined modality therapy than with chemotherapy alone (P = .017) and worse than expected with radiotherapy alone. Six- or 12-month PFTs in completely responding patients revealed improvement within the chemotherapy alone group and no clear trend within the combined modality group. For the group treated with radiation therapy and chemotherapy, there was significantly less improvement after 6 or 12 months in the forced vital capacity (P less than .005) and FEV/1.0 second (P less than .005) than observed for the group treated with chemotherapy alone. Despite the increased incidence of pulmonary toxicity, overall survival favored the combined modality arm (P = .07). Enhanced local control and disease-free survival appeared to compensate for the initial increased pulmonary morbidity and mortality in the group with combined modality therapy.

Limited stage small cell lung cancer treated with concurrent hyperfractionated chest radiotherapy and etoposide/cisplatin

Abstract Forty-one previously untreated patients with limited-stage small cell lung cancer (SCLC) entered a combined-modality study. Patients were initially treated with etoposide and cisplatin and concurrent chest radiotherapy. Patients then received two more cycles of etoposide/cisplatin followed by four cycles of individualized chemotherapy based on in vitro drug sensitivity testing if available, or a standard regimen of vincristine/doxorubicin/cyclophosphamide. Forty patients have completed therapy and are evaluable for response. Twenty-nine (73%) had a complete response and the remaining 11 (27%) achieved partial response. The median potential follow-up is now 3 years (range 4 months to 5 years). The median projected actuarial survival is 27 months with an actuarial survival of >90% at 1 year and 65% at 2 years. Four of 41 patients (10%) have died from treatment toxicity, including three who died of combined-modality pneumonitis and one of neutropenic sepsis. The median projected actuarial survival is nearly twice as long as in our previous combined-modality treatment regimens for limited-stage small cell lung cancer.

A phase II trial of carboplatin (CBDCA) in small-cell and non-small-cell lung cancer with correlation to in vitro analysis of cytotoxicity.

A Phase II trial of carboplatin (CBDCA) was performed in 33 patients with advanced lung cancer, including 15 patients with inoperable Stage III non-small-cell (NSCLC) and 18 patients with relapsed small-cell (SCLC) lung cancer. Initial dosage was 320 mg/m2 infused over 24 h; in the absence of hematologic toxicity, subsequent doses were escalated to 400 mg/m2. Patients received a median of two cycles (range 1–13 for NSCLC and 1–5 for SCLC) of therapy. There were no complete or partial responses among the NSCLC patients. Among the SCLC patients, two had a partial response. In vitro analysis of the cytotoxicity of CBDCA and its parent compound cisplatin by two different methods for 20 NSCLC cell lines suggested that equivalent tumor cell kill is achieved by the two compounds, but this occurs at a log lower concentration of cisplatin than of CBDCA. The in vitro cytotoxicity against NSCLC of CBDCA at a concentration predicted to be in the range produced by the dose employed in this Phase II study correlated well with the resulting very modest in vivo benefit. In vitro, a continuous dose-response relationship exists for CBDCA, suggesting that if higher doses could be administered safely to patients, greater clinical benefit might occur. We conclude that single agent CBDCA in the dosage and schedule administered has less than 20% activity (95% confidence intervals 0–19%) in NSCLC and an 11 % response rate in SCLC (95% confidence intervals 2–34%). Despite this outcome, in vitro data in human NSCLC cell lines suggest higher dosages should perhaps be evaluated before discounting a role for CBDCA in the management of NSCLC.