NSCLCchemotherapy

Introduction

Initial studies with alkylating agents in advanced NSCLC showed decreased survival with chemotherapy, and until recently no agents were available with objective response rates in excess of 20%. UK clinicians' attitudes to chemotherapy for NSCLC have remained negative, despite now wide acceptance of such treatment for small cell lung carcinoma. Recent developments indicate pessimism is misplaced.

Metastatic disease

Tumour response and survival

It is now established that cisplatin-based therapy significantly improves survival and quality of life. In the UK, the most studied regimen is MIC (mitomycin C, ifosfamide, and cisplatin)) which, when compared with best supportive care, has been shown to improve median survival (by ~2 months), 1-year survival (from 18% to 28%), and quality of life.

New drugs have emerged with enhanced activity in NSCLC as single agents and in combination with carboplatin or cisplatin. The majority of combination regimens have yet to be tested in randomized Phase III studies, though paclitaxel/cisplatin proved superior to standard therapy in terms of tolerability and improvement in quality of life in an EORTC trial, and had a significantly superior 2-year survival (14.1% v. 11.3%) in an Eastern Co-operative Oncology Group study.

In a Phase III study by the South Western Oncology Group, response rate and 1-year survival were improved when vinorelbine was added

Table 16.3 New agents for NSCLC

Drug

Patient

1-year

Median survival

Response

no.

survival (%)

(Weeks)

rate (%)

Vinorelbine

621

20

32.5

24

Gemcitabine

572

21

40.6

39

Paclitaxel

317

26

37.3

41

Docetaxel

300

26

41

52

Topotecan

119

13

38

35

RR = response rate; MS = median survival

+ From Bunn, P.A Jr and Kelly, K. (1998) New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 5, 1087-100.

RR = response rate; MS = median survival

+ From Bunn, P.A Jr and Kelly, K. (1998) New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 5, 1087-100.

Table 16.4 New platinum-based combination therapies for NSCLCt

Drug combination

Patient

RR

MS

1-year

nos.

(Weeks)

(%)

survival (%)

Paclitaxel + C

333

46

38

40

Vinorelbine + P

328

41

38

35-40

Paclitaxel + P

286

42

42

36

Docetaxel + P

255

35

35

58

Gemcitabine + P

245

47

57

61

Topotecan + P

22

22

32

26

P = cisplatin; C = carboplatin; RR = response rate; MS = median survival t From Bunn, P.A. Jr and Kelly, K. (1998) New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 5, 1087-100.

P = cisplatin; C = carboplatin; RR = response rate; MS = median survival t From Bunn, P.A. Jr and Kelly, K. (1998) New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 5, 1087-100.

to cisplatin. A large, ongoing American study is making direct comparison in advanced NSCLC of platinum complexes in combination with taxol, gemcitabine, or vinorelbine.

Quality of life

Although established cytotoxic regimens provide objective tumour response rates of the order of 20-30% in advanced NSCLC, symptomatic improvement can be achieved in a greater proportion of patients:

♦ Cough, haemoptysis, and pain are relieved in 70%

Despite this, use of chemotherapy in this setting is limited in UK, and it has been questioned whether the cost of non-surgical treatment for NSCLC (both financial and in terms of treatment-related toxicity) can be justified. However, a Canadian health economic analysis suggests that the cost of gaining a year of life for these patients is between $500 and $7000—small compared with $30 000 basic cost of diagnosis and supportive and terminal care.

Stage III disease

♦ 33% of NSCLC present in Stage III

♦ Trials difficult to interpret

♦ Combination chemotherapy and radiotherapy gives better survival than radiotherapy alone in unresectable disease—3-year survival, 13-23% v. 6%

♦ Poor performance status patients do badly with chemotherapy

Cisplatin, and some of the new drugs like gemcitabine and the taxanes, are potent radiosensitizers and there is interest in concomitant delivery of chemotherapy and radiotherapy to take advantage of potential synergy. As in SCLC there is evidence that concurrent radiotherapy may be more effective than sequential, but toxicity remains a problem and an optimum chemotherapy regimen and fractionation schedule for radiotherapy is yet to be determined.

Where Stage III disease is technically resectable (Stage IIIA disease, where only ipsilateral mediastinal nodes are involved) surgery cures less than 10% of patients, because of a combination of unresected loco-regional disease and occult systemic disease. Chemotherapy improves survival over surgery alone, but timing of this remains to be defined. Several small studies have suggested a survival advantage for pre-operative or neo-adjuvant chemotherapy (with or without radiotherapy) in Stage III disease. Five-year survival rates up to 40% have been reported, but this has been achieved in small, selected groups of patients. Two recent randomized studies have shown significantly improved relapse-free and overall survival for patients given cisplatin-based treatment before and after surgery.

Overall, the data are not dissimilar from that seen with chemotherapy followed by radiotherapy in unresectable disease, and it is not clear if surgery has a role in this situation. On the other hand, only 5-15% of patients undergoing neo-adjuvant therapy have a pathological complete response at surgery, demonstrating the importance of further local treatment if cure is the aim. Large Phase III trials of chemo-radiotherapy pre-surgery (Intergroup) and of chemotherapy followed by radiotherapy or surgery (EORTC) are in progress to help clarify this issue. Other groups are testing efficacy of newer drug combinations in this setting.

Adjuvant therapy

Meta-analysis of adjuvant chemotherapy trials in NSCLC has shown a 5% improvement in 5-year survival for patients treated with a cisplatin-based regimen after surgical resection. This benefit held for patients across Stages IB-IIIA. Such treatment has not however been widely adopted in the UK.

While neo-adjuvant strategies offer potential downstaging of disease, increasing the likelihood of a complete resection and theoretical reduction in risk of tumour dissemination at surgery, no studies have yet shown pre-operative chemotherapy to be superior to postoperative adjuvant therapy.

Conclusion

Chemotherapy for inoperable NSCLC offers benefits similar to those obtained with chemotherapy in SCLC in terms of survival. Results of adjuvant treatment also suggest that a survival benefit comparable to that observed in breast and colorectal cancer can be achieved. Grounds for the current nihilistic view of NSCLC chemotherapy are diminishing, but patients still need to be entered into clinical trials wherever possible in order better to refine current approaches.

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