Combined chemotherapy and radiation in locally advanced nonsmall-cell lung cancer

Combined chemotherapy and radiation in locally advanced nonsmall-cell lung cancer

Reviews Combined chemotherapy and radiation in locally advanced nonsmall-cell lung cancer Jacek Jassem The efficacy of radiotherapy in locally advanc...

677KB Sizes 2 Downloads 347 Views

Reviews Combined chemotherapy and radiation in locally advanced nonsmall-cell lung cancer Jacek Jassem

The efficacy of radiotherapy in locally advanced nonsmall-cell lung cancer is limited. One attempt to improve survival uses a combination of radiation and chemotherapy. These two modalities can be applied in sequence or concurrently, but results from phase III trials of combined therapy versus radiation alone have been inconsistent. Early studies were mostly negative, but more recent trials using platinumbased regimens have shown some survival benefit for combined treatments. The positive impact of chemotherapy has also been shown in a metaanalysis. In recent studies, concurrent chemotherapy and radiation appears better than sequential application. However, the benefit of the combined approach is modest and should be balanced against increased early and late toxicity. The role of new agents such as taxanes, vinorelbine, gemcitabine, and topoisomerase inhibitors in combined modality therapy of non-small-cell lung cancer warrants further clinical investigation. Lancet Oncol 2001; 2: 335–42

Lung cancer is the most common cause of cancer death in the world and its frequency has steadily increased during the past few decades.1 Non-small-cell lung cancer (NSCLC; Figure 1) accounts for more than 75% of all cases of lung cancer and the vast majority of patients present with locally advanced or metastatic disease, ie stage III and IV.2 Thoracic irradiation is the mainstay of treatment for inoperable stage III disease as it provides consistent palliation, however, its curative potential is extremely poor with 5-year survival rates of 3–10%.3–6 Furthermore, at least two randomised studies have shown that in locally advanced, unresectable NSCLC, radiotherapy does not provide a significant survival benefit over placebo or placebo-like chemotherapy.5, 8 Several refinements of radiation techniques have been tested with the aim of improving response rates. Alternative approaches include the use of multileaf beam collimators, altered fractionation schedules, or sophisticated 3-dimensional computerised planning systems, which allow an increase in radiation dose. Although some progress has been made, in most cases radiotherapy cannot eradicate bulky tumours in the thorax. Moreover, it does not prevent uncontrolled systemic disease, which is the major cause of death in locally advanced NSCLC. This review focuses on an avenue of THE LANCET Oncology Vol 2 June 2001

Figure 1. A 77-year-old female smoker with newly-diagnosed non-smallcall lung cancer. A 2 cm nodule is shown in the right middle lobe on plain film. Reproduced with kind permission from Chest 2000: 117; 1232–38 (www.chestjournal.org).

clinical investigation in NSCLC that has produced promising results in clinical studies – the combination of chemotherapy and radiation (Figure 2). Until recently, the role of chemotherapy in locally advanced unresectable NSCLC was a subject for debate. Indeed, the results of a number of randomised studies comparing radiation alone with radiation supplemented by chemotherapy, were negative or inconclusive.9–17 The hesitant attitude towards the use of chemotherapy in locally advanced NSCLC was challanged by a meta-analysis of 22 randomised clinical studies that showed the beneficial effect of chemotherapy added to radiation.18 The overall hazard ratio was 0.90 in favour of chemotherapy, equating with a 10% reduction in risk of death per year. The hazard ratio for trials using cisplatin-based chemotherapy was 0.87. The absolute survival benefit, however, was relatively small (4% after 2 years and 2% at 5 years) raising the question of whether it was large enough to offset the toxic effects of therapy. Moreover, although meta-analysis is a powerful statistical tool, it has many limitations.19 Firstly, the heterogeneity of populations included in the individual studies makes it difficult to identify which patients will JJ is in the Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland. Correspondence: Dr Jacek Jassem, MD, PhD, Department of Oncology and Radiotherapy, Medical University of Gdansk, 7 Debinki St, 80-211 Gdansk, Poland. Tel: +48 58 3492270. Fax: +48 58 3492270. Email: [email protected]

335

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Review

Chemotherapy and radiation in NSCLC

Therapeutic strategies The addition of chemotherapy to radiation may increase cure rate not only by improving tumour control in the thorax, but also by eliminating or delaying the emergence of metastatic disease. The two most frequently tested strategies are first-line chemotherapy followed by radiation, and concurrent application of both methods (Figure 1). Giving chemotherapy first means that drugs can be delivered in standard doses. The aim of this approach is to reduce micrometastatic disease, but it may also reduce the volume of the primary tumour making subsequent irradiation more effective, or even making the tumour resectable. Disadvantages are prolonged total treatment time, postponed irradiation, and a possibility of accelerated repopulation of tumour cells. Chemotherapy applied concomitantly with radiation avoids these drawbacks and it may improve locoregional control by making tumour cells more vulnerable to radiotherapy (radiosensitisation). However, this strategy causes greater toxic effects and usually necessitates a reduction in the dose of chemotherapy.

Sequential strategies Primary CT Primary and adjuvant CT Concomitant strategies Daily CT

Intermittent CT

Combined strategies Primary and concomitant CT

Chemotherapy

Radiotherapy

Figure 2. Approaches to combined chemotherapy and radiation in locally advanced NSCLC.

benefit most from new therapies. Secondly, as the analysis is retrospective, techniques used in the studies, eg chemotherapy regimens and radiotherapy schedules, may have since improved. Meta-analysis may also be flawed due to undetected methodological errors in some trials. There is also a possible publication bias that may overemphasise the effect of chemotherapy, as studies with positive results are more likely to be published.20 Finally, meta-analysis does not provide information about the choice of regimen, associated toxic effects, or quality-of-life issues. Therefore, the most reliable means of evaluating new therapies is large randomised trials. This review focuses on recent phase III trials comparing radiation alone with radiation combined with chemotherapy in patients with locally advanced unresectable NSCLC.

Sequential chemotherapy and radiotherapy Sequential administration of chemotherapy and radiation has been investigated in a number of phase III trials, but their results are inconsistent (Table 1). In most cases, chemotherapy was given before irradiation. Most of the studies performed in the 1980s did not show an advantage for combined modality treatment.9–11, 16, 17 However, some were criticised for using inadequate chemotherapy regimens, suboptimal doses, or too liberal entry criteria (eg patients with more extensive stage III disease or substantial weight loss). In contrast, three large phase III randomised studies (two carried out in the USA and one in France) gave consistently positive results in favour of combined therapy. A study performed by the Cancer and Leukemia Group B (CALGB) included 155 patients with favourable pretreatment characteristics (WHO performance status 0 or 1, and weight loss of less than 5%).21,22 Patients were randomly

Table 1. Phase III studies of sequential chemotherapy and radiation versus radiation alone in NSCLC No. of eligible patients 238 114 353 155 458

302 446

Therapy

Median survival (months)

2-year survival (%)

Difference

RT

10

17

CT-RT-CT*

11

19

NS

RT CT-RT-CT†

10 10

16 21

NS

RT CT-RT-CT‡

10 12

14 21

< 0.05

RT CT§-RT

10 14

13 26

0.012

RT HFX RT㛳 CT§-RT RT CT¶-RT RT CT**-RT

11 12 13 11 11 12 10

22 24 29 17 21 20 16

Reference 10 11 27, 28 21, 22 24, 25

NS 0.04 30 NS 29 NS

*cyclophosphamide, doxorubicin, cisplatin;†methotrexate, doxorubicin, cyclophosphamide, CCNU; ‡cisplatin, vinblastin, CCNU, cyclophosphamide; §cisplatin, vinblastin; 㛳HFX RT, hyperfractionated radiotherapy; ¶cisplatin, etoposide; **mitomycin, ifosfamide, cisplatin; NS, not significant

336

THE LANCET Oncology Vol 2 June 2001

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Chemotherapy and radiation in NSCLC

assigned radiotherapy alone (60 Gy over 6 weeks) or the same course of radiotherapy preceded by two cycles of a combination of cisplatin and vinblastine with fewer toxic effects than other treatments. Vomiting and neutropenic infections were more frequent in patients who received chemotherapy, but this did not affect the administration of radiotherapy. Patient accrual for this study was closed prematurely after an interim analysis showed that the combined treatment was significantly better than radiotherapy alone. The first report of this study showed that 23% of patients recieving combined modality treatment were still alive after 3 years, compared with 11% of those receiving radiotherapy alone.21 The survival benefit of induction chemotherapy was confirmed later on in an update including a 7-year follow-up.22 Median survival in the experimental and control groups was 13.7 months and 9.6 months, respectively. More importantly, there were three-times more combined-modality-treated patients alive at 5 years compared with those receiving radiotherapy alone (17% and 6%, respectively). Recently, a mathematical simulation of the continuation of this trial was presented.23 Despite the conservative assumption of no treatment difference among additional hypothetical patients, the results were significant. The confirmatory US intergroup study included 458 evaluable patients who were randomly assigned to recieve the same two treatments used in the CALGB study, as well as a third group who received hyperfractionated radiotherapy (two daily fractions of 1.2 Gy for a total dose of 69.6 Gy).24,25 Overall survival rates for patients who had received chemotherapy was better than those who received conventional irradiation alone, and the survival rate of hyperfractionated-radiotherapy-treated patients was inbetween these two results. Median survival for conventional radiotherapy, hyperfractionated radiotherapy, and combined chemotherapy and radiotherapy, was 11.4 months, 12.0 months and 13.2 months, respectively.25 Patients receiving primary chemotherapy had significantly fewer distant metastases (other than in the brain).26 Most importantly, however, despite preselection of patients for favourable prognostic factors, 5-year survival was modest in all study arms: 5% for standard radiotherapy, 6% for hyperfractionated radiotherapy, and 8% for chemotherapy followed by radiotherapy. In the French study, 353 patients were randomly assigned irradiation alone (65 Gy in 26 fractions) or radiotherapy preceded by three cycles of vindesine, lomustine, cyclophosphamide, and cisplatin.27,28 Patients whose disease did not progress after primary chemotherapy were given three additional cycles of the same regimen after completion of radiotherapy. Again, the combined-modality approach was associated with survival benefit (3-year survival of 12% and 4% in patients who did and did not receive chemotherapy, respectively). This effect was because of a smaller rate of distant-failure in the combined modality arm (1-year failure rate of 22%, compared with 46% in the control arm), whereas the local tumour control in both arms was relatively poor and virtually the same. Contrary to these positive results two recent studies did THE LANCET Oncology Vol 2 June 2001

Review not show a clear survival benefit from the use of induction chemotherapy. In a British study, 446 patients with locally advanced disease were randomly assigned radiotherapy (40 Gy in 15 fractions) with or without four cycles of mitomycin, ifosfamide and cisplatin first.29 Although median survival was 2 months longer in the chemotherapy-treated group, the difference was insignificant. The other negative study, performed in Sweden, included 302 patients with non-resectable squamous-cell carcinoma.30 Patients were randomly allocated either radiotherapy alone (56 Gy, 2 Gy/day, with a 2-week rest after 38 Gy) or radiotherapy preceded by three courses of cisplatin and etoposide treatment. Chemotherapy produced a trend towards improved survival, but again the difference was insignificant. Finally, two studies evaluated the impact of chest irradiation after primary chemotherapy. In a Japanese study, 63 unresectable NSCLC patients without progression after two cycles of cisplatin-based chemotherapy, were randomly assigned either chest irradiation (5–60 Gy in 5–6 weeks) or no radiotherapy at all.31 Of the patients who did not recieve radiotherapy, those who responded to the previous chemotherapy were allowed to continue on the same regimen, whereas those who did not respond, received different treatments. Patients being given radiotherapy did not receive further chemotherapy. Although median survival was similar in both groups, the proportion of long-term survivors was larger amongst irradiated patients (29% versus 3% at 3 years). This difference was related to the increased local relapse rate in the group receiving chemotherapy alone. It was therefore concluded that chemotherapy has an inadequate effect on bulky intrathoracic disease. In a similar study of the European Lung Cancer Working Party (ELCWP), 115 NSCLC patients who responded to primary chemotherapy were randomly assigned further chemotherapy or chest irradiation (60 Gy given over 6 weeks).32 Despite better local control in the group given radiotherapy, there was no significant difference in survival. The discrepancy between these two studies might have been related to their design: the Japanese study involved patients with stable disease or response after primary chemotherapy, whereas the ELCWP study only included chemotherapy responders. Therefore, patients with stable disease after chemotherapy may derive considerable benefit from chest irradiation, whereas radiotherapy is less effective in responders.

Concomitant chemotherapy and radiotherapy Simultaneous application of chemotherapy and radiation is beneficial in some epithelial cancers including head and neck cancer, anal cancer33 and, most recently, cervical cancer.34,35 Concomitant chemoradiation studies in NSCLC used single-agent platinum compounds or platinum-based multidrug regimens. The radiosensitising properties of cisplatin and carboplatin have been confirmed in preclinical and clinical studies.36,37 Feasibility studies showed that cisplatin is effective as a radiosensitiser when administered at 6–8 mg/m2 daily doses or 30 mg/m2 weekly doses.38,39 Of the several phase III studies using concomitant 337

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Review

Chemotherapy and radiation in NSCLC

Table 2. Phase III studies of concomitant chemoradiation versus radiation alone in NSCLC No. of eligible patients 308

Therapy

Median survival (months)

RT RT+CT* (daily)

169

204

250 215 111 169

131

2-year survival (%)

Difference

12

13

14

26

0.009

Reference 40

RT+CT* (weekly)

12

19

NS

RT RT+CT* (daily)

10 10

13 13

NS

RT HFX RT†

14 14

26 28

NS§

RT+CBDCA‡

17

29

HFX RT†+CBDCA‡

15

20

RT§ RT+CBDCA‡§

13 13

26 29

NS

RT RT+CT* (every 3 weeks)¶

10 11

13 18

NS

RT RT+CT㛳 HFX RT† HFX RT†+CT¶

12 10 8 18

17 19 25 35

HFX RT†+CT** HFX RT† HFX RT†+CT††

13 14 22

27 26 43

41

44

52 42 12 0.003 45 0.003 NS 47 0.021

*cisplatin; †HFX RT, hyperfractionated radiotherapy; ‡carboplatin; §factorial analysis: CBDCA versus no CBDCA; 㛳patients in both arms received induction chemotherapy as well consisting of vinblastine and cisplatin, 㛳methotrexate, doxorubicin, cyclophosphamide, CCNU; ¶carboplatin + etoposide (low-dose, weekly); **carboplatin + etoposide (higher dose, biweekly); †† carboplatin + etoposide (daily); NS, not significant

platinum compounds and radiotherapy,13, 40–44 only one showed improved local control and prolonged survival (Table 2).40 In this study, performed by the European Organization for Research and Treatment of Cancer (EORTC), a total of 331 patients were randomly assigned to one of the three regimens: irradiation alone (30 Gy in 10 fractions, followed by a 3-week rest period and then 25 Gy in 10 fractions), radiotherapy (the same regimen) preceded by daily cisplatin (6 mg/m2), or radiotherapy combined with weekly cisplatin (30 mg/m2). Cisplatin treatment did not increase the incidence of oesophagitis, however, nausea and vomiting were a substantial problem in most combined-modality-treated patients. Survival was significantly improved in the daily-cisplatin group (2-year survival of 26% and 13%, with and without cisplatin, respectively). Patients receiving weekly-cisplatin had a survival rate in between the other groups’, but it was not significantly different to either. Survival benefit in the daily-cisplatin arm was due to improved local control of the disease (p = 0.003). However, it was suggested that the addition of chemotherapy might have only compensated for the suboptimal radiotherapy schedule which was used (55 Gy with a 3-week rest period after 30 Gy). Indeed, 3-year survival for patients recieving radiotherapy alone was only 2%. There were also shortcomings in the other studies using cisplatin alone. For example, one study used a suboptimal radiotherapy schedule (45 Gy in 15 fractions),41 and another used low cisplatin doses (70 mg/m2 every 3 weeks).42 The efficacy of this strategy thus remains undetermined. Concurrent application of multidrug platinum-based chemotherapy and radiation was investigated in two phase III studies in Yugoslavia. In the first study 169 patients 338

were randomly assigned to one of three treatment schedules: hyperfractionated radiotherapy (64.8 Gy; two daily fractions of 1.2 Gy), radiotherapy combined with weekly chemotherapy (carboplatin 100 mg on days 1 and 2, and etoposide 100 mg on days 1 to 3), or radiotherapy combined with chemotherapy given every second week (carboplatin 200 mg on days 1 and 2, and etoposide 100 mg on days 1 to 5).45 The combination of hyperfractionated radiation and chemotherapy, particularly in the twoweekly regimen, produced a high frequency of acute and late toxic-effects.46 The 3-year survival was highest in the group given weekly chemotherapy (23%); the difference between this and the radiotherapy-alone group (7%) approached statistical significance. A second study by the same authors included 111 patients recieving an increased dose of hyperfractionated radiotherapy (69.6 Gy; two daily fractions of 1.2 Gy) with or without concomitant daily chemotherapy (carboplatin and etoposide; 50 mg each administered intravenously).47 Chemotherapy did not significantly increase the rate of acute and late high-grade toxic effects. Both overall survival and local control were substantially better with concomitant chemoradiation, but there was no difference in distant metastasis-free survival between the groups. These two studies indicate that, in the case of concurrent chemoradiation, low-dose, continuous chemotherapy may be better than higher doses applied intermittently.

Sequential versus concomitant chemotherapy and radiotherapy Two recent randomised trials have directly compared concomitant and sequential administration of chemoTHE LANCET Oncology Vol 2 June 2001

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Review

therapy and radiation. In a Japanese study, 320 patients were given two cycles of primary chemotherapy consisting of mitomycin C, vindesine and cisplatin (MVC), followed by chest irradiation (56 Gy in 28 fractions), or the same chemotherapy given concomitantly with radiotherapy (28 Gy in 14 fractions followed by a 10-day rest period and then 28 Gy in 14 fractions)48. Concomitant chemotherapy and radiotherapy produced a significant (p = 0.04) survival advantage compared with the sequential approach (Figure 3). Median survival for concomitant and sequential treatment was 16.5 versus 13.3 months, respectively, and 5year disease-free survival rates were 27% and 19%, respectively. Concomitant treatment was associated with greater myelosuppression, however, the frequency of oesophagitis (the most severe non-haematological toxiceffect of combined-modality treatment) did not differ between the groups. The low rate of oesophagitis accompanying concomitant chemoradiotherapy may be related to the split-course irradiation used in this group. Analysis of the failure pattern showed that prolonged survival with concomitant chemotherapy and radiation was related to enhanced intrathoracic tumour control (at 3 years 34% versus 21% with the sequential approach).49 The three-group study conducted by the Radiation Therapy Oncology Group (RTOG) involved 611 patients with NSCLC randomly assigned to recieve two cycles of primary chemotherapy (cisplatin and vinblastine) followed by radiation (60 Gy in 6 weeks), the same chemotherapy applied concomitantly with standard radiation, or variant chemotherapy (cisplatin and oral etoposide) applied concomitantly with hyperfractionated radiation (69.6 Gy, two daily fractions of 1.2 Gy).50 As in the Japanese study, initial results of this trial showed that the concomitant strategy using daily radiotherapy provides significant (p = 0.04) survival benefit, but the difference was not significant. This result was achieved at the expense of a dramatic increase in grade 3–4, acute, nonhaematological toxic effects (48% versus none with sequential therapy).

Other combined modality strategies In another attempt to show the benefit of preradiation chemotherapy, CALGB carried out a feasibility study of two hybrid strategies. The first strategy involved administration of maintenance chemotherapy after irradiation, and the second involved weekly carboplatin with irradiation (in both instances patients were managed with primary chemotherapy). Maintenance chemotherapy was given to improve local control and reduce the risk of distant relapse, and concurrent carboplatin was expected to increase local

Survival rate (%)

Chemotherapy and radiation in NSCLC

100 90 80 70 60 50 40 30 20 10 0

p = 0.03998

Concurrent Sequential

0

1

2

3

4

5

6

7

Years Figure 3. Overall survival in patients with NSCLC according to treatment group. (Courtesy of K Furuse, et al.)

control by radiosensitisation of tumour cells. Concomitant carboplatin caused fewer toxic effects and more likely to be completed than adminitration of adjuvant chemotherapy.51 Consequently, a phase III intergroup study was initiated in which 283 patients, all of whom had recieved primary chemotherapy with two cycles of vinblastine and cisplatin (a regimen used in the previous CALGB studies), were randomly assigned to recieve radiation therapy (60 Gy over 6 weeks) with or without concurrent carboplatin (100 mg/m2 weekly).52 Although patients receiving carboplatin suffered more severe neutropenia, thrombocytopenia, and anaemia, the study confirmed the feasibility of the approach. The addition of carboplatin decreased the failure rate in the thorax, but distant relapses occurred less frequently in the control group. As a result, the use of carboplatin did not have a significant impact on overall disease control and survival.

The role of new agents Recently, several new agents including taxanes, vinorelbine, gemcitabine, and topoisomerase inhibitors, have shown promise for the treatment of NSCLC. Some of these drugs also enhance radiation activity in vitro and consequently they might produce better results than ‘traditional’ agents. For example, taxanes (paclitaxel and docetaxel) enhance the cytotoxic effect of radiotherapy by arresting cells in the G2/M phase, the most radiosensitive phase of the cell cycle.53,54 Phase II trials using these compounds concomitantly with radiation assessed feasibility and established that this approach has encouraging activity.55,56 Gemcitabine is a potent radioenhancer but standard weekly doses of 800 mg/m2 were associated with unacceptable pulmonary toxic-effects.57,58 Consequently, combined studies which are underway use low cytotoxic doses (300 mg/m2) or radiosensitising doses

Table 3. Sequencing of chemotherapy and radiation versus clinical benefit Sequencing

Better local control

Better distant control

Reference

Concomitant chemoradiation

0.03

NS

40

Concomitant chemoradiation

0.015

NS

47

Primary and adjuvant chemotherapy

NS

< 0.001

28

Primary chemotherapy

NS

0.045

26

Primary chemotherapy

NS

NS

48

Concomitant chemoradiation

0.04

NS

48

THE LANCET Oncology Vol 2 June 2001

339

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Review Search strategy and selection criteria Data for this article were identified by a computerised bibliographic search in the MEDLINE database supplemented by hand searches through the abstracts of large meetings, bibliographies of books and specialist journals. Trials were eligible if they were published in English from 1988 onwards, as full papers or as abstracts. Trials involving 50 or more evaluable patients per study group were analysed, but smaller studies were only cited.

(50 mg/m2) of this drug. Finally, vinorelbine is a promising agent both in primary chemotherapy regimens and concomitant radiotherapy regimens.59 A recent randomised phase II study (CALGB 9431) showed the feasibility and high activity of three novel regimens (gemcitabine, paclitaxel and vinorelbine, each combined with cisplatin) applied before and concomitantly with radiotherapy.60 The median survival in this study exceeded that of previous similar studies carried out by CALGB. However, novel regimens for the combined modality treatment of NSCLC have not yet proved better than traditional regimens in randomised trials.

Conclusions The interpretation of many combined modality studies in locally advanced NSCLC is difficult because of small patient samples and methodological flaws. Nevertheless, it may be concluded that chemotherapy applied as an adjunct to radiation improves survival and alters the course of this disease. In some studies, primary chemotherapy seemed to reduce the rate of distant metastases, whereas concomitant chemoradiation provided better local control of the tumour (Table 3). It should be noted, however, that patients in these studies had favourable prognostic factors and underwent careful staging procedures. Thus, extending this aggressive strategy to all patients may not be appropriate. In many centres at present, combined modality approaches using chemotherapy and radiation have become standard in the care of selected patients with good performance status and minimal weight loss. This strategy has also been recommended by the American Society of Clinical Oncology.61 Of the two combined modality methods (concomitant and sequential administration of chemotherapy and radiation), the former seems to provide better locoregional tumour control and overall survival. However, the beneficial effects of this approach should be balanced against increased early and late toxic-effects. The absolute gain from all types of combined chemotherapy and radiation in unresectable NSCLC is still modest on average and the vast majority of patients will eventually succumb to locoregional failure or metastatic disease. Moreover, a clinical benefit of similar magnitude was achieved by the administration of continuous hyperfractionated accelerated radiotherapy (CHART), ie radiotherapy delivered 1.5 Gy, 3 times a day for a total of 54 Gy, lasting 12 consecutive days.62 The need for improvement of current methods 340

Chemotherapy and radiation in NSCLC

underlies a continuous search for more effective strategies. Further studies on the basis of recent positive results should focus on identifying the means of optimal interactions between chemotherapy and radiotherapy. This research should define the most effective types and doses of anticancer agents, as well as the optimal features of radiotherapy used in combined modality strategies (eg conformal 3-dimensional irradiation or CHART). New studies should include sufficient numbers of patients so that small, yet relevant survival differences can be detected. With new approaches, there will hopefully be better control of both macroscopic intrathoracic tumours and distant micrometastatic disease. Identification of prognostic and biological predictive markers should mean that patients can be separated into groups requiring different therapeutic approaches. Given the increased toxicity of this treatment modality, quality-of-life issues should also be taken into account. Until recently this goal had been given little attention in lung cancer trials. Quality of life was considered difficult to assess, mainly due to its multidimensional nature and the lack of standardisation. In recent years, however, several instruments for quality of life evaluation (eg EORTC QLQ-C30 questionnaire supplemented by disease-specific modules) have been developed. These methods have typically been used in chemotherapy studies on patients with disseminated disease whereas their usefulness within the framework of combined modality treatments has not had the same amount of recognition. Finally, due to increasing financial constraints, future trials should evaluate the economic implications of the addition of chemotherapy to radiation. This issue may become particularly relevant when the use of relatively expensive new-generation compounds is involved. As in the quality of life analysis, the cost-efficacy evaluation of new therapies is considered relatively complex. Nevertheless, it has to be assured that the specific benefits they offer are great enough to justify their cost. Acknowledgements

I thank Marie-Ann Seel for editorial assistance. References

1 Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999; 49: 33–64. 2 Ihde DC, Minna JD. Non-small cell lung cancer I. Biology, diagnosis and staging. Curr Probl Cancer 1991; 15: 61–104. 3 Coy P, Kennelly GM. The role of curative radiotherapy in the treatment of lung cancer. Cancer 1980; 45: 698–702. 4 Lee RE. Radiotherapy of bronchogenic carcinoma. Semin Oncol 1974; 1: 245–52. 5 Johnson DH, Einhorn LH, Bartolucci A, et al. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med 1990; 113: 33–38. 6 Dillman RO, Berry C, Ryan KP, et al. Recent outcomes for patients with carcinoma of the lung. Cancer Invest 1991; 9: 9–17. 7 Hoffman PC, Maurer AM, Vokes EE. Lung cancer. Lancet 2000; 355: 479–85. 8 Roswit R, Patno ME, Rapp P, et al. The survival of patients with inoperable lung cancer: a large scale randomised study of radiation therapy versus placebo. Am J Radiol 1968; 90: 688–97. 9 van Houtte P, Klastersky J, Renaud A, et al. Induction chemotherapy with cisplatin, etoposide and vindesine before radiation chemotherapy for nonsmall-cell lung cancer. A randomised study. Antibiot Chemother 1988; 41: 131–37. THE LANCET Oncology Vol 2 June 2001

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Chemotherapy and radiation in NSCLC

10 Mattson K, Holsti LP, Holsti P, et al. Inoperable non-small cell lung cancer: radiation with or without chemotherapy. Eur J Cancer Clin Oncol 1988; 24: 477–82. 11 Morton RF, Jett JR, McGinnis WL, et al. Thoracic radiation therapy alone compared with chemoradiotherapy for locally unresectable non-small cell carcinoma of the lung. Ann Intern Med 1991; 115: 681–86. 12 Trovo MG, Minatel E, Veronesi A, et al. Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced epidermoid bronchogenic carcinoma. A randomized study. Cancer 1990; 65: 400–04. 13 Soresi E, Clerici M, Grilli R, et al. A randomized clinical trial comparing radiation therapy plus cis-dichlorodiammine platinum in the treatment of locally advanced non-small cell lung cancer. Semin Oncol 1988; 15: 20–25. 14 Gregor A, Macbeth FR, Paul J, et al. Radical radiotherapy and chemotherapy in localized inoperable non-small-cell lung cancer: a randomized trial. J Natl Cancer Inst 1993; 85: 997–99. 15 Planting A, Helle P, Drings P, et al. A randomized study of highdose split course radiotherapy preceded by high-dose chemotherapy versus high-dose radiotherapy only in locally advanced non-small cell lung cancer. An EORTC Lung Cancer Cooperative Group trial. Ann Oncol 1996; 7: 139–44. 16 Crino L, Latini P, Meacci M, et al. Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small cell lung cancer. Ann Oncol 1993; 4: 847–51. 17 Wolf M, Hans K, Becker H, et al. Radiotherapy alone versus chemotherapy with ifosfamide/vindesine followed by radiotherapy in unresectable locally advanced non-small cell lung cancer. Semin Oncol 1994; 21: 42–47. 18 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. 19 Le Lorier J, Grégorie G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomised, controlled trials. N Engl J Med 1997; 337: 536-42. 20 Dickersin K. The existence of publication bias and risk factors for its occurrence. J Am Med Assoc 1990: 263: 1385–89. 21 Dillman RO, Seagren SL, Herndon J, et al. A randomized trial of induction chemotherapy plus high-dose radiotherapy vs. radiotherapy alone in stage III non-small cell lung cancer. N Engl J Med 1990; 329: 940–45. 22 Dillman RO, Herndon J, Seagren SL, et al. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996; 88: 1210–14. 23 Donaldson N, Dillman RO, Wallace J, Ortiz-Hurlado A. Sequential re-analysis of a phase-III clinical trial in non-small cell lung cancer. Eur Respir J 2000; 15: 821–27. 24 Sause W, Scott C, Taylor S, et al. RTOG 88-08, ECOG 4588, preliminary results of a phase III trial in regionally advanced, unresectable non-small cell lung cancer. J Natl Cancer Inst 1995; 87: 198–205. 25 Sause W, Kolesar P, Taylor S, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer. Chest 2000; 117: 358–64. 26 Komaki R, Scott CB, Sause T, et al. Induction cisplatin/vinblastine and irradiation vs irradiation in unresectable squamous cell lung cancer: failure patterns by cell type in RTOG 88-08/ECOG 4588. Int J Rad Oncol Biol Phys 1997; 39: 537–44. 27 Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung cancer: first analysis of a randomised trial in 353 patients. J Natl Cancer Inst 1991; 83: 417–23. 28 Le Chevalier T, Arriagada R, Tarayre M, et al. Significant effect of adjuvant chemotherapy on survival in locally advanced nonsmall-cell lung carcinoma [letter]. J Natl Cancer Inst 1992; 8: 58. 29 Cullen MH, Billingham LJ, Woodrofee CM, et al. Mitomycin, ifosfamide and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17: 3188–94. 30 Brodin O, Nou E, Mercke C, et al. Comparison of induction chemotherapy before radiotherapy with radiotherapy only in patients with locally advanced squamous cell carcinoma of the lung. Eur J Cancer 1996; 32A: 1893–90. 31 Kubota K, Furuse K, Kawahara M, et al. Role of radiotherapy in combined modality treatment of locally advanced non-small cell THE LANCET Oncology Vol 2 June 2001

Review lung cancer. J Clin Oncol 1994; 12: 1547–52. 32 Sculier JP, Paesmans M, Lafitte JJ, et al. A randomised phase III trial comparing consolidation treatment with further chemotherapy to chest irradiation in patients with initially unresectable locoregional non-small cell lung cancer responding to induction chemotherapy. Ann Oncol 1999; 10: 295–303. 33 Jassem J, Begg AC, Stewart FA, et al. Combined chemotherapy and radiotherapy. In: Peckham M, Pinedo HM, Veronesi U. Oxford Textbook of Oncology. Oxford: Oxford University Press. 1995; 811–22. 34 Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340: 1137–43. 35 Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 340: 1144–53. 36 Dewit L. Combined treatment of radiation and cisdiamminedichloroplatinum (II): a review of experimental and clinical data. Int J Radiat Oncol Biol Phys 1987; 13: 403–26. 37 Canetta R, Franks C, Smaldone L, et al. Clinical status of carboplatin. Oncology 1987; 1: 61–69. 38 Pinedo HM, Karim AB, van Vliet WH, et al. Daily cisdichlorodiammineplatinum (II) as a radio-enhancer: a preliminary toxicity report. J Cancer Res Clin Oncol 1983; 105: 79–82. 39 Van Harskamp G, Boven E, Vermorken JB, et al. Phase II trials of combined radiotherapy and daily low-dose cisplatin for inoperable, locally advanced non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1987; 13: 1735–38. 40 Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 1992; 326: 524–30. 41 Trovo NG, Minotel E, Fravelun G, et al. Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1992; 24: 11–16. 42 Blanke C, Ansari R, Montravadi R, et al. A phase III trial of thoracic irradiation with and without concomitant cisplatin for locally advanced unresectable non-small cell lung cancer: A Hoosier Oncology Group study. J Clin Oncol 1995; 13: 1425–29. 43 Bonner JA, McGinnis WL, Stella P, et al. The possible advantage of hyperfractionated thoracic radiotherapy in the treatment of locally advanced nonsmall cell lung carcinoma. Results of a North Central Cancer Treatment Group phase III study. Cancer 1998; 82: 1037–48. 44 Ball D, Bishop J, Smith J, et al. A randomized phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial. Radiother Oncol 1999; 52: 129–36. 45 Jeremic B, Shibamoto Y, Acimovic L, et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol 1995; 13: 452–58. 46 Jeremic B, Jevremovic S, Mijatovic L, et al. Hyperfractionated radiation therapy with and without concurrent chemotherapy for advanced non-small cell lung cancer. Cancer 1993; 71: 3732–36. 47 Jeremic B, Shibamoto Y, Acimovic L, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Clin Oncol 1996; 14: 1065–70. 48 Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent vs sequential thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small cell lung cancer: five-year median follow-up results. J Clin Oncol 1999; 17: 2692–99. 49 Furuse K, Hosoe S, Masuda N, et al. Impact of tumor control on survival in unresectable stage III non-small cell lung cancer (NSCLC) treated with concurrent thoracic radiotherapy (TRT) and chemotherapy (CT). Proc Am Soc Clin Oncol 2000; 19: (abstr) 484a. 50 Morsac B, Scott C, Curran W, et al. A quality-adjusted time without symptoms and toxicity (QTWIST) analysis of Radiotherapy Oncology Group (RTOG). Proc Am Soc Clin Oncol 2001; 20: (abstr) 313a. 51 Clamon G, Herndon J, Eaton W, et al. A feasibility study of extended chemotherapy for locally advanced non-small cell lung cancer: a phase II trial of Cancer and Leukemia Group B. Cancer Invest 1994; 12: 273–82.

341

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Review 52 Clamon G, Herndon J, Cooper R, et al. Radiosensitization with carboplatin for patients with unresectable stage III non-small cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 1999; 17: 4–11. 53 Choy H, Browne MJ. Paclitaxel as a radiation sensitizer in nonsmall cell lung cancer. Semin Oncol 1995; 22: 70–74. 54 Mason KA, Hunter NR, Milas M, et al. Docetaxel enhances tumor radioresponse in vivo. Clin Cancer Res 1997; 3: 2431–38. 55 Koukourakis MI, Bahlitzanakis N, Froudarakis M, et al. Concurrent conventionally fractionated radiotherapy and weekly docetaxel in the treatment of stage IIIb non-small-cell lung carcinoma. Br J Cancer 1999; 80; 1792–96. 56 Choy H, Safran H, Akerley W, et al. Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer. Clin Cancer Res 1998; 4: 1931–36. 57 Milas L, Fuji T, Hunter N, et al. Enhancement of tumorradioresponse in vivo by gemcitabine. Cancer Res 1999; 59: 107–14.

Dendritic cells

58 Vokes EE, Gregor A, Turrisi AT. Gemcitabine and radiation therapy for non small cell lung cancer. Semin Oncol 1998; 25: 66–69. 59 Gralla R, Harper P, Johnson S, et al. Vinorelbine (navelbine) in the treatment of non-small cell lung cancer: recent developments in combination chemotherapy and radiotherapy. Ann Oncol 1999; 10: S47–51. 60 Vokes EE, Leopold KA, Herndon JE, et al. CALGB Study 9431: a randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy (Ind CT) and concomitant chemoradiotherapy (XRT) for unresectable stage III non-small cell lung cancer (NSCLC). Lung Cancer 2000; 29: 49. 61 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. 62 Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. Lancet 1997; 350: 161–65.

Clinical picture Brachial plexopathy affecting the development of Beau’s lines unilaterally A 54-year-old secretary developed metastatic breast cancer in her right brachial plexus, producing an ipsilateral C6–C8

sensorimotor deficit. After four cycles of docetaxel at 3-week intervals, she drew her medical team’s attention to the abnormal changes in her fingernails. Transverse indentations had developed across the nails of her left but not her right hand. The nails on the right hand did change some weeks later, when, after the patient had responded to the treatment, subtle transverse coloured lines without indentation began to appear. The mechanism underlying the characteristic indentations of Beau’s lines is thought to be slowed growth of the dorsal nail plate relative to the ventral plate. Beneath the nail fold, the dorsal plate grows from the proximal nail matrix, pivoting up and over the more distally generated ventral plate. The proximal matrix is presumed to be more sensitive to the insults associated with Beau’s lines than the distal matrix. If all nail growth is arrested, as in the case of neuropathic immobility, no differential between the dorsal and ventral nail plates can occur, so that despite repeated chemotherapeutic insult, Beau’s lines will not form. If nail growth recommences slowly, milder manifestations of the phenomenon, such as colour change, may appear. DR Camidge and DA Cameron Western General Hospital, Edinburgh, UK. Correspondence: Dr DR Camidge, University Department of Oncology, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland, UK. Tel: +44 (0)131 537 2265. Fax: 0131 537 1029. Email: [email protected]

342

THE LANCET Oncology Vol 2 June 2001

For personal use. Only reproduce with permission from The Lancet Publishing Group.