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Lung Cancer Highlights

Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence: Thomas J. Lynch, Jr., M.D., Hematology-Oncology, Room 201 Cox Building, 100 Blossom Street, Boston, Massachusetts 02114-2617, USA. Telephone: 617-724-1136; Fax: 617-724-1137; e-mail: lynch.thomas{at}mgh.harvard.edu

Adjuvant therapy does not work. Second-line therapy works modestly. Paclitaxel/carboplatin and cisplatin/ vinorelbine work equally well in advanced disease. These are the major headlines from the 1999 ASCO lung cancer sessions. Two long-awaited North American cooperative group studies were reported at this year's meeting that will have a great impact on the practice of thoracic oncology. Dr. Steven Keller reported the results of Eastern Cooperative Oncology Group (ECOG) 3590, a randomized study of adjuvant radiotherapy versus chemoradiotherapy in patients with completed resected stage II and IIIA non-small cell lung cancer (NSCLC). This study showed that there was no benefit to the addition of four cycles of cisplatin/VP-16 to radiation as adjuvant therapy. In Southwest Oncology Group (SWOG) 9509, comparing cisplatin/vinorelbine to paclitaxel/carboplatin in patients with advanced NSCLC, Dr. Karen Kelly reported that these two regimens are identical in terms of response and survival. Dr. Kelly reported that paclitaxel/carboplatin had less nausea and less neutropenia but was more expensive than cisplatin/vinorelbine. Other notable studies presented this year were two randomized trials of second-line docetaxel in patients who received prior platinum-containing chemotherapy and an intriguing study of weekly, single-agent paclitaxel in advanced disease.

Early Stage Non-Small Cell Lung Cancer

Prospective Randomized Trial of Postoperative Adjuvant Therapy in Patients with Completely Resected Stages II and IIIa Non-Small Cell Lung Cancer: An Intergroup Trial (E3590).SM Keller, S Adak, H Wagner, A Herskovic, BJ Brooks, MC Perry, RB Livingston, DH Johnson. ( Abstract 1793)

Study Design and Results

This study is a randomized comparison of adjuvant radiation therapy (5,040 cGy in 28 daily fractions) versus radiation therapy (5,040 cGy in 28 daily fractions) with concurrent administration of cisplatin (60 mg/m² day 1) and VP-16 (120 mg/m² days 1 through 3). Four cycles of chemotherapy were planned. To be eligible for this study patients had to have either a thorough mediastinal lymph node sampling or lymph node dissection at the time of surgery. Patients were required to have a performance status of 0 or 1 and to be randomized within 42 days of either a lobectomy, bilobectomy, or a pneumonectomy. Patients were stratified according to weight loss, histology, nodal biopsy technique, and stage. Four hundred eighty-eight patients were randomized over six years. Stage IIIA patients made up 54% of the group with the remainder (46%) being stage II. The two groups were well balanced for prognostic factors. Of the 488 patients entered, 27% were ineligible, most because they lacked proper documentation of nodal disease. Thus, there were 351 patients who were eligible for analysis with a median follow-up of 40.5 months. At the meeting, a detailed analysis of results based on intent to treat and based only on eligible patients showed no differences in the conclusions reached. Survival and response data for all randomized patients based on intent to treat are presented in Table 1.

As would be expected there were notable differences in toxicity. The rate of grade 3/4 leukopenia and esophagitis were 8.8% and 1.3% in the radiation alone arm and 25% and 65% in the combined modality arm, respectively. However these differences did not impact on treatment related mortality. The authors concluded that adjuvant chemotherapy with cisplatin/VP-16 does not improve outcome in patients with stage II and IIIA NSCLC.

Commentary

The role of adjuvant chemotherapy is unclear in completely resected stage II and IIIA NSCLC. Until this current trial was completed the most often cited trial was that of the Lung Cancer Study Group (LCSG) [1]. The LCSG found that CAP (cyclophosphamide, adriamycin, and cisplatin) plus radiation was superior in terms of disease free but not overall survival to radiotherapy alone in a group of patients with adenocarcinoma. However the LCSG study had incomplete staging and the trial used chemotherapy that today is considered less active and passé. Thus, both the current trial and the LCSG trial failed to show a benefit to adjuvant therapy.

It is interesting that some of these same criticisms of the LCSG study can be made of the current Keller study attesting to the difficulty in performing adjuvant trials. The Intergroup attempted to mandate aggressive mediastinal lymph node evaluation in this trial, yet only 77% of patients had adequate sampling. This did not impact on the outcomes reported in this study but is an important lesson for future studies of adjuvant therapy and the difficulties of doing multimodality protocols. Many will question the choice of chemotherapy. It must be noted that this trial was designed in 1989 when cisplatin/VP-16 was the standard of care. Many would agree that the more modern drugs such as paclitaxel, docetaxel, gemcitabine, and vinorelbine are more active than etoposide. However in Dr. Belani's trial reported at ASCO in 1998 [2] there was no significant difference in either survival or response rate between carboplatin/paclitaxel and cisplatin/etoposide in advanced disease. The burden remains on future trialists to show that these newer agents improve outcome as adjuvant therapy.

In his discussion at ASCO, Dr. Keller noted that the outcome of both stage II and IIIA patients was superior to what one would predict from past studies. Part of this can be explained by stage migration due to the many advances in staging over the past decade. It should also be noted that patients in this study were those who did not have bulky stage IIIA disease and are not likely to be comparable to those entered on trials of mediastinoscopically staged IIIA NSCLC or inoperable stage IIIA patients discussed later in this paper. Because of the changing baseline, the need for concurrent control groups in future studies is critical.

Currently there are at least eight ongoing international studies designed to address the question of adjuvant chemotherapy in resected NSCLC. Hopefully these studies will show a benefit to the use of the newer agents. As of now, chemotherapy for stage II disease cannot be considered standard of care and patients should be entered onto trials when available.

Phase III Trial of Neo-Adjuvant Chemotherapy (NCT) in Resectable Stage I (Except T1N0), II, IIIA Non-small Cell Lung Cancer: The French Experience. A Depierre, B Milleron, D Moro, S Chevret, D Braun, E Quoix, B Lebeau, J Breton, E Lemarie, S Gouva, N Paillot, J Brechot, H Janicot, F Lebas, P Terrious, P Foucher, M Monchatre, D Coetmeur, J Clavier, A Vileneuve, V Westeel, C Chastang. French Thoracic Co-operative Group. (Abstract 1792)

Study Design and Results

The French group presented a randomized trial comparing induction chemotherapy followed by surgery to surgery alone in resectable lung cancer. Three hundred seventy-three patients were randomized to immediate surgery or two cycles of MIP (mitomycin 6 mg/m² day 1, ifosfamide 1.5 mg/m² days 1 through 3, cisplatin 30 mg/m² days 1 through 3) followed by surgical resection. Patients who responded to chemotherapy received two cycles of MIP postoperatively. Radiotherapy was given to patients with N2 or T3 disease.

Three hundred seventy-three patients were entered and 355 were eligible (equally distributed between the two arms). One hundred sixty-seven had N2 disease and were staged as IIIA. Chemotherapy was highly effective with an 11% complete remission rate and a 53% partial remission rate for an overall response rate of 64%. Radiotherapy was given to 72 patients in the immediate surgery arm and only 41 patients in the chemotherapy arm. Survival results are shown in Table 2.

Commentary

This trial by DePierre et al. is the first large study that examines the role of induction chemotherapy for patients with early stage lung cancer. The authors observe a survival difference favoring the induction chemotherapy arm however this is not statistically significant. One explanation for the improvement in the induction therapy arm is that there were more patients with N2 disease in the surgery alone arm. A second reason that the difference is not statistically significant is that the study is slightly underpowered. The authors based their statistical analysis on having the study powered to detect a 15% improvement in absolute survival at two years assuming that the survival in the surgery alone arm would be 40%. However the actual two-year survival for this group was 52%. Thus the study was underpowered to detect a clinically relevant difference in survival. This statistical issue makes it impossible to make any firm conclusions. The data are suggestive but more work is needed to bring clarity to this issue.

A similar approach to treating early lung cancer is being pursued by the BLOT investigators [3]. This team is looking at induction therapy with carboplatin and paclitaxel in patients who have a negative mediastinoscopy. At this year's ASCO data from the phase II BLOT study were presented that show that this approach is safe and feasible. A major difference between the BLOT study and the DePierre trial is that the BLOT study requires mediastinoscopy and therefore examines a group that has a better overall prognosis and, perhaps, might be more likely to benefit from induction therapy. The concept of using induction chemotherapy is intriguing and should be pursued, particularly using novel agents and combinations.

First-Line Chemotherapy for Advanced NSCLC

A Randomized Phase III Trial of Paclitaxel Plus Carboplatin Versus Vinorelbine Plus Cisplatin in Untreated Advanced Non-Small Cell Lung Cancer: A Southwest Oncology Group Trial. K Kelly, J Crowley, PA Bunn, R Livingston, D Gandara. ( Abstract 1777)

Study Design and Results

SWOG 9509 is the first trial to compare two of the new generation doublets for advanced non-small cell lung cancer. This study is a randomized trial of cisplatin (100 mg/m² day 1) and vinorelbine (25 mg/m² days 1, 8, 15, and 21) given on a 28-day cycle versus carboplatin (AUC = 6) and paclitaxel (225 mg/m² day 1) given on a 21-day cycle. All patients were required to have a performance status (PS) of 0 or 1, no prior chemotherapy, and measurable disease. The study was designed with a power of 0.94 to detect a 50% increase in median survival with paclitaxel/carboplatin compared to cisplatin/vinorelbine based on a one-sided log rank test (12 months versus eight months). The required sample size was thus 400 patients.

Patient characteristics were well balanced between the two arms. Age, gender, stage, race, and weight loss were similar between the two groups. In this study, 89% of patients had stage IV disease. Data on response, survival and toxicity are shown in Table 3.

The results of SWOG 9509 are important because they offer a direct comparison between regimens that have become standard of care for advanced lung cancer in different parts of the world. The results of this study show that these regimens are identical in terms of response and overall survival. Furthermore they are identical to that seen with these combinations in other trials. The cisplatin/vinorelbine arm of SWOG 9509 is identical with the cisplatin/vinorelbine arm of SWOG 9308—the study that concluded that cisplatin/vinorelbine is superior to cisplatin alone in advanced disease [4]. The paclitaxel/carboplatin has the same median survival and response as the paclitaxel/carboplatin arm of the Belani study presented at ASCO in 1998 [2].

One concern mentioned at the ASCO meeting is that the response rate of both of the arms of the SWOG study was lower than those reported by European and Japanese investigators at this meeting. For example Dr. Masuda [5] presented data using irinotecan/cisplatin that had a 43% response rate and a 49% one-year survival. However it should be noted that Dr. Masuda's study was comprised of 37% stage IIIB patients, which may explain much of the improved response rate and survival data. In European studies and Japanese studies there is often a higher portion of stage III patients than in U.S. advanced lung cancer trials. This may reflect a more prevalent role for combined chemotherapy and radiation in North America for patients with stage III disease.

There are some important differences between the paclitaxel/carboplatin and cisplatin/vinorelbine arms of this study. Neuropathy was significantly worse in the paclitaxel/carboplatin arm, while neutropenia and nausea were worse in the cisplatin/vinorelbine arm. The increased neuropathy may correlate with the dose of paclitaxel. Some investigators feel that 200 mg/m² or 175 mg/m² may be equally efficacious with less potential for neuropathy than the 225 mg/m² dose used in this trial. This dose is being studied in ongoing trials [6].

More patients in the cisplatin/vinorelbine arm stopped therapy because of toxicity but this was not enough to effect either the response rate or the overall survival. A quality of life analysis was done that suggested that the quality of life between the two arms was similar. However not all patients completed the quality of life analysis, which is a major drawback. This is especially true when patients who were the sickest and likely had the most impaired quality of life failed to fill out the forms.

This trial is notable for its detailed assessment of the cost and resource utilization of both regimens. Paclitaxel/ carboplatin was substantially more costly than cisplatin/ vinorelbine. This was primarily due to increased cost of drug. Utilization of other resources was similar between both arms of the study.

Which regimen should be standard in advanced NSCLC? From the current SWOG study both regimens emerge as candidate doublets upon from which to build. Also, both are equally good choices for use outside of the protocol setting. Some physicians will be influenced by the toxicity difference favoring paclitaxel/carboplatin, particularly if the paclitaxel dose is lowered to decrease the rate of neuropathy. Others will be swayed by the increased cost of the paclitaxel/carboplatin regimen. This may only be a temporary issue if, as expected, paclitaxel becomes available in a generic formulation in the future. The most important issue is which regimen should be used to incorporate into novel therapeutic strategies. The future therapy of advanced lung cancer will require agents that attack novel targets if we are going to make substantial progress against this disease. Both paclitaxel/carboplatin and cisplatin/vinorelbine are good candidate doublets to add to agents such as antiangiogenesis drugs, signal transduction pathways inhibitors, and tumor vaccines. Differences in the toxicity profile of the two doublets may influence which regimen is chosen to add to a given novel therapy.

CALGB 9731: Phase II Trial of Weekly Paclitaxel for Advanced Non-Small Cell Lung Cancer (NSCLC).W Akerley, J Herndon, MJ Egorin, A Lyss, H Kindler, D Savarese, CA Sherman, MD Rosen, M Ratain, MR Green. ( Abstract 1783)

Study Design and Results

The CALGB presented an intriguing study of weekly paclitaxel in previously untreated advanced NSCLC. Patients were chemotherapy naïve and had stage IIIB and IV NSCLC. There were 39 patients entered onto this phase II cooperative group protocol. Therapy consisted of paclitaxel given at 150 mg/m² over 3 h weekly. Patients with stable or responding disease were treated until toxicity or progression. As a group, the 39 patients had a PS of 0 (45%) or 1 (55%) with adenocarcinoma being the most prominent histology (61%). Results including toxicity, survival, and response are shown in Table 4.

This abstract is important because it explores two important areas in the treatment of patients with advanced NSCLC. The first is that this is a nonplatinum approach and the response and survival data are the best seen to date by the Cancer and Leukemia Group B (CALGB). This study also explores the use of single-agent chemotherapy. Single agents such as paclitaxel, gemcitabine, docetaxel, and vinorelbine have survival rates similar to those seen with older combinations. The CALGB is now investigating a trial of single-agent paclitaxel versus the combination of carboplatin and paclitaxel. The strategy of using sequential single agents is well established for metastatic breast and colorectal cancer. Now that we have more active single agents it may be that this strategy may prove attractive for patients with lung cancer.

For weekly paclitaxel to be useful, efforts must be made to reduce the incidence and severity of neuropathy. The authors note that 50% of patients will have significant neuropathy within four months of treatment. They also note that when the dose of paclitaxel was reduced by 50%, there was no further progression of neuropathy and, in fact, some patients improved. Strategies to reduce the degree of neuropathy will include dose reduction, lengthening of infusion rate, or using this agent with a neuroprotective agent.

Second-Line Therapy for Metastatic Lung Cancer

Phase III Trial of Docetaxel 100 mg/m² or 75 mg/m² Versus Vinorelbine/Ifosfamide for Non-Small Cell Lung Cancer (NSCLC) Previously Treated with Platinum Based Chemotherapy.F Fossella, R DeVore, R Kerr, J Crawford, R Natale, F Dunphy, L Kalman, D Gandara, F Gamza, L Hammershaimb, Y Kim, W Crist. ( Abstract 1776)

Randomized Study of Taxotere Versus Best Supportive Care in Non-Small Cell Lung Cancer Patients Previously Treated with Platinum Based Chemotherapy.F Shepherd, R Ramlau, K Mattson, L Gressot, M O'Rourke, M Vincent, R Burkes, N Levitan, B Bergman, P Kraszko, L Baez, T Lynch, R Rudd, J Berille, Y Kim, S Coughlin, R Gralla. ( Abstract 1784)

Study Design and Results—Abstract 1776

Patients with advanced lung cancer who progressed after at least one prior regimen that contained platinum were entered in this trial. Randomization was to one of three arms: docetaxel at 75 mg/m² day 1, docetaxel at 100 mg/m² day 1, or either vinorelbine (30 mg/m²/week) or ifosfamide (2 g/m² days 1-3). Patients had to have a performance status of 0-2. There were no restrictions on the number of prior regimens. Patients with prior paclitaxel were eligible for this study.

Patients were well balanced for known prognostic factors between the three arms. Three hundred seventy-three patients were enrolled at 23 sites. Table 5 shows the response rates, survival, and toxicity data.

Study Design and Results-Abstract 1784

Since the principle of second-line therapy has yet to be established, Shepherd et al. compared docetaxel to best supportive care in patients who had received prior cisplatin. One hundred ninety-six patients were randomized to either docetaxel (100 mg/m² for the first 49 patients, at which point dose was reduced to 75 mg/m² for the next 55 patients) or to best supportive care. Patients were evaluated every two cycles and were eligible for continued therapy if they had either stable disease or response. The principle objective in this study was overall survival. Distribution of patients between the two treatment arms was well balanced by known prognostic factors including sex, age, number of prior regimens, best response to prior platinum containing regimen, and performance status. Unlike study 1776, patients were not eligible who had prior paclitaxel. Results including response, survival, and significant toxicity are shown in Table 6.

The abstracts by Dr. Fossella and Dr. Shepherd are important studies that are the first to establish the role of second-line therapy in patients with advanced NSCLC. It must be emphasized that the magnitude of the benefit seen in these studies is modest. However, in both studies, docetaxel at the dose of 75 mg/m² resulted in improved survival. This improvement in survival occurred despite relatively modest response rates in both studies. The response rate seen in these trials is roughly half of that seen in the phase II trials of docetaxel. This is likely the result of patient selection for a single institution phase II trial compared with patient selection for a multicentered randomized study, particularly one involving a best supportive care arm. Investigators at Fox Chase have found that gemcitabine has a 20% response rate in patients who have had prior carboplatin/paclitaxel [8]. It is likely that this response rate will be similar to docetaxel in a randomized study.

An important question remains regarding the use of docetaxel in patients who have had prior taxane. The Shepherd study does not help to clarify this issue because patients with prior taxane were excluded. In the Fosella study an analysis of patient response based on prior taxane (about 40% of patients) found no significant difference between those who had prior taxane compared with those who did not. However, a survival analysis was not done for this group of patients. It is possible that paclitaxel and docetaxel are not mutually cross resistant in advanced NSCLC. It is well established in breast cancer that patients can respond to docetaxel who have progressed on paclitaxel. In addition, patients can respond to 96-h infusional paclitaxel after progressing on 3-h paclitaxel.

Finally, which patients should be selected for second-line therapy? It is critical that second-line therapy be offered to those who are most likely to benefit—principally those who are fit and have a PS of 0 or 1. Response rates to initial therapy are lower in patients with a PS of 2 as shown in an abstract presented by Dr. Johnson in a poster session at this year's ASCO meeting [9]. It should also be pointed out that the availability of docetaxel as an effective second-line therapy should not preclude development of new agents. It is preferable to encourage these patients to participate in clinical trials looking at novel approaches in NSCLC.

Novel Agents for Locally Advanced NSCLC

A Randomized Phase II Study of Gemcitabine or Paclitaxel or Vinorelbine with Cisplatin as Induction Chemotherapy (Ind CT) and Concomitant Chemoradiotherapy (XRT) for Unresectable Stage III Non-Small Cell Lung Cancer (NSCLC) (CALGB Study 9431).EE Vokes, KA Leopold, JE Herndon II, J Crawford, MC Perry, AA Miller, MR Green.Cancer and Leukemia Group B, Chicago, Illinois.(Abstract 1771)

Study Design and Results

Five drugs have had a significant impact on the treatment of patients with advanced NSCLC: paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan. These drugs combined with a platinum compound have improved response rates and prolonged survival in stage IV disease. However, all would agree that there has been no significant impact on the curability of lung cancer since most studies of these newer agents have been in patients with stage IV disease. In CALGB 9431, Dr. Vokes has set out to determine the activity and feasibility of three of these compounds (paclitaxel, vinorelbine, and gemcitabine) combined with radiation therapy in a potentially curable treatment program for patients with locally advanced disease.

In CALGB 9431, patients with unresectable stage III NSCLC with an excellent performance status were randomized to one of three arms. This study was designed as a randomized phase II study—not to compare each of these arms to each other but to determine if any or all of these arms warranted further evaluation. The design of the study is shown in Table 7.

The trial by Vokes shows that each of these three regimens can be given with cisplatin and radiation therapy for patients with locally advanced NSCLC. The gemcitabine arm produced more neutropenia and thrombocytopenia but these were manageable toxicities. Importantly, this study showed that gemcitabine could be given safely with radiation with an acceptable rate of esophagitis and pneumonitis.

CALGB 9431 was not designed to compare each arm to each other but to determine if any of these regimens deserve further study. In this light, it is helpful to compare Vokes' results with previous work by the CALGB in the setting of unresectable stage III disease. Doing so is complicated by changes that have taken place in the approach to stage IIIA disease over the past decade. In 1999, patients may be treated with induction therapy followed by surgery, whereas in 1986 they may have been included in the CALGB studies of unresectable stage III disease. However in the same light, improved staging of metastatic disease has likely occurred as well, which would favor the more recent studies. With these limitations, Table 9 compares Vokes' study to the study of Dillman using cisplatin/vinblastine/radiation [10]. Vokes' study uses chemotherapy and radiation given in the concurrent setting whereas in Dillman the chemotherapy and radiation are given sequentially. There are emerging data in lung cancer presented at this year's ASCO meeting by Furuse [11] that concurrent chemoradiation is superior to sequential therapy.

Acknowledgments

We gratefully acknowledge the cooperation of Kirin Pharmaceuticals and Excerpta Medica, Japan.

References

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7. Miller V, Fossella F, DeVore R et al. Docetaxel (D) benefits lung cancer symptoms and quality of life (QoL) in a randomized phase III study of non-small cell lung cancer (NSCLC) patients previously treated with platinum-based therapy. [Abstract 1895] 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, 1999.
8. Rosvold E, Langer C, Schilder R et al. Salvage therapy with gemcitabine in advanced non-small cell lung cancer (NSCLC) progressing after prior carboplatin-paclitaxel. [Abstract 1797] 34th Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, 1998.
9. Johnson D, Zhu J, Schiller J et al. E1594—a randomized phase III trial in metastatic non-small cell lung cancer (NSCLC) —outcome of PS 2 patients (Pts): an Eastern Cooperative Group Trial (ECOG). [Abstract 1779] 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, 1999.
10. Dillman R, Herndon J, Seagren S et al. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210-1215.[Abstract/Free Full Text]
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