Combined modality treatment for Stage III non-small cell lung cancer

LUNG CANCER ~,,~,,~"'­

Lung Cancer 12 Suppl. 2 (1995) S41-S52

IASLC

Combined modality treatment for Stage III non-small cell lung cancer Philip Bonomi Section of Medical Oncology. Rush University Medical Center. Chicago. IL 60612. USA Received 7 December 1994; accepted 7 February 1995

Abstract There are increasingreports of studies in whichcombined modality treatment is being tested in stage III non-small cell lung cancer. Randomized trials in which sequential chemoradiotherapy has been compared to radiation alone and in which single agent cisplatin and simultaneous thoracic radiation were compared to radiation are reviewed and discussed. The largest and the most mature phase II trials of preoperative chemotherapy are also included in this review. Similarly the results from recently reported small randomized trials evaluating preoperative treatment are described. Potential future directions for clinical trials are suggested, including the incorporation of new agents in combined modality regimens.

Keywords: Non-small cell lung cancer (NSCLC); Combined modality treatment, Stage III NSCLC

1. Introduction Lung cancer is the leading cause of cancer deaths in men and in women in the United States. In 1994 it is estimated that 172 000 new cases of lung cancer will be identified [1] and 80% (138000) of these individuals will have non-small cell carcinomas (NSCLC). Although it is widely known that NSCLC patients frequently present with locally advanced disease, it is difficult to get an exact figure regarding the number of Stage III patients. However, a recent report from Germany has described the stage distribution of 3823 clinically staged non-small cell lung cancer patients. Stage III disease was identified in 44% of their cases, and they observed an equal number of Stage IlIa and Stage I1Ib patients (22% each) [2]. It seems reasonable to assume that a similar proportion of American patients have Stage I1Ia/I1Ib disease. Based on this assumption 60 000 cases of Stage III NSCLC can be expected to be identified in the United States in 1994. 0169-5002195/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDl 0169-5002(95)00463-B

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Recognizing that locally advanced NSCLC is a major health care problem in the United States and throughout the world, clinical investigators have been testing combined modality treatment in Stage III NSCLC during the last decade. This report will review the results of randomized trials and of selected Phase II trials in which combined modality treatment has been tested. 2. Local therapy In 1986, Mountain and his colleagues introduced a new international staging system which subdivided locally advanced disease into subgroups which have been designated lIla and IIIb [3]. Patients who are classified as Stage lIla have locally advanced disease which can be encompassed by a surgical resection. In contrast, Stage IIIb patients have localized disease which is beyond the limits of resection. Certain subsets of Stage lIla patients, such as those who have been classified as surgical pathological Stage T3NO- I have a 5-year survival rate of approximately 40% with surgery alone [4]. Unfortunately, this group of patients represents a small subset of Stage lIla patients. The majority of these patients have ipsilateral mediastinal lymph node metastases (N2), and surgical resection provides a relatively small chance of long-term survival [1]. Martini and Flehinger [5] were able to resect 18% of patients who had mediastinal lymph node metastases which were detected by routine chest X-ray. Within the subset of resected patients, the 5-year survival rate was 9% for an overall survival rate of less than 2% [5]. Similarly, Pearson was able to completely resect 51% of patients who were found to have ipsilateral mediastinal lymph node metastases by mediastinoscopy. The 5-year survival rate for this selected subset was 18%for an overallS-year survival rate of 9% in patients who had N2 disease which was not detected on chest X-ray, but was identified by mediastinoscopy [6]. Based on the relatively low long-terin survival results observed with surgical treatment, radiation therapy has become the primary treatment for the majority of Stage lIla non-small cell lung cancer patients. Although radiation provides palliation for many of these patients, the median survival using continuous radiation at doses of SO-60 Gy has been 9-12 months, and the best 2-year survival rates have been 18 and 25% [7,8]. More recent trials in which patients have been classified as Stage lIla versus IIIb according to the new staging system have shown similar median survivals of 9-10 months for both lIla and I1Ib [9,10]. In one of these trials, the 2-year survival rate was 20% for Stage lIla patients versus 12% for Stage I1Ib patients (P 0.004) [10] while in the other study, the 2-year survival rate for Stage IlIa and I1Ib was 17 and 18%, respectively (P 0.78) [9]. In the early 1980s, a variety of cisplatin containing combination regimens were being tested in Phase III trials which included patients with advanced non-small cell lung cancer. In the majority of these trials, regimens were tested in Stage IV patients. None of the regimens emerged as clearly superior with respect to the response rate or survival. In general, the response rate was approximately 25%, and the median survival was 6 months, and the l-year survival rate was approximately 20% [11-13].

=

=

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In the mid-1980s, several investigators reported higher response rates for cisplatin containing combination regimens in Stage III patients [14]. These investigators observed response rates of approximately 50% in Stage III patients who were treated with regimens which had produced a response rate of 25% in Stage IV patients. Although more recent studies have reported somewhat lower response rates for similar regimens in Stage III patients [15,16], it still appears that chemotherapy produces response rates in Stage III disease which are approximately twice as high as response rates observed in Stage IV disease [17]. 3. Non-surgical randomized trials testing sequential chemotherapy and radiation Encouraged by the higher response rates observed with combination chemotherapy regimens in Stage III patients, a number of investigators have designed studies in which two courses of combination chemotherapy followed by radiation were compared to radiation therapy alone [15,16,18-22]. The seven Phase III trials which have been reported since 1988 can be grouped as follows. Non-cisplatin regimens, CAP regimens [18,19] (cyclophosphamide, doxorubicin, cisplatin) [20,21], and cisplatin-vinca alkaloid regimens [15,16,22]. The trials which tested non-cisplatin regimens [18,19] and two trials testing CAP regimens showed no significant difference in median or long-term survival. In contrast, the regimens which included cisplatin and vinca alkaloid showed a modest but statistically significant improvement in survival (Table I) for patients who received combined modality treatment [15,16,22]. In one of these trials, there was a significant reduction in the rate of appearance of distant metastases suggesting that the survival advantage was related to the effect of systemic therapy on disseminated micrometastases [16]. The 2-year survival rate was higher for patients treated with chemotherapy and radiation in

Table I Randomized trials of thoracic radiation vs. sequential chemoradiation in non-small cell lung cancer: cisplatin-vinca regimens Investigator

Dillman et al. (15) Arriagada et al. [161 Sause et al. (22)

Regimen

RT VP-RT RT VCPC-RT RT VP-RT

N

77 78 177 176 452 b

Survival MST (months)

eX,)

2-year survival

9.7 13.8 10 12 11.4 13.8

13 26 14 21 19 32

P-value

0.006 0.08" 0.03

MST, median survival time In months; VP, vinblastine-cisplatin: VCPC. vindesine-cisplatincyclophosphamide-Lomustine. "Results have been updated and the P-value is 0.02. Le Chevalier T, Arriagada R. Quoix E et al. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung carcinoma. J Natl Cancer Inst 1992; 84: 58. b452 patients were entered on a three-arm study.

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each trial which tested cisplatin plus a vinca alkaloid. The absolute improvement in the 2-year survival rates were 7% [16], 12% [15], and 13%, [22]. However, the relative improvements in the 2-year survival rate were 50% [16], 70% [15] and 100% [22]. In two of these studies [15,22], eligibility was limited to patients who had not lost > 5% of their usual body weight and whose ECOG performance status was 0-1. Therefore, it is reasonable to say that sequential treatment with cisplatin and a vinca alkaloid followed by thoracic radiation therapy could be used as standard treatment for unresectable Stage III non-small cell lung cancer patients whose functional and nutritional status are good. At least, this regimen should be considered as a reference arm for future randomized studies testing combined modality treatment in locally advanced disease. Also, improving the 2-year survival rate would appear to be a realistic objective of future randomized trials. 4. Non-surgical randomized trials of radiation versus simultaneous cisplatin Cisplatin has been shown to enhance the effect of radiation therapy both in vitro and in animal models [23]. These observations have led several investigators to compare treatment with simultaneous cisplatin and thoracic radiation with radiation therapy alone [24-27]. Three of these studies were two-arm trials [24,26,27], but the fourth study included three arms which consisted of radiation therapy alone versus either daily cisplatin or weekly cisplatin given simultaneously with radiation therapy [25]. Trials in which cisplatin was given weekly or less often than weekly failed to show a difference in survival [24,25,27]. In contrast, the trials which tested daily cisplatin showed conflicting results (Table 2) [25,26]. In the first study, patients who received daily cisplatin and radiation survived significantly longer than patients who received radiation only [25]. In addition, these investigators observed significantly improved local control for the patients who received combined modality treatment suggesting that cisplatin's enhancement of radiation therapy was the primary reason for the improved survival. The rate of appearance of distant metastases was not affected by cisplatin. The other trial which tested daily cisplatin and simultaneous radiation therapy failed to show a survival difference [26]. The explanation for the inconsistent results

Table 2 Randomized trials of thoracic radiation vs, daily cisplatin and simultaneous radiation in non-small cell lung cancer Investigator

Schaake-Koning et al. [251 Trovo et al. [261

Regimen

RT C-RT RT C-RT

N

108 102 88 85

Survival MST (months)

NA NA 10.3 10

2-year survival

P-value

('Yo)

13

0.009

26 15 15

0.89

MST, median survival in months; RT, radiation therapy; C-RT, cisplatin-radiation therapy.

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observed with daily cisplatin and simultaneous thoracic radiation is not readily apparent. Both groups of investigators used the same daily dose of cisplatin, but the radiation therapy schedules were considerably different. In the 'positive trial', the total dose of radiation therapy was 54 Gy and a split course schedule [25] was used, while in the 'negative trial', radiation was given on continuous schedule and the total dose was 45 Gy [26]. These results were somewhat surprising because studies testing radiation therapy alone have shown less favorable results in patients who have received radiation therapy on a split course schedule. The reason for the inferior results observed with split course radiation alone is believed to be due to regrowth of the tumor cells during the rest periods. It is possible that chemotherapy inhibits tumor regrowth when it is given simultaneously with radiation. In addition, the rest period for patients treated with daily cisplatin and simultaneous split course radiation may have allowed more cells to express lethal injury resulting in recruitment of cells into the cell cycle when the second course of cisplatin and radiation was given. Theoretically this scenario could have produced a greater overall cell kill. The results with split course radiation and concurrent cisplatin are provocative, and they suggest that preclinical studies should explore different schedules of chemotherapy and radiation which should be tested in clinical trials. Reported randomized trials have focused on testing single agent cisplatin's radiation potentiation effect. At the present time there are no reports of randomized trials in which thoracic radiation and simultaneous treatment with a cisplatin containing combination chemotherapy regimen has been compared to radiation therapy alone. Clinical investigators have observed encouraging results in limited stage small cell lung cancer patients who were treated with cisplatin, VPI6, and simultaneous thoracic radiation therapy [28,29]. This method of treatment has resulted in median survival durations of 20 months and 2-year survival rates of approximately 40% [28,29]. Although this regimen has not been compared to older regimens using chemotherapy alone or different schedules of sequential chemotherapy and radiation, results with cisplatin, VPl6 and simultaneous thoracic radiation are certainly better than have been reported previously. In addition, the use of simultaneous cisplatin, VPl6 and thoracic radiation as preoperative treatment in Stage IlIa nonsmall cell lung cancer has shown 2-year survival rates of approximately 40% [30,31]. These observations suggest that simultaneous chemotherapy and radiation should be tested in a randomized trial in Stage III non-small cell lung cancer patients who are not operative candidates. The etoposide-cisplatin regimen would appear to be the leading choice to test the concept of simultaneous chemotherapy and radiation because toxicity has been acceptable when it was combined with radiation in Phase III SCLC trials [28,29] and when it was used in Phase II preoperative trials in NSCLC [30,31].

5. Phase II trials of preoperative treatment A variety of chemotherapy and chemoradiotherapy regimens have been tested as preoperative treatment in Stage III non-small cell lung cancer. It is difficult to compare these trials because the stages of the patients and the methods used to stage the

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Table 3 Preoperative MVP trials in NSCLC treatment results Investigator

Kris et al. [331 Burkes et al. [351

N

73 55

Resected

Hist CR

(%)

(%)

60

12

19

51

6

21.3

Survival MST (months)

2-year survival (%)

35 29"

MST, median survival time in months. "29% of the patients survived for 6 years.

patients in these trials have not been uniform. Recently, Shepherd has done an extensive review of the data reported from 15 Phase II trials which included 621 patients [32]. The most commonly studied approaches have consisted of 2-3 courses of chemotherapy alone or combined with radiation. Of the chemotherapy only regimens, mitomycin, vinblastine, and cisplatin have been the most extensively studied. Two of the largest trials with the longest follow up have been reported by Kris et al. [33] and by Burkes et al. [34]. The results of their studies are summarized in Tables 3 and 4. Both investigators observed identical rates of resectability (60%) and the histologic complete remission rates were amazingly similar, 10 and 12%. In addition, the median survival durations and the 2-year survival rates were virtually identical. In contrast, there were significant differences in toxicity. In their initial report, the Toronto group [34] described an overall treatment related mortality of 23% while the Sloan-Kettering investigators observed an overall treatment related mortality of 3% [33]. It appears that the major reason for the difference in lethal toxicity is related to patient selection. The Toronto group observed four preoperative deaths secondary to sepsis in patients who had pre-existing post-obstructive pneumonia. Subsequently, the Toronto group has treated an additional 20 patients and the overall rate of lethal toxicity has decreased to 15% [35], suggesting that with additional experience with this preoperative regimen, lethal toxicity appears to have decreased. Another commonly tested Phase II preoperative regimen has consisted of cisplatin and etoposide given simultaneously with thoracic radiation. In a multi-institution trial, which has been conducted by SWaG investigators, 127 patients were treated with two courses of cisplatin and VP16 given at the beginning and conclusion of a 45-Gy continuous course of radiation therapy [36]. In two consecutive Phase II trials

Table 4 Toxicity for preoperative MVP trials in NSCLC Investigator

N

Pre-operative (%)

Operative (%)

Late (%)

Total (%)

Kris et al. [331 Burkes et al. [351

73 55

1.4 8

2

NA 2

3 15

8

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P. Bonomi / Lung Cancer 12 Suppl. 2 (1995) S41-S52 Table 5 Preoperative VPI6-cisplatin radiation in NSCLC: treatment results Investigator

Albain et al. [36) Bonomi and Faber [30)

N

127 74"

Resected

Hist CR

(%)

(%)

Survival MST (months)

(%)

67 70

15 19

13/15 22

34/38 45

2-year survival

MST, median survival in months. "31% of patients were classified as T3NO.

which have been done at Rush Medical Center [30], split course, rather than continuous radiation has been given simultaneously with cisplatin-etoposide. In addition, continuous infusion of 5-fluorouracil has been included in the chemotherapy regimen. The resectability rate, histologic complete remission rate, and the 2-year survival rates were virtually the same (Tables 5,6). Preoperative, and operative mortality rates were also very similar. However, the SWOG investigators observed a relatively high rate of late lethal toxicity (8%) [36]. This was not observed in the Rush series [30].

6. Randomized trials of surgery versus preoperative chemotherapy followed by surgery Two groups of investigators [37,38] have conducted small Phase III trials in which surgery alone was compared to three courses of chemotherapy followed by surgery. In one of the trials the regimen consisted of mitomycin, ifosfamide, and cisplatin [37], and in the other it consisted of etoposide, cisplatin and cyclophosphamide [38]. Both groups of investigators observed acceptable toxicity with preoperative chemotherapy, and both observed significant improved survival in the combined modality treatment (Table 7). In both of these small randomized trials, the survival results for chemotherapy and surgery were considerably better than the survival reported for larger Phase II trials which tested preoperative treatment [30,33,35,36]. Also, large randomized non-surgical trials in which two courses of chemotherapy consisting of cisplatin plus a vinca alkaloid followed by radiation compared to radiation have revealed a modest survival improvement [15,16,22]. Therefore, it is likely that larger randomized trials will confirm a survival advantage from preoperative chemotherapy but it is also likely that larger trials will show that the magnitude of the survival

Table 6 Toxicity for preoperative VPl6-cisplatin and radiation in NSCLC Investigator

N

Pre-operative (%)

Operative (%)

Late (%)

Total (%)

Albain et al. [36) Bonomi and Faber [30)

127 74

2 3

8 6

8 0

16 7

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Table 7 Randomized trials of surgery vs. preoperative chemotherapy-surgery: treatment results Investigator

Rosell et al. [371 Roth et al. [38]

Regimen

Surgery MIC Surgery Surgery CEP Surgery

N

30 30 32 28

MST a

Treatment Resected

Mortality

(%j

(%j

90 85

6 6 6 3

66 61

% 3-year

P-value

survival

8 26 II

64

0 30 15 56

<0.001 0.008

MST, median survival time in months; MIC , mitomycin, ifosfamide, cisplatin; CEP, cyclophosphamide, etoposide, cisplatin.

benefit will not be as striking as the difference observed in the small randomized studies [37,38] . Brazilian investigators have also conducted a small Phase III trial testing preoperative treatment [39] . In this study, all patients received preoperative treatment consisting of either simultaneous cisplatin, 5-FU and radiation therapy, or mitomycin, vinblastine, and cisplatin. These investigators observed a significantly higher response rate, significantly higher rate of resection, and significantly higher freedom from progression, in the group which was treated with simultaneous chemotherapy and radiation. Although this is an example of another small randomized trial testing preoperative treatment, the results are thought provoking. They suggest that further study of preoperative simultaneous chemoradiation is warranted.

7. Conclusions At the present time the results of clinical trials support the following conclusions. First, treatment with two courses of a chemotherapy regimen which consists of cisplatin plus a vinca alkaloid given prior to thoracic radiation produces a modest survival advantage over radiation therapy alone [15,16,22]. Second, weekly simultaneous single agent cisplatin and thoracic radiation has not improved survival when compared to radiation alone [24,25,27]. In contrast, randomized trials in which radiation alone has been compared to radiation and simultaneous daily cisplatin have shown conflicting results [25,26]. Third, although some trials have shown relatively high rates of lethal toxicity, in general investigators have found that the use of preoperative chemotherapy or chemoradiotherapy is feasible [32]. Fourth, two small randomized trials have shown a significant survival advantage for patients treated with three courses of preoperative cisplatin containing chemotherapy compared to patients who had surgery only [37,38]. Lastly, in a small randomized trial preoperative concurrent chemoradiation therapy was superior to preoperative chemotherapy [39].

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8. Future directions With increasing evidence that survival is improved by treatment with cisplatin containing chemotherapy regimens plus local therapy, clinical investigators have the luxury of designing new treatment strategies which can build upon the recent positive results. However, at the same time they are faced with the dilemma of how to allocate Stage III patients for future clinical trials. Hopefully investigators can reach a consensus regarding the following questions. First, should the IIIa/IIIb staging system serve as the basis for assigning a patient to a surgical trial versus a non-surgical trial? Are there subcategories of N2 disease which will determine whether a patient should go into surgical or non-surgical trial? Lastly, should patients whose stage is T4NO-I-x be treated in a surgical or a non-surgical trial? With respect to treatment strategies, priority needs to be established regarding the concepts to be tested. For instance, should future non-surgical studies test sequential chemoradiation utilizing newer chemotherapy regimens or should concurrent chemotherapy and radiation be compared to sequential chemotherapy in a Phase III trial? The RTOG plans to test the latter concept in a randomized trial which will compare sequential chemoradiotherapy to simultaneous chernoradiotherapy, In patients who are potential surgical candidates, a variety of studies could be explored. First, treatment with chemoradiotherapy, plus or minus surgery would address the question of the value of surgery in patients with locally advanced disease. A recently activated intergroup study in which all patients will be treated with cisplatin and VPI6, and concurrent radiation, with a subsequent comparison of additional radiation versus surgery, will address the question of the value of surgery in this group of patients. Although sequential chemoradiotherapy has shown a survival advantage over radiation alone in recent randomized trials, many physicians still consider radiation therapy alone the standard treatment for locally advanced disease. Therefore, it would be reasonable to compare radiation therapy alone as the 'standard treatment' to combined modality treatment which includes pulmonary resection. This type of study is being done by Canadian investigators who are comparing radiation therapy to vinblastine-cisplatin followed by surgery. Based on the results from the two small randomized trials [37,38] in which surgery was compared to chemotherapy followed by surgery, it would be reasonable to conduct a larger randomized trial comparing surgery to chemotherapy followed by surgery to obtain additional data regarding the magnitude of the survival difference between surgery alone versus chemotherapy and surgery. In fact, French investigators are conducting a randomized study in which patients are randomized to surgery alone versus chemotherapy followed by surgery. At this point, approximately 200 patients have been accrued [40]. Within the last several years, Phase II trials have identified drugs which produce response rates ~ 15°A, in NSCLC [41]. The recently discovered agents include new classes of drugs, older agents used at a higher dose or on new schedules, and analogues of older drugs. In general, new analogues of older drugs and dose and schedule variations of older drugs have not produced significant advances in cancer treatment. It seems likely

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that testing agents with new mechanisms of action will be more fruitful. Two of the more promising classes of drugs are the taxanes and topoisomerase inhibitors. Taxol has produced response rates of 21% [42] and 24% [43]. Although these trials were small, it is interesting that the I-year survival rate was 40% in each study. CPTlI, a topoisomerase I inhibitor has also shown promising results in NSCLC (response rate = 32%) [44]. These agents should be evaluated in Phase II combined modality trials.

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