3.2 Locally Advanced Non-Small Lung Cancer
3.2.1 Radiochemotherapy in Locally Advanced Non-Small Cell Lung Cancer
Branislav Jeremi ´c and Aleksandar Dagovi´c
B. Jeremi´c, MD, PhD
Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 226, 81675 Munich, Germany
A. Dagovi´c, MD, MSc
Department of Oncology, University Hospital, Zmaj Jovina 30, 34000 Kragujevac, Serbia
CONTENTS
3.2.1.1 Introduction 207
3.2.1.2 Radiation Therapy Alone 208
3.2.1.3 Neoadjuvant (Induction) Chemotherapy Followed by Radiation Therapy 209 3.2.1.4 Concurrent Radiochemotherapy 211 3.2.1.5 Neoadjuvant (Induction) Chemotherapy
Followed by Radiation Therapy Versus Concurrent Radiochemotherapy 213
3.2.1.6 Optimisation of Concurrent Radiochemotherapy 214
3.2.1.7 New Approaches in Radiation Therapy and Chemotherapy of Locally Advanced Non-Small Cell Lung Cancer 216 3.2.1.8 Conclusions 217
References 218
3.2.1.1 Introduction
Locally advanced non-small-cell lung cancer (LA- NSCLC) represents a heterogeneous group of pa- tients. According to the two staging systems widely adopted in the community of thoracic oncologists (Mountain 1986, 1997), this is synonymous to stage III, although numerous, mostly non-surgical reports, included also a proportion of patients with stage II disease into this group of patients. It should be noted that these staging systems are surgical, i.e. the major principle is surgical extirpation of the tumour and lymph nodes. The only issues which matter in these systems are the size of the tumour (e.g. 3 cm or 5 cm in largest diameter), its location (e.g. 2 cm or more from the carina), and extent of invasion into neigh- bouring structures (e.g. chest wall or heart). These systems do not take tumour volumes into account
at all! That said, one major principle of anticancer action of both radiation therapy and chemotherapy, log-cell kill, is not considered to any extent. This is an extremely important issue, especially in a number of tumours which could have similar tumour vol- ume, but which could have been assigned a different stage in the case of a different location or invasion of neighbouring structures. This has necessitated a revi- sion of current staging systems, in order to take also tumour volume into account, as well as other factors such as presence or absence of pleural effusion, etc.
Another problem is that surgical systems used in the last two decades have grouped a number of T and N designations into the same stage. Even with a subdi- vision (to IIIA and IIIB), made in the fi rst system used (Mountain 1986), there were still a number of vari- ous T and N designations. After moving T3No to stage IIB, in the recent staging system revision (Mountain 1997), there is still a total of 11 different designations;
four in stage IIIA (T3N1, T3N2, T1N2, and T2N2) and seven in stage IIIB (T4N0, T4N1, T4N2, T4N3, T1N3, T2N3, and T3N3)! However, there has been no full in- vestigation, even in cases of big multi-institutional, cooperative group trials, into outcome results of these various T and N substaging designations, i.e. there is no data on whether, e.g. T1N3 is better than T4N1, or indeed whether they were similar in outcome. This applies for all other staging designations in both sur- gical and non-surgical studies. We are, therefore, left without crucial information: what is the real impact of increasing T and N substage and is there a “trade- off ” when the adverse effect of increasing T stage is, perhaps, levelled-off with decreasing N stage, or per- haps which one of these two substaging designations may be more important than the other one and if so, then when exactly? As a result of not solving these crucial questions, a community of thoracic oncolo- gists continues to use surgical system in the design, performance and reporting of clinical studies. The change of staging system currently used and its bet- ter defi nition, followed by proven validity and utility, must be one of the priorities of future clinical work.
Hopefully, this will provide more details regarding
impact of a particular T and N substaging designa- tion and lead to more precise evaluation of the out- come of both non-surgical treatment modalities.
LA-NSCLC has been the major battleground for in- vestigating various treatment options. While surgery (e.g. in very selected T4N0), radiation therapy (al- tered fractionation regimens with curative intention in stage III or palliative hypofractionated regimens in mostly stage IIIB patients) and chemotherapy (in stage IIIB in numerous clinical studies investigating effect of various chemotherapeutic agents) can all be used alone in this disease, this is not such frequent practice nowadays in the majority of patients who can tolerate more intensive (combined) treatment approaches owing to the mounting evidence that the vast majority of patients should be treated with such a combined modality approach. In practice this means, a bimodality (radiochemotherapy) or a trimodality approach, the latter being detailed in Chap. 3.2.2.
3.2.1.2
Radiation Therapy Alone
Traditionally, LA-NSCLC has been managed by radia- tion therapy alone. Because radiation therapy was rel- atively well tolerated and offered good palliation, and because there have been few alternatives, there have been only a few studies validating its effi cacy. The Veterans’ Affairs group reported on a study where ra- diation therapy had been compared to best support- ive care for LA-NSCLC. There was an improvement in the median survival time with radiation therapy, although no 2-year survivors were seen in either arm (Roswit et al. 1968). It should be clearly stated that at the time of this study staging procedures were rather primitive and it is likely that many patients in both arms probably had Stage IV disease (if modern imaging had been used). Also, radiation therapy tech- niques used in this study should also be considered outdated. More recently, similar results were obtained in a randomised study. The 2-year survival was 18%
with radiation therapy dose of 50 Gy versus 0% for observation with palliative radiotherapy when severe local symptoms developed (Reinfuss et al. 1999). In another randomised cooperative group study from the US, patients were randomised to radiation ther- apy versus single agent vindesine (Johnson et al.
1990), while the third arm comprised both modali- ties. The study showed no survival advantage for ra- diation therapy. Again, however, it should be stressed that there was a substantial crossover in this trial,
with many patients in the vindesine arm ultimately receiving thoracic radiotherapy. This study suggested no survival advantage to “early” radiation therapy but this should not be interpreted to imply no advantage at all for radiation therapy.
In spite of the shortcomings of these studies, radi- ation therapy has been considered as the mainstay of therapy for locally advanced non-small cell lung can- cer. In the benchmark trial, continuous-course RT of 50- to 60-Gy doses has been shown to be superior to the 40-Gy split-course or continuous-course schedule (Perez et al. 1986) Consequently, the 60-Gy continu- ous-course schedule has been adopted as the standard radiation therapy in many radiotherapeutic centres all over the world, especially in the US. However, the results obtained with radiation therapy alone are un- satisfactory for locally advanced non-small-cell lung cancer, since the median survival time was approxi- mately 9–10 months and the overall 5-year survival rate was only 3%–6% in prospective randomised tri- als (Holsti and Mattson 1980; Petrowich et al.
1981; Perez et al. 1987). Various retrospective and prospective randomised studies have revealed that both local and systemic failure play an important role in the poor survival of these patients (Petrowich et al. 1977; Cox et al. 1979; Perez et al. 1986). Thus, vari- ous means of increasing the likelihood of both local and systemic control were sought.
Various altered fractionation RT regimens have been used in order to improve local control (Cox et al. 1993; Saunders and Dische 1990; Byhardt et al.
1993). The Radiation Therapy Oncology Group (Cox et al. 1990) has investigated hyperfractionated radia- tion therapy with 1.2 Gy b.i.d. fractions and reported improved survival in a subgroup of patients with fa- vourable prognostic factors treated with hyperfrac- tionated radiation therapy with doses >69.6 Gy com- pared to that obtained with the standard treatment (60 Gy/30 fractions over 6 weeks). Continuous hyper- fractionated accelerated radiation therapy was tested against standard fractionation radiation therapy in inoperable non-small cell lung cancer, including a pro- portion of stage I/II patients and it is shown to carry some benefi t (Saunders et al. 1999). Unfortunately, this treatment design was extremely complicated for daily clinical practice which has prevented it from widespread use, even in the UK. Current attempts to modify it include the omission of weekend days or neoadjuvant chemotherapy, both of which effectively destroy its underlying principle, namely, accelerated fractionated radiation therapy to combat accelerated tumour clonogenic proliferation. Attempts have been seen in recent years to combine acceleration and hy-
perfractionation in a less demanding regimen, such as hyperfractionated accelerated radiation therapy which also proved to be effective in this setting. More data, however, are needed before widely accepting it in clinical practice.
What these altered fractionated regimens con- fi rmed is the duality of failure patterns, with both lo- cal and distant failure playing an important role in ultimate outcome of patients treated with radiation therapy alone. These facts were recognised several decades ago and, coupled with poor survival fi gures, they stressed the need for inclusion of chemotherapy to better control this disease. The reason for add- ing chemotherapy to radical radiation therapy was to improve local/regional control while, at the same time, addressing the issue of possible distant spread, not addressed by radiation therapy. Unfortunately, the results were not encouraging and not different from that obtained with radiation therapy alone.
Chemotherapy was usually given as an adjuvant (i.e. post-radiation therapy) and it consisted of non- platinum based drugs (Reynolds and O’Dell 1978;
White et al. 1982). Failure of these studies was usu- ally explained by radiation therapy-induced fi brotic changes in lungs that prevented successful blood/
drug perfusion and, therefore, drug supply to the tumour-bearing area, and/or relative ineffi ciency of drugs available at that time, mostly non-platinum based chemotherapy (Reynolds and O’Dell 1978;
White et al. 1982).
Regardless of this, radiation therapy and chemo- therapy, mostly platinum-based, were considered as necessary components of successful treatment. And they have been increasingly practised around the world in the last two decades. A number of possible combinations have arisen, largely exploiting different aspects of such combinations, and frequently focusing on the issue of scheduling. Induction (neo-adjuvant) chemotherapy followed by radical radiation therapy (Dillman et al. 1990; Sause et al. 1995), “sandwich”
chemotherapy and radiation therapy (LeChevalier et al. 1992), as well as concurrent radiochemotherapy (Schaake-Koning et al. 1992; Jeremic et al. 1995, 1996, 1998) have all gained widespread use, some- times with very similar results obtained with these different approaches. To further obscure the overall picture, both radiation therapy and chemotherapy have evolved over the years. A number of different time/dose/fractionation radiation therapy regimens have been used (Cox et al. 1990; Byhardt et al. 1993;
Saunders and Dische 1990). They paralleled the in- troduction of the third generation of drugs, namely paclitaxel (Johnson et al. 1996; Herscher et al. 1998),
docetaxel (Millward et al. 1996; Mauer et al. 1998), vinorelbine (LeChevalier et al. 1994; Masters bet al. 1998), gemcitabine (Manegold et al. 1997; Vokes et al. 1998), irinotecan (Fukuoka et al. 1992; Oshita et al. 1997) and topotecan (Lynch et al. 1994; Perez- Soler et al. 1996).
3.2.1.3
Neoadjuvant (Induction) Chemotherapy Followed by Radiation Therapy
As stated many times, the major aim of this type of radiochemotherapy is to decrease tumour burden and to combat micrometastatic disease, believed to be present from the outset. When radiation ther- apy follows induction chemotherapy, the effects of chemotherapy may permit delivery of radiation to a reduced tumour volume. Increased drug delivery with less overall toxicity is also possible compared to concurrent administration. Potential disadvantages of induction treatment include a prolonged overall treatment time, excessive toxicity due to chemother- apy preventing or delaying the delivery of radiation and chemotherapy-induced tumour cell resistance resulting in reduced radiation effi cacy, as well as accelerated tumour clonogenic repopulation, also expected to occur during the chemotherapy phase of the combined treatment (Byhardt et al. 1998;
Byhardt 1999). There have been many phase II trials designed to evaluate whether or not survival is im- proved with the addition of induction chemotherapy to radiation therapy in patients with locally advanced non-small cell lung cancer versus radiation therapy alone. Although these trials have had confl icting re- sults, several phase III trials (Table 3.2.1.1) and three meta-analyses have demonstrated a survival benefi t, confi rmed with recent updates providing long-term data.
In North America, the Cancer and Leukemia Group B (CALGB) 8433 trial is the landmark study of sequential radiochemotherapy versus radiation ther- apy alone for the treatment of locally advanced non- small cell lung cancer (Dillman et al. 1990). Between 1984 and 1987, 155 patients with clinical or surgical T3 or N2 and M0 non-small cell lung cancer were randomised to induction chemotherapy followed by radiation therapy or radiation therapy alone. All pa- tients had a good performance status and minimal weight loss prior to study entry. Induction chemo- therapy consisted of cisplatin (100 mg/m2, days 1 and 29) and vinblastine (5 mg/m2, days 1, 8, 15, 22 and 29).
Radiation therapy to a total dose of 60 Gy in 30 frac- tions was the same in both arms and began on day 50 in the combined-modality arm. The addition of che- motherapy did not impair the ability to deliver radia- tion therapy, with 88% of patients in the combined- modality arm and 87% of patients on the radiation therapy alone arm completing radiation therapy per protocol. Although there were no treatment-related deaths on either arm, the addition of chemotherapy increased the number of hospital admissions for vomiting (5% vs. 0%) and infection (7% vs. 3%). In the initial report, induction chemotherapy improved median survival (13.8 vs. 9.7 months, p=0.0066) and doubled the number of long term survivors with 23%
of patients treated with radiochemotherapy surviv- ing 3 years compared to 11% of those treated with radiation alone, prompting early closure of the study.
Long-term 7-year follow-up confi rmed that induc- tion chemotherapy improves long-term and median survival (13.7 vs. 9.6 months, p=0.012) compared to radiation therapy alone (Dillman et al. 1996). Three other modern cisplatin-based trials have confi rmed the CALGB experience.
The Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group trial randomised 458 eligible patients with good performance status, mini- mal weight loss and locally advanced non-small cell lung cancer to receive once-daily radiation therapy to 60 Gy in 2-Gy fractions with or without induction cisplatin and vinblastine (Sause et al. 1995). Patients randomised to a third arm received radiation therapy twice daily to a total dose of 69.6 Gy. Median survival was statistically superior (p=0.03) for the combined modality arm (13.8 months) versus either the stan- dard radiation therapy arm (11.4 months), or the
twice daily radiation therapy arm (12.3 months).
Final results of this study confi rmed an improvement in median survival for combined-modality therapy, but 5-year survival rates remained poor at less than 10% (Sause et al. 2000).
French experience with induction chemotherapy followed by radiation therapy was provided in a trial with radiation alone versus combined chemora- diation (LeChevalier et al. 1991). In this phase III trial, 353 patients with unresectable locally advanced squamous cell or large cell lung carcinoma were ran- domised to receive either radiation therapy alone (65 Gy in 2.5-Gy fractions) or three monthly cycles of cisplatin-based chemotherapy followed by the same radiation therapy regimen. There was a signifi cant decrease in distant metastases for the combined-mo- dality arm and the median (12.0 vs. 10.0 months) and 2-year survival rates (21% vs. 14%, p=0.02) were also improved (LeChevalier et al. 1992). Re-analysis re- vealed that only 8% of patients had continued local control at 5 years (Arriagada et al. 1997). Five-year survival rates remained poor at 6% and 3%, likely sec- ondary to the high rate of local failure on both arms.
The Medical Research Council randomised 447 eligible patients with good performance status and localised, inoperable non-small cell lung cancer to receive radiation therapy alone or cisplatin-based in- duction chemotherapy followed by radiation therapy (Cullen et al. 1997). On both arms, the median radi- ation therapy dose was low at 50 Gy. Median survival was improved with the addition of chemotherapy (13.0 vs. 9.9 months, p=0.056), although this differ- ence was of borderline signifi cance.
As demonstrated by the above randomised tri- als, the addition of platinum-based induction che-
Author CT RT dose
(Gy)
MST (months)
p Value 3-Year survival Dillman et al. (1990) VP 60
60
13.7 9.6
0.012 23%
11%
Sause et al. (1995) VP 60 60
13.8 11.4
0.03 NR
NR LeChevalier et al. (1991) VCPC 65
65
12.0 10.0
NR 21%a
14%a Cullen et al. (1997) MIC 50b
50b
13.0 9.9
0.056 14%
10%
Table 3.2.1.1. Randomised trials of induction chemotherapy followed by radiation therapy versus radiation therapy alone
CALGB, Cancer and Leukemia Group B; MRC, Medical Research council; CT, che- motherapy; RT, radiation therapy; MST, medians survival time; VP, vinblastine, cis- platin; VCPC, vindesine, cyclophosphamide, cisplatin, lomustine; MIC, mitomycin, ifosfamide, cisplatin; NR, not reported.
a 2-Year survival; b median radiation therapy dose.
motherapy to radiation therapy results in improved survival versus radiation therapy alone. This is par- ticularly true for short-term survival, but modest improvements in long-term survival have also been observed. Several smaller randomised trials have failed to confi rm a survival benefi t for the addition of induction chemotherapy, but these trials may have lacked the power to detect small differences in survival (Mattson et al. 1988; Morton et al. 1991;
Crino et al. 1993; Planting et al. 1996). Three large meta-analyses have demonstrated a small but consis- tent survival benefi t for the addition of induction che- motherapy to radiation therapy for locally advanced non-small cell lung cancer (Non-Small Cell Lung Cancer Collaborative Group 1995; Marino et al. 1995; Pritchard and Anthony 1996).
Since it was recognised that this type of combined radiation therapy and chemotherapy may bring an increase in the locoregional failures, attempts were made to include a more intensive latter (radiation therapy) part of the treatment. In such an attempt, Clamon et al. (1999) compared induction chemo- therapy consisting of cisplatin/vinblastine followed by standard radiation therapy (60 Gy in 30 daily frac- tions) with or without concurrent 100 mg/m2/week of carboplatin. There was no difference between the ra- diosensitized and non-radiosensitized groups regard- ing overall survival (the median survival time: 13.4 vs.
13.5 months; 4-year survival: 13% vs. 10%; p=0.74).
These results showed a more sobering picture about induction cisplatin/vinblastine followed by standard radiation therapy that does not necessarily obtain good and lasting results, being inferior in the study of Clamon et al. (1999) to that expected from previous two studies (Dillman et al. 1990; Sause et al. 1995).
They showed that even when sensitised by carbopla- tin, standard fraction radiation therapy can not com- pensate for accelerated proliferation of surviving tu- mour clonogenics which occurs during the induction (chemotherapy) phase of treatment. Furthermore, the results of the study by Clamon et al. (1999) do not dif- fer from those obtained by hyperfractionated radia- tion therapy alone in the Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study (Sause et al. 1995) or the same hyperfractionated ra- diation therapy (69.6 Gy using 1.2 Gy twice-daily) in the study of Jeremic et al. (1996).
More recently, in an attempt to further intensify the second part (radiation therapy) of the combined treatment, Vokes et al. (2002) reported on a ran- domised phase II study by the Cancer and Leukemia Group B (9431) which used two cycles of induction chemotherapy (cisplatin/gemcitabine or cisplatin/
paclitaxel or cisplatin/vinorelbine) followed by two cycles of the same chemotherapy concurrently with conventionally fractionated radical radiation ther- apy (66 Gy) in 175 patients with unresectable stage III non-small cell lung cancer. Response rates were 74%, 67% and 73% for the three arms, respectively.
While the median survival time for all patients was 17 months, 3-year survival rates for the three groups were 28%, 19% and 23%, respectively. Authors con- cluded that the use of concurrent radiochemotherapy could have led to the improvement in outcome when compared to previous Cancer and Leukemia Group B experience with induction treatments (Dillman et al. 1990, 1996; Clamon et al. 1999).
3.2.1.4
Concurrent Radiochemotherapy
This combined modality approach denotes the admin- istration of both modalities at the same time, mean- ing that chemotherapy is given during the radiation therapy course. A number of variations exist, includ- ing chemotherapy being administered on a 3-weekly basis, bi-weekly, weekly, or daily, although concur- rent radiochemotherapy employing third generation drugs (e.g. paclitaxel) also involved administration of the drug twice or thrice weekly. Whatever the design of concurrent radiochemotherapy, its main aim is to address the issue of locoregional and distant disease at the same time, from the outset of the treatment as intensively as possible. This, unfortunately, may lead to increased toxicity (mostly acute) which may require dose reductions or treatment interruptions, both adversely infl uencing treatment outcome. On the other hand, with this approach three radiobio- logical premises, namely spatial cooperation, inde- pendent cell kill and synergistic action, as postulated by Steel and Peckham (1979), can be exploited.
The initial question regarding the effectiveness of concurrent radiochemotherapy was whether it is more effective than radiation therapy alone. In a number of studies radiation therapy alone was tested against concurrent radiochemotherapy, the latter aiming mostly on an improvement at local tumour control. Prospective randomised phase III studies investigating this issue are outlined in Table 3.2.1.2 (Soresi et al. 1988; Schaake-Koning et al. 1992;
Trovo et al. 1992; Blanke et al. 1995; Jeremic et al. 1995, 1996; Bonner et al. 1998; Ball et al. 1999;
Groen et al. 2004). Some of the negative studies may be criticised because of a relatively low total radiation
therapy dose (Soresi et al. 1988; Trovo et al. 1992) and chemotherapy being given in an insuffi cient to- tal dose (Soresi et al. 1988). All three positive stud- ies used protracted chemotherapy dosing. While an European Organization for Research and Treatment of Cancer study (Schaake-Koning et al. 1992) tested both daily and weekly cisplatin with split-course ra- diation therapy, showing superior outcome for daily cisplatin/radiation therapy, Jeremic et al. fi rst used bi-weekly, and weekly(Jeremic et al. 1995), and then daily (Jeremic et al. 1996) carboplatin/etoposide with hyperfractionated radiation therapy doses of 64.8(Jeremic et al. 1995) and then 69.6 Gy (Jeremic et al. 1996). In these two consecutive studies, the best results were obtained with low-dose daily chemo- therapy given during the hyperfractionated radiation
therapy course, with very encouraging 4- to 5-year survival rates being approximately 20% (Jeremic et al. 1995, 1996). As a rule, survival advantage in these three studies was a consequence of an advantage at local tumour level. Obviously, low-dose daily chemo- therapy acted synergistically with radiation therapy, and enhanced its effects on local tumour level. As expected, no infl uence on distant metastasis control was noted. Recently, Cakir and Egehan (2004) pro- vided additional evidence that concurrent radiation therapy (64 Gy in 32 daily fractions) and cisplatin (20 mg/m2, days 1–5, weeks 2 and 6) offers survival advantage over the same radiation therapy alone. At 3 years, 10% patients survived in the combined group while only 2% survived in the radiation therapy lone group. The combined treatment approach also of-
Table 3.2.1.2. Randomised studies of RT versus RT and concurrent platinum-based CHT
Author RT
(dose/fractionation)
CHT drugs/timing
MST (months)
Survival 2-year 3-year Soresi et al.
(1988)
50.4 Gy in 28 fx Same
-
P, 15 mg/m2, weekly
11 16 Schaake-Koning et al.
(1992)
55 Gy split course Same
Same
-
P, 30 mg/m2, weekly P, 6 mg/m2, daily
12 12 14
19%
30%
31%
2%
13%
13%
Trovo et al.
(1992)
45 Gy in 15 fx Same
-
P, 6 mg/m2, daily
10 10
13%
13%
Blanke et al.
(1995)
60–65 Gy in 30–33 fx Same
-
P, 70 mg/m2, day 1, 22, and 43
10 11
13%
18%
Jeremic et al.
(1995)
64.8 Gy (1.2 Gy b.i.d.) Same
Same
-
C, 100 mg, day 1,2; E, 100 mg, E, day 1–3; weekly C, 200 mg, day 1,2; E, 100 mg, day 1-5; weeks 1, 3, 5
8 18 13
25%
35%
27%
6.6%
23%
16%
Jeremic et al.
(1996)
69.6 Gy (1.2 Gy b.i.d.) Same
-
C/E, each 50 mg, daily
14 22
26%
43%
11%
23%
Bonner et al.
(1998)
60 Gy in 30 fx 60 Gy in 40 fx split +/- CHT
-
P, 30 mg/sqm; E, 100 mg/
sqm, day 1–3 and 28–30 8.6 11.6
5%
22%
Ball et al.
(1999)a
60 Gy in 6 weeks Same
60 Gy in 3 weeks Same
-
C, 70 mg/m2 x 5 days, weeks 1 and 5 -
C, 70 mg/m2 x 5 days, week 1
13.8 17.0 14.4 15.0
26%
29%
28%
20%
10%
8%
13%
5%
Groen et al.
2004
60 Gy in 30 fx Same
-
C, 840 mg/m2, CI, 6 weeks 11.7 11.8 Cakir and Egehan
2004
64 Gy in 32 fx Same
-
P, 20 mg/m2 x 5days, weeks 1 and 6
9b 16b
2%
10%
RT, radiotherapy; CHT, chemotherapy; MST, median survival time; P, cisplatin; C, carboplatin; E, etoposide; fx, fractions.
a Includes patients with early stage; b estimated from the available survival curve.
fered better locoregional control (p=0.0001) and dis- ease-free survival (p=0.0006), confi rming previous observations of superiority of combined radiation therapy and platinum chemotherapy over radiation therapy alone.
Additionally, those studies/arms which used high- dose chemotherapy concurrently with radiation therapy observed no impact either on distant metas- tasis control, or on a local level. Another advantage of low-dose concurrent chemotherapy over high-dose chemotherapy and concurrent radiation therapy is that the former type of concurrent radiochemother- apy leads to less high-grade acute toxicity and, conse- quently, better treatment compliance, less treatment interruptions, which infl uence treatment outcome (Cox et al. 1993).
3.2.1.5
Neoadjuvant (Induction) Chemotherapy Followed by Radiation Therapy Versus Concurrent Radiochemotherapy
The induction chemotherapy studies showed a sur- vival advantage for the combined approach owing to the improvement in the distant metastasis control, a fi nding in contrast to that of the concurrent approach studies, which unequivocally showed improvement in survival owing to the improvement in locoregional tumour control. Putting these data into the perspec- tive of exploitable mechanisms of combined radia- tion and chemotherapy (Steel and Peckham 1979), one must identify the induction regimens as those enabling the therapeutic benefi t due to spatial coop- eration only. No independent cell kill can be noted because there was no signifi cant difference in locore- gional tumour control, as one may expect if such independent cell kill would have happened. Also, no enhancement of tumour response can be noted for the same reason. Contrary to these fi ndings, in concurrent studies, spatial cooperation did not work, while both independent cell kill and enhancement of tumour response may have occurred. In the low-dose (daily) chemotherapy arms of the concurrent studies, however, it seems unlikely that independent cell kill occurred (and if so, then to a much lesser degree), thus leaving enhancement of tumour response as the only viable alternative.
Confi rmation of these premises was recently pro- vided by El Sharouni et al. (2003) who investigated the infl uence of waiting times for radiotherapy after induction chemotherapy by comparing CT scans
done at the end of induction chemotherapy and those done for the purpose of radiotherapy planning. In 41% of potentially curable tumours they turned into incurable ones, with the median potential tumour doubling time being 29 days, much less than previ- ously thought.
Since both of these approaches proved to be fea- sible and effective in practice, the next logical step, therefore, was to compare induction chemotherapy followed by radical radiation therapy with concur- rent radiation therapy and chemotherapy. Currently, there are only two prospective randomised phase III studies evaluating concurrent versus induction chemotherapy and radiation therapy. Furuse et al. (1999, 2000) were the fi rst to compare mitomy- cin, cisplatin, and vindesine chemotherapy given as either induction followed by radiation therapy (56 Gy) and the same mitomycin, cisplatin, and vin- desine given concurrently with radiation therapy.
Their fi rst publication showed superior median sur- vival time and 5-year survival (the median survival time, 16.5 vs. 13.3 months; 5-year survival, 16% vs.
9%; p=0.039) for concurrent regimen (Furuse et al.
1999). Subsequent data analysis, focusing on pat- terns of failure, identifi ed an improvement in local tumour control (median time, 10.6 vs. 8.0 months;
5-year, 34% vs. 20%; p=0.0462) as a reason for an im- provement in survival (Furuse et al. 2000). More re- cently, Curran et al. (2000) and Komaki et al. (2000) reported on the Radiation Therapy Oncology Group study 9410 which evaluated the same induction che- motherapy followed by radiation therapy as used by the Cancer and Leukemia group B 8433 (Dillman et al. 1990) and the Radiation Therapy Oncology Group 8808/Eastern Cooperative Oncology Group 4508 (Sause et al. 1995). It was compared with ei- ther standard fraction radiation therapy (60 Gy) and cisplatin/etoposide or hyperfractionated ra- diation therapy (69.6 Gy) and cisplatin/etoposide.
Both the standard radiochemotherapy and hyper- fractionated radiochemotherapy arms had better median survival times than the induction arm (17.0 vs. 16.0 vs. 14.6 months), although only standard radiochemotherapy was statistically signifi cantly better than induction chemotherapy (Curran et al. 2000). Pattern of failure analysis showed that the best local control was in the hyperfractionated ra- diochemotherapy arm, confi rming indirectly the observations of Jeremic et al. (1995, 1996) that high-dose hyperfractionated radiation therapy is an advantageous approach. Furthermore, and contrary to studies using low-dose chemotherapy concurrent with high-dose radiation therapy, it was shown once
again that high-dose chemotherapy bears a risk of exceptional acute toxicity when given with high- dose standard or hyperfractionated radiation ther- apy. This fi nding is not just limited to the Radiation Therapy Oncology Group 9410 but was also seen in similar studies (Byhardt et al. 1995; Lee et al. 1996;
Komaki et al. 1997). Confi rmation of more frequent high-grade toxicity recently came from preliminary results from the recent Canadian meta-analysis (Rakowitch et al. 2004). In that analysis, radiation therapy and concurrent low-dose, daily chemother- apy carried somewhat lower risk of acute toxicity, including high-grade neutropenia when compared to that observed with radiation therapy and concur- rent high-dose chemotherapy, another advantage of radiation therapy and concurrent low-dose, daily chemotherapy.
3.2.1.6
Optimisation of Concurrent Radiochemotherapy
These two large prospective randomised trials solved the question of the “standard” treatment option in lo- cally advanced non-small cell lung cancer. Additional evidence that concurrent radiochemotherapy should be the standard of care in locally advanced non-small cell lung cancer comes from the recent Southwest Oncology Group phase II study by Albain et al.
(2002) which used two cycles of cisplatin/etoposide concurrently with conventionally fractionated 45 Gy in pathologic Stage IIIB non-small cell lung cancer.
In the absence of progressive disease, an additional 16 Gy was administered with two additional cycles of cisplatin/etoposide. The median survival time was 15 months and 5-year survival was 15%. However, grade 4 neutropenia was observed in 32% patients, grade 3–4 anaemia in 28% patients and grade 3–4 esopha- gitis in 20% patients.
Recent attempts to refi ne concurrent radiation therapy and platinum-based chemotherapy include reports by Jeremic et al. (1998, 2001) and Lau et al.
(2001)who both tried to address the issue of some- what poorer distant metastasis control by increas- ing the dose of chemotherapy. While Jeremic et al.
(1998) tested the addition of weekend carboplatin/
etoposide to concurrent hyperfractionated radiation therapy (69.6 Gy) and low-dose daily carboplatin/et- oposide in phase II study leading to a promising me- dian survival time of 29 months and 5-year survival in 25%, the results of their subsequent prospective
randomised trial showed no advantage for weekend chemotherapy when compared to no weekend che- motherapy (MST, 22 vs. 20 months; 5-year survival, 23% vs. 20%; p=0.57) (Jeremic et al. 2001). Lau et al. (2001) used concurrent radiation therapy (61 Gy) and chemotherapy consisting of twice weekly pa- clitaxel for 6 weeks and once weekly carboplatin for 6 weeks. Two cycles of consolidation paclitaxel and carboplatin were offered to patients who achieved a complete response, partial response, or stable dis- ease. The median survival time was 17 months and 2-year actuarial survival rate was 40%. More recently, and quite encouragingly, the South West Oncology Group reported a trial in which concurrent cisplatin/
etoposide/radiation therapy was followed by three cycles of adjuvant high-dose docetaxel (Gandara et al. 2003). The median survival in this phase II study was an extremely impressive 26 months, and this has become the basis for ongoing South West Oncology phase III studies. Most recently, Sakai et al. (2004) re- ported on a phase II study which employed bi-weekly docetaxel and carboplatin with concurrent radiation therapy (60 Gy in 30 daily fractions) followed by con- solidation chemotherapy with docetaxel plus carbo- platin in patients with stage III unresectable NSCLC.
Among 32 evaluable patients, an impressive response rate of 91% was obtained. The median survival time was 27 months and a 2-year survival was 61%. High- grade toxicity was low.
It is likely that we will witness more similar studies in the future and for that reason we believe more emphasis should be placed on the patterns of failure during such treatments, especially because these treatment approaches would need further confi rmation in prospective randomised fashion.
By virtue of their intervention, they all have two parts, a concurrent one and a consolidation one, with the same or different drugs being adminis- tered during the latter part of combined treatment.
Regardless of the underlying principle for such an intervention, these studies nicely outlined overall results, relapse-free survivals and clearly docu- mented toxicity. The latter was divided between the concurrent and the consolidation part and we have all been able to learn more about the exact toxicity which the fi rst or the second parts of the treatment were leading to. Unfortunately, this did not happen with the patterns of failure. While these studies presented very detailed patterns of failure in general, this was done for the whole time period of the study (treatment plus follow-up). This way we only learned about the total patterns of failure and not about which type of failure was observed
when, i.e. after concurrent or after consolidation part, and more particularly in which patients after the concurrent part, although some studies man- dated consolidation chemotherapy in non-pro- gressing patients.
Why is an exact pattern of failure important? It is important from several standpoints, some of which are briefl y outlined here. Firstly, there are several types of patients after the initial (concurrent) part of radiochemotherapy and they can easily be sepa- rated regarding the response. While it is extremely unlikely that those achieving a stable disease (SD) would benefi t from the consolidation chemother- apy, those with either a complete response (CR) or a partial response (PR) seem likely candidates (although not all of them) to benefi t from the con- solidation chemotherapy. Separation, therefore, of pattern of failure occurring in likely (CR and PR) and unlikely (SD) candidates could be used for fur- ther studies of similar design with respect to, e.g.
eligibility criteria. Secondly, and more importantly, among likely candidates (CR and PR) to benefi t from consolidation chemotherapy, a distinction should be made between those achieving CR and those achieving PR after concurrent radioche- motherapy. This is so since different mechanisms (precisely, different location) of action of consoli- dation chemotherapy would be expected. In the CR patients, consolidation chemotherapy would target microscopic disease both intrathoracically and ex- trathoracically, while in the PR patients, it would have to deal with clinically overt intrathoracic dis- ease and a microscopic one extrathoracically. It is obvious that pattern of failure in these two distinct groups of patients would then clearly show how and where consolidation chemotherapy is actu- ally acting and to what extent (clinical versus sub- clinical). Of additional importance is that with a clear pattern of failure, we would be able to open the door to investigating the determinants of treat- ment outcome such as cross-resistance between drugs or drugs and radiotherapy. This would also lead to investigating more of the inherent nature of these treatment modalities such as total dose or fractionation (for radiotherapy) or one or more drug(s) combination(s) (e.g. the same or different drugs in the concurrent and the consolidation part of the treatment), especially important due to the forthcoming generation of drugs waiting to enter wide clinical practice.
Although identifying patterns of failure in pa- tients achieving different responses after concurrent radiochemotherapy may require some additional
measures and likely place additional burden on in- vestigators and hospitals, this effort would ultimately be rewarding. This way we would be able to discrimi- nate between different patients and different options and to proceed (or not) with a consolidation therapy in one or more patient subsets, an approach which would ultimately lead to a better patient-tailored treatment sequence, a must for any clinical research into lung cancer in the future.
One of the unsolved question on “optimisation” of concurrent radiochemotherapy, particularly from the standpoint of radiation oncology, is the type of frac- tionation; conventional, once daily or altered frac- tionation, employing multiple fractions per day (hy- perfractionation). The Radiation Therapy Oncology Group 8311 study (Cox et al. 1990) showed a possible advantage only for a hyperfractionated radiation therapy dose of 69.6 Gy, 1.2 Gy b.i.d. fractionation (but not beyond it) over standard 60 Gy given in 30 daily fractions in a favourable subset of locally advanced non-small cell lung cancer. The Radiation Therapy Oncology Group study 9410, while not statistically de- signed to directly compare standard vs. altered frac- tionation, appeared to show no survival difference be- tween conventional, once daily and hyperfractionated radiation therapy when both given with concurrent chemotherapy. Interestingly, when compared to con- ventionally fractionated radiation therapy, hyperfrac- tionated radiochemotherapy offered better local con- trol in the Radiation Therapy Oncology Group 9410, but this did not translate into a difference in survival.
Another study came to the same conclusion, albeit of somewhat different treatment approach. In the North Central Cancer Treatment Group/Mayo Clinic phase III study (Schild et al. 2002) conventionally frac- tionated radiation therapy (60 Gy) was compared to split-course hyperfractionated radiation therapy us- ing 30 Gy given in 20 fractions on 10 treatment days for 2 weeks with a 2-week break after which another 30 Gy were given using the same fractionation. Both conventionally fractionated and hyperfractionated radiation therapy groups received concurrent cispla- tin/etoposide. No difference in toxicity was seen and no statistically signifi cant difference in treatment out- come, although hyperfractionated radiation therapy offered numerically slightly better survival, and local control.
More recently, the Eastern Cooperative Oncology Group completed a randomised trial comparing standard fractionation radiation therapy versus hy- perfractionated accelerated radiation therapy. All patients in both arms received induction chemo- therapy with carboplatin/paclitaxel, though concur-
rent chemotherapy was not used. Unfortunately, the study did not meet its accrual goals and was closed early; nonetheless 111 patients were analysed and the results suggest a slight though statistically in- signifi cant advantage to hyperfractionated acceler- ated radiation therapy (median survival and 2- and 3-year actuarial survival: 22.2 months, 48% and 20%
vs. 13.7 months, 33% and 15%, respectively) (Belani et al. 2003).
Further attempts to optimise the treatment ap- proach in this disease include radiation therapy given concurrently with “third generation” drugs.
While all “third generation” drugs have been tested in this setting, prospective randomised phase III studies are lacking. Nevertheless, it seems that pacli- taxel/carboplatin combination has similar effi cacy and likely less toxicity than either cisplatin- or other multiagent-based chemotherapy(Kelly et al. 2001;
Schiller et al. 2002). A number of phase II studies tested this combination (Choy et al. 1998, 2000; Lau et al. 2001) with promising results. The fi rst prospec- tive study comparing radiation therapy/paclitaxel versus radiation therapy alone showed an advan- tage for radiation therapy/paclitaxel (the median survival time, 15.2 vs. 12 months; p=0.027) (Ulutin and Pak 2003). Testing paclitaxel/carboplatin com- bination and standard-fraction radiation therapy (63 Gy) in three schedules, Choy et al. (2002) used either pre-radiation therapy chemotherapy followed by radiation therapy (arm 1), pre-radiation therapy and concurrent radiochemotherapy (arm 2) and concurrent radiochemotherapy and post-radiation therapy chemotherapy (arm 3). Although this phase II randomised study was not designed to statisti- cally compare treatment arms, the best results were nevertheless achieved in arm 3 (the median survival time, 16.1 months; 2-year survival, 33%). Also, in arm 2 there was suboptimal compliance with con- current radiochemotherapy after induction chemo- therapy. It is expected that a number of ongoing or recently completed studies bring new insight into the issue of optimisation of radiation therapy and chemotherapy in this disease.
3.2.1.7
New Approaches in Radiation Therapy and Chemotherapy of Locally Advanced Non- Small Cell Lung Cancer
Some of the newer approaches regarding chemother- apy have been mentioned above. It is also expected
that additional new drugs will become more readily available in the future and that the process of their initial clinical testing (phase I–III) will include testing for their radioenhancing potentials which would go parallel to their testing for anticancer chemotherapy purposes. In this way, we would be able to learn about drug properties earlier, both alone or in combination with radiation therapy and to address important is- sues of optimal sequencing radiation therapy and chemotherapy in locally advanced disease.
Regarding radiation therapy, wide application of powerful computers has made a substantial impact on treatment planning and delivery. Three-dimensional conformal radiation therapy is now increasingly be- ing practised world-wide. With radiation therapy fi elds tailored to include only detectable tumour, more focused and escalated radiation therapy doses can be given. Phase I/II studies have shown that radiation therapy doses to the order of >80 Gy are frequently being used with acceptable toxicity (Armstrong et al. 1993, 1997; Robertson et al. 1997), and that the radiation therapy concept of the necessity of elec- tive nodal irradiation may be challenged. It should, however, be mentioned that even with limited fi eld radiation therapy in three-dimensional conformal radiation therapy, some incidental elective nodal ir- radiation always occurs, and may approach 45–50 Gy, considered as the radiation therapy dose necessary for elective treatment (Martel et al. 1999; Rosenzweig et al. 2001). In addition to increasing target coverage and allowing radiation dose escalation, the use of three-dimensional conformal radiation therapy also allows more accurate prediction of toxicity of a given course of radiation therapy (Graham 1997; Kwa et al. 1998).
Intensity-modulated radiotherapy has also been used in locally advanced non-small cell lung cancer and potential advantages of intensity-modulated ra- diation therapy become evident when one compares the three-dimensional conformal radiation therapy and intensity-modulated radiation therapy plans (Yorke 2001). With intensity-modulated radiation therapy, the prescription dose could be increased in the majority of cases. This was coupled with the decreased lung dose and improved planning target volume uniformity, as well as signifi cantly reducing cumulative radiation therapy dose to the oesopha- gus, while maintaining the same or higher dose to gross disease (Giraud et al. 2001). While extracra- nial stereotactic radiosurgery and stereotactic frac- tionated radiation therapy were initially used only for small (early stage) (Uematsu et al. 1998; Hara et al. 2002; Fukumoto et al. 2002; Nagata et al. 2002;
Whyte et al. 2003; Hof et al. 2003; Timmerman et al.
2003; Onimaru et al. 2003) tumours, its application is slowly extending to tumours classifi ed as locally advanced. It is not unrealistic to expect that extracra- nial stereotactic radiosurgery and stereotactic frac- tionated radiation therapy will play an important role in metastatic non-small cell lung cancer, particularly in cases with favourable characteristics (response to chemotherapy, single metastatic lesion, small pri- mary tumours, etc.). However, it should be clearly emphasised that proper selection of patients remains a prerequisite for the use of these new technologies in locally advanced and/or metastatic non-small cell lung cancer.
Although hardly termed a “new approach”, the use of radioprotectors attracted renewed clinical interest in the protection of radiation therapy-induced toxicity.
Several studies reported on the use of amifostine dur- ing radiation therapy and chemotherapy in lung can- cer. Antonodou et al. (2001) performed a randomised phase III trial of radiation therapy with or without daily amifostine in patients with advanced stage lung can- cer. The incidence of pneumonitis >2 was signifi cantly lower in the amifostine group as well as incidence of esophagitis >grade 2, and the protective effect of ami- fostine also produced lower incidence of late damage, with no effect on treatment outcome. Further evidence came from Komaki et al. (2002) who administered amifostine twice weekly before treatment in patients with inoperable non-small cell lung cancer treated with concurrent radiochemotherapy. They observed that Morphine intake to reduce severe esophagitis was signifi cantly lower in the amifostine arm, as well as was the incidence of acute pneumonitis in the treatment arm. Finally, a randomised double-blind study (Leong et al. 2003) showed a trend for fewer patients showing toxicity in the amifostine group. The Radiation Therapy Oncology Group has just reported preliminary results of the study Radiation Therapy Oncology Group 98- 01, which randomised patients to intensive chemora- diation (induction carboplatin/paclitaxel followed by hyperfractionated radiation therapy to 69.6 Gy with concurrent weekly carboplatin/paclitaxel) with or without amifostine four times per week during radia- tion therapy. Although there was no difference in the rate of grade 3 esophagitis, patient-reported area-un- der-the-curve swallowing dysfunction scores were sig- nifi cantly lower in the amifostine group (Movsas et al.
2003). It is expected that more studies addressing the is- sue of optimal protection with amifostine will provide more data on further optimisation before becoming a standard adjunct to radiation therapy or radiochemo- therapy treatments in the future.
3.2.1.8 Conclusions
Locally advanced non-small cell lung cancer is one of the major targets for clinical research in lung can- cer. While it has to date accounted for approximately 40% of all cases, it is expected that widespread use of positron emission tomography (leading to more precise staging of patients) will likely decrease the number of patients falling into stage III non-small cell lung cancer. This is because patients clinically or even pathologically staged as IIIB and a minority of those staged as IIIA will actually have metastatic burden from the outset, undiagnosed with current diagnostic tools. This is supported by simple observation of the natural history of this disease, regardless of the treat- ment: there are always some patients who fail distantly several months or a year after the diagnosis. These pa- tients are likely to be ones who would be upstaged by the use of positron emission tomography and moved to stage IV (metastatic disease). On the other hand, it is expected that a proportion of patients with early stages (I and II) non-small cell lung cancer will also be upstaged, and will likely increase the number of patients actually having stage III (locally advanced) disease. Whatever predominates, locally advanced non-small cell lung cancer will remain one of the ma- jor focuses of clinical research in lung cancer simply because major improvements occurred here and they have occurred owing to optimised combined modal- ity treatments, notably combined radiation therapy and chemotherapy. His is even more so since it had been shown that patients with clinical stage IIIA non- small cell lung cancer treated with concurrent radio- chemotherapy have equivalent outcome when com- pared to those treated with induction chemotherapy followed by surgical resection (Taylor et al. 2004).
These results largely confi rmed the Integroup trial 0139 preliminary data presented during ASCO 2003 (Albain et al. 2003) in which both approaches (induc- tion treatment included radiotherapy as well!) were deemed as feasible. The surgical arm achieved supe- rior progression-free survival but this was achieved at the expense of an increase in treatment-related deaths in this group. The latter fact accompanied with the substantial effects of radiation therapy added to pre- operative chemotherapy, led authors to suggest that longer follow-up is necessary to give better insight into this issue. Nevertheless, radiation therapy and chemotherapy will further evolve in the near future and will bring us to the exiting era of more successful clinical research, leading ultimately to better outcome in this disease.
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