Scheduling of chemotherapy and radiotherapy in locally advanced non-small cell lung cancer

LUNG CANCER Lung Cancer 12Suppl. 2 (1995) S53-S6\

~~ lASLC

Scheduling of chemotherapy and radiotherapy In locally advanced non-small cell lung cancer James F. Bishop Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne 3002, Victoria, Australia

Received 24 October 1994; accepted 7 March 1995

Abstract In scheduling chemotherapy and radiotherapy for locally advanced non-small cell lung cancer (NSCLC), chemotherapy can be given pre-radiotherapy or concurrently as a single agent or in combination, Optimal scheduling has yet to be established. Optimal preradiotherapy for NSCLC requires further development but cisplatin with vinblastine, vindesine, etoposide or navelbine appear the best currently available. A number of new drugs show potential for enhancing radiation effects. Concurrent chemotherapy and radiotherapy has been tested in a number of experimental tumours in cell culture. In these systems cisplatin, carboplatin, 5-fluorouracil, mitomycin-C and other agents appear to improve cell kill compared to chemotherapy alone. Mouse xenograft models allow the study of various concurrent drug and radiation schedules including the effect of radiation with cisplatin, carboplatin, paclitaxel and gemcitabine. In these systems, cisplatin in divided doses shows optimal enhancement with fractionated radiotherapy. There are a number of drug candidates for concurrent chemotherapy and radiotherapy programs. Clinical studies in head and neck cancer, esophageal cancer, small cell lung cancer and NSCLC show promising results with concurrent chemotherapy and radiotherapy. Cisplatin given daily with radiotherapy improved survival in NSCLC compared to cisplatin given weekly with radiotherapy or to radiotherapy alone. To study the toxicity of radiation and concurrent carboplatin, we have studied 170 patients with unresectable locally advanced NSCLC in a 4-arm randomized trial. An analysis of the first 100 patients entered revealed significantly more neutropenia (P < 0.0001) and thrombocytopenia (P < 0.004) with the combined modality arms. Esophagitis was worse on all three experimental arms but was significantly more prolonged with accelerated radiotherapy arms. In general, the program was well tolerated. It is anticipated that these laboratory and clinical studies will better define optimal schedules for concurrent chemotherapy and radiotherapy. However, combined modality treatment already has an important place in the treatment of locally advanced NSCLC. Keywords: Combined chemotherapy radiation; Non-small cell lung cancer

0169·5002/951$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(95)00460-1

S54

i.F. Bishop! Lung Cancer 12 Suppl. 2 (1995) S53-S61

1. Introduction Lung cancer remains the major type of cancer in Australia, with age-standardized incidence rates of 52.6 and 14.5 per 100 000 person-years for men and women, respectively [I]. Each year there will be approximately 146000 deaths from lung cancer in the USA [2,3]. Worldwide, approximately one third of all lung cancer cases (representing nearly 50000 patients per year in the United States) are locally advanced, non-small cell lung cancer (NSCLC). Patients with locally advanced Stage III non-small cell cancer survive 9-12 months following 50-60 Gy thoracic radiation alone [4-6]. Patients progress at the primary site and at distant sites presumably due to uncontrolled micro-metastases at presentation. Thus, the aim of combined modality chemotherapy and radiotherapy is to optimise local control and control of distant metastases. This dual aim immediately poses three major dilemmas for clinical investigators designing clinical trials. Firstly, what is the optimal systemic chemotherapy to control micro-metastatic NSCLC? Secondly, should chemotherapy be given before, concurrently or after radiotherapy? Thirdly, if given concurrently, what is the optimal daily schedule of chemotherapy and radiotherapy?

2. Optimal systemic chemotherapy in NSCLC The optimal systemic chemotherapy for NSCLC is controversial. Only five older agents cisplatin, mitomycin C, ifosfamide, vindesine and vinblastine are regarded as having an objective response rate of more than 15% [7]. Carboplatin has produced low response rates and prolonged survival. There are a number of newer agents including paclitaxel, docetaxel, gemcitabine and CPT-II which may be potentially more active in NSCLC [8-15]. Paclitaxel is a novel anti-microtubule agent developed from the bark of Taxus brevifolia or the Pacific yew [16]. It acts by stabilising microtubules and preventing cell division. With adequate premedication it can safely be given in the great majority of cancer patients. Phase II studies of paclitaxel have produced objective responses in 20-24% of patients with NSCLC [17-19]. Docetaxel is a semi-synthetic taxoid. Phase II studies in advanced lung cancer have produced response rates from 23 to 38% [20-22]. Further studies with both these agents alone or in combination with cisplatin and other agents are ongoing in NSCLC [23,24]. Paclitaxel has also undergone Phase I studies as a radiosensitizer with concurrent radiotherapy in NSCLC [25]. The most commonly used chemotherapy combinations are cisplatin with either vindesine, etoposide, vinblastine or navelbine [27-29]. Navelbine cisplatin has shown superior results to a vinblastine cisplatin in one randomised study [29]. Although further confirmation is necessary, navelbine cisplatin appears one of the most active older combinations in NSCLC. It is likely that new combinations incorporating some of the new agents, probably with cisplatin, will prove to enhance the systemic control of NSCLC.

J.F. Bishop/ Lung Cancer 12 Suppl. 2 (1995) S53-S61

S55

3. Sequencing of chemotherapy and radiotherapy There are a number of large randomized trials which have used a combined modality treatment in unresectable locally advanced NSCLC. In these studies, chemotherapy has preceded radiotherapy with the major aim to control systemic micro-metastases (Table 1). Investigators at the Institute Gustave-Roussy compared radiotherapy to 65 Gy alone versus radiotherapy with a chemotherapy combination of vindesine, cyclophosphamide, cisplatin and lomustine (VCPC) in 353 patients [30]. In that study, median survival was significantly improved with a median survival of 12 months in the combined modality arm and only 10 months with radiotherapy alone. In addition, the time to systemic relapse was significantly reduced in the combined modality arm. A CALGB study by Dillman et al. also showed a significant survival advantage using cisplatin vinblastine for two courses prior to radiotherapy [27]. Median survival was prolonged from 9.6 months with radiotherapy alone to 13.7 months with combined modality treatment. This study was repeated by RTOG as two of the three arms in a randomized study which also compared hyperfractionated radiotherapy to 69.5 Gy [31]. Preliminary results seem to confirm the CALGB findings of a survival advantage for the combined modality arm with median survival of 11.4 months with radiotherapy alone, 12.3 months for hyperfractionated radiotherapy and 13.8 months for the vinblastine cisplatin plus radiotherapy arm [31]. There are conflicting studies which have not shown an advantage for pre-radiation chemotherapy in locally advanced NSCLC [4,5]. However, in these studies the chemotherapy used was CAP (cyclophosphamide, doxorubicin, cisplatin) with a cisplatin dose of 40 mg/m/,

Table I Randomized trials of radiotherapy (RT) versus sequential chemotherapy and radiotherapy (CT + RT) in locally advanced NSCLC Reference

No. patients

Treatment

Median survival (months)

P-value

Le Chevalier et al. [301

353 155

Sause et al. [311

452

Morton et al. [41

121

Mattson et al. [51

238

10 12 9.6 13.7 11.4 12.3 13.8 10.3 10.4 10.3 10.9

0.02

Dillman et al. [271

RT CT+RT RT CT+RT RT RT (Hyper)" CT+RT RT CT+RT RT CT+RT

aHyper, hyperfractionated radiotherapy to 69.5 Gy. *NS, not significant or P > 0.05.

0.01 0.03

NS* NS*

J.F. Bishop / Lung Cancer 12 Suppl . 2 (1995) S53-S61

556

Table 2 Major toxicities on the Peter MacCallum Cancer Institute study of chemotherapy-radiation in locally ad. anced non-small cell lung cancer (see also Fig. I, refs. [51,52)) Treatment

Arm I RT Arm III AcRT Arm III RT+C Arm IV AcRT+C

No . patients 25 26 25 24

Neutropenia", WHO Grade

Esophagitis", WHO Grade

0 100 96 50 73

2

0 4 17 9

0 0

13 14

3

4

0

0 0 13 5

0 0 8 0

22 0 4 4

35 19 21 17

2

3

4

35 46 46 39

9 31 25 39

0 4 5 0

RT, radiotherapy; AcRT , accelerated radiotherapy; C, carboplatin. "Arms III and II vs. Arm III vs. IV, P < 0.0001. bArm I vs. Arm II, P = 0.0017; Arm II vs. Arm III, P =0.011; Arm II vs. Arm IV, P =0.98. Comparisons between groups were tested using a Mann -Whitney V-test.

A recent large meta-analysis studied 22 randomized trials in 3033 patients comparing radiotherapy with or without chemotherapy [32]. In that analysis, patients with pre-radiotherapy cisplatin-based chemotherapy had significant but modest prolongation of survival compared to radiotherapy alone. The hazard ratio for cisplatin-based chemotherapy was 0.87 with an estimated survival advantage of 4% at 2 years and 2% at 5 years. There appeared no advantage for non-platinum containing chemotherapy regimens in this meta-analysis. Thus, it appears that combined modality treatment with pre-radiation cisplatin-based chemotherapy is an important but modest step forward in the treatment of locally advanced NSCLC.

4. Concurrent chemotherapy and radiotherapy Concurrent chemotherapy and radiotherapy is being tested in NSCLC hypothesizing that local control can be enhanced while possibly adding some control of micrometastases. The major unanswered questions are, what is the optimal chemotherapy, whether the chemotherapy should be single agent or a combination, what is the optimal day to day sequence of chemotherapy and radiotherapy when given concurrently, should pre-radiotherapy chemotherapy be given in addition, what is the optimal radiotherapy schedule and what are the short and long term toxicities of concurrent therapy? The principle which has been used is to maintain full dose radiotherapy then introduce concurrent chemotherapy. There are a number of drug candidates which could be used clinically to potentiate radiation induced cancer cell kill. The potentiation of cisplatin and carboplatin of radiation induced cytotoxicity has been shown in hypoxic bacterial spores, tumour cells in vitro and in animal tumours [33-37]. In laboratory studies increasing platinum levels in experimental tumours, equitoxic doses of cisplatin and carboplatin resulted in six times more intra-tumour platinum in carboplatin versus cisplatin treated mice [37]. While the clinical relevance of these findings is unknown, carbo-

J.F. Bishop i Lung Cancer 12 Suppl. 2 (1995) 553-561

S57

platin toxicity is often easier for the patient suggesting it is a good candidate for concurrent programs. Other drug candidates include older drugs such as mitomycin C and 5-fluorouracil, the taxoids, paclitaxel and docetaxel, gemcitabine, lonidamine and benzotriazines [38-40]. Many of the newer agents have not been adequately tested for radiation enhancing effects. There are few experimental models which investigate what might be the optimal scheduling of concurrent chemotherapy and radiotherapy. Kallman and his colleagues have performed a series of experiments using fractionated radiotherapy and various chemotherapy schedules concurrently in murine tumours in vivo [41]. In these experiments, tumour growth delay was measured as well as an estimate of the likely therapeutic gain in tumour compared to toxicity to normal tissue. This experimental model clearly shows there are optimal ways to combine concurrent radiotherapy with drugs. The greatest therapeutic gain was achieved with cisplatin given in divided daily doses. This effect could be enhanced further by cyclophosphamide given on day-lor with interleukin-l to protect normal tissues. In another experimental model in nude mice, a human tumour xenograft of a squamous cell carcinoma was subjected to concurrent chemotherapy and radiotherapy [42]. A number of drugs have been tested in this model given as single or daily bolus or continuous infusions. Consistent with Kallman's data, twice daily fractionated radiotherapy with cisplatin in five daily doses was associated with significant growth delay. In other tumours such as small cell lung cancer, anal carcinoma, cervix cancer and head and neck cancer, studies suggest an advantage for concurrent chemotherapy and radiotherapy [43-46]. In limited stage small cell lung cancer, Turrusi and colleagues showed that concurrent cisplatin etoposide with concurrent twice daily radiotherapy produced good long-term survival and impressive local disease control of over 90%. Preliminary results of an ECOG randomized trial of 358 patients receiving concurrent cisplatin etoposide chemotherapy and daily versus twice daily radiotherapy showed no differences in overall response, response duration or survival [47]. However, twice daily radiotherapy was associated with a significant improvement in intra-thoracic relapse rate (30% vs. 74%) compared with daily radiotherapy. Twice daily radiotherapy was also associated with significantly more esophagitis. The study of Murray et al. of concurrent chemotherapy with radiotherapy given early or late showed a significant survival advantage for early concurrent radiotherapy [48]. Brain relapses were also reduced with the early radiotherapy. These studies in limited stage small cell lung cancer suggest that concurrent cisplatin-based chemotherapy and radiotherapy can be given to the chest with acceptable toxicity, that it may be associated with better local control and that scheduling-of radiotherapy has implications for local control, possibly patterns of relapse and survival. There are few randomized studies of concurrent chemotherapy and radiotherapy in NSCLC. Schaake-Koning and her colleagues performed a randomized trial in locally advanced NSCLC comparing split course radiotherapy to 55 Gy plus weekly cisplatin at 30 mg/m! versus radiotherapy plus cisplatin 6 mg/m' daily x 10 doses versus

S58

J.F. Bishop/Lung Cancer /2 Supp/. 2 (/995) S53-S6/

radiotherapy alone [49] . Overall survival was significantly improved in patients receiving the daily cisplatin plus radiotherapy with 26% alive at 2 years compared to 13%in the radiotherapy alone group. Subset analysis showed that daily cisplatin radiotherapy produced a significant improvement in local control but did not improve time to distant metastasis. Combined modality treatment was associated with more myelosuppression and more nausea and vomiting but the incidence of esophagitis was surprisingly similar comparing combined modality arms to radiation alone. Overall, there was little Grade 3 or 4 toxicity. The authors concluded that daily cisplatin improved survival and local control. The Peter MacCallum Cancer Institute has performed a Phase I study of concurrent carboplatin with standard radiotherapy or accelerated radiotherapy [50]. Toxicity was acceptable leading to a randomized study of standard radiotherapy 60 Gy in 6 weeks versus accelerated radiotherapy 60 Gy in 3 weeks versus standard radiotherapy plus concurrent carboplatin 70 mg/m 2 daily x 5 on weeks I and 5 versus accelerated radiotherapy plus carboplatin on week I. Accrual is nearly complete but interim toxicity analysis has been completed for the first 100 patients and has been reported (Table 2) [51 ,52]. This analysis showed that there was significantly more severe neutropenia on both carboplatin arms. Esophagitis was worse on all three experimental arms but was significantly more prolonged on the accelerated radiotherapy arms. The median duration of esophagitis was 1.4 months with standard radiotherapy alone, 1.6 months with standard radiotherapy plus carboplatin, 3.2 months with accelerated radiotherapy alone and 2.4 months with accelerated radiotherapy plus carboplatin. Grade 3 and 4 esophagitis was only 9% with standard radiotherapy but 35% with accelerated radiotherapy. In spite of this, the program was in general well tolerated and awaits final analysis for treatment efficacy. The CALGB is comparing two courses of cisplatin vinblastine followed by concurrent radiotherapy with carboplatin versus the same initial chemotherapy plus radiotherapy alone. This study incorporates appropriate systemic chemotherapy for control of micro-metastasis and examines the place of concurrent chernoradiotherapy on both local control and metastatic relapse.

5. Conclusions In summary, there are three major dilemmas facing clinical investigators studying the optimal scheduling of chemotherapy and radiotherapy in locally advanced NSCLC. Firstly, the optimal systemic chemotherapy to control micro-metastases is not known. However, combinations of cisplatin with vinblastine, vindesine, etoposide or navelbine reflect the best currently available treatments. It is likely that newer combinations will be improvements. Second, the optimal sequence of chemotherapy before or during radiotherapy or both is not known. However, there is now more data to suggest that preradiotherapy platinum based chemotherapy gives a modest survival advantage possibly in its role of controlling micro-metastases . There is evidence in both small cell lung cancer and NSCLC that concurrent chemo-radiotherapy can improve local control. In lung cancer, there is a reasonable expectation that improved local control can impact on survival.

J.F. Bishop/ Lung Cancer /2 Suppl. 2 (/995) 553-56/

S59

Third, in patients having concurrent therapy, the optimal day to day schedule has not been established. There is now some evidence to suggest divided doses of cisplatin is important. The scheduling of radiotherapy early or late and the frequency of daily radiotherapy treatment also requires further study. It appears likely that combined modality treatment is an important step forward to control locally advanced

NSCLC.

References [II Giles G, Farrugia H, Silver B, Staples M, editors. Cancer in Victoria. Melbourne, Australia: T&H Hunter Publishers, 1992. [21 Epidemiology cancer statistics, 1991. CA Cancer J Clin 1991; 41: 19-36. [31 Parkin OM. Trends in lung cancer worldwide. Chest 1989; 96 Suppl: 5-8. [41 Morton R, Jett JR, McGinnis WL, Earle JF et al. A thoracic radiation therapy alone compared with combined chemo-radiotherapy for locally unresectable non-small cell lung cancer. A randomized phase III trial. Ann Intern Med 1991; 115: 681-686. [51 Mattson K, Holsti LR, Holsti L et al. Inoperable non-small cell lung cancer: radiation with or without chemotherapy. Eur J Cancer Oncol 1988; 24: 477-482. [61 Perez CA, Bauer M, Emamai B et al. Thoracic radiation with or without levamisole in unresectable non-small cell carcinoma of the lung: a phase III randomized trial of RTOG. Int J Radiat Oncol Bioi Phys 1988; 15: 1337-1346. 171 Kris M, Cohen E, Giralla R. An analysis of 134phase II trials in non-small cell lung cancer (Abstr), Proceedings of the World Congress on Lung Cancer 1989; Toronto: 39: 233. [81 Murphy W, Fossella F, Winn R et al. Phase II study of Taxol in patients with untreated advanced non-small cell lung cancer. J Natl Cancer Inst 1993; 85: 384-388. [9] Chang A, Kim K, Glick J et al. Phase II study of Taxol, Merbarone and Piroxantrone in Stage IV non-small cell lung cancer: The Eastern Cooperative Oncology Group results. J Natl Cancer Inst

1993; 85: 388-394. [10] Cerny T, Wanders S, Kaplan S et al. Taxotere is an active drug in non-small cell lung cancer (NSCLC): a phase II trial of the Early Clinical Trials Group (ECTG) (Abstr). Proc Am Soc Clin Oncol 1993; 12: 331. [II] Rigas JR, Francis PA, Krix MG et al. Phase II trial of taxotere in non-small cell lung cancer (NSCLC) (Abstr). Proc Am Soc Clin Oncol 1993; 12: 336. [12] Burris H, Eckardt J, Fields S et al. Phase II trials of Taxotere in patients with non-small cell lung cancer (Abstr). Proc Am Soc Clin Oncol 1993; 12: 335. [13) Anderson H, Lund B, Hansen HH et al. Phase II study of gemcitabine in non-small cell lung cancer (NSCLC) (Abstr). Proc Am Soc Clin Oncol 1991; 10: 848. [14) Abratt R, Bezwoda WB, Falkson G et al. Efficacy and safety of gemcitabine in non-small cell lung cancer (NSCLC): phase II study results. Proc Am Soc Clin Oncol 1993; 12: 1130. [15) Fukuoka M, Negoro S, Niitani H et al. A phase II study ofa new camptothecin derivative. CPT-II. in previously untreated non-small cell lung cancer. Proc Am Soc Clin Oncol 1990: 9: 226. [16) Rowinsky EK, Donerhower RO. The clinical pharmacology of paclitaxel. Semin Oncol 1993; 20 Suppl 3: 16-25. [17) Chang AY, Kim K, Glick J, Anderson T, Karp 0, Johnson O. Phase II study of taxol, merberone and piroxantrone in stage IV non-small cell lung cancer: the Easter Cooperative Oncology Group results. J Natl Cancer Inst 1993; 85: 388-394. [18) Murphy WK, Fossella FV, Winn RJ, Shin OM, Hynes HE. Phase II study of taxol in patients with untreated advanced non-small cell lung cancer. J Natl Cancer Inst 1993; 85(5): 384-388. [19) Eisenhauer EA. Taxol in advanced non-small cell lung cancer. J Nat! Cancer Inst 1993; 85(5):

346-347. [20) Francis PA, Rigas JR, Kris MG, Pisters KM, Orazen JP, Woolley KJ, Heelan RT. Phase II trial of docetaxel in patients with stage III and IV non-small cell lung cancer. J Clin Oncol 1994: 12(6): 1232-1237.

S60

J.F. Bishop/ Lung Cancer 12 Supp/. 2 (1995) 553-561

(21) Fossella FV, Lee JS, Murphy WK, Lippman SM, Calayag M, Pang A, Chasen M. Phase II study of docetaxel for recurrent or metastatic non-small cell lung cancer. J Clin Oncol 1994; 12(6): 1238-1244. (22) Cerny T, Kaplan S. Docetaxel (taxotere) is active in non-small cell lung cancer: a phase II trial of the EORTC Early Clinical Trials Group. Br J Cancer 1994; 70(2): 384-387. [:'1) Millward MJ, Zalcberg J, Webster LK, Zimet A, Rischin D, Laird J, Toner GC, Cosolo W, Urch M, Blanc C, Bishop JF. Initial results of a phase I trial of docetaxel (taxotere) and cisplatin in patients with advanced lung cancer (Abstr). Proceedings of the 8th NCI-EORTC Symposium on New Drugs in Cancer Therapy 1994; 8: 201. (24) Ehinger DS. Overview of paclitaxel (Taxol) in advanced lung cancer. Semin Oncol 1993; 20 (4 Suppl 3): 46-49. (25) Choy H, Rodrignez FF, Koester S, Hilsenbeck S, Von Hoff DD. Investigation of taxol as a potential radiation sensitizer. Cancer 1993; 71(11): 3774-3778. (26) Choy H, Akerley W, Safarin H, Brown M, Rege V, Papa A, Glantz M, Capstrano M, Puthawala Y, Goderberg C, Leone L. A phase I trial of concurrent weekly taxol administered as a 3 h infusion and radiation therapy for advanced non-small cell lung cancer (Abstr). Proc Am Soc Clin Oncol 1994; 13: 360. [27] Dillman RO, Stephen L, Seagren M, Propert R et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in Stage III non-small cell lung cancer. New Engl J Med 1990; 323: 940-945. (28) Ruchdeschel J, Findelstein D, Ettingor D et al. A randomized trial of the four most active regimens for metastatic non-small cell lung cancer. J Clin Oncol 1986; 4: 14-22. (29) Le Chevalier T, Brisgand D, Douillard JY et al. Randomized study of vinorelbine cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a European multi-center trial including 612 patients. J Clin Oncol 1994; 12: 360-367. (30) Le Chevalier T, Arriaganda R, Tarayre M et al. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung carcinoma (letter). J Natl Cancer Inst 1992; 84: 58. (31) Sause W, Scott C, Taylor S et al. RTOG 8808, ECOG 4588. Preliminary analysis of a phase III trial in regionally advanced unresectable non-small cell lung cancer (Abstr), Proc Am Soc Clin Oncol 1994; 13: 325. (32) Pignon JP, Stewart LA, Souhami RL, Arrigand R. A meta-analysis using individual patient data from randomized clinical trials of chemotherapy in non-small cell lung cancer: survival in the locally advanced setting (Abstr). Proc Am Soc Clin Oncol 1994; 13: 334. (33) Richmond RC, Powers EL. Radiation sensitisation of bacterial spores by cisdichlorodiammineplatinum (II). Radiat Res 1976; 68: 251-257. (34) Double EB, Richmond RC: Radiosensitization of hypoxic tumour cells by cis- and transdichlorodiammine platinum (II). Int J Radiat Oncol Bioi Phys 1979; 5: 1335-1339. (35) Bellany AS, Hill BT. Interactions between clinically effective anti tumour drugs and radiation in experimental systems. Biochem Biophys Acta 1984; 738: 125-166. [36] Richmond RC, Khokhan ERR, Teicher BA et al: Toxic variability and radiation sensitization by Pt(II) analogs in Salmonella typhimurium cells. Radiat Res 1984; 99: 609-626. (37) Double EB, Richmond RC, O'Hara JA et al. Carboplatin as a potentiator of radiation therapy. Cancer Treat Rev 1985; 12 Suppl A: 111-124. (38) Brown JM, Lemmo MJ. Potentiation by the hypoxic cytotoxin SR4233 of cell killing by fractionated irradiation of mouse tumours. Cancer Res 1990; 50: 7745-7749. [39] Choy H, Akerley W, Sarafin H et al. A phase I clinical trial of concurrent weekly taxol administered as a three hour infusion and radiotherapy for non-small cell lung cancer (Abstr). Proc Am Soc Clin Oncol 1994; 13: 360. (40) Privitera G, Battista CG, Patain C et al. Phase II double-blind randomized study of lonidamine and radiotherapy in epidermoid carcinoma of the lung. Radiother Oncol 1987; 10: 285-290. (41) Kallman RF. The importance of schedule and drug dose intensity in combinations of modalities. Int J Radiat Oneol Bioi Phys 1994; 28: 761-771. [42] Joschko MA, Webster LK, Bishop JF, Groves J. Development of a human tumour model for drug radiation scheduling (Abstr). Proc Am Assoc Cancer Res 1994; 34: 357.

J.F. Bishop / Lung Cancer 12 Suppl. 2 (1995) S53-S61

S61

[43] Turrisi AT. The integration of platinum and radiotherapy in the treatment of lung cancer. Semin Oncol 1991; 18: 1473-1479. [44] Nigro NO, Vaitkeviceus VK, Herskovic AM. Preservation of function in the treatment of cancer of the anus. In: DeVita VT, Hellman S, Rosenberg SA, editors. Important advances in oncology. Philadelphia, PA: Lippincott, 1989; 161-177. [45] Thomas G, Dembo A, Fules A et al. Concurrent chemo-radiation in advanced cervical cancer. Gynecol Oncol 1990; 38: 446-451. [46] Bachaud J, David J, Boussin G, Nicolas D. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Bioi Phys 1993; 20: 243-246. [47] Johnson DH, Kim K, Turrisi AT et al. Cisplatin and etoposide plus concurrent thoracic radiotherapy administered once versus twice daily for limited stage small cell lung cancer: preliminary results of an intergroup trial (Abstr), Proc Am Soc Clin Oncol 1994; 13: 333. [48] Murray N, Coy P, Pater J et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited stage small-cell lung cancer. J Clin Oncol 1993; II: 336-344. [49] Schaake-Konig C, van den Bogaert W, Dalesio 0 et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. New Engl J Med 1992; 326: 524-530. [50] Ball D, Bishop JF, Crennan E et al. Concurrent radiotherapy and carboplatin in non-small cell lung cancer: a pilot study using conventional and accelerated fractionation. Australas Radiol 1991; 35: 66-67. [51] Ball D, Bishop JF, Smith J et al. A phase III study of accelerated radiotherapy with and without carboplatin in non-small cell lung cancer: an interim toxicity analysis of the first 100 patients. Int J Radiat Oncol Bioi Phys (in press) 1995. [52] Bishop JF, Ball D, Crennan E et al. Radiation and Carboplatin combined modality therapy in nonsmall cell lung cancer. Semin Oncol 1994; 21 Suppl 6: 91-96.