XV - Statistical Analysis and Trial Design

Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.

Title: General Thoracic Surgery, 6th Edition

Copyright 2005 Lippincott Williams & Wilkins

> Table of Contents > Volume II > Section XVI - Carcinoma of the Lung > Chapter 111 - Chemotherapy of Non Small-Cell Lung Cancer

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Chapter 111

Chemotherapy of Non Small-Cell Lung Cancer

Martin H. Cohen

Non small-cell lung cancer (NSCLC) chemotherapy has been the subject of several reviews, including those of Calvo and Belani (2001), Johnson and Sandler (2001), Kim and Murren (2002), and Ferreira (2002) and Sorenson (2001) and their associates. These reviews uniformly suggest that progress is being made, that active and novel chemotherapy drugs and active and novel drug combinations continue to be identified. They also show that patients benefit from treatment, as evidenced by symptom relief, tumor shrinkage, and increased disease-free and overall survival, and that the future can be viewed optimistically. My purpose is to present treatment results in a way that permits the reader to decide the merits of these conclusions. Because of the many manuscripts and abstracts that might be cited in a review of this type, all abstracts were excluded (insufficient information and short follow-up), as were all studies with a median follow-up of less than 1 year (imprecise survival estimates); whenever possible, nonrandomized trials were also excluded.

Advanced (metastatic) NSCLC provides the setting for the initial evaluation of new chemotherapy drugs and new chemotherapy regimens. Practical as well as ethical reasons justify this practice. Practically, the population of lung cancer patients at most centers forms a pyramid, with a relatively small percentage of favorable stage I patients at the apex of the pyramid and relatively large numbers of patients with a poorer prognosis and unresectable and metastatic disease at the pyramid base. Because of the poor prognosis and the symptomatic nature of advanced disease, treatment is readily justified. Furthermore, patients with advanced disease generally have measurable, or nonmeasurable but evaluable, disease, a requirement for chemotherapy efficacy studies.

From an ethical standpoint, it is appropriate to establish the safety and efficacy of a new treatment in a poor prognosis group before taking the regimen to a population with a better prognosis. Although neoadjuvant (protochemotherapy, induction chemotherapy, preoperative chemotherapy) treatment patients have measurable disease, they are not appropriate candidates for previously untested drug regimens because of their potential resectability and long-duration survival.

Must some minimal response rate be achieved in patients with advanced disease before a regimen is deemed sufficiently active to be used in patients with less advanced disease? This question has no definitive answer. On the basis of breast cancer results reported by Tormey (1982) and Tranum (1982) and their associates, however, it appears that regimens active in the adjuvant setting have achieved overall response rates of about 50%, with complete response rates of 10% to 15% in patients with advanced disease.

In 1997, the American Society of Clinical Oncology (ASCO) published clinical practice guidelines for the treatment of unresectable NSCLC. Chemotherapy, ideally with a platinum-based regimen, was recommended both for patients with unresectable locally advanced disease (stage III) and metastatic disease (stage IV) who were Eastern Cooperative Oncology Group/ Zubrod/World Health Organization performance status 0, 1, and possibly 2 (Table 111-1). The duration of chemotherapy should be no more than eight cycles. Chemotherapy should be initiated early, at a time when the patient has good performance status. Selected stage IV patients may be initially treated with an investigational agent. Such patients should be removed from study and treated with an active chemotherapy regimen if they do not have an objective tumor response after two cycles of treatment.

Table 111-1. Performance Status Scales

ECOG Performance Status Karnofsky Performance Status
0 Fully active, able to carry on all predisease performance without restriction. 100 Normal, with no complaints or evidence of disease.
90 Able to carry on normal activity but with minor signs of illness present.
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). 80 Normal activity but requiring effort. Signs and symptoms of disease more prominent.
70 Able to care for self, but unable to work or carry on other normal activities.
2 Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours. 60 Able to care for most needs, but requires occasional assistance.
50 Considerable assistance and frequent medical care required; some self-care possible.
3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 40 Disabled; requiring special care and assistance.
30 Severely disabled; hospitalization required but death not imminent.
4 Completely disabled, cannot carry on any self-care; totally confined to bed or chair. 20 Extremely ill; supportive treatment and/or hospitalization required.
10 Imminent death
5 Dead 0 Dead
ECOG, Eastern Cooperative Oncology Group.

The ASCO guidelines made two other important points. The first is that patients, especially stage IV patients, should actively participate in chemotherapy treatment decisions. Survival of such patients is often short, and most chemotherapy regimens produce at least moderate toxicity. Some patients, as described by Yellen and Cella (1995) and by Brundage and colleagues (2001), are risk adverse, whereas others will accept toxicity for a chance of increased survival. There is also an issue regarding appropriate end points for advanced-disease NSCLC clinical trials. Whereas survival is the gold-standard end point, the

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possible utility of evaluating quality-of-life and symptom-control end points should be further explored.

The results of chemotherapy in patients with advanced NSCLC are strongly influenced by patient prognostic factors. Using data obtained from placebo-treated patients enrolled in Veterans Administration Lung Study Group trials, Zelen (1973) demonstrated that performance status was a major prognostic factor for survival. Patients with good performance status in whom disease was confined within an acceptable thoracic radiation therapy portal (i.e., limited disease) had a median survival of 28 weeks versus 7 weeks for individuals with poor performance status. Corresponding survival times for patients with extensive disease were 26 and 1.4 weeks, respectively. Nearly every study since then has confirmed or extended this observation. Other important clinical prognostic factors for response and survival are listed in Table 111-2.

Table 111-2. Advanced Non Small Cell-Lung Cancer: Clinical Prognostic Factors

Parameter Good Prognosis Reference
Performance status Eastern Cooperative Oncology Group 0 1, Karnofsky 100 80 Stanley (1980)
Stage Lower stage Green et al (1971)
Gender Female Palomares et al (1996)
Weight loss None or slight Palomares et al (1996)
Bone, skin, brain metastases None Paesmans et al (1995)
Hemoglobin level Normal Takigawa et al (1996)
White blood cell count Normal Paesmans et al (1995)
Lactate dehydrogenase level Normal O'Connell et al (1986)
Albumin level Normal Fatzinger et al (1984)
Calcium level Normal Paesmans et al (1995)
Sodium level Normal Muers et al (1996)
Treatment response Yes O'Connell et al (1986)

An important question concerns whether NSCLC patients with poor prognostic factors should be offered standard chemotherapy regimens. This issue is most relevant to performance status (PS) 2 patients. Sweeney and colleagues (2001) demonstrated that PS 2 patients enrolled in a trial evaluating three cisplatin- and one carboplatin-containing chemotherapy doublets had large numbers of hematologic and nonhematologic adverse events and that their overall survival was poor. These outcomes were attributed to disease

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process, that is, the frequency of significant comorbidities noted in PS 2 patients when compared with patients with a performance status of 0 to 1. Other investigators, including Albain (1991) and Paesmans and their associates (1995), have drawn similar conclusions.

The evolution of NSCLC combination chemotherapy trials has proceeded through three generations. The first, the 1970s generation, evaluated non-cisplatin-containing regimens; the second, the 1980s to early 1990s generation, evaluated cisplatin or a cisplatin derivative with chemotherapy drugs available in that decade. The third (present) generation is evaluating newer chemotherapy agents, including paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine (Gemzar), semisynthetic camptothecin derivatives (irinotecan and topotecan), and the newer class of molecularly targeted drugs with or without cisplatin or a cisplatin derivative. In addition to different drug regimens, the three generations also differ in criteria for patient eligibility for clinical trials (Tables 111-3 and 111-4). Thus, the Eastern Cooperative Oncology Group trials, from 1978 to the present, included only ambulatory (PS 0 2) patients and excluded patients with brain metastases. The Southwest Oncology Group similarly adopted more stringent performance status eligibility criteria by 1980 and, in 1993, further limited study entry to PS 0 to 1 patients. It is uncertain whether the modest improvement in median survival seen in the more recent trials listed in Tables 111-3 and 111-4 is a result of better treatment or better patient selection.

Table 111-3. Non Small-Cell Lung Cancer Eastern Cooperative Oncology Group Advanced Disease Trials: Patient Eligibility

Eligibility Criteria Activation Year
1975 1976 1978 1979 1981 1984 Present
Performance status 0 3 0 3 0 2 0 2 0 2 0 2
Central nervous system metastases Yes Yes No No No No
Cisplatin regimensa 0/7 2/10 0/2 0/2 3/4 5/5
Median survival (weeks) 13 34 12 27 20 21 18 21 29 23 32
Reference Creech et al (1981) Ruckdeschel et al (1981a) Ruckdeschel et al (1981b) Ruckdeschel et al (1984) Ruckdeschel et al (1985) Bonomi et al (1989)
a Number of cisplatin-containing regimens/total number of regimens.

Table 111-4. Non Small-Cell Lung Cancer Southwest Oncology Group Advanced Disease Trials: Patient Eligibility

Eligibility Criteria Activation Year
1974 1979 1980 1983 1993
Performance status 0 4 0 4 0 3 0 3 0 1
Central nervous system metastases Yes Yes Yes Yes ?
Cisplatin regimensa 0/2 0/1 2/3 5/52/2
Median survival (weeks) 16 23 20 24 21 26 26 34
Reference Livingston et al (1977) Miller et al (1982) Miller et al (1986) Weick et al (1991) Wozniak et al (1998)
aNumber of cisplatin-containing regimens/total number of regimens.

Further evidence for a change in patient eligibility criteria for clinical trials over the past three decades is noted in the review of Breathnach and associates (2001) of 22 years of phase III NSCLC trials. The authors point out that 8 (89%) of the 9 randomized clinical trials initiated between 1984 and 1994 included only patients with performance status 0 to 2, compared with 12 (50%) of the 24 trials initiated between 1973 to 1983. Similarly, patients with brain metastases were included in 3 (33%) of the 9 trials initiated in the later time period, as compared with 14 (58%) of the 24 trials initiated earlier.

Stage migration is another factor that may improve current chemotherapy results. Over the past 25 years, new diagnostic technology has greatly increased our ability to detect otherwise occult disease. As described by Black and Welch (1993), the resulting upward stage migration improves survival of all disease stages and makes stage-specific historic comparisons invalid.

One way to gauge the efficacy of NSCLC chemotherapy is to analyze trials that randomized patients to chemotherapy or supportive care, the latter consisting of no systemic cytotoxic treatment or low-dose, presumably ineffective, chemotherapy. Fourteen trials of this design are listed in Table 111-5. Seven of these trials, reported by Ranson (2000), Rapp (1988), Cormier (1982), Cartei (1993), Thongprasert (1999),

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Roszkowski (2000), and Anelli (2001) and their associates, demonstrated that the median survival of chemotherapy-treated patients was significantly longer than that of the supportive care control group. Survival was improved for patients receiving cisplatin-based regimens and for patients receiving treatment that did not include cisplatin. In two other trials, described by Ganz and associates (1989) and Luedke and colleagues (1990), median survival results approached statistical significance in favor of the chemotherapy-treated group. In three of the five remaining studies, a trend was noted toward improved survival of chemotherapy-treated patients, the exceptions being the studies of Anderson (2000) and Lad (1981) and their associates. Despite these positive results, there are some caveats. In three of the listed trials, by Rapp (1988), Woods (1990), and Luedke (1990) and their colleagues, nearly identical vindesine cisplatin (120 mg/m2) treatment schedules were used in relatively prognostically comparable patients. Median survival of chemotherapy-treated patients in these studies varied from 24.7 to 32.6 weeks. This 8-week median survival difference is comparable to the difference generally seen between the chemotherapy and supportive care study arms. The one outlying study in Table 111-5 is the trial of Cormier and colleagues (1982). In that trial the 8.5-week median survival of the supportive care group is considerably shorter than the 16.5- to 25-week median survivals reported for other supportive care groups.

Table 111-5. Advanced Non Small-Cell Lung Cancer: Single-Agent or Combination Chemotherapy versus Supportive Care or Suboptimal Single-Agent Chemotherapy

Chemotherapy Regimen (P dose, mg/m2) No. of Patients Performance Status 0 1 (%) Limited Stage (%) % Response (CR/CR + PR) Median Survival (wk) p value Reference
G 150 30 59 24.7 NS Anderson et al (2000)
SC 150 27 61 25.6
Pa 79 1/16 29.5 0.037 Ranson et al (2000)
SC 78 20.8
C, A, P (40) 43 58 14 0/15 24.7 Rapp et al (1988)
Vn, P (120) 44 57 18 2/25 32.6 0.05
SC 50 60 10 17 0.01
Vl, P (120) 22 73 0 0/22 20.4 0.09 Ganz et al (1989)
SC 26 69 0 4/12a 16.6
Vn, P (120) 97 73 27 6/28 27 0.33 Woods et al (1990)
SC 91 73 41 17
C, E, P/M, VP, CC (80) 62 65 40 0/21 34.3 0.15 Cellerino et al (1991)
SC 61 62 43 21.1
Vn, M 143 58 43 1/23 20.4 Luedke et al (1990)
Vn, P (120) 150 56 39 2/16 24.7 0.06
Vn 141 57 43 0/1 14.8
C, A, M, P 37 73 59 3/44 27.4 0.26 Lad et al (1981)
CC 35 74 41 0/0 25
Mx, A, C, CC 20 70 45 0/35 30.5 0.0005 Cormier et al (1982)
SC 17 53 53 8.5
VP, P (70) 44 59 0/11 21.7 NS Kaasa et al (1991)
SC 43 60 16.5
C, M, P (75) 52 48 0 37 0.0001 Cartei et al (1993)
SC 50 50 0 17
I, E, P 96 0/40 25.6
M,Vl, P 93 0/42 35.1 0.0003 Thongprasert et al (1999)
SC 98 17.8
Doc 137 81 56 0/13.1 26 0.04 Roszkowski et al (2000)
SC 70 77 47 24.7
M/Vl/P or others 47 0 55 0.0018 Anelli et al (2001)
SC 43 0 23
A, Adriamycin (doxorubicin); C, cyclophosphamide; CC, lomustine; CR, complete response; DOC, docetaxel; E, epirubicin; G, gemcitabine; I, ifosfamide/mesna; M, mitomycin C; Mx, methotrexate; NS, not stated; P, cisplatin; Pa, Paclitaxel; PR, partial response; SC, supportive care; Vl, vinblastine; Vn, vindesine; VP, etoposide.
aAfter radiation therapy.

In analyzing survival differences between chemotherapy and supportive care patients in Table 111-5, it is also important to look at chemotherapy response rates. Only three trials had a response rate above 30% (two noncisplatin and one cisplatin-containing regimens). The median response rate for cisplatin-containing combinations was 22%. Because response rates were less than 50%, median survival

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was determined by the survival of nonresponding patients. This observation does not negate a possible benefit of chemotherapy; rather, it suggests that response rate may not be a sensitive measure of chemotherapy effectiveness.

Randomized trials of chemotherapy versus supportive care have been evaluated in four meta-analyses, those of Grilli (1993), Marino (1994), and Souquet (1995) and their associates and the Non Small Cell Lung Cancer Collaborative Group (1995). Each study demonstrated a significant, although modest, benefit of chemotherapy. Perhaps the best of these studies was that of the Non Small Cell Lung Cancer Collaborative Group. This meta-analysis, using updated data on individual patients, demonstrated that cisplatin-based chemotherapy combinations were associated with a hazard ratio of 0.73, equivalent to an absolute improvement in survival of 10% [confidence interval (CI) 5% to 15%] at 1 year or to an increased median survival of 1.5 months (CI 1.0 to 2.5 months).

A second test of chemotherapy efficacy in patients with advanced NSCLC comes from randomized trials of combination versus single-agent chemotherapy. Fourteen trials with this design are listed in Table 111-6. Seven of these trials demonstrated a statistically significant median survival advantage: the studies by Elliott (1984), Le Chevalier (1994), Einhorn (1986), Wozniak (1998), and Sandler (2000) and their colleagues favoring combination chemotherapy and the trials of Crawford (1996) and Bonomi (1989) and their associates favoring single-agent treatment. Navelbine and carboplatin were the active single agents used in the trials of Crawford (1996) and Bonomi (1989) and their colleagues. The combination regimens that significantly increased survival were gemcitabine cisplatin, vindesine cisplatin, and Navelbine cisplatin. None of the drug combinations using three or more drugs was associated with significant survival improvement. This is a potentially important observation because the optimal number of drugs

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to be used in a treatment regimen has not been rigorously defined. First-generation chemotherapy regimens often included four or five drugs [e.g., COMB (cyclophosphamide, vincristine, MeCCNU, bleomycin), CAMP (cyclophosphamide, Adriamycin, methotrexate, procarbazine), MACC (methotrexate, Adriamycin, cyclophosphamide, CCNU), and BACON (bleomycin, Adriamycin, cyclophosphamide, vincristine, nitrogen mustard)]. More recent investigators favor two-drug regimens. Advantages of the latter approach are that each drug can be used at doses closer to its optimal single dose and that toxicity is more predictable when chemotherapy is combined with radiation therapy.

Table 111-6. Advanced Non Small-Cell Lung Cancer: Combination Chemotherapy versus Single-Agent Chemotherapy

Chemotherapy Regimen (P dose, mg/m2) No. of Patients Performance Status 0 1 (%) Limited Stage (%) % Response (CR/CR + PR) Median Survival (wk) p value Reference
Vn, P (100) 43 80 69 0/33 47.7 0.008 Elliott et al (1984)
Vn 45 79 69 0/7 17.4
Nvb, P (120) 206 80 39 /30 40.0 0.04 Le Chevalier et al (1994)
Vn, P 200 82 35 /19 32.0 0.01
Nvb 206 77 41 /14 31.0
5FU, L 68 72 0 0/3 22.0 0.03 Crawford et al (1996)
Nvb 143 79 0 0/12 30.0
Vn, P (120) 41 44 17 0/27 26.0 Einhorn et al (1986)
Vn, P, M (60) 41 46 5 0/20 17.0 0.03
Vn 42 45 10 0/14 18.0
Vn, P (80) 77 47 48 0/29 45.0 NS Kawahara et al (1991)
P (80) 78 43 46 0/12 39.0
VP, P (120) 103 79 49 5/26 34.7 0.87 Rosso et al (1990)
VP 113 86 45 1/7 26.0
VP, P (120) 81 52 33 0/26 22.0 0.33 Klastersky et al (1989)
P 81 62 35 0/19 26.0
M, Vl, P (40) 176 76 0 1/20 22.7 Bonomi et al (1989)
Vl, P (60) 175 76 0 1/13 25.1
M, Vl, P/C, A, Mx, Pr 172 77 0 2/13 25.0 0.008
I 88 79 0 1/6 26.0
CP 88 82 0 0/9 31.7
M, Vl, P, Mx (40) 52 21 0/25 27.0 > 0.5 Niell et al (1989)
M 53 19 0/19 23.6
C 41 29 0 0/5 20.8 Davis et al (1980)
C, CC 47 19 0 0/8 17.1 >0.3
C, CC, A 36 25 0 0/6 19.3
P (100) 262 88 30 1/11 33.0 0.004 Sandler et al (2000)
G, P (100) 260 80 33 1/29 40.0
P (100) 209 100 92 0/12 26.0 0.0018 Wozniak et al (1998)
Nvb, P (100) 206 100 92 2/24 35.0
P (100) 207 82 70 1/17 35.0 0.86 Gatzemeier et al (2000)
Pac, P (80) 207 82 70 2/25 37.0
G 72 83 24 0/18 29.0 NS ten Bokkel Huinink et al (1999)
VP, P (100) 75 91 25 0/15 33.0
A, Adriamycin (doxorubicin); C, cyclophosphamide; CC, lomustine; CP, carboplatin; CR, complete response; 5FU, 5-fluorouracil; G, gemcitabine; I, iproplatin; L, leucovorin; M, mitomycin C; Mx, methotrexate; NS, not stated; Nvb, Navelbine; P, cisplatin; Pac, Paclitaxel; Pr, procarbazine; PR, partial response; Vl, vinblastine; Vn, vindesine; VP, etoposide.

The design of several of the studies listed in Table 111-6 called for patients who received single-agent chemotherapy to receive additional therapy (combination regimens or new single agents) at disease stabilization or progression. Similarities of survival between patients receiving initial combination or single-agent chemotherapy might then be a result of second-line therapy in the latter group. Generally, however, fewer than one-half of the single-agent-treated patients actually received second-line therapy. Responses to second-line therapy were infrequent, and no survival differences were noted between individuals receiving and not receiving that therapy. Consequently, single-agent survival results likely reflect the efficacy of that drug.

In the vindesine or vinblastine cisplatin studies listed in Table 111-6, as opposed to those in Table 111-5, there was variability in the cisplatin dose (60 to 120 mg/m2). Median survival rates varied from 25.1 to 47.7 weeks. Because of differences in patient prognostic factors from study to study and because of differences in data analysis, including exclusion of early treatment failures in the study of Elliott and colleagues (1984), these reports cannot be used to determine a cisplatin dose effect on median survival.

The focus of the previous discussion on chemotherapy efficacy was median survival. Also important is whether chemotherapy produces any long-term survivors. This information is hard to discern. Many trials are reported too early to have accurate long-term survival information, and results typically are not updated. One study specifically addressing the issue of prolonged survival after chemotherapy was by Finkelstein and colleagues (1986). They reviewed 893 cases of metastatic disease treated according to Eastern Cooperative Oncology Group protocols. Overall, 168 (19%) of 893 patients survived for more than 1 year, and 36 (4%) survived for more than 2 years. As expected, the majority of long-term survivors were patients with favorable pretreatment prognostic factors who responded to therapy. Small percentages of unfavorable patients, however (i.e., those with performance status of 2, greater than 10% weight loss, large primary tumors, multiple metastatic sites, and no response to chemotherapy), were included in the long-surviving group.

If, as indicated in Tables 111-5 and 111-6, survival gains with combination chemotherapy are modest at best, should patients with advanced NSCLC be offered treatment? This question is irrelevant at research centers where patients are offered research protocols seeking better therapy. In nonprotocol settings, the question is probably also irrelevant because the main rationale for chemotherapy is symptom palliation. Patients with advanced NSCLC are generally symptomatic. Table 111-7 indicates that 30% or fewer of such patients are ECOG performance status 0 (Karnofsky 100 or 90, i.e., normal activity and asymptomatic) at presentation. Common symptoms, based on data from Ruckdeschel and associates (1986), are listed in Table 111-8. Chemotherapy treatment often results in palliation of symptoms. Table 111-9 summarizes five studies that demonstrate this effect by Hardy (1989), Gridelli (1997), Thatcher (1995), Ellis (1995), and Tummarello (1995) and their colleagues. As evident from these studies, symptomatic improvement may occur in the absence of chemotherapy response. This finding was reported in regard to breast cancer treatment by Brunner (1975), Coates (1987), and Tannock (1988) and their colleagues. It might be expected that symptomatic improvement would lead to improved quality of life. Quality-of-life data for NSCLC patients are sparse to date and, when available, are difficult to interpret due to missing data, multiplicity of comparisons, and other statistical issues. Improved quality-of-life instruments and analysis

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methodology, as indicated by Hollen and associates (1997), might considerably improve future data quality.

Table 111-7. Patients with Advanced Non Small-Cell Lung Cancer Who Are Performance Status 0 at Presentation

No. of Patients Percentage Performance Status 0 Reference
486 19 Ruckdeschel et al (1986)
432 21 Ruckdeschel et al (1984)
203 9 Fukuoka et al (1991)
699 19 Bonomi et al (1989)
216 18 Rosso et al (1990)
160 3 Kawahara et al (1991)
105 13 Elliott et al (1984)
125 13 Sandler et al (2000)
120 12 Frasci et al (2000)
1,207 30 Schiller et al (2002)

Table 111-8. Presenting Symptoms in Patients with Advanced Non Small-Cell Lung Cancer

Symptom Percentage of Patients
Pain
   Chest 33
   Bone 30
   Shoulder/arm 17
Respiratory
   Cough 46
   Dyspnea 39
   Hemoptysis 17
Other
   Anorexia 36
   Hoarseness 10

Table 111-9. Advanced Non Small-Cell Lung Cancer: Symptom Palliation with Chemotherapy

No. of Patients Impact on Cancer Response (%) Median Survival (wk) Symptom Benefit (%) Reference
Cough Dyspnea Pain
24 21 24 71 65 63 Hardy et al (1989)
43 23 36 43 28 42 Gridelli et al (1997)
332 20 35 40 44 26 32 Thatcher et al (1995)
120 32 21 66 59 60 Ellis et al (1995)
46 33 26 40 67 44 Tummarello et al (1995)

In deciding whether to recommend chemotherapy for a patient with advanced disease, risk benefit considerations should be used. Generally, only ambulatory patients should be considered for treatment because risk more often exceeds benefit in nonambulatory individuals. As summarized by Simes (1985), risks of treatment include treatment toxicities up to and including death, cost, the inconvenience of receiving chemotherapy, and the possibility of increased hospitalization. Benefits include symptom palliation, increased survival, the psychological benefits of knowing everything was done, and the altruistic benefit of possibly helping future patients.

Elderly patients constitute a special population when decisions regarding the suitability of chemotherapy are made. In clinical practice elderly patients, as summarized by Yellen (1994) and Hutchins (1999) and their colleagues as well as by Frasci (2002), are often not offered chemotherapy or receive less aggressive chemotherapy than do younger patients. Retrospective data to support this practice are contradictory: The FONICAP data, summarized by Rinaldi and colleagues (1994), provide support for less aggressive therapy for patients older than 70, and the Eastern Cooperative Oncology Group data, summarized by Langer and associates (2000), indicate that patients 70 years or older had outcomes comparable, except for leukopenia and neuropsychiatric toxicity, to younger patients.

Several trials targeting an elderly patient population have now been completed. The ELVIS trial published by the Elderly Lung Cancer Vinorelbine Italian Study Group (1999) randomized 191 patients with stage IIIB/IV disease who were 70 years or older to best supportive care plus vinorelbine 30 mg/m2 on days 1 and 8 of a 21-day schedule (76 patients) or to best supportive care alone (78 patients). Seventy-six percent of patients in each group were performance status 0 to 1, and approximately 70% of patients in each group had metastatic disease. In the first report of this trial by the Elderly Lung Cancer Vinorelbine Italian Study Group (1999), only 154 of the 191 randomized patients were analyzed, presumably because of insufficient follow-up (30 patients) or lack of data (7 patients). The objective response rate of vinorelbine-treated patients was 19.7%. Median survival was longer (28 vs. 21 weeks) and the percentage of 1-year survivors was greater (32% vs. 14%) for vinorelbine-treated patients (log rank P value = 0.03).

Two years later a second report of this trial was published by Gridelli (2001). Again, only 154 of the 191 randomized patients were reported. Surely the 30 patients with insufficient follow-up could now be analyzed. The failure to update survival raises a serious question concerning the applicability of the study results.

Two other phase III randomized trials of chemotherapy in elderly patients have been completed. The first, reported by Frasci and associates (2000), compared vinorelbine to gemcitabine plus vinorelbine, and the second, reported by Gridelli and colleagues (2001), compared gemcitabine to gemcitabine plus vinorelbine. The former study demonstrated a significant survival advantage favoring the combination (median survival 7 months vs. 4.5 months and 1-year survival rate 30% vs. 13%), whereas the latter study failed to show a survival advantage for the gemcitabine plus vinorelbine combination (median survival 7.6 months vs. 6.6 months and 1-year survival rate 31% vs. 26%).

Based on these data, it appears that elderly patients who meet protocol eligibility criteria tolerate and benefit from chemotherapy treatment. A goal of future studies is to best identify that patient group. Whereas performance status is obviously an important discriminator, comorbidity indices, as summarized by Extermann and colleagues (1998) and by Extermann (2000) are likely to also be good discriminators. It is also necessary to more fully explore social status. Individuals who lack transportation to a medical facility or individuals who live alone and have faulty memory are not likely to receive chemotherapy.

If chemotherapy is to be offered to all NSCLC patients, how long should treatment continue? In responding patients, chemotherapy is generally continued for the duration of response unless toxicity is severe. In patients with stable disease, duration of treatment is less clear. A randomized trial by Buccheri and associates (1989) addressed this issue. After two or three cycles of treatment with methotrexate, Adriamycin, cyclophosphamide, and lomustine (MACC), 74 patients with stable disease were randomized to either continue or discontinue therapy. Time to progression and median survival were similar for both groups. Although a slight improvement in physical symptoms was noted in the

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continued treatment group, this was partially or wholly negated by increased chemotherapy toxicity.

Smith and associates (2001), using a cisplatin-based chemotherapy regimen, randomized patients at the start of treatment to receive either three or six courses of mitomycin C, vinblastine, and cisplatin treatment every 21 days. This trial enrolled 308 patients with stage IIIB or IV NSCLC. Median survival was 6 versus 7 months, respectively, and 1-year survival was 22% versus 25% (P = 0.2). Median duration of symptom relief was 4.5 months (both arms), and 8% versus 18% had continuing symptom relief at 1 year (P = 0.4). Quality-of-life parameters were assessed at the completion of each treatment cycle. As anticipated, no differences emerged between the two groups for the first three courses of chemotherapy. Subsequently, patients randomized to continue on chemotherapy had increased fatigue (P = 0.03) and a trend toward increased nausea and vomiting (P = 0.06). There was a nonsignificant trend toward increased global health, physical functioning, and emotional well-being in those randomized to three courses.

A third trial, reported by Socinski and colleagues (2002), compared four cycles of carboplatin (AUC 6) and paclitaxel 200 mg/m2 every 21 days (arm A) to the same treatment regimen continued until disease progression (arm B). For second-line therapy, patients were to receive paclitaxel at 80 mg/m2 per week. Eligibility included stage III/IV NSCLC and a Karnofsky performance status of 70 or higher. Two hundred thirty patients were randomized. The groups were comparable for age, performance status, sex, stage, histology, and race. The objective response rate in arm A was 22%, versus 24% for arm B. Median survival was 8.6 versus 8.5 months, 1-year survival was 28% versus 34%, and 2-year survival was 15% versus 11%, respectively. None of these differences was statistically significant. Only 45% of study patients, 48 from arm A and 55 from arm B, received second-line therapy. The majority of patients (62 of 103) received protocol-specified weekly paclitaxel. The most common reason for an alternative regimen was residual grade 2 or 3 peripheral neuropathy.

Another approach to the evaluation of optimal duration of chemotherapy was taken by Larsen and collegues (1995). They retrospectively evaluated eight phase II NSCLC chemotherapy trials to determine, according to WHO criteria, the time from therapy onset to objective response. The median time was 54 days. By day 84 of treatment, 35 (81%) of the 43 responding patients had achieved their response. Because of cumulative treatment toxicity and the inconvenience of clinic visits, the authors suggested that 84 days was a reasonable chemotherapy cut-off date in nonresponding patients.

Based on these data, there seems to be insufficient evidence to determine the optimal number of cycles of chemotherapy to be offered to a patient. Stopping therapy prior to progression may be attractive because it would allow for retreatment with the same regimen at the time of symptomatic or objective progression. Treatment duration may become a moot point, however, since new oral drugs, administered daily for prolonged periods of time, are now being tested. Furthermore, future NSCLC chemotherapy may be divided into remission induction, remission consolidation, and remission maintenance phases, with different drugs employed in each phase.

Two other chemotherapy concepts have been tested in patients with advanced NSCLC. The first involves the use of alternating, noncross-resistant drug combinations. The purpose of this therapy, based on the Goldie and Coldman (1979) mathematical model, is to delay or prevent the emergence of drug-resistant clones of cancer cells. Table 111-10 summarizes the alternating combination chemotherapy arms from four randomized trials comparing that therapy to either supportive care or a single-drug combination. In no case did the alternating noncross-resistant drug combination produce statistically significant survival improvement.

Table 111-10. Alternating Combination Chemotherapy

Chemotherapy Regimen No. of Patients Performance Status 0 1 (%) Limited Stage (%) % Response (CR/CR + PR) Median Survival (wk) Reference
C, E, P/M, VP, CC 62 65 40 0/21 34.3 Cellerino et al (1991)
M, Vl, P/C, A, Mx, Pr 172 77 0 2/13 25.0 Bonomi et al (1989)
P, Vl/M, Vl 125 56a 38b 4/17 21.6 Weick et al (1991)
F, O, M/C, A, P 114 55a 39b 1/10 21.6 Weick et al (1991)
A, Adriamycin (doxorubicin); C, cyclophosphamide; CC, lomustine; CR, complete response; E, epirubicin; F, 5-fluorouracil; M, mitomycin C; Mx, methotrexate; O, vincristine; P, cisplatin; Pr, procarbazine; PR, partial response; Vl, vinblastine; VP, etoposide.
aThe percentage of patients with performance status 0 1 may be higher because patients with that performance status but with weight loss >10% were excluded.
bThe percentage of limited-disease patients may be lower because only patients with bone, brain, or lung metastases were excluded.

A second strategy to improve chemotherapy results involves the use of high-dose-intensity (mg/m2 per week) regimens. As documented by Frei and Canellos (1980), many chemotherapy drugs, especially alkylating agents, have a steep dose response relation. An early study demonstrating the importance of dose was done by Gralla and associates (1981). These investigators randomly selected patients to receive vindesine plus high-dose (120 mg/m2) or low-dose (60 mg/m2) cisplatin therapy. Median duration of response and median survival of responding patients were both significantly

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longer with high-dose cisplatin treatment (Table 111-11). The results of this trial provided impetus for two studies of high-dose chemotherapy with autologous bone marrow support by Williams (1989) and Gomm (1991) and their colleagues. Both studies yielded disappointing results, with response rates and survival durations similar to those seen with conventional chemotherapy. Because of the availability of bone marrow colony-stimulating factors, which, as demonstrated by Lieschke and Burgess (1992), decrease the duration of chemotherapy-induced myelotoxicity, additional trials testing the dose-intensity hypothesis are likely.

Table 111-11. Vindesine-Platinum Treatment of Advanced Non Small-Cell Lung Cancer: Effect of Cisplatin Dose Intensity

Cisplatin Dose (mg/m2) Percentage Response Rate Median Response Duration (mo) Responders' Median Survival (mo)
60 46 5.5 10.0
120 40 12.0 21.7

Many of the chemotherapy regimens currently used for the treatment of NSCLC include a platinum drug, cisplatin or carboplatin. Because of the toxicity associated with cisplatin treatment, many investigators substitute carboplatin for cisplatin. The obvious issue is whether the two drugs have equivalent activity. Current knowledge suggests equivalent activity in NSCLC. A study reported by Klastersky and associates (1990) compared cisplatin (120 mg/m2, day 1) and carboplatin (325 mg/m2, day 1) in combination with etoposide (VP16; 100 mg/m2, days 1, 2, and 3) in 228 advanced NSCLC patients. Although there was a trend in objective response rate favoring cisplatin (27% vs. 16%; P = 0.07), there was no significant difference in survival. A second trial, summarized by Jelic and colleagues (2001), compared cisplatin (120 mg/m2) and carboplatin (500 mg/m2) in combination with vindesine and mitomycin C in 221 stage IIIB/IV NSCLC patients. Although there was no significant difference in response rates (37% vs. 36%, respectively), there was a statistically significant advantage in time to progression and overall survival for patients receiving the carboplatin regimen.

With the recognition that carboplatin plasma clearance is linearly related to glomerular filtration rate, the mg/m2 carboplatin dosing has been replaced by dosing based on the free carboplatin plasma concentration versus time curve (AUC). Carboplatin dose, based on the formula of Calvert and colleagues (1989), equals the desired AUC multiplied by the glomerular filtration rate plus 25. Glomerular filtration rate is commonly calculated by the Cockroft and Gault (1976) formula, which is [140 - age (yr)][weight (kg)]/[72 serum creatinine (mg/dL)]. For women, the glomerular filtration rate is 0.85 of this product.

Is there a best chemotherapy regimen that must be used for the first-line treatment of stage IIIB/IV NSCLC patients? The U.S. Food and Drug Administration (FDA) has currently approved four cisplatin-containing chemotherapy doublets (cisplatin plus paclitaxel, docetaxel, gemcitabine, or vinorelbine) as well as single-agent vinorelbine for this patient group. Studies designed to determine the optimal treatment regimen have been performed by the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Italian Lung Cancer Project. The Eastern Cooperative Oncology Group study, summarized by Schiller and associates (2002), randomly assigned a total of 1,207 stage IIIB or IV patients to one of four treatment regimens: cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. The last regimen, although not approved by the FDA, is commonly used in the United States. The overall response rate for all treatments was 19% and the median survival was 7.9 months. The 1-year survival rate was 33%, and the 2-year survival rate was 11%. None of the four regimens offered a significant advantage over the others.

The Southwest Oncology Group study, reported by Kelly (2001) and Ramsey (2002) and their colleagues, compared vinorelbine plus cisplatin versus paclitaxel plus carboplatin. Response rates were 28% versus 25%, median survival was 8 months in both arms, and 1-year survival was 36% versus 38%.

The Italian Lung Cancer Project study, reported by Scagliotti and associates (2002), randomized 612 patients to receive either gemcitabine plus cisplatin, paclitaxel plus carboplatin, or vinorelbine plus cisplatin. Approximately 80% of patients in each arm had metastatic disease, and 92% to 95% of patients were performance status 0 to 1. Response rates were 30%, 32%, and 30%, respectively. Median survival was 9.8 months, 9.5 months, and 9.5 months, respectively. Multivariate analysis indicated that a performance status of 2 and the presence of two or more metastatic sites were negative prognostic factors for survival. When adjusted for these factors, there was no effect of treatment on survival.

On the basis of these results, it can be concluded that a standard regimen for the treatment of advanced or metastatic NSCLC has not yet been defined. As indicated previously, survival might not be the most sensitive indicator of clinical benefit in this patient group. Long-duration symptom improvement and improvement in performance status might be better indicators of benefit.

Docetaxel has been approved by the U.S. Food and Drug Administration for second-line treatment of advanced or metastatic NSCLC. The basis for approval was a single trial, reported by Shepherd (2000) and Leighl (2002) and their colleagues, comparing docetaxel chemotherapy to best supportive care. In that trial patients who had failed prior platinum-based therapy were randomized to docetaxel 75 mg/m2 (55 patients), docetaxel 100 mg/m2 (49 patients), or to best supportive care (100 patients). Approximately two-thirds of the study patients were male, 20% were stage III, and 75% were performance status 0 to 1. The partial response

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rate (intent to treat population) was approximately 6% for both docetaxel regimens. Median survival for docetaxel 75 mg/m2 treatment was 7.5 months; for docetaxel 100 mg/m2 treatment, 5.9 months; and for best supportive care, 4.6 months; P = 0.047 for docetaxel-treated patients compared with best supportive care (study-specified primary analysis) and P = 0.01 for docetaxel 75 mg/m2 treated patients compared with best supportive care. One year survival was 37%, 19%, and 19% for the three treatment groups, P = 0.003 for docetaxel 75 mg/m2 compared with best supportive care.

There is no approved third-line NSCLC therapy. Several of the newer molecularly targeted chemotherapy drugs, including ZD1839 (Iressa) are seeking approval for this indication.

Studies to define the effect of chemotherapy dose on treatment outcome have been performed for paclitaxel and for platinum drugs. Paclitaxel in combination with carboplatin has been evaluated by Kosmidis and colleagues (2000), and paclitaxel in combination with cisplatin has been evaluated by Bonomi and collaborators (2000). Paclitaxel was administered as a 3-hour infusion in the Kosmidis study and as a 24-hour infusion in the Bonomi study. Cycles were repeated every 3 weeks. In the carboplatin trial, patients were randomized to paclitaxel 175 mg/m2 or 225 mg/m2 along with carboplatin (AUC 6); whereas in the cisplatin trial, randomization was between paclitaxel 135 mg/m2 and 225 mg/m2 along with cisplatin 75 mg/m2. A third arm in the latter trial included cisplatin plus etoposide treatment.

Chemotherapy-naive NSCLC patients, stage III or IV, and those with measurable or evaluable disease were recruited to both trials. Patients with PS 0 to 2 were eligible for the carboplatin study, whereas the cisplatin study was restricted to PS 0 to 1 patients.

The Kosmidis trial accrued 198 patients, 99 randomizing to each arm. The two groups were comparable for relevant prognostic factors, and each group received a median of five cycles of chemotherapy. Response rates for the low and high paclitaxel treatment were 25.6% and 31.8%, respectively (P = 0.73). Median survival time was 9.5 months and 11.4 months (P = 0.16). One-year survival was 37% and 44%, respectively (P = 0.35). Toxicity, especially neurotoxicity, was more frequent with high-dose paclitaxel: 19% versus 9% for grade 2 toxicity, and 4% versus 1% for grade 3/4 toxicity.

The Bonomi trial accrued 201 patients to the high-dose paclitaxel arm, 198 to the low-dose arm, and 200 to the etoposide plus cisplatin arm. Patient characteristics, including age, sex, performance status, weight loss, and measurable disease, were comparable for all three treatment groups. Disease stage was comparable for the two paclitaxel groups, but there were fewer stage IIIB patients (15% versus 23% in the etoposide plus cisplatin arm). Kaplan-Meier survival estimates for all paclitaxel-treated patients were significantly longer (median 9.9 months vs. 7.6 months, and 1-year survival 38.9% vs. 31.8%; p = 0.048) than survival for etoposide-treated patients. There was no significant difference in median or 1-year survival for the 250 mg/m2 or 135 mg/m2 dose levels of paclitaxel (high dose, 10.0 months and 40.3%; low dose, 9.5 months and 37.4%).

A third trial reported by Glorieux and collaborators (2001) administered paclitaxel 200 mg/m2 or 175 mg/m2 as a 3-hour infusion together with carboplatin (AUC 6) to two consecutive cohorts of stage IIIB/IV NSCLC patients. One hundred and thirty consecutive eligible patients were studied, 99 in the high-dose and 30 in the low-dose cohort. Response rates were 23.2% and 25.8%, respectively. Median survival was 254 and 222 days, respectively. Toxicity was relatively comparable for the two treatment groups. In conclusion, none of the cited studies suggest a dose response relation for paclitaxel in paclitaxel plus platinum treatment.

A trial reported by Gralla and colleagues (1981) suggested that cisplatin dose intensity might be important in obtaining optimal treatment results. In that trial, 85 patients were randomized to receive either high-dose (120 mg/m2) or low-dose (60 mg/m2) cisplatin in combination with vindesine (see Table 111-11). The response rates were 46% (low-dose cisplatin) and 40% (high-dose cisplatin). Median duration of response favored the high-dose cisplatin arm (12.0 months vs. 5.5 months). Median survival (21.7 months vs. 10.0 months) was reported for responding patients only. The small number of study patients, the nearly identical response rates, and the exceptionally long median response duration and median survival of responders receiving high-dose cisplatin make it difficult to conclude that cisplatin 120 mg/m2 was superior to platinum 60 mg/m2.

A subsequent study by Klastersky and collaborators (1986) randomized patients to receive cisplatin 60 mg/m2 or 120 mg/m2 on day 1 in combination with etoposide 120 mg/m2 on days 3, 5, and 7 every 3 to 4 weeks. Study patients (125 receiving cisplatin 60 mg/m2, and 116 receiving cisplatin 120 mg/m2) had stage III/IV disease, PS 0 to 2, and measurable or evaluable lesions. Fewer than 10% of patients on each arm had received prior chemotherapy. Response rates were 25% and 29%, respectively. Median survival was 33 weeks and 28 weeks, respectively. Thus, there was no improvement in response or survival with high-dose as compared with lower-dose cisplatin treatment.

A more recent trial, reported by Gandara and associates (1993), randomized patients to a standard cisplatin dose (50 mg/m2 on days 1 and 8 every 28 days), high-dose cisplatin (100 mg/m2 on days 1 and 8 every 28 days), or high-dose cisplatin plus mitomycin C (8 mg/m2 on day 1). All patients had metastatic disease, were chemotherapy naive, and had a PS of 0 to 2. The intent to treat population included 323 patients: 105 standard-dose cisplatin, 108 high-dose cisplatin, and 110 high-dose cisplatin plus mitomycin C. Response rates were 12%, 14%, and 27%, respectively. Median survival was 6.9, 5.3, and 7.2 months, respectively. The delivered

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dose intensity of cisplatin was 94%, 82%, and 78% of the projected cisplatin dose intensity for the three treatment arms. Thus, there was no statistically significant impact of cisplatin dose intensity on response or survival.

The effect of carboplatin AUC on response and survival was retrospectively analyzed by Sculier and colleagues (1999) using data obtained from a randomized trial comparing a combination of carboplatin (200 mg/m2 on day 1) and cisplatin (30 mg/m2 on days 2 and 3) with or without ifosfamide (1.5 g/m2 on days 1, 2, and 3). Five hundred and five patients were studied. Two different methods the Calvert and Cockcroft formulas or the Chatelut equation were used to convert carboplatin mg/m2 doses to carboplatin AUC. Using the Calvert/Cockcroft method, patients were divided as follows: AUC less than or equal to 3, 137 patients; AUC 3 to 4, 260 patients; and AUC greater than 4, 99 patients. Response rates were 24%, 24%, and 23%, respectively. Survival results were comparable for all carboplatin AUC groups (specific numbers not provided). Grade 3/4 thrombocytopenia was highly related to carboplatin AUC dose, with a 20% incidence at carboplatin AUC greater than 4 compared with a 6% incidence at carboplatin AUC less than or equal to 3. Therefore, over the carboplatin AUC dose range studied, carboplatin AUC was not significantly associated with treatment efficacy.

NEW CHEMOTHERAPY APPROACHES

Increased understanding of the genetic abnormalities accompanying the malignant phenotype has led to the development of a new generation of anticancer agents targeting tumor angiogenesis, tumor proliferation, and apoptosis. Interested readers are referred to summaries by Bonomi (2001), Shepherd (2001), and Ferreira and associates (2002).

The best-known and most successful drug in this class is imatinib mesylate (Gleevec). As summarized by Couzin (2002), Gleevec produces hematologic remissions in nearly 100% of newly diagnosed patients with chronic myelogenous leukemia (CML). CML is a unique cancer, however, since a single genetic abnormality, the chromosome 9 21 translocation resulting in the formation of the Philadelphia chromosome, is sufficient to produce the disease. NSCLC is a more complex disease, requiring the presence of multiple mutations for phenotype expression.

One of the first molecularly targeted drugs to complete NSCLC phase II/III clinical trials was ZD1839 (Iressa), a putative inhibitor of the epidermal growth factor receptor. Phase II data, as summarized by Wilkinson (2002) and by Twombley (2002), revealed an approximate 10% response rate among 139 NSCLC patients who had failed two or more prior chemotherapy treatments (third line). In addition to the limited third-line data, results were also available from two large, well-designed, and well-conducted first-line randomized trials that enrolled about 2,000 patients. In each of these randomized studies, Iressa or placebo was administered with a platinum-containing chemotherapy doublet. Treatment results were unequivocal, with Iressa failing to significantly improve response rate, time to progression, or survival.

These results will obviously influence future trials of both Iressa as well as other molecularly targeted agents. Perhaps these drugs will work best as single agents or perhaps they should be used to maintain remissions rather than to induce them.

SUMMARY

In conclusion, I offer my view of the state of the art of NSCLC chemotherapy. It appears that our current drug regimens are sufficiently active to palliate symptoms during the limited lifespan of most patients with newly diagnosed, advanced or metastatic disease and good performance status. Survival benefit from chemotherapy is modest in this group of patients.

Acknowledging the many thousands of patients who have participated in the various trials, it can be stated that all the treatment approaches evaluated to date are feasible. Efficacy is harder to define: Patient populations differ, follow-up is often too short to determine survival accurately, and other efficacy parameters, such as symptom relief or quality of life, are infrequently or inadequately analyzed. Because several new chemotherapy drugs have been identified as active in NSCLC and because novel molecularly targeted drugs are entering into clinical trial, it is likely that several more years will be required to sort out the most active drug therapy. Properly designed, randomized trials are required to determine efficacy, in broadest terms, and to define subsets of patients that might benefit from specific approaches. This strategy does not preclude simultaneous phase II testing of new drugs and new drug combinations in patients with disseminated disease and a good prognosis.

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General Thoracic Surgery. Two Volume Set. 6th Edition
General Thoracic Surgery (General Thoracic Surgery (Shields)) [2 VOLUME SET]
ISBN: 0781779820
EAN: 2147483647
Year: 2004
Pages: 203

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