Current Trends in Breast & Lung Cancer Treatment
Editorial: Current Trends in Breast Cancer Treatment
R. Martin York, MD, Piedmont Hospital, Atlanta, Georgia
Therapeutic options in the treatment of breast cancer have expanded considerably over the past few years. Advances have been made in every aspect of the disease. Nowhere is this more evident than supportive care, where the development of new antiemetic medications, growth factors, biphosphonates, and potent, broad-spectrum antibiotics have provided significant and positive impact on quality of life issues inherent in the chemotherapeutic treatment of breast cancer.
There have been a number of new and exciting chemotherapeutic agents developed over the past several years. These include docetaxel (Taxotere®), paclitaxel (Taxol®), vinorelbine (Navelbine®), and gemcitabine (Gemzar®). Additionally, hormone therapies have been developed to compliment and perhaps replace tamoxifen (Nolvadex®). There are a number of new selective estrogen receptor modulators that have become commercially available. Studies are currently being conducted to determine which agents and potential combinations will be the most efficacious.
One of the most exciting advancements has been the development of the monoclonal antibody trastuzumab (Herceptin®). This novel entity offers an entirely new approach to chemotherapy with a mechanism of action completely different from traditional chemotherapeutic agents.
In the enclosed review, there are a number of clinical studies that examine some of these developments.
There are three studies that evaluate adjuvant therapy. The first is from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-21. Researchers examined patients who were node negative and less than 1 cm, and tried to determine if monotherapy with tamoxifen was as effective as radiotherapy and whether the addition of tamoxifen to radiotherapy was superior to either modality alone. The results are very convincing. Patients receiving only tamoxifen had a 10% recurrence rate, while those receiving only radiation therapy had a 4.8% recurrence rate, and combination therapy produced a recurrence rate of 2%. Interestingly, the group that received tamoxifen had a reduction of contralateral breast cancer by 65%. This confirms data from previous clinical studies.
The second study, conducted at Yale University, was designed to determine if the utilization of radiation therapy after lumpectomy would increase the frequency of secondary primary malignancies. Researchers reviewed 1,029 patients and compared them with historical controls. Despite the problems inherent in retrospective studies utilizing historical controls, the conclusions were reassuring: at 15 years, there was no increased risk of second malignancies in the group that received radiation.
The third adjuvant study was an NSABP study of 2,008 women who were estrogen receptor (ER) negative and node negative. Two questions were addressed-whether a doxorubicin (Adriamycin®)/cyclophosphamide (Cytoxan®) (AC) regimen was therapeutically equivalent to a cyclophosphamide/methotrexate/fluorouracil (Adrucil®) (CMF) regimen and whether adding tamoxifen to either regimen provided additional benefits. The results of the study were not surprising-the addition of tamoxifen made no difference to treatment outcome. In addition, four treatment cycles of AC were equivalent to six treatment cycles of CMF. This is in accordance with the recent National Institutes of Health consensus conference examining adjuvant therapy in the treatment of breast cancer. The assembled experts agreed that AC and CMF chemotherapeutic regimens could be considered therapeutically equivalent, but also concluded that adjuvant therapy regimens containing doxorubicin provided additional benefit in terms of enhanced cure rate: approximately 1% to 3%.
Four studies are reviewed on the use of some of the newer agents in metastatic breast cancer. The first study was conducted in France with 38 patients, median age of 49, with a performance status of 0; they received aggressive therapy with doxorubicin, docetaxel, and vinorelbine with dose escalation. Twenty of the patients had liver metastases and 20 had received prior chemotherapeutic treatment. The results were quite astonishing, with a complete remission rate of 36% and an overall response rate of 94%. This is an unusually high response rate, particularly in clinical studies designed to evaluate what are considered traditional chemotherapeutic agents. If these numbers can be reproduced in other clinical studies, this chemotherapeutic regimen could potentially become the standard of care for metastatic breast cancer. Studies are currently underway utilizing this combination.
The next chemotherapy study was from Greece utilizing docetaxel and vinorelbine in 35 patients with metastatic breast cancer. Median age was 60 years and the response rate in this study was a more modest 42%. This study provides an interesting opportunity to compare and evaluate clinical outcomes from similar regimens as in the aforementioned study conducted in France.
A third study from Italy utilized vinorelbine and paclitaxel. This combination showed an overall response rate in the metastatic setting of 49%. These results appear more in accordance with previously established clinical outcomes in earlier studies of metastatic breast cancer.
The fourth study from Germany evaluated epirubicin (Ellence®), the anthracycline of choice in Europe. Five-hundred ninety-seven patients were randomized to epirubicin and cyclophosphamide (EC) or epirubicin and paclitaxel (ET). Overall, there was no statistically significant difference in outcomes, although it was noted that those patients receiving adjuvant therapy with CMF had a better clinical response when it was given in combination with ET than with EC. Although historically associated with the potential for serious myocardial toxicity, it is interesting that only a 1% instance of congestive heart failure occurred with epirubicin treated patients. It remains to be seen whether this treatment option will become more popular in the United States.
The final study is one that is very exciting. It was conducted at Boston's Dana- Farber Cancer Institute utilizing combination therapy of trastuzumab and vinorelbine. There were 40 patients that received the combination weekly. The treatments were well tolerated, with a response rate (when used as first line) of 84%. This confirms prior studies that demonstrated that trastuzumab enhances response rates when given in combination therapy-up to 50% in previously conducted studies. This development is of tremendous importance in evolving treatment options utilizing monoclonal antibody technology in adjuvant therapy. Ongoing clinical studies continue to evaluate the development of the most efficacious breast cancer treatment options.
The Role of Radiotherapy and Tamoxifen in the Management of Small Node- Negative Invasive Breast Cancer Treated with Lumpectomy: Preliminary Results of the National Surgical Adjuvant Breast and Bowel Project
Norman Wolmark et al., NSABP, Pittsburgh, Pennsylvania; Abstract 271, American Society of Clinical Oncology
Preliminary results of the NSABP protocol B-21 confirmed the benefit of radiation therapy in node-negative women with invasive breast cancer 1.0 cm or smaller. The findings tested the hypothesis of whether in a subset of women radiation could be eliminated or replaced with another intervention.
Wolmark et al. found that the combination of radiotherapy and tamoxifen (Nolvadex®) was more effective than either radiotherapy or tamoxifen alone in node-negative patients. Secondarily, the result showed that tamoxifen alone was responsible for a notable reduction in contralateral breast cancers, yet there was no significant difference in overall mortality or breast cancer-related mortality.
The study, conducted from 1989 to 1998, included 1,009 patients with node- negative invasive breast cancer 1.0 cm or smaller. The aim was to determine the best means of preventing ipsilateral breast cancer recurrence by comparing tamoxifen with radiotherapy, or the combination of both.
Patients were treated with lumpectomy and axillary node dissection, then randomized into 3 treatment groups: tamoxifen alone, radiotherapy alone, and radiotherapy plus tamoxifen. At a median follow-up of 68 months, cumulative 5- year risk of recurrence was over 10% with tamoxifen versus 4.8% with radiation plus placebo (p = 0.01). The cumulative 5-year recurrence risk with radiation plus tamoxifen was 2% versus 4.8% with radiation plus placebo (p = 0.0001).
The rate of ipsilateral recurrence was 2.8% with radiation plus tamoxifen versus 10.7% with tamoxifen alone (p = 0.0000002). The rate of ipsilateral recurrence was twofold greater in the group treated with tamoxifen alone, compared to radiation alone (p = 0.009).
Contralateral breast cancer occurred in 11 of the 336 patients (3.3%) receiving radiotherapy alone and in 8 of the 673 (1.2%) patients receiving only tamoxifen, which is a significant 65% relative reduction (p = 0.04). There were no significant differences in overall or breast cancer-related mortalities for the three groups. There were 13 deaths in each of the single-modality groups and 14 in the combined-therapy group.
Trastuzumab and Vinorelbine for HER-2-Positive Metastatic Breast Cancer: A Phase II Study
Harold Burstein et al., Dana-Farber Cancer Institute, Boston, Massachusetts; Abstract 392, American Society of Clinical Oncology
This study found that combination therapy with trastuzumab (Herceptin®) and vinorelbine (Navelbine®) is active in women with HER-2-positive tumors and metastatic breast cancer, supporting preclinical data suggesting synergy between these two agents.
The study opened as second-line or third-line therapy for women with metastatic breast cancer, but it was later expanded to include this combination as first-line metastatic therapy. A total of 982 weekly treatments were administered to 40 patients.
Patients received trastuzumab (4 mg/kg first dose, 2 mg/kg weekly thereafter) and vinorelbine (25mg/mІ/week intravenously), which was reduced to 15 mg/mІ for absolute neutrophil count (ANC) 750-1250 or held if ANC was less than 750. Vinorelbine dose adjustment was required for 194 treatments.
Responses were seen in 30 of the 40 patients (75%), including 2 complete responses and 28 partial responses. The response rate in HER-2 overexpressors at the 3+ level was 80%, and was 55% for 2+ overexpressors.
Activity was noted regardless of prior chemotherapy for metastatic disease. Response rate as first-line therapy for metastatic disease was 84%; as second- line therapy, 64%; and as third-line therapy, 71%. The response rate was 88% among patients with prior exposure to anthracyclines, and 50% in patients with prior taxane exposure.
The combination was well-tolerated, with minimal alopecia and few gastrointestinal side effects. The major adverse effect was neutropenia, with grades 3 and 4 seen in 28% and 10%, respectively; leukopenia was noted in 31% and 5%, manageable with dose adjustments.
Three patients developed grade 2 cardiac toxicity (asymptomatic decline in left ventricular ejection fraction [LVEF] of 10-20% or to LVEF less than the lower limit of normal), and were all taken off the study. No patients had symptomatic heart disease or heart failure, and no significant changes in the LVEF occurred after the second cycle.
Second Malignancies After Treatment of Early-Stage Breast Cancer: Lumpectomy and Radiation Therapy Versus Mastectomy
Edward Obedian et al., Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut; J Clin Oncol 2000; 18:2406-2412
The rate of second malignancies was nearly identical after a median follow-up of nearly 15 years for patients who received breast-conserving surgery followed by radiation therapy, compared with patients who underwent mastectomy without irradiation.
Researchers have historically known that conservative surgery with radiation therapy offers early-stage breast cancer patients local control, breast conservation, and survival rates equivalent to those offered by treatment with mastectomy. However, what has remained unknown are the long-term consequences of irradiation on the development of second malignancies. The purpose of this study was to compare this risk in 2 groups of early-stage breast cancer patients spanning a 20-year period. The researchers also evaluated for potentially confounding factors such as smoking, adjuvant systemic therapy, and specific radiotherapy techniques.
From 1970 to 1990, some 1,029 breast cancer patients underwent lumpectomy and radiation therapy (LRT) at Yale New Haven Hospital. Obedian et al. selected a comparison group from 1,387 breast cancer patients who underwent mastectomy (MAST) without postoperative radiation. The surgically treated group had a similar stage of disease, prognosis, follow-up duration, and tumor size as the LRT group.
After 15 years, the second breast malignancy rate was 10% for both groups. The risk of any second malignancy was almost identical for both groups-17.5% for LRT and 19% for MAST. The risk of a second non-breast malignancy was 11% for LRT and 10% for MAST. There were fewer contralateral breast tumors in patients undergoing adjuvant hormonal therapy, although this was not statistically significant. Adjuvant use of chemotherapy did not significantly affect the risk of second malignancies.
In the subset of patients 45 years of age or younger at the time of treatment, second breast and non-breast malignancy rates were 10% and 5%, respectively, for LRT versus 7% and 4% for MAST (not statistically significant). Upon further investigation of these LRT patients, second lung malignancies were associated with a history of tobacco use. Patients who continued to smoke at the time of radiation therapy had a 20% risk of developing a second malignancy by 15 years, compared with 16% of nonsmokers.
Although the difference is not statistically significant, patients 45 years or younger in the MAST group had a 3% lower risk of developing contralateral breast cancer after 15 years than did the patients in the LRT group (7% versus 10%, respectively). Researchers reported that older radiation treatment techniques may have been responsible for the excess risk reported.
With a 15-year median follow-up, these data should reassure women considering lumpectomy followed by irradiation as a treatment option, the investigators concluded.
ATN (Adriamycin-Taxotere-Navelbine): A Phase I-II Multicentre Study in First- Line Therapy of Metastatic Breast Cancer
Gael Deplanque et al., Hopitaux Universitie de Strasbourg-Departement d'Oncologie Medicale, Strasbourg, France; Abstract 401, American Society of Clinical Oncology
A new combination treatment of doxorubicin hydrochloride (Adriamycin®), docetaxel (Taxotere®), and vinorelbine (Navelbine®) yields a very high response rate in this first-line therapy pilot study.
Deplanque et al. previously reported on the efficacy and feasibility of the combined doxorubicin hydrochloride/docetaxel/vinorelbine therapy. The results were encouraging enough to warrant this new Phase I-II study in front-line therapy for metastatic breast cancer.
The current study included 38 patients whose median age was 49 years, median WHO performance status of 0, and median number of metastatic sites was 2. Twenty patients had liver metastases and 20 patients had received adjuvant anthracyclines.
The treatment was in four dose escalation steps: doxorubicin 50 mg/mІ, docetaxel 85-100 mg/mІ, and vinorelbine 20-30 mg/mІ on day 1 given every 3 weeks, with G-CSF support of 5 mg/kg from day 3 until neutrophil recovery (day 8 to day 11). Additional oral medications given on days 4 through 11 included fluconazole (Diflucan®), acyclovir (Zovirax®), and antiseptic mouthwashes.
Complete responses occurred in 13 of the 36 evaluable patients (36.1%). Partial responses occurred in 21 patients, for an overall response rate of 94.4%. The Kaplan-Meier estimate of median time to progression was 17.9 months, and overall survival was 24.1 months.
No toxic deaths occurred. The main grade 3 and 4 adverse effects were neutropenia (53%), febrile neutropenia (7.4%), thrombocytopenia (2.3%), anemia (2.8%), and mucositis (1.4%). Additional side effects were alopecia in all patients, mild edema in 4 patients, nail changes in 7 patients, cardiotoxicity grade 2-3 in 3 patients, and neuropathy grade 2-3 in 4 patients.
The researchers concluded that this ATN combination yielded very high response rates at each dose level while having acceptable toxicity, and suggested it deserves further evaluation.
Chemotherapy With or Without Tamoxifen for Patients with ER-Negative Breast Cancer and Negative Nodes: Results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-23
Bernard Fisher et al., NSABP, Pittsburgh, Pennsylvania; Abstract 277, American Society of Clinical Oncology
Four cycles of AC [doxorubicin hydrochloride (Adriamycin®) and cyclophosphamide (Cytoxan®)] over 3 months offers the same survival benefit as a 6-month course of 121 treatments of CMF [cyclophosphamide, methotrexate (Rhumatrex®), and fluorouracil (Efudex®, Fluoroplex®)] in women with ER- negative tumors and negative nodes. This conclusion comes from the largest-to-date, head-to-head study of the 2 widely used treatments, NSABP B-23.
The study also assessed the effect of tamoxifen (Nolvadex®) in these patients and concluded there was no benefit, perhaps because the tumors were all ER- negative. (Since the study began in 1991, it has been learned that tamoxifen, which stops estrogen from binding to its cellular receptor as one of its main mechanisms of action, probably has no effect in cancer that is not influenced by estrogen.)
The study followed 2,008 women with early-stage, node-negative breast cancer between 1991 and 1998. Patients were randomized into 4 treatment groups: 1) CMF and placebo; 2) CMF and tamoxifen; 3) doxorubicin/cyclophosphamide and placebo; and 4) doxorubicin/cyclophosphamide and tamoxifen. Four cycles of AC were given over 63 days, and 6 cycles of CMF were given over 6 months. The average time on the study was 67 months.
Regardless of the treatment used, disease-free survival after 5 years was approximately 82%, and overall survival was approximately 89%. There were no significant differences according to regimen (CMF versus AC) or according to whether or not tamoxifen was given. There were also no reported substantial differences in toxicity between the regimens.
Principal investigator Bernard Fisher, MD, concluded that AC can be substituted easily for CMF, sparing months of treatment. Additionally, there was no benefit of adding tamoxifen in the adjuvant treatment of patients with ER-negative breast cancer in local recurrence, systemic recurrence, or contralateral breast cancer development.
Docetaxel and Navelbine as First-Line Chemotherapy (CT) in Advanced Breast Cancer (ABC). A Phase II Study of the Hellenic Cooperative Oncology Group
Dimitrios Pectasides et al., Hellenic Cooperative Oncology Group, Athens, Greece; Abstract 435, American Society of Clinical Oncology
The combination of docetaxel (Taxotere®) and vinorelbine (Navelbine®) as first- line chemotherapy showed activity in this Phase II study of patients with advanced breast cancer.
Docetaxel and vinorelbine have both demonstrated activity as single agents for the treatment of metastatic breast cancer. The 2 drugs have different mechanisms of action, and in preliminary studies have demonstrated therapeutic synergy in combination.
The Hellenic Cooperative Oncology Group study included 35 chemotherapy- naпve patients with a median age of 60 years. There was locoregional disease in 20 patients (57.1%), distant metastasis in 26 (74.3%), and visceral metastasis in 17 (48.6%). Sixteen patients (45.7%) received adjuvant chemotherapy, and seven were treated with anthracyclines or regimens containing mitoxantrone (Novantrone®).
All patients were treated every 3 weeks with vinorelbine 20 mg/mІ on days 1 and 8 infused over 20 minutes, and docetaxel 85 mg/mІ on day 8 infused over 1 hour with pre-medication. A total of 179 cycles were administered. The median relative dose intensity was 0.87 (range 0.1-1.2) for vinorelbine and 0.8 (range 0.2-1.0) for docetaxel.
At a median follow-up of 5.1 months, complete responses were achieved in two patients (5.7%), and partial responses in 13 (37.1%), resulting in an overall response rate of 42.8%. The median time to tumor progression was 6 months (range of 0.7 to 13+), and the median survival was 11.3 months (range of 0.9 to 13+). Twelve patients progressed and 6 died. Toxicity grades 3-4 included leukopenia (25.7%), anemia (8.6%), neutropenia (8.6%), thrombocytopenia (2.9%), stomatitis (5.7%), diarrhea (5.7%), fatigue (2.9%), and constipation (2.9%). All patients had alopecia.
In conclusion, the combination of docetaxel and vinorelbine was modestly active in advanced breast cancer, easily administered on an outpatient basis, and produced a manageable toxicity profile.
Multicentre Phase III Study in First Line Treatment of Advanced Metastatic Breast Cancer. Epirubicin/Paclitaxel Vs. Epirubicin/Cyclophosphamide. A Study of the AGO Breast Cancer Group
Hans Luck et al., Volker Medical University, Hannover, Germany; Abstract 280, American Society of Clinical Oncology
This AGO study of 597 patients determined that the combinations of epirubicin (Ellence®)/paclitaxel (Taxol®) (ET) and epirubicin/cyclophosphamide (Cytoxan®) (EC) were equally active in advanced metastatic breast cancer. Though ET was associated with a lower rate of primary progression, there was not statistically significant difference in median progression-free survival. Metastatic breast cancer patients who received prior adjuvant therapy, however, obtained a significant benefit in terms of delayed time to progression from the combination of ET as compared to EC. Epirubicin is used more commonly than doxorubicin in Europe.
The study randomized patients to epirubicin 60 mg/mІ over 1 hour plus paclitaxel 175 mg/mІ over 3 hours or epirubicin 60 mg/mІ plus cyclophosphamide 600 mg/mІ (EC) every 3 weeks. Each group received a median of 6 cycles. Treatment was completed as planned in 52% of the ET arm and 43% of the EC arm, and patients were followed for a median of 72 weeks.
Luck et al. reported that the time to progression-the primary endpoint of the study-was delayed by 7 weeks in patients receiving ET, from 39 weeks to 32 weeks (p = 0.007). Response rates were 46% for the ET arm and 40% for EC. Overall survival was similar for the two groups of patients-73 weeks for ET and 88 weeks for EC (p = 0.92).
In a subgroup analysis, patients who had received adjuvant therapy (one-third of all patients, primarily CMF) had a near doubling in time to progression. ET recipients progressed at a median of 38 weeks, whereas EC recipients recurred at a median of 21 weeks, for a difference of 17 weeks (p = 0.02).
The hematologic toxicities were slightly higher in the EC arm but not severe, and no patients developed febrile neutropenia. Alopecia, nausea, and vomiting occurred slightly more frequently in the EC arm; however, neuropathy was more common in the ET arm. Only 1% of ET patients and no EC patients developed grade 3-4 cardiac toxicity.
First-Line Chemotherapy with Vinorelbine and Paclitaxel as Simultaneous Infusion in Advanced Breast Cancer
P. Vici et al., Department of Medical Oncology II, Regina Elena Institute for Cancer Research, Rome, Italy; Oncology 2000; 58 (1): 3-7
In this study of patients with previously untreated advanced breast cancer, vinorelbine (Navelbine®) combined with paclitaxel (Taxol®) was shown to be an active, well-tolerated regimen.
Vinorelbine has historically demonstrated activity as a single agent for the treatment of metastatic breast cancer, and in preliminary studies, vinorelbine plus paclitaxel have suggested synergy. Against this background, Vici et al. carried out a Phase II trial in chemotherapy-naпve patients.
The 41 evaluable patients in the 16-month study received vinorelbine 25 mg/mІ and paclitaxel 150 mg/mІ, both by 3-hour infusion on day 1 in 3-week cycles. The first 10 patients received G-CSF on days 7-12.
The overall response rate was 49%, with 2 complete responses (5%) and 18 partial responses (44%). The median time to response was 2 months, median time to progression was 7 months, and median survival was 22 months. Myelosuppression was the dose-limiting toxicity, with grade 4 neutropenia in 21% and neutropenic fever in 7%.
Vici et al. concluded that the combination of vinorelbine and paclitaxel was a well-tolerated and active regimen in advanced breast cancer, with results similar to more toxic regimens. In addition, the researchers suggest this to be a useful combination in patients with anthracycline contraindications.
Editorial: Current Trends in Lung Cancer Treatment
Thomas Lynch, MD, Assistant Professor of Medicine, Massachusetts General Hospital, Boston
Lung cancer is the leading cause of cancer-related mortality in the United States and is a growing cause of death worldwide. Non-small cell lung cancer (NSCLC) comprises 80% of the cases of lung cancer and a similar proportion of deaths. One reason for the high death toll from NSCLC is that so few patients present with localized surgically curable disease. More than 60% of patients present with disease that is incurable at presentation-either stage IV metastatic disease or stage IIIB disease with a pleural effusion. While a cure is not possible in this setting, treatment has been shown to prolong survival and improve quality of life. Over the past 5 years, 5 drugs have emerged as having improved efficacy compared to prior agents in this disease-vinorelbine (Navelbine®), gemcitabine (Gemzar®), paclitaxel (Taxol®), docetaxel (Taxotere®), and irinotecan (Camptosar®). At the 2000 ASCO meeting in New Orleans, several trials using these agents were presented that describe significant advances in the care of patients with advanced lung cancer.
What regimen is optimal for patients with stage IV disease? This was a major theme of 2 landmark US studies reported within the past 24 months. In 1999 at the ASCO meeting in Atlanta, Dr. Karen Kelly presented the results of the Southwest Oncology Group Study (SWOG) 9509, which showed that cisplatin (Platinol®)/vinorelbine and carboplatin (Paraplatin®)/paclitaxel were equivalent regimens for the treatment of advanced disease. The results of the Eastern Cooperative Oncology Group Study (ECOG) 1594 build upon the SWOG experience by comparing cisplatin/gemcitabine, cisplatin/docetaxel, and carboplatin/paclitaxel to the ECOG standard of cisplatin/paclitaxel. The 4 arms of the ECOG trial and the 2 arms of the SWOG study produced remarkably similar median survival data (8 months) and 1 year survival (35%). The response rates seen in the ECOG study (18%) were inferior to those seen in the SWOG study (26%). This difference may be due to slight differences in patient characteristics between the two trials. The ECOG trial and the SWOG study confirm that all 5 of the regimens tested are reasonable choices for patients with advanced disease.
The overall impact of these 2 large American studies is to affirm that oncologists have several options in the care of patients with advanced disease. Many US oncologists prefer to use carboplatin rather than cisplatin-a major reason for the increased use of carboplatin/paclitaxel in the US. It is not entirely clear that cisplatin and carboplatin are equivalent in NSCLC. A randomized European trial presented at ECCO 10 (the 10th European Cancer Conference in Vienna, Sept. 12-16, 1999) suggests that cisplatin may be superior to carboplatin in the treatment of advanced disease. However, there are clear drawbacks to the use of cisplatin in terms of toxicity and ease of administration, and many oncologists feel that the potential benefits in advanced disease are not worth the cost. The question of the equivalence of cisplatin and carboplatin will be answered in 2 large international studies. In a study led by Belani et al. presented at the 2000 World Lung Cancer Meetings in Tokyo, cisplatin/docetaxel is compared to cisplatin/vinorelbine and carboplatin/docetaxel. Preliminary analysis of the Belani trial suggests that the carboplatin/docetaxel arm is better tolerated. A second, Phase III study comparing carboplatin/gemcitabine to a cisplatin standard is underway.
Can platinum be omitted altogether? The abstract by Jay Walls, MD, from US Oncology in Houston, Texas, provides some intriguing answers. Walls treated 71 patients with docetaxel 60 mg/mІ on day 1 along with vinorelbine 15 mg/mІ on days 1 and 8, every 3 weeks. The response rate of 21% and 1-year survival of 35% is comparable to that seen using cisplatin-based therapies. Furthermore, the acute and chronic toxicities appear to be lower with the omission of platinum. Others have combined gemcitabine with vinorelbine and found similar results to those noted by Walls. Finally, in a randomized trial presented at ASCO, Dr. Kosmidis found that the non-platinum combination of gemcitabine/paclitaxel had similar efficacy to carboplatin/paclitaxel in advanced disease.
Future progress in the treatment of advanced lung cancer will result from the combination of novel therapies with established chemotherapy. Never before have there been as many new agents with novel mechanisms available for clinical trials in lung cancer. The abstract by DeVore is one example of the use of such a novel agent, anti-VEGF monoclonal antibody, in combination with chemotherapy. The results reported by DeVore are intriguing since they indicate that the combination of chemotherapy with the anti-VEGF monoclonal antibody may have excellent activity with a very long median survival. However, this abstract also points out the potential for new toxicities in that 6 patients developed life-threatening hemoptysis, and 4 died. Further work with this combination is underway.
Eastern Cooperative Oncology Group (ECOG) 1594 Establishes Benefit of Chemotherapy, But No Regimen Superior
Joan Schiller, University of Wisconsin School of Medicine, Madison; Abstract 2, American Society of Clinical Oncology
Dr. Schiller presented the largest trial to date in advanced non-small cell lung cancer (NSCLC) comparing three new regimens to the ECOG standard arm of cisplatin (Platinol®) with paclitaxel (Taxol®) given by 24 hour infusion. The standard arm was chosen since it was deemed to be the most active regimen in a prior ECOG study in which it was compared to cisplatin and etoposide (VePesid®). This study demonstrated the equivalency of the four regimens in terms of most outcomes.
ECOG 1594 included 1,207 patients and compared three platinum-based regimens containing third-generation drugs active against NSCLC to a reference regimen of 24-hour paclitaxel/cisplatin in stage IIIB and stage IV patients. The experimental arms were gemcitabine (Gemzar®)/cisplatin, docetaxel/cisplatin, and carboplatin (Paraplatin®)/paclitaxel. Specific doses and schedules were cisplatin 75 mg/mІ on day 1 plus paclitaxel 175 mg/mІ/24 hours every 3 weeks (reference arm); gemcitabine 1000 mg/mІ on days 1, 8, and 15 plus cisplatin 100 mg/mІ on day 1 every 4 weeks; docetaxel 75 mg/mІ on day 1 plus cisplatin 75 mg/mІ on day 1 every 3 weeks; and paclitaxel 225 mg/mІ/3 hours on day 1 plus carboplatin AUC 6 on day 1 every 3 weeks. Important differences between these arms include: the gemcitabine-containing arm included a higher dose of cisplatin and this arm also had a longer cycle length (28 vs. 21 days).
The trial found no statistically significant differences between the regimens, in terms of overall response rate (18.7%), 1-year survival (33.5%), and overall survival. The gemcitabine/cisplatin arm, however, offered a statistically significant 1-month advantage in time to progression (4.5 months versus 3.5; p = 0.02) but had more nausea/vomiting and more renal toxicity than the other arms. The results of the study provided reassurance that there are a number of chemotherapy options that can extend survival in patients with NSCLC.
Incorporation of Docetaxel Into Chemotherapy-Radiotherapy Regimen Improves Outcome in NSCLC: Results of SWOG 9504
David Gandara et al., University of California Cancer Center, Davis; Abstract 1916, American Society of Clinical Oncology
Dr. David Gandara for the Southwest Oncology Group presented results that are among the best ever reported for the treatment of patients with locally advanced NSCLC. This trial selected patients with locally advanced N3 or T4 disease. Patients had to have pathologic confirmation of this status. Patients were treated with cisplatin (Platinol®) and etoposide (VePesid®) with concurrent radiation. After the period of chemo-radiotherapy, they received 3 cycles of docetaxel (Taxotere®).
The Phase II non-randomized trial included 83 patients treated with cisplatin 50 mg/mІ on days 1, 8, 29, and 36; with etoposide 50 mg/mІ on days 1-5 and 29- 33, with concurrent radiotherapy (1.8-2.0 Gy/day) starting on day 1 (61 Gy total). This was followed by consolidation docetaxel 75-100 mg/mІ every 21 days for 3 cycles.
The radiographic response in 83 patients included 3 complete responses (4%) and 49 partial responses (59%). Stable disease was noted in 23 (28%), and 8 patients progressed (9%).
The treatment was relatively well tolerated. Hematologic toxicity included grade 3-4 neutropenia in 56% of patients; however, the duration was brief and only 6 patients developed neutropenic fever. There was one case of grade 3 thrombocytopenia, 1 infection-related death, and 3 deaths from pulmonary complications.
The incorporation of docetaxel in SWOG 9504 achieved a 1-year survival rate of 78%, a 2-year survival rate of 48%, and a median survival of 22 months. Following surgery or radiotherapy alone, the expected survival in this group of patients is generally less than 10%. The addition of chemotherapy has improved upon this figure, however, and the current SWOG study achieved the most favorable survival to date.
A previous SWOG trial utilized the first part of this regimen, but without docetaxel as consolidation therapy. Instead, patients were treated with additional cycles of cisplatin/etoposide. That strategy achieved a 2-year survival rate of 34% and median survival of 15 months. Future studies will compare the SWOG approach with a randomization after docetaxel to a novel oral agent or placebo.
First-Line Therapy of Taxotere and Navelbine in Patients with Advanced Non- Small Cell Lung Cancer: A Phase II Study
Jay Walls et al., US Oncology, Houston; Abstract 2158, American Society of Clinical Oncology
Platinum is responsible for much of the toxicity associated with chemotherapy for patients with advanced NSCLC. Thus there is great interest in the development of non-platinum containing regimens. This Phase II study by Walls et al. showed that docetaxel (Taxotere®) plus vinorelbine (Navelbine® ) achieved similar survival results as platinum agents, but without many of the serious toxicities that usually accompany platinum-based regimens.
The multicenter study included 71 patients (median age 66; ECOG status 0-2) who had not received any prior chemotherapy with stage IIIB (n = 8) or stage IV (n = 63) non-small cell lung cancer (NSCLC). The predominant histology was adenocarcinoma.
All patients received docetaxel 60 mg/mІ by intravenous infusion (IV) over 1 hour on day 1, followed by vinorelbine 15 mg/mІ IV over 6-10 minutes on days 1, 8, and 15 every 3 weeks, plus pretreatment with dexamethasone.
In the 65 evaluable patients the overall response rate was 21.5%-comparable to that seen using platinum containing regimens. Survival at 1 year was 35%, again similar to survival achieved with platinum-containing regimens. Treatment was well-tolerated. Grade 3/4 leukopenia occurred in 18% of patients, stomatitis in 10%, pneumonia in 4%, and neutropenic fever in 4%.
Researchers concluded that the 35% 1-year survival rate-and the absence of serious toxicity-suggests there may be a role for the combination of docetaxel and vinorelbine in the treatment of advanced NSCLC.
Cisplatin-Gemcitabine vs. Cisplatin-Gemcitabine-Vinorelbine vs. Cisplatin- Gemcitabine-Paclitaxel in Advanced Non-Small Cell Lung Cancer. First-Stage Analysis of a Southern Italy Cooperative Oncology Group (SICOG) Phase III Trial
R. G. Comella et al., National Tumor Institute, Naples, Italy; Abstract 1933, American Society of Clinical Oncology
This study is one of several from the Southern Italy Cooperative Oncology Group that looked at gemcitabine (Gemzar®), cisplatin (Platinol®), vinorelbine (Navelbine®) and paclitaxel (Taxol®) in various combinations to treat NSCLC. A previously reported trial found that the combination of cisplatin, gemcitabine, and vinorelbine (PGV) was associated with a significant improvement in survival compared to cisplatin and vinorelbine (Comella, P. et al. J Clin Oncol, 2000; 18:1451-1457).
At ASCO 2000, Comella et al. reported an interim analysis of a study comparing cisplatin-gemcitabine (PG), cisplatin-gemcitabine-vinorelbine (PGV), and cisplatin-gemcitabine-paclitaxel (PGT), with survival as the primary endpoint.
This study, which began in October of 1997, includes 360 patients with locally advanced or metastatic NSCLC. Patients were randomized to receive 1 of the 3 regimens: PGV (cisplatin 50 mg/mІ on day 1; gemcitabine 1000 mg/mІ; vinorelbine 25 mg/mІ on days 1 and 8, every 3 weeks); PG (cisplatin 100 mg/mІ on day 1; gemcitabine 1000 mg/mІ on days 1, 8, and 15, every 4 weeks); or PGT (cisplatin 50 mg/mІ; gemcitabine 1000 mg/mІ; paclitaxel 125 mg/mІ on days 1 and 8 every 3 weeks).
Interim analysis was performed in September of 1999 when enrollment included 247 patients (approximately 81 per treatment arm). Survival data from the first 60 patients in each arm with more than 12 weeks follow-up (11 months median) showed that 103 patients overall had died, and median survival time for the entire group was 48 weeks. Differences in survival among 3 arms were inconclusive and did not meet the criteria for stopping the study early, therefore, the trial awaits final analysis after the planned sample size is reached.
A Randomized Phase III Trial of Paclitaxel Plus Carboplatin vs. Paclitaxel Plus Gemcitabine in Advanced Non-Small Cell Lung Cancer: A Preliminary Analysis
Paris Kosmidis et al., Hellenic Cooperative Oncology Group, Athens, Greece; Abstract 1908, American Society of Clinical Oncology
The results of this preliminary study from the Hellenic Cooperative Oncology Group indicate the combination of paclitaxel (Taxol®) plus gemcitabine (Gemzar®) and the commonly used regimen of paclitaxel plus carboplatin (Paraplatin®) differ little in efficacy and toxicity in patients with advanced NSCLC.
Kosmidis et al. studied 329 patients with inoperable NSCLC stages IIIA, IIIB, and IV who had never received chemotherapy. Patients were well-matched for baseline demographic and tumor characteristics between the two groups and had a World Health Organization (WHO) performance status of 0-2.
The patients were randomized into 2 groups: Group A (n = 165) and Group B (n = 164). On day 1, Group A patients received paclitaxel 200 mg/mІ in a 3-hour infusion, plus an infusion of carboplatin (AUC of 6). Group B patients received paclitaxel 200 mg/mІ in a 3-hour infusion on day 1, plus gemcitabine 1 mg/mІ on days 1 and 8. Both treatment regimens were given every 3 weeks.
Of the 123 evaluable patients in Group A, responses were seen in 28.7%. Of the 130 evaluable patients in Group B, the overall response rate was 36.5% (p = 0.17).
The median time to progression was 6.9 months for Group A and 7.2 months for Group B (p = 0.47). Median survival was 10.7 months for Group A and 12.3 months for Group B (p = 0.47). One-year survival was 41.3% for Group A and 51.3% for Group B. Toxicity was mild, and there were no toxic deaths in either group.
This preliminary study from Greece indicates that both drug combinations are effective and have similar toxicity in patients with advanced NSCLC.
A Randomized Phase II Trial Comparing RhuMAb VEGF (Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor) Plus Carboplatin/Paclitaxel to CP Alone in Patients with Stage IIIB/IV NSCLC
Russell DeVore et al., Vanderbilt University, Nashville, Tennessee; Abstract 1896, American Society of Clinical Oncology
Clearly, new agents are needed to treat patients with advanced lung cancer. Drugs that target angiogenesis are promising agents against lung cancer. At ASCO 2000, DeVore et al. provided preliminary evidence that recombinant humanized monoclonal antibody to vascular endothelial cell growth factor (rhuMAb VEGF) may increase response rate and prolong time to disease progression in patients with previously untreated NSCLC.
DeVore's study included 99 patients with advanced NSCLC. None had received previous chemotherapy. Mean age of the patients was 62 years, 61% were male, 93% had ECOG status 0-1, 61% had adenocarcinoma histology, and 19% had squamous carcinoma.
All patients received treatment with carboplatin (Paraplatin®) (AUC 6) plus paclitaxel (Taxol®) (200 mg/mІ) (CP) every 3 weeks for 6 cycles. As part of a randomized Phase II trial they then received either CP only (Group A); CP plus low-dose rhuMAb VEGF (7.5 mg/kg every 3 weeks) (Group B); or CP plus high-dose rhuMAb VEGF (15 mg/kg every 3 weeks until progression) (Group C).
Improvements in both response rates and time to progression were noted for patients receiving the chemotherapy plus high-dose anti-VEGF therapy. Patients receiving high-dose anti-VEGF had a response rate of 40%, according to independent review. By investigator analysis, response rate was 31% in this arm. In the control arm, the response rates were 31% by independent review and 19% by investigator review; responses in the low-dose arm were 21% and 28%, respectively. Patients with cavitation had the highest response rates of all anti-VEGF high-dose therapy, 51% versus 31% in the controls and 25% in the low-dose arm.
Time to disease progression was also improved in the high-dose anti-VEGF arm: 7.4 months, versus 4.2 for controls and 4.3 for the low-dose arm, which were determined by investigator review. By independent review, time to progression was 7 months, 6 months, and 3.9 months, respectively.
There was substantial concern, however, over the occurrence of sudden and life-threatening hemoptysis in 6 rhuMAb VEGF-treated subjects, which was fatal in 4 subjects. Most of these patients had squamous cell histology. The researchers did not feel the occurrence of the adverse effect should warrant discontinuation of research into this otherwise-promising therapy, but they are proceeding cautiously with further studies.
Phase I/II Study of Gemcitabine Plus Vinorelbine as First-Line Chemotherapy of Non-Small Cell Lung Cancer
Vito Lorusso et al., Oncology Hospital, Bari, Italy; J Clin Oncol 2000;18:405
Lorusso et al. sought to determine the maximum-tolerated dose of gemcitabine (Gemzar®) when combined with a fixed dose of vinorelbine (Navelbine®) in the treatment of NSCLC. They found this combination to be not only active, but well tolerated.
In this study, 68 patients with stage IIIB/IV NSCLC were treated with vinorelbine at a fixed dose of 30 mg/mІ IV and gemcitabine at increasing dose levels from 800-1500 mg/mІ IV on days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred for gemcitabine at 1500 mg/mІ in the Phase I study, when 3 of 5 patients developed grade 4 thrombocytopenia.
In Phase II, therefore, the gemcitabine dose was set at 1200 mg/mІ and the regimen was administered every 3 weeks for a maximum of 8 cycles. Of 52 evaluable patients, 19 (36%) responded-39% of stage IIIB patients and 33% of stage IV patients. Median time to disease progression was 29 weeks and median survival was 54 weeks. One-year survival was 64% for stage IIIB patients and 29% for stage IV patients.
Hematologic toxicity was generally mild, with grade 4 leukopenia observed in 3 patients (6%) and thrombocytopenia in 4 patients (8%), however, the incidence increased dramatically in patients over 70 years of age, in whom grade 3/4 leukopenia (52%) and thrombocytopenia (24%) was noted more frequently than seen in younger patients.
The researchers concluded that the combination of vinorelbine and gemcitabine is effective and well tolerated in the treatment of NSCLC.
Phase I and Pharmacologic Study of Docetaxel and Irinotecan in Advanced Non- Small Cell Lung Cancer
M. Masuda et al., Osaka Prefectural Habikino Hospital and Kinki University School of Medicine, Osaka, Japan; J Clin Oncol 2000;18(16): 2996-3003
In this study, docetaxel (Taxotere®) and irinotecan (Camptosar®) (CPT-11) resulted in an encouraging response rate in advanced NSCLC.
Previous preclinical trials showed the potentiation of single-agent activity with sequential administration of both irinotecan and docetaxel. Those encouraging findings led to this Phase I study for patients with advanced NSCLC. Masuda et al. wanted to determine the maximum-tolerated dose (MTD) of docetaxel combined with irinotecan and the dose-limiting toxicities of this combination.
The study included 32 patients with advanced NSCLC, who had no prior chemotherapy, ECOG performance status 0-2, and a life expectancy of at least 3 months.
Patients were treated with docetaxel (60 minutes, day 2) plus CPT-11 irinotecan (90 minutes, days 1, 8, and 15) at 4-week intervals. The starting doses of docetaxel and irinotecan were 30 and 40 mg/mІ, and doses were escalated in 10 mg/mІ increments until the MTD was reached. The total number of treatment cycles administered per patient ranged from 1 to 5.
The MTD of docetaxel/CPT-11 was found to be 50/60 mg/mІ (level 5A), or 60/50 mg/mІ (level 5B). The most frequent dose-limiting toxicity of this combination- diarrhea (67%)-caused the researchers to close the trial at dose level 5B.
Of the 30 evaluable patients, 11 patients had partial responses (37%). The median survival time was 48 weeks and the 1-year survival rate was 44.9%.
Masuda et al. concluded that the response rate in this study was encouraging and was within the range of results obtained with cisplatin-containing regimens. Superiority will be evaluated in further (Phase II) trials using the same dose levels.
Phase III Comparison of Sequential vs. Concurrent Chemoradiation for Patients with Unresected Stage III Non-Small Cell Lung Cancer: Initial Report of Radiation Therapy Oncology Group (RTOG) 9410
Walter Curran et al., Bodine Center for Cancer Treatment, Philadelphia, Pennsylvania; Abstract 1891, American Society of Clinical Oncology
The combination of chemotherapy and radiation clearly improves outcome in locally advanced NSCLC. This has been established in landmark studies by the CALGB, RTOG, and Institute Gustave Roussy. A remaining key unanswered question is the importance of delivering therapy in a concurrent fashion. The randomized trial by Curran et al. for the RTOG was presented at ASCO 2000 and updated at the World Lung Cancer Meetings in Tokyo.
The RTOG trial randomized 611 patients with newly diagnosed, unresectable stage II-III NSCLC to 1 of 3 arms. Arm 1 was standard sequential chemotherapy with cisplatin (Platinol®) 100 mg/mІ on days 1 and 29, and vinblastine (Velban®, Velsar®) 5 mg/mІ/weekly x 5 with 60 Gy thoracic radiotherapy beginning on day 50. Arm 2 used the same chemotherapy regimen with 60 Gy of radiotherapy beginning on day 1 (concurrent daily). Arm 3 employed cisplatin (VePesid®) 50 mg/mІ on days 1, 8, 29, and 36 with oral etoposide 50 mg BID x 10 on weeks 1, 2, 5, and 6 with 69.6 Gy in 1.2 Gy BID fractions beginning day 1 (concurrent BID).
In 597 analyzable patients, the rates of grade 3-4 nonhematologic toxicity were higher with concurrent than with sequential therapy, at 30% for sequential, 48% for concurrent daily, and 62% for concurrent BID. Late toxicity rates were similar and there were no differences in grade 5 toxicity.
Median survival was 14.6 months for the sequential group, 17.0 months for the concurrent daily group, and 15.6 months for the concurrent BID group. The difference between sequential and concurrent daily was significant (p < 0.05) when reported more recently at the World Lung Cancer Meetings in Japan.
The investigators concluded that there may be an advantage to concurrent therapy, but there does not appear to be an advantage to twice-daily radiation. This study supports the continuing investigation of concurrently delivered chemotherapy and radiation.