Robert T. Heelan

Bronchioloalveolar Pathologic Subtype and Smoking History Predict Sensitivity to Gefitinib in Advanced Non–Small-Cell Lung Cancer

PURPOSE Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, induces radiographic regressions and symptomatic improvement in patients with non-small-cell lung cancer (NSCLC). Phase II trials suggested female sex and adenocarcinoma were associated with response. We undertook this analysis to identify additional clinical and pathologic features associated with sensitivity to gefitinib. PATIENTS AND METHODS We reviewed medical records, pathologic material, and imaging studies of all 139 NSCLC patients treated on one of three consecutive studies of gefitinib monotherapy performed at our institution. We identified patients experiencing a major objective response and compared their clinical and pathologic features with the others. Univariate and multivariable analyses were performed on potential predictive features associated with sensitivity to gefitinib. RESULTS Of 139 patients, 21 (15%; 95% CI, 9% to 21%), experienced a partial radiographic response. Variables identified as significant in univariate analysis included adenocarcinoma versus other NSCLC (19% v 0%; P=.004), adenocarcinoma with bronchioloalveolar features versus other adenocarcinomas (38% v 14%; P<.001), never smoker status versus former/current (36% v 8%; P<.001), and Karnofsky performance status > or =80% versus < or =70% (22% v 8%; P=.03). Multivariable analysis revealed the presence of adenocarcinoma with any bronchioloalveolar features (P=.004) and being a never smoker (P=.006) were independent predictors of response. CONCLUSION Our data suggest that individuals in whom gefitinib is efficacious are more likely to have adenocarcinomas of the bronchioloalveolar subtype and to be never smokers. These observations may provide clues to mechanisms determining sensitivity to this agent and suggest that NSCLC has a different biology in patients who never smoked and those with bronchioloalveolar carcinoma.

Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas.

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 103/μl (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 103/μl (range 0.4–7.2). Thrombocytopenia - 100.0 × 103/μl was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.

Preoperative chemotherapy for stage IIIa (N2) lung cancer: The Sloan-Kettering experience with 136 patients

From 1984 to 1991, 136 patients with histologically confirmed non-small cell lung cancer and stage IIIa (N2) disease received two to three cycles of MVP (mitomycin + vindesine or vinblastine + high-dose cisplatin) chemotherapy. All patients had clinical N2 disease, defined as bulky mediastinal lymph node metastases or multiple levels of lymph node involvement in the ipsilateral mediastinum or subcarinal space on chest roentgenograms, computed tomographic scans, or mediastinoscopy. The overall major response rate to chemotherapy was 77% (105/136). Thirteen patients had a complete response and 92 patients had a partial but major response (> 50%). The overall complete resection rate was 65% (89/136) with a complete resection rate of 78% (82/105) in patients with a major response to chemotherapy. There was no histologic evidence of tumor in the resected specimens of 19 patients. The overall survival was 28% at 3 years and 17% at 5 years (median, 19 months). For patients who had complete resection, the median survival was 27 months and the 3-year and 5-year survivals were 41% and 26%, respectively. There were seven treatment-related deaths, five of which were postoperative deaths. To date, 33 patients, all of whom had complete resection, have had no recurrence after treatment. These results demonstrate that (1) preoperative chemotherapy with MVP produces high response rates in stage IIIa (N2) disease, (2) high complete resection rates occur after response to chemotherapy, and (3) survival is longest in patients who have a complete resection after major response to chemotherapy.

Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib

PURPOSE We conducted this phase II trial to determine the efficacy of erlotinib in patients with bronchioloalveolar carcinoma (BAC) and adenocarcinoma, BAC subtype, and to determine molecular characteristics associated with response. PATIENTS AND METHODS Patients (n = 101) with BAC (n = 12) or adenocarcinoma, BAC subtype (n = 89), were enrolled. All patients received erlotinib 150 mg daily. Epidermal growth factor receptor (EGFR) mutation, EGFR copy number, EGFR immunohistochemistry (IHC), and KRAS mutation status were analyzed in available tumors. The primary end point was response rate (RR). RESULTS Overall RR was 22% (95% CI, 14% to 31%). In patients with pure BAC, the RR and median survival were 20% and 4 months, as compared with 23% and 19 months in those with adenocarcinoma, BAC subtype. No patient (zero of 18; 95% CI, 0% to 19%) whose tumor harbored a KRAS mutation responded to erlotinib. Patients with EGFR mutations had an 83% RR (15 of 18; 95% CI, 65% to 94%) and 23-month median OS. On univariate analysis, EGFR mutation and copy number were associated with RR and PFS. EGFR IHC was not associated with RR or progression-free survival (PFS). After multivariate analysis, only EGFR mutation was associated with RR and PFS. No molecular factors were associated with overall survival. CONCLUSION Erlotinib is active in BAC and adenocarcinoma, mixed subtype, BAC. Testing for EGFR and KRAS mutations can predict RR and PFS after treatment with erlotinib in this histologically enriched subset of patients with non-small-cell lung cancer (NSCLC). These data suggest that histologic subtype and molecular characteristics should be reported in clinical trials in NSCLC using EGFR-directed therapy.

FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer.

PURPOSE The chemotherapy regimens of high-dose methotrexate, high-dose fluorouracil (FU), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and leucovorin (FAMTX) and etoposide, Adriamycin, and cisplatin (EAP) have both been reported in nonrandom assignment trials to have high overall response rates and substantial complete response rates in patients with gastric cancer, as well as major toxicities of myelosuppression. Here we report a prospective, stratified, random-assignment comparison of the two combinations in previously untreated patients with advanced gastric cancer. PATIENTS AND METHODS Sixty patients were entered onto the trial, 30 receiving EAP and 30 FAMTX. All patients had measurable or assessable tumor masses. Patient entry was stopped at the point when significant toxicity differences were seen at interim analysis. RESULTS Response rates were similar between the two arms (FAMTX, 33% [95% confidence interval (CI), 16% to 50%]; EAP, 20% [95% Cl, 6% to 34%]). Three FAMTX and no EAP patients had complete remissions. The median survival for the two arms were similar (EAP, 6.1 months; FAMTX, 7.3 months). At 1 year, 7% of EAP and 17% of FAMTX patients were alive. EAP caused significantly more myelosuppression (leukopenia, P = .002; anemia, P = .03; thrombocytopenia, P = .0001) than did FAMTX. EAP also resulted in significantly longer hospitalizations per study month (8 v 5 days). Four EAP patients died of lethal toxicity, whereas no FAMTX patients died of treatment-related causes (P = .04). CONCLUSIONS FAMTX is at least as active as EAP and is significantly less toxic. Although both regimens remain investigational, the toxicities of FAMTX are more manageable. Further studies involving FAMTX in both the adjuvant and advanced disease setting are underway.

Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection.

One hundred eighty-five patients who underwent surgery within 6 months of completing chemotherapy were identified from 360 patients with nonseminomatous germ cell tumors (NSGCT) treated with Memorial Hospital front-line cisplatin- or carboplatin-based combination chemotherapy protocols between 1979 and 1988. Clinical, pathologic, and radiologic features were correlated with the pathologic findings at surgery. The size of a residual retroperitoneal mass, the degree of shrinkage that occurred with chemotherapy, and the presence of teratomatous elements in pretreatment pathology specimens were each correlated with the pathologic findings of retroperitoneal resections after chemotherapy. Multivariable logistic regression analysis of those undergoing retroperitoneal resections identified the size and shrinkage of the residual mass and the prechemotherapy lactate dehydrogenase (LDH) and alphafetoprotein (AFP) levels as the best predictors of finding only necrotic debris. No factors could be found, however, that could selectively exclude patients who had residual viable malignancy or teratoma in the retroperitoneum. Of 39 patients with residual retroperitoneal masses measuring less than or equal to 1.5 cm in maximal diameter, three had residual malignancy and five had teratoma resected. No factors were identified for residual lung or mediastinal masses that could be used to select a group of patients who could safely avoid surgery. If serum markers have normalized after chemotherapy for NSGCT, resection of all residual abnormalities on imaging studies of the retroperitoneum, lungs, and mediastinum is recommended. In addition, retroperitoneal lymph node dissection (RPLND) is recommended for all patients with initial bulky metastases (greater than or equal to 3 cm in diameter) in the retroperitoneum, irrespective of the findings of postchemotherapy computed tomography (CT).

Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer.

PURPOSE A phase II study of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) as initial chemotherapy for metastatic breast cancer was conducted. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was used to ameliorate myelosuppression, the anticipated dose-limiting toxicity. PATIENTS AND METHODS Twenty-eight patients with bidimensionally measurable breast cancer who had not received prior chemotherapy for metastatic disease were treated. Taxol was administered at 250 mg/m2 as a continuous 24-hour intravenous (i.v.) infusion every 21 days. rhG-CSF was administered at 5 micrograms/kg/d subcutaneously on days 3 through 10. RESULTS Objective responses were observed in 16 of 26 assessable patients (62%; 95% confidence interval, 41% to 80%). There were three (12%) complete responses (CRs) and 13 (50%) partial responses (PRs). Ten of 16 patients (63%) who had received prior adjuvant chemotherapy responded, which included one CR and four PRs among eight patients who had received prior doxorubicin-containing therapy. Responses were observed in all sites of metastatic disease. The median time to first objective response was 5 weeks (range, 1 to 14). Administration of rhG-CSF was associated with a short duration of neutropenia (median, 2 days with absolute neutrophil count < 500 cells/microL). Eight of 26 patients (31%) who received more than one course received subsequent therapy without dose reduction. One hundred seventy-eight cycles of treatment were administered, with a median of six cycles per patient (range, one to 19). Eight courses (4.5%) were associated with admissions for neutropenic fever. Twenty-two patients (79%) did not require admission for neutropenic fever. Treatment was well tolerated. Adverse effects included generalized alopecia in all patients. Myalgias, arthralgias, and peripheral neuropathy were mild. No hypersensitivity reactions and no cardiac toxicity were observed. CONCLUSION Taxol is highly active as initial chemotherapy for metastatic breast cancer. Administration of rhG-CSF reduced the incidence, depth, and duration of neutropenia, compared with published prior experience. Further studies of Taxol in breast cancer, including combinations with other active agents, are clearly warranted.

Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy.

To determine the frequency and prognostic importance of pretreatment clinical characteristics in patients currently undergoing treatment for stage III non-small-cell lung cancer (NSCLC), data were collected on 378 patients receiving high-dose (120 mg/m2) cisplatin plus vinca alkaloid combination chemotherapy regimens since 1978. Variables analyzed included age, sex, weight loss, performance status, histologic subtype, presence of extrathoracic metastases, number of metastatic organ sites, presence of liver, bone, or brain involvement, prior radiation or surgery, and serum lactate dehydrogenase (LDH). The effect of a major response to chemotherapy on survival was also investigated. Using multivariable analyses, the following were found to be associated with outcome: initial performance status, with patients having a performance status of 80% to 100% having an increased major objective response rate and survival; bone metastases, which were adversely predictive of response rate and survival; elevated serum LDH and male sex, both of which were associated with shortened survival and remission duration; and the presence of two or more extrathoracic metastatic organ sites, which was associated with shorter survival. When major objective response with chemotherapy was included in a conditional multivariable analysis, it was strongly associated with longer median survival. Information from this analysis may be useful when comparing the response data of completed studies in similar patients, in designing future trials, and in the selection of cisplatin plus vinca alkaloid therapy for individual patients with advanced NSCLC.

Phase II trial of docetaxel in patients with stage III and IV non-small-cell lung cancer.

PURPOSE This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Docetaxel was administered to 29 patients with unresectable stage III and IV NSCLC at a dose of 100 mg/m2 intravenously (IV) over 1 hour every 21 days. No premedication was given to the first 16 patients. Premedication with diphenhydramine was instituted for the remainder. No patient had previously received chemotherapy. Seven patients had undergone prior radiation therapy. RESULTS All patients were assessable for response and toxicity. Eleven of 29 patients (38%) had a major objective response (95% confidence interval, 21% to 58%). The median duration of response was 5.3 months. Febrile neutropenia occurred in 41% of patients and in 11% of 134 courses of docetaxel. Nonhematologic toxicities included infusion-related hypersensitivity reactions, fluid retention, rash, alopecia, and sensory neuropathy. Premedication with diphenhydramine did not decrease the incidence of infusion-related hypersensitivity reactions. CONCLUSION At this dose and schedule, docetaxel demonstrates significant antitumor activity in patients with advanced NSCLC. Further investigations of this agent in NSCLC are indicated.

Practical Management of Patients With Non–Small-Cell Lung Cancer Treated With Gefitinib

PURPOSE The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non-small-cell lung cancer with tumors progressive after chemotherapy. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with non-small-cell lung cancer. METHODS This article reviews gefitinibs indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response. RESULTS We present our recommendations for the management of rash and diarrhea caused by this agent. CONCLUSION This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.