Median Duration Of Disease Control Research Articles

Combination chemotherapy of irinotecan with fluoropyrimidine in taxane, anthracycline, and fluoropyrimidine-pretreated metastatic breast cancer

e12003 Background: Irinotecan (I) has some efficacy in taxane (T) and anthracycline (A)-refractory breast cancer, and combination of I and fluoropyrimidine (F) shows synergistic effects in preclinical model. We conducted this study to reveal the clinical outcomes of I and F combination therapy in T, A, and F-pretreated metastatic breast cancer. Methods: We consecutively enrolled metastatic breast cancer patients treated with I and F combination chemotherapy from 2000 to 2008 in Seoul National University Hospital. They all had been previously heavily treated with T, A, and F. We retrospectively analyzed the clinical outcomes. Results: Twenty-five patients were enrolled. The median age was 38 years (range: 30–56years). The performance status was: ECOG 1 (11 patients), 2 (13), and 3 (1). The most commonly involved site was bone (16 patients), liver (13), and lung (12). The biologic subtype was: hormone receptor (+) 17 patients, HER-2 (+) 2, triple-negative (TNBC) 6. The median time from diagnosis of metastatic breast cancer to the initiation of IF therapy was 34 months (range: 12–97 months). The used regimens were: FOLFIRI (18 patients), TS-1/ irinotecan (6), capecitabine/irinotecan (1). Response was evaluable in 24 patients. There was no CR/PR. Stable disease was shown in 29.2% and 70.8% was PD, that is disease control rate was 29.2% (95% CI:10–45%). The median duration of disease control was 3.9 months (95% CI 3.7–4.2, range 2.4–11). The progression-free survival was 1.4 months (95% CI:0.7–21, range: 0.5–11.4), and overall survival was 6 months (95% CI: 4.2–7.8, range: 1–23). According to the biologic subtypes, the median PFS was 2.0 vs. 1.3 months (p=0.895) and OS was 4 vs. 6 months (p=0.807) respectively in TNBC VS Non-TNBC. In multivariate analysis, patients with good PS showed longer OS (p = 0.035). The Gr 3/4 hematologic toxicity was: neutropenia 18.6%, anemia 1.3%, thrombocytopenia 1.3%. And the major Gr 3/4 non-hematologc toxicity was: diarrhea (4%), hand-foot syndrome (0%), fatigue (0%). No treatment-related death was occurred. Conclusions: Treatment of I combined with F might be an option in metastatic breast cancer patients heavily treated with T, A, and F, irrespective of TNBC. Further prospective studies are warranted. No significant financial relationships to disclose.

A phase II study of S-1 plus irinotecan and oxaliplatin in heavily-treated patients with metastatic colorectal cancer

Three-drug combination of fluoropyrimidine, irinotecan and oxaliplatin has shown survival benefits in patients with metastatic colorectal cancer (mCRC). Recently we performed a phase II study of a new 3-drug regimen, TIROX (S-1 plus irinotecan and oxaliplatin) to evaluate efficacy and safety in refractory mCRC patients. Patients with refractory to all of 3 drugs, age > or = 18 years, PS 0-2, > or = 1 measurable lesion(s) and adequate organ functions were eligible. S-1 was given 40 mg/m(2) twice a day on D1-14, oxaliplatin 85 mg/m(2) and irinotecan 150 mg/m(2) on D1 every 3 weeks. The primary endpoint was overall response rate (ORR). Between Mar 2007 and Nov 2007, 19 patients (of 18 planned) were enrolled; median age 50 years; M/F 12/7; PS 0/1/2 5/13/1; colon/rectum 11/8. By intent-to-treat analysis, ORR was 21.1% (95% CI, 8.7-43.7) and disease control rate was 52.6% (95% CI 31.5-72.8) with four PRs and six SDs. Median duration of disease control was 4.3 months (95% CI 1.7-6.9). Median PFS was 2.6 months (95% CI 2.2-2.9) and median OS was 9.8 months (95% CI 5.3-14.4) after median F/U of 15.4 months. G3/4 toxicities per pt included neutropenia (five, 26.3%), febrile neutropenia (two, 10.5%), thrombocytopenia (one, 5.3%), diarrhea (two, 10.5%) and fatigue (two, 10.5%). TIROX seemed to be feasible and efficacious for refractory mCRC patients, and could be an alternative for patients with good PS but no further treatment options.

Phase II study of S-1 plus irinotecan and oxaliplatin for refractory, heavily treated metastatic colorectal cancer

15116 Background: Three-drug combination of fluoropyrimidine, irinotecan and oxaliplatin is known to be active for metastatic colorectal cancer (mCRC). In vitro synergy has been reported with each drug, thus combination of all 3-drug may overcome refractoriness to each other. We had performed phase I study to determine doses of phase II study of S-1 plus irinotecan and oxaliplatin (TIROX) for untreated mCRC, favorable responses were also observed in heavily-treated mCRC in phase I. We performed a phase II study of TIROX to evaluate efficacy and safety in refractory, heavily treated mCRC patients (pts) with no further treatment option. Methods: Pts with refractory to all of 3 drugs, age ≥ 18 yrs, PS 0–2, ≥ 1 measurable lesion(s) and adequate organ functions were eligible. S-1 was given 40 mg/m2 twice a day on D1–14, oxaliplatin 85 mg/m2 and irinotecan 150 mg/m2 on D1 every 3 weeks. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression free survival (PFS) and overall survival (OS). Results: Between Mar 2007 and Nov 2007, 19 pts (of 18 planned) were enrolled; median age 50 yrs; M/F 12/7; PS 0/1/2 5/13/1; colon/rectum 11/8. Median OS from initial diagnosis of mCRC to the TIROX was 20.9 months (mo) and G1 sensory neuropathy was noted in 15 pts at baseline. TIROX was their 3rd line regimen in 3 (15.8%), 4th in 13 (57.9%) and ≥ 5th in 3 pts (15.8%). Bevacizumab and cetuximab was exposed previously to 4 and 7 pts, respectively. By intent-to-treat analysis, ORR was 21.1% (95% CI, 8.7 - 43.7) and disease control rate was 52.6% (95% CI 31.5 - 72.8) with 4 PRs and 6 SDs. The median duration of disease control was 4.3 mo (95% CI 1.7–6.9). Median PFS was 2.6 mo (95% CI 2.2 - 2.9) and median OS was not reached with median FU of 7.5 mo. G3/4 toxicities per pt included neutropenia (5, 26.3%), leucopenia (3, 15.8%), febrile neutropenia (2, 10.5%), thrombocytopenia (1, 5.3%), diarrhea (2, 10.5%) and fatigue (2, 10.5%). Conclusions: TIROX seemed to be feasible for refractory, heavily-treated mCRC pts. Combination of previously exposed agents may have activity against refractory mCRC and could be an alternative for pts with good PS but no further treatment options. No significant financial relationships to disclose.

A phase I study of nilotinib alone and in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors (GIST): Study update

10553 Background: A previous analysis of a phase I study demonstrated that nilotinib has promising clinical activity in patients (pts) with GIST who are resistant to prior tyrosine kinase inhibitors (TKIs) including imatinib. The current analysis of a phase 1 study reports on the efficacy and long-term safety of nilotinib alone and in combination with IM. Methods: Pts with imatinib-resistant GIST received nilotinib alone (400 mg orally BID) or escalating doses of nilotinib (200 mg QD, 400 mg QD, or 400 mg BID) in combination with IM (400 mg orally BID), or nilotinib 400 mg BID plus IM 400 mg QD. Results: A total of 53 pts received nilotinib, alone (n = 18, 5 IM-intolerant) or in combination with IM (n = 35). Thirty-nine pts (74%) were resistant, refractory, and/or intolerant to one or more prior therapies. Sixteen pts received combination therapy at the nilotinib 400 mg BID/IM 400 mg QD dose (N 400BID/IM 400QD). Median duration of therapy in this combination arm was 217 days (range, 27–492) versus 186 days (range, 8–718) for nilotinib alone. Grade 3/4 AEs were experienced by 9 (50%) pts in the nilotinib alone arm and 7 (44%) pts in the N 400BID/IM 400QD arm. The most common of these was grade 3 GI disorders, which occurred in 8 (44%) pts in the nilotinib alone arm and 2 (12.5%) pts in the N 400BID/IM 400QD arm. One pt on nilotinib alone experienced dose- limiting hyperbilirubinemia; 3 patients on N 400BID/IM 400QD experienced dose-limiting rash. No patients experienced QTcF > 500 msec. Two pts, one on nilotinib alone and one in the N 400BID/IM 400QD arm, achieved partial response (PR) lasting 197 days and 176 days, respectively. Thirteen pts (72%) and 9 pts (56%) in the nilotinib alone and N 400BID/IM 400QD cohorts, respectively, experienced stable disease (SD). Median progression-free survival was 168 days for nilotinib alone and 203 days for N 400BID/IM 400QD. Median duration of disease control (CR, PR or SD) was 158 days for nilotinib alone and 259 days for the N 400BID/IM 400QD cohort. Conclusions: Nilotinib, alone and in combination with IM, has significant activity in pts with GIST who are resistant to prior TKIs. The efficacy and safety of nilotinib in third- line GIST are being studied in an ongoing phase III trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Amgen, Bayer, GlaxoSmithKline, Infinity, MedImmune, Novartis, Pfizer, PharmaMar, Roche, sanofi-aventis GlaxoSmithKline, MedImmune, Novartis, Pfizer, PharmaMar, Roche, SigmaTau Amgen, Bristol-Myers Squibb, Infinity, Jansen Cilag, Novartis, OSI Oncology, Pfizer, SigmaTau Infinity, Novartis, Pfizer Novartis, PharmaMar

A Multicenter Phase II Study of Docetaxel in Combination with Gefitinib in Gemcitabine-Pretreated Patients with Advanced/Metastatic Pancreatic Cancer

Purpose: To evaluate the efficacy and tolerance of the docetaxel/gefitinib combination as second-line treatment in patients with advanced pancreatic cancer. Patients and Methods: Twenty-six patients pretreated with gemcitabine-based chemotherapy were enrolled in the study. Docetaxel (75 mg/m², i.v.) was administered every 3 weeks for a maximum of 6 cycles and gefitinib (250 mg/day, p.o.) was given continuously. Results: Five (19.2%) patients achieved stable disease. The median duration of disease control was 4.8 months (range 1–13.2), the median time to disease progression 2.1 months (range 1–7.3) and the median survival time 2.9 months (range 1–13.9). Grade 3/4 neutropenia was recorded in 9 (34.6%) patients, although only 1 (3.8%) developed grade 2 febrile neutropenia. One (3.8%) patient experienced grade 3 fatigue and 2 (7.7%) grade 3 diarrhea. Grade 1/2 rash was observed in 13 (50%) patients. There were no treatment-related deaths. Conclusion: The docetaxel/gefitinib combination, although safe, has no activity as salvage treatment for advanced pancreatic cancer after failure of gemcitabine-based chemotherapy.

Sequential therapy with sorafenib and sunitinib in renal cell carcinoma

5106 Background: Sunitinib and sorafenib are two small-molecule tyrosine kinase inhibitors (TKI) that have been shown to have antitumor activity in advanced renal cell carcinoma (RCC). However, the optimal sequence of first- and second-line therapies with sunitinib and sorafenib is still unclear. The purpose of this study was to assess whether an objective disease response could be identified in patients after receiving sequential treatment with these two agents. Methods: Patients who had progressed or experienced unacceptable toxicity after first-line therapy with either sunitinib or sorafenib and then subsequently received second-line therapy with the other TKI agent were evaluated for their response to sequential treatment using RECIST criteria. Results: Thirty-seven patients were identified (29 male and 8 female) with a median age of 62 years (range 32–75). Twenty-three patients received sorafenib followed by sunitinib (Group A), and 14 patients received sunitinib followed by sorafenib (Group B). According to Memorial Sloan-Kettering prognostic model, 35% of patients in Group A had favorable risk, 52% had intermediate and 13% had poor risk, whereas 50% of patients in Group B had favorable risk, 43% had intermediate and 7% had poor risk. Three patients (13%) in Group A and two (14%) in Group B switched TKI due to toxicity, while all remaining patients switched due to disease progression. For patients in Group A, median duration of stable disease after starting sunitinib was 32 weeks (range 6–37 weeks)(median follow up 266 days); 9% were not evaluable for response to treatment; 34% had disease progression; and four patients (17%) had an objective partial response of 31%, 36%, 27% and 50%, respectively. For patients in Group B, median duration of stable disease after starting sorafenib was 8 weeks (range 4–10 weeks) (median follow up 179 days); 7% were not evaluable for response to treatment; 50% had disease progression; and one patient (7%) had no evidence of disease after tumor resection. The median duration of disease control in Groups A and B was 42 weeks (range: 10–113 wks) and 30.5 weeks (range: 4–56 wks), respectively. Conclusions: While disease control was observed in both sequences, the duration of response was longer in patients receiving sorafenib followed by sunitinib. [Table: see text]

Phase II Study of Erlotinib in Advanced Non–Small-Cell Lung Cancer After Failure of Gefitinib

This study was designed to evaluate the efficacy and toxicity of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) who experienced disease progression after treatment with gefitinib. The study included stage IIIB/IV recurrent or metastatic NSCLC patients who received two or three prior chemotherapy regimens and showed progressive disease within 4 months of gefitinib therapy discontinuation. Patients received erlotinib 150 mg/d until disease progression or unacceptable toxicity. Epidermal growth factor receptor (EGFR) mutations and other genetic abnormalities were analyzed from available tumor samples. Patient and disease characteristics (N = 21) included median age 56 years; number of prior chemotherapy regimens (three; n = 11); female sex (n = 11); adenocarcinoma (n = 15); and never-smoker status (n = 11). Among the 17 patients with tumor samples available, EGFR mutations were detected in five. The disease control rate (DCR) and response rate (RR) for all patients were 28.6% and 9.5%, respectively. The median duration of disease control was 125 days. The median time to progression and overall survival were 60 days and 158 days, respectively. Patients who had stable disease (SD) while receiving gefitinib showed significantly higher DCR (75% v 17.6% in non-SD patients; P = .050) and RR (50.0% v 0% in non-SD patients; P = .029). Among 17 patients with biomarker results available, those lacking EGFR mutations who had SD while receiving gefitinib showed significantly higher DCR and RR. Erlotinib seems to be a potential therapeutic option for the treatment of advanced NSCLC patients with wild-type EGFR who had SD while receiving gefitinib.

A phase II study of erlotinib treatment in advanced non-small cell lung cancer after failure of gefitinib: Is a clinical benefit still achievable?

7609 Background: To evaluate the efficacy and toxicity of erlotinib in patients (pts) with advanced NSCLC who had progression after treatment with gefitinib. Methods: The study included stage IIIB/IV recurrent or metastatic NSCLC pts who have received 2 or 3 prior chemotherapy regimens and showed documented disease progression during or within 4 months after treatment with gefitinib. Pts received erlotinib 150 mg daily until disease progression or unacceptable toxicity. We analyzed EGFR mutations and other genetic abnormality from available tumor samples. Results: Pts and disease characteristics (n = 21) included median age 56 years; number of prior chemotherapy regimens (two, n=10; three, n=11); male (n=10); adenocarcinoma (n=15); and smoking status (never, n=11; former, n=3; current, n=7). Among the 17 pts with tumor samples available, EGFR mutation were detected in 5 (29.4 %). The DCR and RR for all pts were 28.6% (95% CI, 16.7 to 59.6%) and 9.5% (95% CI, 5.6 to 19.8%). All responders were EGFR nonmutants, with long duration of disease control on prior gefitinib therapy (>180 days). The median duration of disease control was 125 days (95% CI, 73–261 days). The median progression-free survival and overall survival were 60 days (95% CI, 43–77 days) and 158 days (95% CI, 141–175 days), respectively. Pts who had SD on gefitinib showed significantly higher DCR (75% vs. 17.6% in non-SD pts, P= 0.050) and RR (50.0% vs. 0% in non-SD pts, P= 0.029). These pts also showed longer median PFS (140 vs. 37 days in non-SD pts, P= 0.005) and OS (not reached vs. 120 days in non-SD pts, P= 0.043). Among 17 pts with biomarker results available, EGFR nonmutants who had SD on gefitinib showed significantly higher DCR (100% vs. 21.4% in non-SD and/or EGFR mutants, P= 0.029) and RR (RR, 66.7 % vs. 0 % in non-SD and/or EGFR mutants, P= 0.022). Conclusions: Erlotinib seems to be a potential therapeutic option for the treatment of selected pts with gefitinib-nonresponsive, EGFR nonmutant, advanced NSCLC. No significant financial relationships to disclose. [Table: see text]

Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study

4013 Background: The OPTIMOX2 study was designed to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: OPTIMOX2 is a large phase II study performed before the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU2 until progression then reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 202 pts were included between Feb 2004 and Apr 2006. Response rates were (OPTIMOX1/OPTIMOX2): CR+PR 63%/61%. Median PFS were OPTIMOX1/OPTIMOX2) 8.3/6.7 months (p=.04). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 10.8m in the OPTIMOX1 arm and 9.0m in the OPTIMOX2 arm, p=.32. Median duration of chemotherapy-free interval (CFI) in the OPTIMOX2 arm was 4.6 months. Patients with poor prognostic factors had a shorter CFI, p=.01. Median overall survival was 24.6m in the OPTIMOX1 arm and 18.9m in the OPTIMOX2 arm, p=.05. Median survivals (OPTIMOX1/OPTIMOX2) were not reached/28.7m in patients with good prognostic and 20.9/14.5m in patients with poor prognostic. Conclusions: Maintenance LV5FU therapy prolongs PFS and OS, especially in patients with poor prognosis. CFI can be recommended only in selected patients without adverse prognostic factors. Our next study, DREAM, is evaluating maintenance therapy with targeted agents alone. No significant financial relationships to disclose.

Targeting of Epidermal Growth Factor Receptor in Patients Affected by Biliary Tract Carcinoma

TO THE EDITOR: A study by Philip et al published in the July 1, 2006, issue of the Journal of Clinical Oncology shows the therapeutic benefit of epidermal growth factor receptor (EGFR) blockade with erlotinib in patients with biliary tract carcinoma. The results are interesting because in a cohort composed of 24 chemotherapy-refractory patients and 18 chemotherapy-naive patients, erlotinib as a single agent can achieve disease control in 50% of patients with a median duration of disease control of 5.1 months. However, the authors conclude that the activity of erlotinib is modest because only 17% of the patients achieved the primary end point of the study, which was progression-free survival at 24 weeks. Although gefitinib and erlotinib are active in unselected patients with non–small-cell lung cancer (NSCLC), clinical characteristics and tumor molecular markers associated with enhanced benefit have been identified. Notably, mutations in the tyrosine kinase domain of EGFR were subsequently found to be associated with sensitivity to small molecule inhibitors in NSCLC. Emerging data also suggest that increased EGFR copy number is a predictor of response to gefitinib therapy, regardless of EGFR kinase domain mutational status. Furthermore, in contrast to wild-type EGFR, the EGFR mutations are mutually exclusive of K-Ras mutations, which are found in biliary tract carcinomas with a particularly high incidence in some geographical areas. Mutations of the EGFR kinase domain have recently been described by our group in 15% of biliary tract carcinoma specimens. One of these mutations was a T790M substitution, which is known to correlate with an acquired resistance to small molecule inhibitor treatment in NSCLC. Whereas 28% of the EGFR-positive patients were progression free at 24 weeks, the study by Philip et al, based on the lack of correlation between EGFR expression level and treatment outcome in other tumor types, includes six undetermined and seven EGFRnegative patients. This patient number is too small to provide evidence of any correlation. Thus, it would be of interest to know if other molecular analyses, such as sequencing of EGFR tyrosine kinase or of downstream members of the signaling pathway, like K-Ras, B-Raf or PTEN, or EGFR gene amplification, have been planned in this group of biliary tract cancer patients treated with erlotinib. This finding will have extraordinary implications and will serve as a critical step toward individualized patient-specific treatment plans based on the molecular constitution of the tumor of each individual.

OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study

3504 Background: The OPTIMOX1 study (JCO 2006) has shown that the strategy of 6 cycles of FOLFOX7 followed by maintenance therapy and FOLFOX reintroduction was as active and better tolerated than FOLFOX4 until progression. The aim of the OPTIMOX2 study was to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: Initially planned as a phase III study, OPTIMOX2 was downgraded to a large phase II study since the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU until progression and reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 187/200 planned pts were included between Feb 2004 and Nov 2005. Response rates were (OPTIMOX1 arm/OPTIMOX2 arm): CR 2%/2%, PR 54%/51%, stable 24%/33%, progression 11%/7%, non assessable 9%/7%. Median PFS were (OPTIMOX1 arm/OPTIMOX2 arm) 36/28 weeks (p=.01), PFS in responders 41/30 weeks (p=.001), PFS in stable patients 34/26 weeks (p=.23). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 41 weeks in the OPTIMOX1 arm and 36 in the OPTIMOX2 arm, p=.17. Median duration of chemotherapy-free interval in the OPTIMOX2 arm was 25 weeks (5.7 months). Conclusions: Maintenance LV5FU therapy prolongs PFS. The quality of life of almost 6 months CFI can balance a small advantage in DDC for maintenance therapy. Our next goal is to evaluate maintenance therapy with targeted agents alone. [Table: see text]

Correlation Between the Response to Cetuximab Alone or in Combination With Irinotecan and the Activated/Phosphorylated Epidermal Growth Factor Receptor in Metastatic Colorectal Cancer

Despite staining positive for the epidermal growth factor receptor (EGFR), a significant number of EGFR-expressing colorectal cancers are resistant to cetuximab, a chimeric monoclonal antibody directed against EGFR. Activation of EGFR through the autophosphorylation of its tyrosine residues stimulates different signaling downstream pathways and may reflect the level of receptor utilization by the tumor. This study investigated activated/phosphorylated EGFR (pEGFR) in 23 patients with EGFR-positive metastatic colorectal cancer refractory to irinotecan and treated with cetuximab, alone or in combination with irinotecan. Seven patients received cetuximab, and 16 patients received cetuximab plus irinotecan. Among the 23 patients, six (26%) had a partial response, 10 (44%) had stable disease, and seven (30%) had progressive disease. Median duration of disease control (partial response + stable disease) was 6 months. Nineteen out of 20 EGFR-positive tumors (95%) stained positive for pEGFR and had a median pEGFR immunohistochemical score of 5. Disease control rates differed between patients with a pEGFR immunohistochemical score >or= 7 (7/7, 100%) and less than 7 (7/13, 53.8%), showing a trend toward higher disease control in patients with high levels of pEGFR (>or= 7) who were treated with cetuximab with or without irinotecan (P = .05).

Retrospective study of compassionnal treatment of gefitinib 250 mg/d in non small cell lung cancer (NSCLC). The Hopital Avicenne experience

7348 Background: Gefitinib (Iressa), an inhibitor of the intracellular tyrosine kinase domain, has demonstrated useful activity in advanced pre-treated NSCLC (IDEAL I/II). Methods: Patients (pts) were treated with gefitinib 250mg/day. Endpoints included time to treatment failure (TTF). Results: 33 patients were assessed: median age (range), 61 (38–82) years; male/female, 21/12; performance status (PS) 1/2, 11/22; advanced disease (III A/IIIB/IV) 1/1/29, 31 pts were treated; median number of prior chemotherapy regimens (range), 3(1–4). 31 patients were treated and evaluable for time to Failure (TTF) according to PS status: 4.8 months (PS 1) and 5 months (PS 2). Median duration of disease control (stable disease and symptom control) was 4.9 months. Median TTF for Patients with bronchoalveolar adenocarcinoma (BAC) and adenocarcinoma (n=18) was 4 months and 3 months for patients with squamous-cell carcinoma and large cell carcinoma (n= 13). One patient treated for BAC with leptomeningeal carcinomatosis was fr...

Gefitinib in patients with non-small cell lung cancer (NSCLC): The Royal Marsden experience

7099 Background: Gefitinib (Iressa), an inhibitor of the intracellular tyrosine kinase domain, has demonstrated useful activity in advanced pre-treated NSCLC (IDEAL I / II). The clinical efficacy of gefitinib was assessed as part of an Expanded Access Programme. Methods: Patients (pts)were treated with gefitinib 250mg/day. Endpoints included overall survival (OS)and time to treatment failure (TTF). Objective and symptom response (OR, SR) were assessed at 1 month intervals. Results: 140 patients were assessed: median age (range), 65 (35–88) years; male/female, 80/60; performance status (PS)0/1/2/3, 1/45/37/17%; advanced disease (IIIB/IV), 123pts; median number of prior chemotherapy regimens (range), 1 (0–4). 124 patients were evaluable for OR: partial responses (PR) 6%; stable disease (SD) 55%; progressive disease (PD) 39%. Median duration of disease control (PR + SD) was 13 weeks (95% CI 9–17). 130 patients were evaluable for SR: symptom improvement (SI) 30%; No change (NC)33%; worsening symptoms (WS) 37%. Median duration of symptom control (SI+NC) was 11 weeks (95% CI 9–13). The most common toxicity was diarrhoea (Grade 3: 4.5%; Grade IV: 1%). 1 patient died of suspected pneumonitis. Median OS and TTF was 20 weeks (95% CI 15–25) and 8 weeks (95% CI 7–9) respectively. Patients (n=12) with bronchoalveolar adenocarcinoma (BAC) had significantly longer TTF than adenocarcinoma and squamous-cell carcinoma (median duration was 13, 8 and 9 weeks respectively, p=0.04). OR and SI for patients with BAC was 9.1% and 50% respectively. Pts with a PS of 3 had significantly lower OS and TTF (8 and 5 weeks respectively), and OR and SI was 0% and 13.3% respectively. Number of prior chemotherapy regimens did not significantly alter survival. Conclusions: This large series of patients treated with gefitinib at 250mg/day, demonstrated similar survival and symptom response to published phase II data. Pts with BAC appeared to benefit more than other histological subtypes. Despite low toxicity, gefitinib does not benefit those with poor PS. However, gefitinib can benefit heavily pre-treated patients, since the number of prior chemotherapy regimens did not influence survival. No significant financial relationships to disclose.

Interferon-α and chemohormonal therapy for patients with advanced melanoma

The treatment of metastatic melanoma remains unsatisfactory despite encouraging results with biotherapy and combination chemotherapy. Combining these two modalities may improve outcomes for such patients. Patients who were eligible for this study had metastatic melanoma and were in good medical condition. The following regimen was used: dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 administered intravenously (i.v.) daily x 3 days every 3 weeks, carmustine 150 mg/m2 i.v. every 6 weeks, tamoxifen 10 mg administered orally twice a day, and interferon-alpha2b 3.0 thousandths of an International Unit (mIU)/m2 administered subcutaneously on Days 1, 3, and 5 of each week a patient was on study. Patients were analyzed for toxicity, tumor response, and survival. Because of severe toxicity, partway through the trial the regimen was modified as follows: dacarbazine and cisplatin were given at the same dose every 4 weeks, and carmustine was reduced to 100 mg/m2 every 8 weeks. Forty-two patients with a median age of 61 years were enrolled. Twenty had liver metastases and 18 had lung metastases. Forty patients were evaluable for toxicity, 17 at the original dose and 23 at the new dose; of these, 35 were evaluable for response. Hematologic toxicity was severe at the original dose: 10 patients had a nadir < 500/microL, 10 had platelets < 25,000/microL, and 2 discontinued treatment because of toxicity. At the reduced dose, 5 had a nadir absolute neutrophil count < 500, and 10 had platelets < 25,000. Of the 35 patients evaluable for response, there were 10 partial responses (29%) and 2 minimal responses. Median duration of disease control was 4 months. Median survival was 8.9 months. One partial and one minimal responder were removed from the study because they experienced toxicity while still responding. The addition of interferon-alpha to this chemohormonal therapy regimen greatly increased toxicity without improving the response rate or survival for patients with metastatic melanoma.

Treatment of chronic granulocytic leukemia with melphalan

Thirty-three patients with newly diagnosed chronic granulocytic leukemia (CGL) were treated with melphalan between 1968 and 1976. Within 3 mo of beginning therapy subjective and objective disease parameters improved. Disease control was easily maintained with this agent until hematologic exacerbation occurred. The median duration of disease control was 25.3 mo, and the median duration of survival was 28.6 mo. Serious side effects were not produced. Thus melphalan appears to be another agent that may be used to control the manifestations of CGL prior to hematologic exacerbation.

Treatment of Chronic Granulocytic Leukemia With Melphalan

Thirty-three patients with newly diagnosed chronic granulocytic leukemia (CGL) were treated with melphalan between 1968 and 1976. Within 3 mo of beginning therapy subjective and objective disease parameters improved. Disease control was easily maintained with this agent until hematologic exacerbation occurred. The median duration of disease control was 25.3 mo, and the median duration of survival was 28.6 mo. Serious side effects were not produced. Thus melphalan appears to be another agent that may be used to control the manifestations of CGL prior to hematologic exacerbation.

A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer.A southeastern cancer study group project

In an ongoing prospective randomized study, 113 evaluable patients have received either a three-drug combination that included cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) or a five-drug combination including cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone (CMFVP) given intermittently 1 week out of 4. Responses (64%), median duration of response (32 weeks), and median duration of disease control (32 weeks) achieved with CAF were superior to those achieved with CMFVP (37%, 22 weeks, 17 weeks, respectively). Morbidity secondary to CAF was significant, with nausea and vomiting, malaise, total alopecia, and granulocytopenia being the main features.

Hydroxyurea in the Management of the Hematologic Complications of Chronic Granulocytic Leukemia

The effect of hydroxyurea in 35 patients with chronic granulocytic leukemia (CGL), who either had entered an accelerated phase of the disease or had experienced excessive myelosuppression following alkylating agents, was studied. By either intravenous or oral administration, the drug was successful in reducing peripheral leukocyte and blast counts in all cases and in reducing splenomegaly in 13 of 17 patients. The median duration of disease control was 75 days in myeloproliferative acceleration and 27 days in frank blastic transformation. Mild nausea and vomiting were experienced by most patients, but reversible bone marrow suppression occured in only three patients. The drug proved useful in 19 patients who demonstrated myeloproliferative acceleration, especially in controlling excessive leukocytosis and/or thrombocytosis. Rapid reduction of an elevated blast cell count was achieved in nine patients who presented in blastic crisis, in an attempt to eliminate the associated risk of cerebral vascular leukostasis. Five patients who required treatment for their disease following splenectomy in the chronic phase were also well controlled. Hydroxyurea appears to have a definite role in the management of these hematologic complications of CGL.

Hydroxyurea in the management of the hematologic complications of chronic granulocytic leukemia

The effect of hydroxyurea in 35 patients with chronic granulocytic leukemia (CGL), who either had entered an accelerated phase of the disease or had experienced excessive myelosuppression following alkylating agents, was studied. By either intravenous or oral administration, the drug was successful in reducing peripheral leukocyte and blast counts in all cases and in reducing splenomegaly in 13 of 17 patients. The median duration of disease control was 75 days in myeloproliferative acceleration and 27 days in frank blastic transformation. Mild nausea and vomiting were experienced by most patients, but reversible bone marrow suppression occured in only three patients. The drug proved useful in 19 patients who demonstrated myeloproliferative acceleration, especially in controlling excessive leukocytosis and/or thrombocytosis. Rapid reduction of an elevated blast cell count was achieved in nine patients who presented in blastic crisis, in an attempt to eliminate the associated risk of cerebral vascular leukostasis. Five patients who required treatment for their disease following splenectomy in the chronic phase were also well controlled. Hydroxyurea appears to have a definite role in the management of these hematologic complications of CGL.