Treatment Strategies for Metastatic Non–Small-Cell Lung Cancer

c omprehensive review Treatment Strategies for Metastatic Non-–Small-Cell Lung Cancer David H. Johnson

This review article provides evidence to support the use of chemotherapy for non–small-cell lung cancer (NSCLC). Chemotherapy plays an important role in the management of advanced NSCLC. Chemotherapy offers symptom palliation, modest but real survival benefits and improves quality of life. The survival benefits achieved with newer drug regimens offer chemotherapy as a strategy for the treatment of NSCLC patients with good performance, no medical or psychological contraindications. Clinical Lung Cancer, Vol. 1, 34-41, 1999

Key words: Non–small-cell lung cancer, Chemotherapy, Prognosis, cisplatin, carboplatin

Non–small-cell lung cancer (NSCLC) is well-established as the leading cause of cancer-related deaths in most industrialized nations. Sadly, the incidence of lung cancer in developing countries is increasing at an alarming rate as well.1 Because of the dismal prognosis associated with this disease, patients with advanced disease often are treated only with symptomatic care both here and abroad.2,3 In general, chemotherapy frequently is viewed as ineffective by non-oncologists and therefore is rarely recommended.2,3 Over the past two decades, however, it has become clear that cisplatin-based chemotherapy is associated with a modest survival advantage and is capable of providing a measure of palliation. Equally important, existing data indicate chemotherapy can be cost-effective.4 Given these observations, it is appropriate for many advanced-stage NSCLC patients to receive chemotherapy. This article reviews the evidence supporting the use of chemotherapy in NSCLC, as well as results of recent clinical trials investigating the role new agents play in lung cancer therapy.

entailed administration of palliative radiotherapy, corticosteroids, analgesics, and antibiotics, if required. Although the individual studies yielded contradictory results, a meta-analysis of these data indicated that cisplatin-based chemotherapy provides a modest survival benefit in virtually all stages of NSCLC.11 For example, in stage IV disease, there is a 27% reduction in the probability of death in the year following diagnosis with cisplatin-based chemotherapy compared with supportive care alone (Table 1). The results of this meta-analysis were recently affirmed in a large, well-conducted randomized trial in Great Britain in which supportive care was compared to mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy (plus supportive care) in advanced NSCLC.12 Patients with advanced non–small-cell lung cancer treated with MIC chemotherapy survived an average of 6.7 months compared to just 4.8 months in those managed with best supportive care alone. This difference mirrors the survival benefit identified in the meta-analysis and is statistically significant (p=0.03).

Chemotherapy Versus Best Support Care in NSCLC

Cisplatin Dose Response

The therapeutic nihilism surrounding the use of chemotherapy in advanced NSCLC prompted a series of studies in the early 1980s in which chemotherapy was prospectively compared to best supportive care alone.5-10 Best supportive care usually

Although the aforementioned meta-analysis confirmed that cisplatin-based chemotherapy is beneficial in NSCLC, the optimal dose of cisplatin in this malignancy still is not well-defined. Laboratory studies suggest a dose response for cisplatin may exist

Submitted: February 1, 1999

Address for correspondence: David H. Johnson, Division of Medical Oncology, Vanderbilt University School of Medicine, 1956 The Vanderbilt Clinic, Nashville, TN 37232, U.S.A. Phone: 615-343-9454 Fax: 615-3437602; e-mail: [email protected]

Introduction

Accepted: June 20, 1999

34

August, 1999

Revised: June 18, 1999

Table 1

Chemotherapy vs. Supportive Care in NSCLC

Agent

Hazard Ratio

P-Value

Median Survival

1-Year Survival

Alkylating Agents

1.26 (0.96-1.66)

0.095

-1 month

-6%

Vinca Alkaloid or Etoposide

0.87 (0.64-1.20)

0.4

0.5 month

4%

Cisplatin

0.73 (0.63-0.85)

<0.0001

1.5 month

10%

Data modified from Non-Small-Cell Lung Cancer Collaborative Group. Chemotherapy in non-small-cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 1995; 311:899-909.

for NSCLC.13 In keeping with this observation, nearly 20 years ago, Gralla and colleagues reported an apparent survival benefit with high-dose cisplatin (120 mg/m2) compared to low-dose cisplatin (60 mg/m2) among responders to chemotherapy.14 The latter study established a practice standard that has been difficult to change, despite the fact that subsequent randomized trials failed to confirm a definite relationship between cisplatin dose (60 mg/m2 to 120 mg/m2) and survival.15-17 Instead, it is more likely that there is a threshold dose for cisplatin – i.e., dose below which no therapeutic benefit is obtained. This putative threshold dose also has not been well-characterized. However, since higher doses of cisplatin clearly contribute to greater toxicity without obvious therapeutic benefit, it seems reasonable to limit the dose of platinum to no more than 100 mg/m2. In randomized trials, cisplatin doses of ≥ 60-80 mg/m2 yield relatively modest toxicities and survival outcome which is essentially equivalent to that achieved with higher cisplatin doses.15,16 For these reasons, cisplatin dose should be limited to between 60 mg/m2 and 100 mg/m2 in the setting of advanced disease.

Cisplatin Versus Carboplatin Much has been written about the relative activities of cisplatin and carboplatin in NSCLC.18,19 Based on cooperative group studies conducted more than 10 years ago, some experts characterized carboplatin as "ineffective" in NSCLC, largely because its objective response rate is <15% (an arbitrary level of "activity").2022 However, more recent data actually suggest that cisplatin and carboplatin may be relatively interchangeable in advanced NSCLC. Indeed, if the activity of single-agent cisplatin is assessed using data from studies conducted between 1985 and 1995, the response rate is quite similar to that observed with single-agent carboplatin (Table 2).21-26 For example, in Southwest Oncology Group (SWOG) trial 9308, cisplatin produced an objective response rate of just 12% in metastatic NSCLC.27 In Eastern Cooperative Oncology Group (ECOG) trial 1583, the activity of carboplatin in a simi-

lar patient population was 9%.23 Furthermore, with the recognition that carboplatin is renally excreted, more rational dosing schedules have been developed.28 Even in the absence of a platinum dose response, the ability to individualize drug dosing helps ensure the patient receives an "appropriate" dose of carboplatin and minimizes the likelihood of excessive toxicity. Finally, in at least two randomized trials conducted in patients with metastatic NSCLC, carboplatin-based chemotherapy produced equivalent survival to an identical regimen containing cisplatin.29,30 Taken together, these data indicate that one can justifiably substitute carboplatin for cisplatin in the treatment of NSCLC.

Optimal Chemotherapy for Advanced NSCLC While existing data clearly indicate chemotherapy is warranted in appropriately selected patients with advanced NSCLC, the optimal chemotherapy regimen remains elusive. Prior to 1990, most treating oncologists employed regimens consisting of cisplatin plus a vinca alkaloid or an epipodophyllotoxin. More recently, clinicians have begun to use regimens that employ newer agents with demonstrated activity against NSCLC including the taxanes, vinorelbine, gemcitabine, and the topoisomerase I interacting agents. These agents are appealing either because they possess novel mechanisms of action or because they are somewhat less toxic than their older congeners. However, the question is: do these newer agents add anything to the effectiveness of singleagent cisplatin in advanced NSCLC? Table 3 is a compilation of randomized trials in which cisplatin alone was compared to cisplatin plus one of the newer agents.27, 31-33 For comparison purposes, an older study is included in which cisplatin and cisplatin plus etoposide were prospectively compared.26 In virtually every study, the combination of the newer agent and cisplatin proved superior to singleagent cisplatin. Although not every expert agrees,34 these studies appear to establish the utility of combination therapy over singleagent therapy in advanced NSCLC. Choosing among the many options is a somewhat daunting task since there appears to be no major advantage for one regimen over all others.

Vinorelbine-Based Therapy Vinorelbine was among the first of the so-called third generation agents to demonstrate improved activity against NSCLC, Table 2

Comparison of Cisplatin & Carboplatin Response Rates in Advanced NSCLC Cisplatin

Carboplatin

Patient Number

511

208

Response Rate

12%

12%

Median Survival

26 weeks

30 weeks

Data compiled form Bonomi et al,23 Kreisman et al,22 Kramer et al,21 Gandara et al,17 Wozniak et al,25 Klastersky et al.26

August, 1999

35

Treatment Strategies for Lung Cancer Table 3

Cisplatin vs. New Combination Regimens in Advanced NSCLC

Regimen/ Author

Response Rate

Median Survival

1-Year Survival

Cisplatin Cisplatin + Etoposide

19% 26%

6.0 months 5.1 months

25% 25%

9% 31%

7.6 months 8.7 months

26% 39%

17% 26%

8.6 months 8.1 months

35% 30%

14% 28%

6.4 months 8.0 months

21% 33%

12% 26%

6.0 months 8.0 months

20% 36%

Klastersky, 1990

26

Cisplatin Cisplatin + Gemcitabine Sandler, 1998*32 Cisplatin Cisplatin + Paclitaxel Gatzemeier, 1998

31

Cisplatin Cisplatin + Tirapazamine von Pawel, 1998*33 Cisplatin Cisplatin + Vinorelbine Woznaik, 1998*27

* Survival difference statistically significant; survival difference NOT statistically significant.

both as a single agent and in combination with a platinum compound. Table 4 summarizes the results of several, important phase III trials. The trials conducted by Le Chevalier and Wozniak are particularly noteworthy.27,35 These complimentary studies firmly establish the superiority of vinorelbine plus cisplatin over either agent given alone in patients with good performance status, as both groups reported a modest improvement in median and 1year survival with the combination regimen. Furthermore, the French study found cisplatin plus vinorelbine to be superior to their previous standard regimen of cisplatin plus vindesine. Of further interest is a recently reported Italian trial in which singleagent vinorelbine was compared to supportive care in a group of elderly NSCLC patients (≥ 70 years). Vinorelbine yielded an improvement in the quality of life and overall survival.36 Although it is unclear if one needs to attenuate therapy in older patients up front, single-agent vinorelbine offers an acceptable and relatively nontoxic therapeutic option for those patients.

Paclitaxel-Based Therapy In a recently completed survey of U.S. medical oncologists, paclitaxel proved to be the preferred agent for use with platinum agents in advanced NSCLC.37 The reasons for this preference, however, are not entirely clear. Several randomized trials have been completed using cisplatin or carboplatin plus paclitaxel. These studies are summarized in Table 5. Interestingly, only one of the randomized trials (ECOG 5592) yielded a clear improve-

36

August, 1999

ment in overall survival with the paclitaxel-containing regimen compared to cisplatin alone or older combination regimens. However, even this positive ECOG study required a combining of the two paclitaxel-containing arms into a single group to gain statistical significance.38 In a European trial of similar design, cisplatin plus paclitaxel improved the patients’ quality of life, but failed to yield a survival benefit.39 Similarly, in a randomized trial sponsored by Bristol-Myers, the manufacturer of paclitaxel, carboplatin plus paclitaxel failed to demonstrate a survival advantage compared to cisplatin plus etoposide.40 Thus, in these three trials of similar design – cisplatin-paclitaxel versus cisplatin plus an epipodophyllotoxin – the older regimens performed comparable to the newer ones in terms of overall survival but were somewhat inferior in terms of improved quality of life. Of note, in a recently completed SWOG study, survival with cisplatin plus vinorelbine was essentially equivalent to that achieved with carboplatin plus paclitaxel.41 Reportedly, the toxicity observed with the paclitaxel regimen was somewhat less than that seen with a vinorelbine-containing regimen in the SWOG trial, although this finding may simply reflect the differing toxicity profiles of cisplatin and carboplatin. Several reasons have been proposed for the lack of survival benefit in these randomized paclitaxel trials. The most commom explanation suggests that patients recurring in the control arms of the studies subsequently received second-line therapy with a taxane ( paclitaxel or docetaxel) and that this may have lead to better survival, obscuring any survival difference that might have emerged. This was not as much of a problem in the ECOG trial since paclitaxel was not commercially available during the conduct of the study, perhaps accounting for the "positive" result. The "salvage" chemotherapy hypothesis is based in part on a non-randomized trial conducted by M.D. Anderson investigators in which docetaxel was shown to yield a good survival in patients with recurrent NSCLC following cisplatin-based chemotherapy.42 Similar results have been reported with paclitaxel.43 A randomized follow-up to the M.D. Anderson phase II trial, however, yielded mixed results and cast some doubt on this conjecture.44 Another possible explanation for a lack of survival benefit in some of the randomized trials could relate to the schedule by which paclitaxel is administered.45 Of all the studies listed in Table 4, only the ECOG trial employed a prolonged infusion of paclitaxel (24 hours), whereas the remaining studies used short infusion times (~3 hours). While non-randomized trials seem to suggest there is no difference in the activity of paclitaxel in NSCLC, based on length of administration,46-50 there is reason to believe this may not be a totally settled issue. For example, National Surgical Adjuvant Breast and Bowel Project (NSABP) investigators demonstrated a statistically significant difference in response rates in breast cancer patients given an identical dose of paclitaxel over a short versus a long infusion interval.51 Whether a similar relationship applies in NSCLC or whether such a change is relevant to survival improvement is unknown.52

David H. Johnson Table 4

Vinorelbine in Advanced NSCLC Regimen/ Author

Response Rate

Median Survival

1-Year Survival

Vinorelbine Cisplatin + Vindesine Cisplatin + Vinorelbine

14% 19% 30%

7.2 months 7.4 months 9.3 months

35% 35% 40%

16% 43%

7.4 months 7.7 months

22% 26%

3% 12%

5.1 months 7.0 months

16% 25%

12% 26%

6.0 months 8.0 months

20% 36%

20%

4.9 months 6.5 months

14% 32%

27% 27%

8.0 months 8.0 months

36% 33%

Le Chevalier, 1994*35 Vinorelbine Cisplatin + Vinorelbine DePierre, 1994 5-Flourouracil + Leucovorin Vinorelbine Crawford, 1996* Cisplatin Cisplatin + Vinorelbine Wozniak, 1998*27 Best Supportive Care Vinorelbine ELVIS, 1999*36 Carboplatin + Paclitaxel Cisplatin + Vinorelbine Kelly, 1999 41

* Survival difference statistically significant; survival difference NOT statistically significant.

The dose of paclitaxel administered also may play a role in its activity against NSCLC. In the aforementioned ECOG trial (E5592), paclitaxel was administered at two dose levels -- 135 mg/m2 and 250 mg/m2. The response rates, median times to progression and median survival in the two arms, were essentially identical and both were superior to that achieved with cisplatin plus etoposide.38 By contrast, Greek investigators found median time to progression (4.3 months versus 6.4 months; p=0.044) and median survival (9.5 months versus 11.4 months; p=0.16) were improved when the dose of paclitaxel was escalated (175 mg/m2 or 225 mg/m2) in combination with carboplatin.53 In the latter study, paclitaxel was administered over 3 hours. Just how we should interpret these findings is unclear. At the very least, the available data suggest further study is needed.

Gemcitabine-Based Therapy Like vinorelbine and paclitaxel, gemcitabine is FDA-approved for use against NSCLC. Gemcitabine is an analog of the pyrimidine antimetabolite cytosine arabinoside (ara-C). Its cytotoxic effect is achieved through the competitive incorporation of phosphorylated gemcitabine into DNA. The activity of gemcitabine in solid tumors may be related to its accumulation within tumor cells at much higher levels and for longer intervals than the active metabolite of ara-C.54, 55 Gemcitabine triphosphate also inhibits

the deaminase responsible for its degradation thus leading to "selfpotentiation."56 In preclinical studies, gemcitabine possesses synergistic cytotoxicity with several drugs including cisplatin.57,58 The mechanism of this synergy is not well-defined but may involve inhibition of DNA repair.59 A series of successful phase II trials of cisplatin and gemcitabine60-67 led to pivotal phase III studies which culminated in FDA approval in 1998. A summary of these phase III trials and supporting studies is provided in Table 6. Two important gemcitabine trials are those conducted by the Hoosier Oncology Group (HOG) in which cisplatin plus gemcitabine was compared to cisplatin alone and a Spanish study that compared cisplatin plus gemcitabine to cisplatin plus etoposide.32,68 The HOG trial yielded a modest improvement in median (7.6 vs. 9.1 months: p<0.05) and 1-year survival comparable to that seen in the vinorelbine trials previously discussed. The Spanish group designed a study in which response rate was the main endpoint. In this study, the gemcitabine-containing regimen yielded a superior response rate compared to the etoposide-containing arm (41% vs. 22%; p=0.02). Time to tumor progression (6.9 months versus 4.3 months; p=0.01) and median survival (8.7 months versus 7.2 months; p=0.18) also favored the gemcitabine-treated patients. Gemcitabine is relatively well-tolerated, and like vinorelbine it is being touted for use as a single agent in older or medically compromised patients.69,70 Prima facie, this appears to be a very reasonable recommendation, but randomized data are not yet available. Another possible use for gemcitabine is with trastuzumab, the humanized, monoclonal antibody to HER2/neu. It is wellknown that some lung cancer cell lines express high levels of p185neu, the protein product of HER2/neu.71-73 These particular cell lines appear to be more effective at repairing DNA damage caused by cisplatin and, in turn, are not killed as effectively as cell lines that do not overexpress p185neu. Preclinical data indicate that a combination of cisplatin and gemcitabine may be more active against NSCLC tumors that overexpress p185neu than many of the currently used combinations.59 These data suggest that the combination of cisplatin plus gemcitabine and trastuzumab might be a particularly active regimen in HER2/neu positive tumors. This possibility requires additional study.

Second-Line Chemotherapy in NSCLC To determine if second-line docetaxel is beneficial following cisplatin-based chemotherapy, two randomized trials were recently conducted.73,74 In one study73, patients with recurrent NSCLC were randomized to receive docetaxel at one of two dose levels (75 mg/m2 or 100 mg/m2) or either ifosfamide or vinorelbine (investigator’s choice). Eligible patients had received prior platinum-based chemotherapy and could have received prior paclitaxel. Preliminary results indicate docetaxel imparted a modest survival advantage. Curiously, however, the survival benefit was observed only with the lower of two docetaxel doses (75

August, 1999

37

Treatment Strategies for Lung Cancer Table 5

Paclitaxel in Advanced NSCLC Regimen/ Author

Response Rate

Median Survival

Cisplatin Cisplatin + Paclitaxel

17% 26%

8.6 months 8.1 months

12.5% 25% 28%

7.6 months 9.5 months 10.1 months

Gatzemeier, 1998

31

Cisplatin + Etoposide Cisplatin + Paclitaxel Cisplatin + Paclitaxel + G-CSF

ertheless instructive that more than half of the patients given "toxic" chemotherapy perceived that their symptoms improved. 1-Year This information should be shared with potential candidates for Survival chemotherapy. Patients have indicated a desire to know all infor35% mation pertaining to their prognosis and potential treatment side30% effects. All too often, the treating physician withholds this information.2 32% 37% 40%

Bonomi, 1996*38 Cisplatin + Teniposide Cisplatin + Paclitaxel Giaccone, 1998

41% 43%

14% 22%

9.9 months 9.5 months

37% 32%

27% 27%

8.0 months 8.0 months

33% 36%

40

Cisplatin + Vinorelbine Carboplatin + Paclitaxel Kelly, 1999

9.9 months 9.7 months

38

Cisplatin + Etoposide Carboplatin + Paclitaxel Belani, 1998

28% 41%

41

mg/m2 vs. 100 mg/m2). The authors infer third-line chemotherapy may have influenced survival. This rather confusing outcome suggests the results of this trial should be interpreted with caution. In the second randomized trial, patients who failed prior platinum-based chemotherapy received docetaxel (75 mg/m2 vs. 100 mg/m2) or best supportive care.74 Patients given docetaxel also experienced a slight improvement in median survival (5.9 months versus 4.9 months) and an improved quality of life.75 Like the previous trial, the survival benefit was observed primarily in those patients receiving the lower dose of docetaxel (9.0 months vs. 4.6 months; P=0.016). Of note, none of the patients entered into this study had received prior taxanes. Collectively, these data suggest there may be a small survival benefit and an improved quality of life following second-line docetaxel therapy in patients failing to respond to or relapsing from platinum-containing chemotherapy.

Chemotherapy and Quality of Life in NSCLC contrary,3

Despite widespread perceptions to the combination chemotherapy can improve quality of life in NSCLC patients.12, 39 Tumor-related symptoms such as cough, dyspnea, chest pain and hemoptysis frequently improve following combination chemotherapy, even when there is no overt evidence of tumor regression.69, 75-77 For example, Ellis and colleagues reported tumor-related symptoms improve in approximately 70% of patients treated with a cisplatin-based regimen, even though the tumor regression rate was only 35%. Although this was not a randomized trial and one might argue for a "placebo effect," it is nev-

August, 1999

The number of chemotherapy courses one should administer is controversial. However, a recent randomized trial compared three cycles of mitomycin, vinblastine, and cisplatin to six cycles of the same therapy and found no difference in survival between the two groups (Table 7).78 Furthermore, extrapolating from small-cell lung cancer (SCLC), it seems reasonable to discontinue therapy after four to eight cycles of treatment, unless there is evidence of continued tumor shrinkage and the patient is tolerating therapy without major complication.79, 80

Patient Selection for Chemotherapy

* Survival difference statistically significant; survival difference NOT statistically significant.

38

Number of Chemotherapy Cycles in Advanced NSCLC

In light of the available data, it seems more than appropriate to offer chemotherapy to individuals with advanced NSCLC, provided the individual has a good performance status and there is no medical or psychological contraindication to treatment. Based on the experience of large cooperative groups and selected cancer centers, one should probably reserve chemotherapy for good-perTable 6

Gemcitabine in Advanced NSCLC Regimen/ Author

Response Rate

Median Survival

1-Year Survival

Gemcitabine Cisplatin + Etoposide

18% 15%

6.6 months 7.6 months

-

19% 21%

8.6 months 11.1 months

34% 30%

9% 31%

7.6 months 8.7 months

26% 39%

28% 40%

8.8 months 8.1 months

-

22% 41%

7.2 months 8.7 months

25% 32%

Manegold, 1997 Gemcitabine Cisplatin + Etoposide Perng, 1997 Cisplatin Cisplatin + Gemcitabine Sandler, 1998*32 Mitomycin, Ifosfamide and Cisplatin Cisplatin + Gemcitabine Crino, 1998 Cisplatin + Etoposide Cisplatin + Gemcitabine Cardenal, 1999§68 * Survival difference statistically significant; survival difference NOT statistically significant. Randomized phase II Trials. §Randomized phase III trials; primary endpoint = response rates.

David H. Johnson Table 7

Duration of MVP in Advanced NSCLC 3 Cycles

Objective Response 32% Symptomatic Response 65% Median Survival 6.8 months 1-Year Survival

23%

6 Cycles

37% 75% 7.0 months 23%

Data modified from Smith I, O'Brien M, Norton A, et al. Duration of chemotherapy for advanced non-small-cell lung cancer (NSCLC): A phase III randomized trial of 3 versus 6 courses of mitomycin, vinblastine, cisplatin (MVP). Proc. ASCO 1998; 17:457a (abstract 1759).

formance-status patients (ECOG 0-1).81-83 Patients with ECOG PS 2 do not appear to be good candidates for combination chemotherapy, as the incidence of serious life-threatening toxicity increases substantially. This has been reaffirmed recently in a large ECOG trial in which PS 2 patients were allowed entry largely because the "newer" regimens were perceived to be less toxic.84 Therefore entry criteria were relaxed slightly to allow PS 2 patients to be included. However, the toxicities experienced by this cohort were substantially greater than those observed in PS 01 patients, leading to a suspension in their accrual. Whether such patients could be treated with less aggressive therapy remains to be determined (e.g., single-agent vinorelbine or gemcitabine).35, 69 Individuals with substantial weight loss also are not good candidates for combination chemotherapy and might be better served by use of supportive care measures or possibly the use of single agents if treatment is desired.

Conclusion Chemotherapy clearly plays a central role in the management of advanced NSCLC. In addition to symptom palliation and a modest but real survival benefit,11,75 patients derive an improvement in their quality of life.12,39 Furthermore, the use of chemotherapy can be cost-effective.4 Indeed, the survival benefits achieved with newer drug regimens rival those obtained with chemotherapy in extensive-stage SCLC -- a malignancy generally conceded to be "chemotherapy sensitive." Thus, we can conclude that it is appropriate to offer chemotherapy to all NSCLC patients with advanced disease, a good performance status and no medical or psychological contraindication to its use. Although there remains broad resistance to the use of chemotherapy in this disease,2, 85-87 the available data should help dispel these attitudes.

References

1. Schottenfield D. Epidemiology of lung cancer. In: Pass HI, Mitchell JB, Johnson DH, Turrisi AT, eds. Lung Cancer Principles and Practice. Philadelphia: Lippincott-Raven; 1996:305-321. 2. Slevin ML, Stubbs L, Plant HJ, et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public. BMJ 1990; 300:1458-1460. 3. Perez EA. Perceptions of prognosis, treatment, and treatment impact on prognosis in non-small cell lung cancer. Chest 1998; 114:593-604. 4. Evans WK, Will BP, Berthelot JM, et al. The cost of managing lung cancer in Canada. Oncology 1995; 9 (11 Suppl):147-153.

5. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. J Clin Oncol 1988; 6:633-641. 6. Ganz PA, Figlin RA, Haskell CM, et al. Supportive care versus supportive care and combination chemotherapy in metastatic non-small-cell lung cancer. Does chemotherapy make a difference? Cancer 1989; 63:1271-1278. 7. Woods R, Williams C, Levi J, et al. A randomized trial of cisplatin and vindesine versus supportive care only in advanced non-small-cell lung cancer. Br J Cancer 1990; 66:608611. 8. Kaasa S, Lund E, Thorud E, et al. Symptomatic treatment versus combination chemotherapy for patients with extensive non-small-cell lung cancer. Cancer 1991; 67:2443-2447. 9. Cellerino R, Tummarello D, Guidi F, et al. A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small-cell lung cancer. J Clin Oncol 1991; 9:1453-1461. 10. Cartei G, Cartei F, Cantone A, et al. Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer. J Natl Cancer Inst 1993; 85:794-800. 11. Non-Small-Cell Lung Cancer Collaborative Group. Chemotherapy in non-small-cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311:899-909. 12. Cullen M, Woodroffe C, Billingham L, et al. Mitomycin, ifosfamide and cisplatin (MIC) in non-small-cell lung cancer (NSCLC): 2. Results of a randomised trial in patients with extensive disease. Lung Cancer 1997; 18 (Suppl 1):5. 13. Perez E, Putney J, Gandara D. In vitro dose-response relationship to cisplatin in human non-small-cell lung cancer cell lines. Proc Am Assoc Cancer Res 1989; 30:459 (abstract 1825). 14. Gralla RJ, Casper ES, Kelsen DP, et al. Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: a randomized trial investigating two dosage schedules. Ann Intern Med 1981; 95:414-420. 15. Klastersky J, Sculier JP, Ravez P, et al. A randomized study comparing a high and a standard dose of cisplatin in combination with etoposide in the treatment of advanced nonsmall-cell lung carcinoma. J Clin Oncol 1986; 4:1780-1786. 16. Shinkai T, Saijo N, Eguchi K, et al. Cisplatin and vindesine combination chemotherapy for non–small-cell lung cancer: a randomized trial comparing two dosages of cisplatin. Jpn J Cancer Res 1986; 77:782-789. 17. Gandara DR, Crowley J, Livingston RB, et al. Evaluation of cisplatin intensity in metastatic non-small-cell lung cancer: a phase III study of the Southwest Oncology Group. J Clin Oncol 1993; 11:873-878. 18. Bunn PA, Jr. Clinical experiences with carboplatin (Paraplatin) in lung cancer. Semin Oncol 1992; 19 (1 Suppl 2):1-11. 19. Bunn PA, Jr. The North American experience with paclitaxel combined with cisplatin or carboplatin in lung cancer. Semin Oncol 1996; 23 (6 Suppl 16): 18-25. 20. Bonomi P. Carboplatin in non-small-cell lung cancer: review of the Eastern Cooperative Oncology Group trial and comparison with other carboplatin trials. Semin Oncol 1991; 18 (Suppl 2):2-7. 21. Kramer BS, Birch R, Greco A, et al. Randomized phase II evaluation of iproplatin (CHIP) and carboplatin (CBDCA) in lung cancer. A Southeastern Cancer Study Group trial. Am J Clin Oncol 1988; 11:643-645. 22. Kreisman H, Ginsberg S, Propert KJ, et al. Carboplatin or iproplatin in advanced nonsmall-cell lung cancer: a Cancer and Leukemia Group B Study. Cancer Treat Rep 1987; 71:1049-1052. 23. Bonomi PD, Finkelstein DM, Ruckdeschel JC, et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-c e l l lung cancer: a study of the Eastern Cooperative Oncology Group. J Clin Oncol 1989; 7:1602-1613. 24. Gandara DR, Wold H, Perez EA, et al. Cisplatin dose intensity in non-small-cell lung cancer: phase II results of a day 1 and day 8 high-dose regimen. J Natl Cancer Inst 1989; 81:790-794. 25. Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized Phase III trial of cisplatin (CDDP) vs CDDP plus navelbine (NVB) in treatment of advanced non-small-cell lung cancer (NSCLC): Report of a Southwest oncology group study (SWOG-9308). Proc Am Soc Clin Oncol 1996; 15:374a (abstract 1110). 26. Klastersky J, Sculier JP, Bureau G, et al. Cisplatin versus cisplatin plus etoposide in the treatment of advanced non-small-cell lung cancer. Lung Cancer Working Party, Belgium. J Clin Oncol 1989; 7:1087-1092. 27. Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 1998; 16:2459-2465. 28. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7:1748-1756. 29. Klastersky J, Sculier JP, Lacroix H, et al. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 1990; 8:1556-1562. 30. Jelic S, Radosavjelic D, Elezar E, et al. Survival advantage for carboplatin 500 mg/m2 substituting cisplatin 120 mg/m2 in combination with vindesine and mitomycin C in patients with stage IIIB and IV squamous c-cell bronchogenic carcinoma: A randomized phase III study in 221 patients. Lung Cancer 1997; 18 (Suppl 1):14-15 (abstract 45).

August, 1999

39

Treatment Strategies for Lung Cancer 31. Gatzemeier U, von Pawel J, Gottfried M, et al. Phase III comparative study of high-dose cisplatin (HD-CIS) versus a combination of paclitaxel (TAX) and cisplatin (CIS) in patients with advanced non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1998; 17:454a (abstract 1748). 32. Sandler A, Nemunaitis J, Dehnam C, et al. Phase III study of cisplatin (C) with or without gemcitabine (G) in patients with advanced non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1998; 17:454a (abstract 1747). 33. von Pawel J, von Roemeling R. Survival benefit from Triazone (tirapazamine) and cisplatin in advanced non-small-cell lung cancer (NSCLC) patients: final results from the international phase III CATAPULT I trial. Proc Am Soc Clin Oncol 1998; 17:454a (abstract 1749). 34. Lilenbaum RC, Langenberg P, Dickersin K. Single agent versus combination chemotherapy in patients with advanced non-small-cell lung carcinoma: a meta-analysis of response, toxicity, and survival. Cancer 1998; 82:116-126. 35. Le Chevalier T, Brisgand D, Douillard JY, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-smallcell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994; 12:360-367. 36. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 1999; 91:66-72. 37. Shyr Y, Choy H, Cmelak A, et al. Pattern of practice survey: Non-small-cell lung cancer in the U.S. Proc Am Soc Clin Oncol 1998; 17:463a (abstract 1778). 38. Bonomi P, Kim K, Chang A, et al. Phase III trial comparing etoposide (E) cisplatin (C) versus taxol (T) with cisplatin-G-CSF (G) versus taxol-cisplatin in advanced non-smallcell lung cancer. An Eastern Cooperative Oncology Group (ECOG) trial. Proc Am Soc Clin Oncol 1996; 15:382 (abstract 1145). 39. Giaccone G, Postmus P, Debruyne C, et al. Final results of an EORTC phase III study of paclitaxel vs teniposide, in combination with cisplatin, in advanced NSCLC. Proc Am Soc Clin Oncol 1997; 16:460a (abstract 1653). 40. Belani C, Natale R, Lee J, et al. Randomized phase III trial comparing cisplatin/etoposide versus carboplatin/paclitaxel in advanced and metastatic non–small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1998:455a (abstract 1751). 41. Kelly K, Crowley J, Bunn P, et al. A randomized phase III trial of paclitaxel plus carboplatin (PC) versus vinorelbine plus cisplatin (VC) in untreated advanced non-small cell lung cancer (NSCLC): a Southwest Oncology Group (SWOG) trial. Proc. Am Soc Clin Oncol 1999; 18a (abstract 1777). 42. Fossella FV, Lee JS, Shin DM, et al. Phase II study of docetaxel for advanced or metastatic platinum- refractory non-small-cell lung cancer. J Clin Oncol 1995; 13:645-651. 43. Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pre-treated patients with small-cell-lung cancer. Br J Cancer 1998; 77:347-351. 44. Fossella F, DeVore R, Kerr R, et al. Phase III trial of docetaxel 100 mg/m2 or 75 mg/m2 vs vinorelbine/ifosfamide for non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy (PBC). Proc Am Soc Clin Oncol 1999; 18a (abstract 1776). 45. Arbuck SG. Paclitaxel: what schedule? What dose? J Clin Oncol 1994; 12:233-236. 46. Gatzemeier U, Heckmayr M, Neuhauss R, et al. Phase II study with paclitaxel for the treatment of advanced inoperable non-small-cell lung cancer. Lung Cancer 1995; 12 Suppl 2:S101-S106. 47. Hainsworth JD, Thompson DS, Greco FA. Paclitaxel by 1-hour infusion: an active drug in metastatic non-small-cell lung cancer. J Clin Oncol 1995; 13:1609-1614. 48. Sekine I, Nishiwaki Y, Watanabe K, et al. Phase II study of 3-hour infusion of paclitaxel in previously untreated non-small-cell lung cancer. Clin Cancer Res 1996;2:941-945. 49. Millward MJ, Bishop JF, Friedlander M, et al. Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol 1996; 14:142-148. 50. Tester WJ, Jin PY, Reardon DH, et al. Phase II study of patients with metastatic nonsmall-cell carcinoma of the lung treated with paclitaxel by 3-hour infusion. Cancer 1997; 79:724-729. 51. Mamounas E, Brown A, Smith R, et al. Effect of Taxol duration of infusion in advanced breast cancer (ABC): Results from NSABP B-26 trial comparing 3- to 24-hr infusion of high dose Taxol. Proc Am Soc Clin Oncol 1998; 17:101a (abstract 389). 52. Markman M. Why does a higher response rate to chemotherapy correlate poorly with improved survival?. J Cancer Res Clin Oncol 1993; 119:700-701. 53. Kosmidis P, Mylonakis N, Skarlos D, et al. A multicenter randomized trial of paclitaxel (175 mg/m2) plus carboplatin (6 AUC) versus paclitaxel (225 mg/m2) plus carboplatin (6 AUC) in advanced non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1999; 18a (abstract 1785). 54. Heinemann V, Hertel LW, Grindey GB, et al. Comparison of the cellular pharmacokinetics and toxicity of 2',2'- difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 1988; 48:4024-4031. 55. Hertel LW, Boder GB, Kroin JS, et al. Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'- deoxycytidine). Cancer Res 1990; 50:4417-4422. 56. Xu Y, Plunkett W. Regulation of dCMP deaminase in intact CCRF-DEM cells. Proc Am Assoc Cancer Res 1990; 31:405a (abstract 2402). 57. Tanzer LR, Rutherford PG, Self TD, et al. Antitumor activity of gemcitabine in combination with cisplatin against the human NSCLC xenograft Calu-6. Proc Am Assoc Cancer Res 1995; 36: A1761.

40

August, 1999

58. Nakamura H, Yamaji Y, Fujita T, et al. Synergistic growth inhibition of gemcitabine/cisplatin, and gemcitabine/etoposide on a human lung cancer cell line, RERFLC-OK. Proc Am Assoc Cancer Res 1995; 36: A2425. 59. Tsai CM, Chang KT, Chen JY, et al. Cytotoxic effects of gemcitabine-containing regimens against human non-small cell lung cancer cell lines which express different levels of p185neu. Cancer Res 1996; 56:794-801. 60. Cormier Y, Shepherd F, Burkes R, et al. Phase I study of gemcitabine (GEM) and cisplatin (CP) for advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1994; 13: 342 (abstract 1140). 61. Dunlop D, Cameron C, Dabouis G, et al. Phase I dose-escalation study of cisplatin in combination with gemcitabine in non-small-cell lung cancer. Proc Am Soc Clin Oncol 1994; 13:342 (abstract 1139). 62. Sandler A, Ansari R, McClean J, et al. A Hoosier Oncology Group phase II study of gemcitabine plus cisplatin in non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1995; 14:357 (abstract 1089). 63. Crino L, Scagliotti G, Marangolo M, et al. Cisplatin-gemcitabine combination in nonsmall-cell lung cancer (NSCLC): a Phase II study, Proc Am Soc Clin Oncol 1995; 14:352 (abstract 1066). 64. Steward W, Dunlop D, Cameron C, et al. Phase I/II study of cisplatin in combina-tion with gemcitabine in non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1995; 14:351 (abstract 1064). 65. Anton A, Carrato A, Gonzalez Larriba J, et al. Phase II activity of gemcitabine in combination with cisplatin in advanced non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1996; 15:380 (abstract 1134). 66. Shepherd F, Cormier Y, Evans W, et al. A phase II study of gemcitabine and cisplatin weekly x 3 every 4 weeks in patients with non-small-cell lung cancer. Proc Am Soc Clin Oncol 1996; 15:380 (abstract 1135). 67. Abratt R, Bezwoda W, Goedhals L. Gemcitabine and cisplatin for advanced non-smallcell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1996; 15:380 (abstract 1136). 68. Cardenal F, Lopez-Cabrerizo M, Anton A, et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 1999; 17:12-18. 69. Thatcher N, Hopwood P, Anderson H. Improving quality of life in patients with nonsmall-cell lung cancer: research experience with gemcitabine. Eur J Cancer 1997; 33 (Suppl 1):S8-S13. 70. Thatcher N, Jayson G, Bradley B, et al. Gemcitabine: symptomatic benefit in advanced non-small-cell lung cancer. Semin Oncol 1997; 24 (3 Suppl 8):S8-6-S8-12. 71. Kern JA, Schwartz DA, Nordberg JE, et al. p185neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res 1990; 50:5184-5187. 72. Kern JA, Slebos RJ, Top B, et al. C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas. J Clin Invest 1994; 93:516-520. 73. Pfeiffer P, Clausen PP, Andersen K, et al. Lack of prognostic significance of epidermal growth factor receptor and the oncoprotein p185HER-2 in patients with systemically untreated non-small-cell lung cancer: an immunohistochemical study on cryosections. Br J Cancer 1996; 74:86-91. 74. Fossella FV, DeVore R, Kerr R, et al. Phase III trial of docetaxel 100 mg/m2 or 75 mg/m2 vs vinorelbine/ifosfamide for non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy (PBC). Proc Am Soc Clin Oncol 1999; 18 (abstract 1776). 75. Shepherd F, Ramlau R, Mattson K, et al. Randomized study of Taxotere (TAX) versus best supportive care (BSC) in non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy. Proc Am Soc Clin Oncol 1999; 18:463a. (abstract 1784). 76. Ellis PA, Smith IE, Hardy JR, et al. Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 1995; 71:366-370. 77. Tummarello D, Graziano F, Isidori P, et al. Symptomatic, stage IV, non-small-cell lung cancer (NSCLC): response, toxicity, performance status change and symptom relief in patients treated with cisplatin, vinblastine and mitomycin-C. Cancer Chemother Pharmacol 1995; 35:249-253. 78. Thatcher N, Anderson H, Betticher DC, et al. Symptomatic benefit from gemcitabine and other chemotherapy in advanced non-small-cell lung cancer: changes in performance status and tumour-related symptoms. Anticancer Drugs 1995; 6(Suppl 6):39-48. 79. Smith I, O'Brien M, Norton A, et al. Duration of chemotherapy for advanced nonsmall-cell lung cancer (NSCLC): A phase III randomised trial of 3 versus 6 courses of mitomycin, vinblastine, cisplatin (MVP). Proc Am Soc Clin Oncol 1998; 17:457a (abstract 1759). 80. Buccheri GF, Ferrigno D, Curcio A, et al. Continuation of chemotherapy versus supportive care alone in patients with inoperable non-small-cell lung cancer and stable disease after two or three cycles of MACC. Results of a randomized prospective study. Cancer 1989; 63:428-432. 81. American Society of Clinical Oncology. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 1997; 15:2996-3018. 82. O'Connell JP, Kris MG, Gralla RJ, et al. Frequency and prognostic importance of clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 1986; 4:1604-1614.

David H. Johnson 83. Finkelstein DM, Ettinger DS, Ruckdeschel JC. Long-term survivors in metastatic nonsmall-cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986; 4:702-709. 84. Johnson DH, Paul DM, Hande KR, et al. Paclitaxel plus carboplatin in advanced nonsmall-cell lung cancer: a phase II trial. J Clin Oncol 1996; 14:2054-2060. 85. Johnson D, Zhu G, Schiller J, et al. E1594 - A randomized phase III trial in metastatic non-small-cell lung cancer - outcome of PS 2 patients (PTS): An Eastern Cooperative Group (ECOG) trial. Proc Am Soc Clin Oncol 1999; 17a (abstract 1779). 86. Douglas IS, White SR. Should non-small-cell carcinoma of the lung be treated with chemotherapy? Con: therapeutic empiricism--the case against chemotherapy in nonsmall-cell lung cancer. Am J Respir Crit Care Med 1995; 151:1288-1291. 87. Raby B, Pater J, Mackillop WJ. Does knowledge guide practice? Another look at the management of non- small-cell lung cancer. J Clin Oncol 1995; 13:1904-1911.

August, 1999

41