Lung Cancer 34 (2001) S81– S90
Radiosensitization with chemotherapeutic agents Orazio Caffo * Department of Medical Oncology, Santa Chiara Hospital, 38100 Trento, Italy
Abstract The combination of low-dose chemotherapy and thoracic radiotherapy is one of the treatments proposed in an attempt to improve the prognosis of locally advanced non-small cell lung cancer. Chemotherapeutic drugs administered at subtoxic doses act by means of a radiosensitization mechanism. Platinum-derived drugs have been historically used as radiosensitizers, without cumulative unacceptable toxicity. Many new chemotherapeutic agents, which have shown promising results in terms of disease control in advanced non-small cell lung cancer, show also a radiosensitizing activity. However, the optimal dose and timing of such drugs when used concurrently to radiotherapy are unknown. This paper will review the results obtained using new chemotherapeutic drugs as radiosensitizers. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chemotherapeutic drugs; Radiosensitizers; Advanced non-small cell lung cancer; Optimal dose
1. Introduction Chest radiotherapy (XRT) plays a major role in the locoregional management of the locally advanced nonsmall cell lung cancer (NSCLC) when its local spread is such as to prevent radical surgery. However, locally uncontrolled tumour and distant metastases continue to be serious problems, and the overall 5-year survival rate of patients with advanced NSCLC is less than 5% . Various treatment modalities have been proposed in an attempt to improve the discouraging results obtained with standard XRT. One way of improving cancer control is to modify XRT administration: threedimensional (3D) XRT makes it possible to increase the total dose given to tumoral tissue while reducing normal tissue injury ; similarly, hyperfractionation of XRT allows a greater tumour dose without increasing late toxicity. A second way may be to add full-dose chemotherapy (CT) to XRT; this association, in fact, has the theoretical advantage of ‘spatial cooperation’, with XRT working on local disease and CT sterilising distant metastatic foci . A number of randomised trials comparing XRT alone with XRT +CT have shown an advantage in favour of combined therapy [4 – 8]. Fur* Tel.: +39-461-903451; fax: +39-461-903364. E-mail address: [email protected]
thermore, a meta-analysis of 22 randomised trials including 3033 patients with advanced NSCLC has demonstrated that the combined therapy leads to a 9% reduction in the annual risk of death associated with XRT alone and to a 5-year survival benefit of 2% . It has also been suggested that concurrent therapy is better than sequential treatment . The ASCO has also recommended that combined therapy be considered in patients with locally advanced NSCLC and a good performance status . The main problem is that the optimal dose and timing of CT+ XRT combination are unknown and, when full CT doses are given, additive toxicity frequently requires a modification in the CT and/or XRT schedule and/or dose. However, CT can be administered together with XRT also at low (subtoxic) doses, a treatment modality that acts by means of a radiosensitization mechanism and rarely leads to cumulative or unacceptable toxicity. This review will concentrate on the results obtained using CT as a radiosensitizer.
2. Mechanisms of interaction between XRT and CT In vitro and in vivo studies have clearly demonstrated that many chemotherapeutic agents given at subcytotoxic doses are characterised by radiosensitizing
0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 3 8 2 - 8
O. Caffo / Lung Cancer 34 (2001) S81– S90
activity in tumoral but not normal cells. When used with XRT, these drugs lead to synergistic responses, i.e. their combined action is greater than the sum of their individual activity. It is assumed that radiosensitization increases the lethal damage to the tumour caused by XRT and decreases the ability of cancer cells to repair the damage, which suggests that the maximum synergistic effect can be obtained when the treatments are given concurrently. The main limitation of the concurrent use of CT and XRT is cumulative toxicity, which requires modifications in the CT and/or XRT dose and/or schedule to avoid or limit acute or late damage to normal tissue within the XRT fields. Thoracic XRT may damage the lungs and oesophagus. Lung toxicity is mainly related to the XRT target volume, but also to the dose and fractionation method; the use of new techniques in treatment planning and dose delivery may reduce the exposed volume of normal lung. In patients receiving CT, lung toxicity is influenced by other confounding factors, such as type of CT, timing (sequential vs. concurrent), method of administration (continuous infusion vs. bolus) and dose levels. An experimental study in mice clearly showed that maximum lung damage occurred in the case of simultaneous CT and XRT administration  and this may also be true in the case of the new radiosensitizing drugs. However, the oesophagus is the real limiting organ during concurrent CT+ XRT. The incidence of severe oesophagitis in trials of thoracic XRT alone was less than 5% , but when concurrent chemoradiation treatment was used, oesophagitis occurred more frequently, with an incidence depending on the timing, dose, and type of drug delivery.
used low-dose cisplatin as a radiosensitizer (see Table 1); with an ORR usually over 50% and acceptable oesophageal toxicity (5–16%). Only when cisplatin was associated with other drugs did the oesophagitis rate increase to relevant levels [14,15]. More recently, carboplatin has also been tested as a radiosensitizer. The preliminary results of these trials are similar to those obtained with cisplatin, and the level of toxicity is tolerable (see Table 2).
2.2. Paclitaxel Paclitaxel interferes with mitotic spindle function by enhancing the polymerisation of tubulin  and by producing a block of cells in the G2/M phase of the cell cycle , which is the most sensitive to ionising radiation . It also plays a role in the phosphorylation of the bcl-2 anti-apoptotic oncoprotein and enhances XRT effects by improving the switching on of the apoptotic machinery after XRT-induced DNA damage . In particular, it activates apoptosis in tumour cells without the wild-type p53 function . Safran et al.  studied p53 expression in a group of NSCLC patients treated with paclitaxel and XRT. The response rate was 83% in the patients with wild-type p53 but only 75% in patients with a mutant p53. On the basis of these observations, in vitro studies have demonstrated that paclitaxel is a potent radiation sensitizer for some tumour cell lines .
2.2.1. Paclitaxel alone A number of phase I in vivo studies have considered the combination of concurrent thoracic XRT and different schedules of paclitaxel in advanced NSCLC in an attempt to maximise therapeutic efficacy and minimise normal tissue damage.
2.1. Platinum-deri6ed drugs Platinum-derived drugs are the cornerstones of the systemic treatment of advanced or metastatic NSCLC and, because of their radiosensitization activity, they have been historically used in association with XRT. Many trials have tested the feasibility and efficacy of concurrent administration of XRT and cisplatin, which acts as a radiosensitizer at low doses. Schaake-Koning et al.  compared XRT alone vs. XRT plus weekly cisplatin (30 mg/m2) vs. XRT plus daily cisplatin (6 mg/m2 bolus). Although the response rates were similar in the three arms, there was a significant advantage in favour of XRT plus daily low-dose cisplatin (continuous infusion or bolus) in terms of local relapse-free and OS. Its low toxicity profile makes this association a widely used and manageable treatment, which is capable of enhancing the antitumour efficacy of XRT while limiting additive toxicity. A number of studies have
18.104.22.168. Continuous infusion (7 days/week). An ongoing study  did not find any dose limiting toxicity (DLT) at a dose of 17 mg/m2 per day, and the only relevant toxicity at the next dose level (27 mg/m2 per day) was grade 3–4 lymphopenia in 9/21 patients. All but one of the patients experienced oesophagitis, but it never reached the level of grade 3–4. 22.214.171.124. Continuous infusion (5 days/week). In a study by Herscher et al. , paclitaxel was continuously administered for 5 days/week, with a 2-week interruption. The maximum tolerated dose (MTD) was 105 mg/m2 per week. No grade 3–4 oesophagitis was observed. 126.96.36.199. Daily administration. In the study by Rathmann et al. , 29 patients received two 21-day induction courses of paclitaxel and carboplatin before concurrent radical XRT and daily 1-h infusions of escalating doses
Table 1 Studies based on daily cisplatin administration Author
c pts Cisplatin mg/m2 Administ per day
van Harskamp Boven Trovo Bedini Maggi Hazuka Palazzi Le Pechoux
       
II II II II II II II II
40 33 94 38 18 64 36 34
6 6 6 6 6 5 16* 6
Bolus Bolus Bolus civa civa Bolus civa Bolus
Standard Standard Standard Standard Standard Standard Hyperfraction Hyperfraction
65 65 54 83 61 39 62
10.5 10.5 12
Sarihan  van der Brande 
Bedini Tan Ardizzoni
  
II II II
77 44 32
4 6 5
civa Bolus Bolus
Standard Standard Standard
71.3 75 56
16.9 (5 years) 39 (3 years) 52
21 (3 years)
Accel hyperfraction Standard
42 (2 years)
Standard Split course
Grade 3–4 Esophagitis(%)
Cisplatin after XRT
Followed by surgery 16 14 9
Plus vindesine 2.5 mg/m2 week Plus vindesine 25 mg/m2 Preceeded by induction CT
Preceeded by induction CT Preceeded by induction CT Plus vindesine and followed by CT Plus VP16 18 mg/m2 per day**
O. Caffo / Lung Cancer 34 (2001) S81– S90
63 63.6 (3 years) 56 37 53
* week dose; ** maximum tolerated dose. a civ, continuous intravenous infusion.
Table 2 Studies based on daily carboplatin administration Reference
Carboplatin mg/m2 per day
Median survival 1-year survival
Bolus Bolus or civa
53 (2 years) 63
Accelerated 84 Hyperfractionated
civ, continuous intravenous infusion.
3 33 at 30
10 mg/m2 bolus or civ recommended dose Elderly pts 25 mg/m2 recommended dose followed by 4 courses of carboplatin
12 at 25
Grade 3–4 Esophagitis (%)
Preceeded and followed by CT
34 (3 years)
Plus VP16 30 mg
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O. Caffo / Lung Cancer 34 (2001) S81– S90
of paclitaxel. The recommended daily dose of paclitaxel was 10 mg or 6 mg/m2 ×5 days/week, with oesophagitis being the DLT at the 15 mg/day dose level. The same group is now conducting a phase II trial of paclitaxel 10 mg/day.
188.8.131.52. Twice-weekly administration. Lau et al.  administered a 1-h infusion of paclitaxel twice weekly for 6 weeks (a total of 12 doses) before daily XRT. The starting dose was 25 mg/m2 per day, and the MTD was 35/m2 per day. At MTD, grade 3– 4 oesophagitis was observed in 7/20 patients. 184.108.40.206. Weekly administration. This is the most frequently evaluated schedule of paclitaxel with concurrent XRT. A number of phase I studies have attempted to find the weekly paclitaxel MTD [27– 30]. The recommended dose ranged from 55 to 86 mg/m2 per week, although there is an inverse relationship between XRT dose (and consequently the number of treatment weeks) and paclitaxel MTD. In a phase II trial , paclitaxel 60 mg/m2 per week was given concurrently with XRT. The response rate was 86%, with a grade 3– 4 oesophagitis in 37% of 29 evaluable patients. 220.127.116.11. Bi-weekly administration. The National Cancer Institute of Canada conducted a phase I/II trial of paclitaxel administered every 2 weeks . Of the four escalated doses (45, 90, 120 and 135 mg/m2), the MTD was 135 mg/m2, but DLT (grade 3 neutropenia) prevented the administration of the second dose. Therefore, the recommended dose was 120 mg/m2 every 2 weeks; at this dose, no grade 3– 4 oesophagitis was observed and the response rate was 78%. 2.2.2. Paclitaxel plus carboplatin Paclitaxel plus carboplatin is one of the most widely used combinations in clinical trials of chemoradiation. Choy et al. have conducted two phase II trials. The first involved the weekly administration of paclitaxel 50 mg/m2 per week plus carboplatin AUC 2/week and concurrent standard XRT. The treatment plan was concluded with two additional courses of adjuvant CT. Forty-six percent of the patients experienced grade 3– 4 oesophagitis; the ORR was 75.7% . In the second trial, the patients received the same CT schedule plus concurrent hyperfractionated XRT (1.2 Gy twice daily); the treatment was completed with two additional courses of adjuvant CT. Severe oesophagitis and severe pneumopathy were observed in 25.8 and 16.5% of the patients, respectively. The ORR was 78.6% and the 1-year OS rate was 61.6% . An ongoing phase I/II trial from the Fox Chase Cancer Center is based on two induction courses of paclitaxel and carboplatin followed by concurrent CT
and XRT, with paclitaxel and carboplatin being given at escalated doses every 3 weeks . Belani et al.  administered paclitaxel 45 mg/m2 per week plus carboplatin 100 mg/m2 per week during XRT with a 3-year OS of 39%. Similarly Ratanatharathorn et al.  used paclitaxel 45 mg/m2 per week plus carboplatin AUC 2 during XRT followed by four cycles of adjuvant chemotherapy with carboplatin and paclitaxel reporting a ORR of 77%. An alternative approach designed to reduce additive toxicity is based on the combination of carboplatin plus paclitaxel and 3D conformal XRT. A recent phase I trial tested the feasibility of this combination with escalating XRT doses (from 60 to 74 Gy) after two CT induction courses. The results were encouraging: toxicity was acceptable (grade 3 oesophagitis in 18% of the patients); the response rate was good (70%); and the 1and 2-year survival rates were 69 and 45%, respectively .
2.2.3. Paclitaxel plus cisplatin A phase I study evaluated the combination of cisplatin and paclitaxel with XRT . The designated MTD was paclitaxel 135 and 170 mg/m2 every other cycle and cisplatin 75 mg/m2. In another trial, paclitaxel given as a 24-h infusion with cisplatin and XRT showed an unacceptable haematological and non-haematological toxicity . An Italian phase I study recommended the following doses: 45 mg/m2 per week for paclitaxel plus 35 and 30 mg/m2 per week for cisplatin with standard and hyperfractionated XRT, respectively . Grossi et al.  administered paclitaxel 45 mg/m2 per week plus a low dose of daily cisplatin (5 mg/m2 per day) during XRT and after two induction CT courses. They reported an ORR of 62.5%, with a severe oesophagitis rate of 46%. Similarly, a Finnish study adopted a combination of cisplatin (30 mg/m2 per day) and paclitaxel (30 mg/m2 per day) given for 3 days every 3 weeks during XRT preceded by two induction CT courses. The oesophageal toxicity was acceptable (13% of grade 3–4) and the response rate was 78% . The CALGB study 9431  tested the feasibility and efficacy of two CT induction cycles followed by concurrent CT plus XRT. The patients were randomised to receive one of three cisplatin-based combinations (plus gemcitabine, or paclitaxel, or navelbine) as induction therapy, followed by the same treatment at reduced doses with concurrent XRT. In the paclitaxel arm, chemotherapy consisted of paclitaxel 135 mg/m2 in 3 h plus cisplatin 80 mg/m2 every 3 weeks during XRT. The recently updated results showed an ORR of 61% with a median survival and 1-year OS of 14.1 months and 61%, respectively .
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2.3. Docetaxel Like paclitaxel, docetaxel produces radiosensitization by blocking the cell cycle in the most radiosensitive G2/M phase. Preclinical studies have shown that the radiosensitizing effect of docetaxel is 10 times that of paclitaxel at equimolar concentration . Four phase I trials have tested the use of docetaxel in association with radical XRT in advanced NSCLC. Docetaxel was usually administered weekly during XRT in three trials and on days 1, 8, 22 and 29 in one. In Mauer’s trial , standard chest XRT was delivered in daily fractions of 1.8– 2.0 Gy for a total of 60 Gy; concomitant docetaxel was administered every 3 weeks (one or two doses) or weekly. This study found that the MTD was 40 mg/m2 per cycle for the 3-week schedule and 60 mg/m2 (20 mg/m2 per week) for the weekly schedule. Oesophagitis and lymphopenia were the main toxicity of the combined treatments, regardless of the docetaxel schedule. Considering the XRT fields, the response rate was 8/20. Koukourakis  and Teng  established an MTD of 30 mg/m2 per week (given once a week or 15 mg/m2 fractions given twice a week). The same dose was recommended in Aamdal’s trial , with a modified weekly schedule (the drug was given in weeks 1, 2, 4 and 5). The feasibility of giving docetaxel daily during XRT is under examination in a phase I trial . In a recent phase II trial , the combination of XRT plus weekly docetaxel led to an ORR of 80%, with 34% of the patients experiencing oesophagitis and 11% radiation pneumonitis. Docetaxel has been also used in combination with platinum-derived drugs. In one study, the weekly recommended dose was docetaxel 20 mg/m2 plus carboplatin AUC 1 , whereas another study is attempting to evaluate carboplatin AUC 2 plus docetaxel with XRT after two CT induction courses .
2.4. Gemcitabine Gemcitabine has shown radiosensitizing activity in vitro , but the exact mechanism of this action is not clear. Radiosensitazion occurs at non-cytotoxic doses, increases with prolonged drug exposure, and is greater when the drug is administered before XRT. In a phase I study , the concurrent administration of full-dose gemcitabine (1 g/m2 per week) and XRT had an unacceptable toxicity, which led to the premature closing of the study. A dose-finding study carried out at the M.D. Anderson Cancer Center also found unacceptable oesophageal toxicity when low gemcitabine doses were given concurrently with conventional 2D XRT. This study was continued with escalating gemcitabine doses plus 3D conformal XRT,
and the preliminary results did not show severe oesophagitis at the lowest gemcitabine dose levels . A phase I study is attempting to find the DLT of gemcitabine plus XRT starting from a dose of 300 mg/m2 per week and increasing the number of weeks of administration from 1 to 6, and then increasing the dose to 450 and 600 mg/m2 per week. This ongoing trial is currently evaluating the dose of 450 mg/m2 per week . A weekly combination of cisplatin (12 mg/m2 per week) and gemcitabine plus XRT was tested in a phase I study; the MTD of gemcitabine in this combination was 100 mg/m2 per week, with significant dose-limiting oesophagitis occurring at higher doses . The combination of cisplatin plus gemcitabine given with XRT was incorporated into the CALGB trial 9431 described above , which tested such treatment after induction CT. This study demonstrated that it was feasible to administer gemcitabine 600 mg/m2 on days 1, 8 and cisplatin 80 mg/m2 on day 1 every 3 weeks for two cycles given concomitantly with XRT. The recent results demonstrated an ORR of 70% and a median survival of 17.2 months; however, the severe oesophagitis rate was 52% .
2.5. Vinorelbine Vinorelbine is known to have antitumor activity against NSCLC and is capable of enhancing the efficacy of XRT, with the maximum effect being observed when the cells are in the G2 phase . Gridelli et al.  attempted to find the MTD of daily vinorelbine with concurrent standard XRT, and concluded that it was 4 mg/m2, with or without amifostine protection. Vinorelbine has also been associated with hypofractionated XRT. In a phase I study, it was tested with two different XRT schedules, the conclusion being that its MTD was 20 mg/m2 per week with 850 cGy/fr ×2 and 10 mg/m2 per week with 500 cGy/fr × 12 . Several phase I studies have associated vinorelbine with platinum-derived agents. Cisplatin was used by Masters et al. , who concluded that the recommended dose were cisplatin 80 mg/m2 on day 1 and vinorelbine 15 mg/m2 on days 1 and 8 every 3 weeks. Vinorelbine has been tested in phase II trials in combination with platinum-derived agents. Iaffaioli et al.  used a dose of 30 mg/m2 on day 8 together with carboplatin 250 mg/m2 on day 1 and concurrent XRT; the ORR was 43%, with grade 3 oesophagitis occurring in 5% of the patients. Zatloukal et al.  attempted to avoid additive toxicity by anticipating XRT before vinorelbine administration: the combination of XRT and cisplatin (80 mg/m2 on day 1) plus vinorelbine (12.5 mg/m2 on days 1, 8 and 15) led to oesophagitis in 8% of the patients. In
O. Caffo / Lung Cancer 34 (2001) S81– S90
a subsequent randomised phase II trial, this concurrent treatment led to severe oesophagitis in 30% of the patients, with an ORR of 85% . A Spanish study alternated CT and concurrent CT+ XRT with cisplatin (100 mg/m2 on day 1) or carboplatin and vinorelbine (30 mg/m2 on days 1 and 8) plus accelerated hyperfractionated XRT. The response rate was 58% and the 1-year survival rate 62%; 34% of the patients experienced severe oesophagitis . Finally, a French trial tested split course XRT (2.5 Gy/day × 5) plus a combination of cisplatin (20 mg/m2 per day×5), 5-fluorouracil (350 mg/m2 per day continuous infusion×5 days) and vinorelbine (20 mg/m2 per day on days 1 and 5). The patients experienced unacceptable hematoxicity with a low 2-year survival rate (14%) . In the CALGB trial 9431, vinorelbine was administered at the dose of mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1 every 3 weeks for two cycles given concomitantly with XRT. This combination showed an ORR of 69%, with a severe oesophagitis rate of 24% .
2.6. Irinotecan Irinotecan hydrochloride (CPT11) is derived from camptothecin and acts by inhibiting topoisomerase I. It also potentiates radiation effects in vitro and in vivo [68,69]. A phase I/II study tested the MTD of irinotecan given (starting dose 30 mg/m2 per week, with increments of 15/m2) concurrently with XRT. Severe oesophagitis, pneumonitis and diarrhoea occurred at 45 and, mainly at 60 mg/m2. The conclusion was that the dose for a phase II study was 45 mg/m2 per week, which led to an objective response rate of 76.9% . Another phase I study found that the MTD of CPT11 with XRT was 40 mg/m2 per week, and is now trying to establish the MTD of CPT11 and carboplatin plus XRT . The association of CPT11 (30 mg/m2 per week) plus XRT was also tested in a phase II trial after two courses of induction CT with cisplatin plus CPT11. The observed ORR was 64.7% with a low incidence of severe oesophagitis (4.2%), the median survival was 16.5 months, and 1-year OS was 65.8% . Two concluded phase I trials tested CT plus XRT with CPT11 plus other drugs. The first study combined cisplatin (60 mg/m2 on day 1), irinotecan (40– 60 mg/m2 on days 1, 8 and 15) and XRT. The conclusion was that cisplatin plus CPT11 plus XRT was not feasible because of the need to omit CPT11 administration due to intestinal or haematological toxicity . The second study used XRT split course and recommended the dose of CPT11 60 mg/m2 on days 1, 8 plus cisplatin 80 mg/m2 on day 1 every 4 weeks .
Two other ongoing dose-finding trials are testing CT + XRT with CPT11 plus cisplatin  or plus paclitaxel and carboplatin .
3. Conclusion Many new chemotherapeutic agents are being used in the management of advanced NSCLC with promising results in terms of disease control. Most of these drugs enhance XRT cytotoxic activity, and many phase I/II trials have been conducted in order to evaluate their concomitant use with XRT. Various schedules have been tested in an attempt to avoid severe additive toxicity, but the greater toxicity of most of these novel regimens is a problem. In addition, the lack of phase III trials matching the chemoradiation associations with new drugs do not provide any information about the comparative outcomes of such treatments in terms of anticancer efficacy and cumulative toxicity. A first answer to such questions will come from the conclusive results of the CALGB trial 9431, which has been frequently mentioned in this paper. Further studies are needed before we can take full advantage of the drugs’ radiosensitizing potential and improve disease control in advanced NSCLC.
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