Toxicity and outcome of a phase II trial of taxane-based neoadjuvant chemotherapy and 3-dimensional, conformal, accelerated radiotherapy in locally advanced nonsmall cell lung cancer

Toxicity and Outcome of a Phase II Trial ofTaxane-Based Neoadjuvant Chemotherapy and3-Dimensional, Conformal, Accelerated Radiotherapyin Locally Advanced Nonsmall Cell Lung Cancer

Ana M. Rojas, MD, PhDBasil E. Lyn, BAElena M. Wilson, MDFrances J. Williams, MScNihal Shah, MDJeanette Dickson, MBMichele I. Saunders, MD

Marie Curie Research Wing, Mount Vernon Hos-pital, Northwood, Middlesex, United Kingdom.

BACKGROUND. The objective of this study was to evaluate prospectively the acute

and late adverse effects of taxane/carboplatin neoadjuvant chemotherapy and 3-

dimensional, conformal radiotherapy in patients with locally advanced nonsmall

cell lung cancer (NSCLC).

METHODS. Forty-two patients were entered into a nonrandomized Phase II study of

continuous, hyperfractionated, accelerated radiotherapy (CHART) week-end less

(CHARTWEL) to a dose of 60 grays (Gy). Three cycles of chemotherapy were given

over 9 weeks before radiotherapy. Dose escalation with paclitaxel was from 150 mg/

m2 to 225 mg/m2. Systemic toxicity to chemotherapy was monitored throughout.

Radiation-induced, early, adverse effects were assessed during the first 9 weeks from

the start of radiotherapy, and late effects were assessed from 3 months onward.

Overall survival, disease-free survival, and locoregional tumor control also were

monitored.

RESULTS. Twenty percent of patients failed to receive chemotherapy as planned, pri-

marily because of neutropenia. The incidence of Dische Dictionary Grade �2 and

Grade �3 dysphagia was 57.5% and 10%, respectively, with an average duration of

1.2 weeks and 1.5 days, respectively. By 9 weeks, <3% of patients were symptomatic;

and, eventually, all acute reactions were healed, and there has been no evidence of

consequential damage. At 6 months, the actuarial incidence of moderate-to-severe

pneumonitis was 10%. During this time, all patients were free of severe pulmonary

complications. Actuarial estimates of Grade �2 late lung dysfunction were 3% at

1 year, 10% at 2 years, and remained at this level thereafter. The actuarial 3-year

locoregional control and overall survival rates were 54% and 45%, respectively.

CONCLUSIONS. Neoadjuvant chemotherapy followed by 3-dimensional, conformal

CHARTWEL 60-Gy radiotherapy in patients with advanced NSCLC was feasible and

was tolerated well. Historic comparisons indicated that locoregional tumor control

is not compromised by the use of conformal techniques. Cancer 2006;107:1321–30.

� 2006 American Cancer Society.

KEYWORDS: continuous, hyperfractionated, accelerated radiotherapy week-endless, early morbidity, late morbidity, neoadjuvant chemotherapy, nonsmall-cell lungcancer, 3-dimensional conformal radiotherapy.

A nalyses of patterns of treatment failure indicate that local recur-

rence is a major cause of death in patients with advanced non-

small cell lung cancer (NSCLC) and underpins the belief that local

control is a prerequisite for improved survival.1–3 Bronchoscopic and

radiographic assessment of 353 randomized patients showed a 17%

rate of complete response at the primary site and, at best, a 20% 1-year

Supported by the Cancer Research Campaign UKand by the Mount Vernon Marie Curie ResearchTrust.

Address for reprints: Ana M. Rojas, MD, PhD, MarieCurie Research Wing, Mount Vernon Hospital, North-wood, Middlesex, HA6 2RN United Kingdom; Fax:(011) 44 1923844167; E-mail: [email protected]

Received April 28, 2006; revision received May31, 2006; accepted June 7, 2006.

ª 2006 American Cancer SocietyDOI 10.1002/cncr.22123Published online 10 August 2006 in Wiley InterScience (www.interscience.wiley.com).

1321

locoregional control rate after radical radiotherapy and

radiochemotherapy.4 The demonstration of a radiation

dose-response relation for NSCLC,5 together with the

realization that dose escalation with conventional ra-

diotherapy dose planning and delivery6 has a serious

risk of severe morbidity, has led to the design and eva-

luation of other approaches. Dose intensification to the

primary site has been attempted, for example, with the

use of accelerated, hyperfractionated radiotherapy and

a variety of radiochemotherapy protocols, with varying

degrees of success. More recently, the development of

3-dimensional conformal radiotherapy (3D-CRT) holds

considerable promise for improved locoregional con-

trol from dose escalation while maintaining acceptable

normal tissue effects.7,8

Both treatment acceleration and radiochemother-

apy, in particular concurrent, platinum-based regimens,

can improve treatment outcomes for patients with

NSCLC. For example, the continuous, hyperfractio-

nated, accelerated radiotherapy (CHART) regimen

produced a survival advantage of 9% at 2 years (eq-

uivalent to a 22% reduction in the risk of death) over

conventional 6-week radiotherapy,9 whereas a meta-

analysis of randomized trials of radiochemotherapy

showed a 13% reduction in the risk of death.10 Because

it is possible that an additional survival benefit may be

obtained by combining CHART or CHART-like regi-

mens with chemotherapy, a series of Phase I and II

nonrandomized studies of neoadjuvant chemotherapy

with the CHART week-end less (CHARTWEL) regimen

were undertaken at our center from 1997. The studies

showed that the addition of neoadjuvant chemother-

apy to CHARTWEL heightened acute dysphagia, but

the increase was transient, and there was no evidence

of long-term esophageal complications. Nearly 25% of

patients who received chemoradiotherapy had clinical

evidence of moderate pneumonitis, which was higher

than that observed among patients who received ra-

diation alone, but no signs of severe, late, clinical pul-

monary fibrosis were observed. Relative to late adverse

effects, the higher locoregional control rates observed

with CHARTWEL plus neoadjuvant chemotherapy sug-

gested the possibility of a therapeutic gain.11

More recently, the feasibility of delivering 3D-CRT

with the CHARTWEL regimen, which requires the use

of 3 treatments per day, was evaluated. In addition, the

incidence and severity of adverse effects when 3D-CRT

was combined with neoadjuvant chemotherapy was

monitored. Comparisons with the previous series should

provide a basis for determining whether further radia-

tion dose escalation and/or the introduction of con-

current radiochemotherapy protocols are feasible with

CHARTWEL. This article reports on normal tissue

responses and, as secondary endpoints, locoregional

tumor control and survival in patients with locally ad-

vanced, UICC Stage III or inoperable Stage I/II NSCLC.

Acute morbidity was assessed by scoring the incidence

and severity of dysphagia and the degree of analgesia

required by each patient during and after radiotherapy

for up to 9 weeks. Early and late pulmonary morbidity,

spinal cord morbidity, and esophageal morbidity were

assessed by using clinical and/or radiologic criteria.

Hematologic and gastrointestinal acute toxicity also was

monitored in patients who received chemotherapy.

MATERIALS AND METHODSFrom October 1999 to December 2003, 42 patients

were entered into a nonrandomized prospective study

of 3D-CRT CHARTWEL and neoadjuvant chemother-

apy. Patients who were not suitable for treatment with

chemotherapy because of comorbidity or who de-

clined chemotherapy received 3D-CRT CHARTWEL

alone to 60 grays (Gy). The local ethics committee

granted approval, and written informed consent was

obtained from each patient. Only patients age >18

years with histologically proven, inoperable NSCLC

confined to the thorax who were eligible for radical

radiotherapy and who had a World Health Organiza-

tion performance status of 0 or 1 were selected. Pre-

treatment lung function was assessed by measuring

the forced expiratory volume (FEV). In general, the

FEV in 1 second (FEV1) was >1.5 liters, but patients

who had an FEV1 of 1 to 1.5 liters were included in

the study at the physicians’ discretion. Prior to treat-

ment, patients also had a chest X-ray, bronchoscopy,

computed tomography (CT) scan of the chest, and his-

tology or brush cytology. Serum urea and electrolyte

levels, liver function tests, and ethylenediamine tetraa-

cetic acid (EDTA) clearance were obtained prior to the

first course of chemotherapy and subsequently if indi-

cated. Full blood counts were obtained before each

TABLE 1Patient Demographics and Tumor Staging

Parameter Value

No. of patients 42

Male:female ratio 32:10

Age, y

Range 48–88

Mean 66.8

Median 68.1

Stage

Stage IA 3

Stage IB 10

Stage IIB 6

Stage IIIA 6

Stage IIIB 16

Not known 1

1322 CANCER September 15, 2006 / Volume 107 / Number 6

course of chemotherapy. The presence of liver metasta-

ses was assessed biochemically and by CTor ultrasound

scans. Further investigations to exclude metastases in

other sites were carried out only if they were indicated

clinically.

CHARTWEL to 60 Gy was given in 40 fractions, at

1.5 Gy per fraction, 3 times per day (with a minimum

6-hour interfraction interval), in 15 fractions per week

over 18 to 19 days. Forty-two patients were planned

and treated with 3D-conformal radiotherapy either

alone (n ¼ 12 patients) or combined with chemother-

apy (n ¼ 30 patients). Demographic details and tumor

staging are shown in Table 1. In all, 28 squamous cell

carcinomas, 5 adenocarcinomas, 1 large cell carcinoma,

and 5 tumors characterized as NSCLC were identified

either by histologic and/or cytologic examination. In 3

patients, the histologic classification was not known.

A diagnostic CT scan of the chest and upper ab-

domen was obtained to aid interpretation of the plan-

ning CT scan. The patient was positioned supine with

shoulders and elbows held in flexion by using a metal

external immobilization frame, which was designed

and built in-house. A planning CT scan of the chest

that encompassed the whole of both lungs was then

obtained by using 5-mm contiguous and sequential

slices in quiet respiration. The scan was transferred to

the treatment-planning computer by Dicom link.12

3D-CRT treatment planning was then performed by

using PinnacleTM software (version 4.2f). Skin, lung,

and spinal cord were outlined on each slice through

the chest. Target volumes were defined according to

International Commission on Radiation Units and

Measurements Report 50.13 On each relevant slice, the

gross tumor volume (primary tumor and lymph node

disease; lymph nodes measuring >1 cm short axis) was

marked. Areas for elective lymph node irradiation, a

subset of the clinical target volume, also were marked.

The clinical target volume was determined by expand-

ing of the gross tumor volume by 5 mm to allow for mi-

croscopic invasion, as described in detail elsewhere12;

and the planning treatment volume was determined by

a further expansion of 5 mm to allow for set-up errors

and organ motion. Treatment was then delivered by

using 6-megavolt photons. The primary tumor and

known lymph node disease received a total dose of 60 Gy.

The Phase-1 volume encompassed the primary tu-

mor, the involved hilar and mediastinal lymph nodes,

and suspicious mediastinal lymph nodes (which

received elective lymph node irradiation). Lymph

nodes with a shortest axis >1 cm were considered to

contain metastatic disease. The Phase-2 volume com-

prised a boost dose to the primary tumor and to

known lymph node disease only. Some patients with

small peripheral tumors, in whom the involvement of

mediastinal lymph nodes was unlikely, and patients

who had relatively poor respiratory function were trea-

ted in a single Phase-2 technique. The esophagus gen-

erally was included in the Phase-1 volume and, if it

TABLE 2Scoring Criteria for Early and Late Morbidity *

Morbidity scores 0 1 2 3 4

Acute

Dysphagia None Discomfort on swallowing Soft diet Fluids only Severe difficulty

with fluids

Analgesia None Surface medicine Nonnarcotic medicines Narcotic medicines

Chronic

Dysphagia (stricture) None Caused by tumor Caused by radiotherapy Not known

Lung (clinical) None Symptoms not interfering

with lifestyle

Symptoms requiring treatment Hospitalized/house bound

Spinal cord None L’Hermittes Incomplete paraplegia Complete paraplegia

* Assessment according to the Dische Dictionary scoring system.

TABLE 3Hematologic Toxicity for Each of the 3 Cycles ofNeoadjuvant Chemotherapy

Schedule

(No. of patients)

Mean 6 SEM

Hb concentration

(g/dL)

Mean 6 SEM

WBC count

(3 109/L)

Mean 6 SEM

platelet count

(3 109/L)

MIC (n ¼ 8)

Cycle 1 13.7 6 0.8 7.9 6 0.7 356 6 25

Cycle 2 12.1 6 0.4 5.1 6 0.9 278 6 20

Cycle 3 11.9 6 0.6 4.5 6 0.3 235 6 27

P .06 .002 .002

Tax/Cb (n ¼ 16)

Cycle 1 13.8 6 0.4 9.6 6 0.8 335 6 23

Cycle 2 13.0 6 0.4 9.1 60.8 312 6 23

Cycle 2 12.1 6 0.4 6.9 6 0.5 232 6 25

P .01 .01 .003

SEM indicates standard error of the mean; Hb, hemoglobin; WBC, white blood cell; MIC, mitomycin

C, cisplatin, and ifosfamide; Tax/Cb, taxol plus carboplatin.

3-D Conformal Radiochemotherapy in NSCLC/Rojas et al. 1323

was located close to disease, in the Phase-2 volume,

particularly if there was aortal-pulmonary and subcar-

inal disease. Therefore, the esophagus received a dose

intermediate between that given in Phase 1 (37.5 Gy)

and the full tumor dose (60 Gy). No attempt was made

to avoid the esophagus. The organ was not outlined as

part of the 3D treatment-planning process, and esoph-

ageal dose-volume histograms were not constructed.

Neoadjuvant chemotherapy, which consisted of 3

cycles of paclitaxel plus carboplatin (area under the

concentration-time curve [AUC] � 6; note that the

AUC for EDTA clearance is AUC ¼ [glomerular filtra-

tion rate þ 25] mg/min), was given over 6 weeks be-

fore the start of 3D-CRT. Dose escalation with

paclitaxel was from 150 mg/m2 (n ¼ 5 patients), 175

mg/m2 (n ¼ 5 patients), 200 mg/m2 (n ¼ 6 patients),

and 225 mg/m2 (n ¼ 1 patient). Patients who had a

history of previous malignancy, poor respiratory func-

tion, and/or were to be treated with a single-phase

CRT technique were excluded a priori from the dose-

escalation study. Twelve patients fell into this category

and received mitomycin C (6 mg/m2) plus cisplatin

(50 mg/m2) combined with either ifosfamide (3 mg/

m2) or vinblastine (6 mg/m2). One patient who was

treated off-site was given gemcitabine together with

carboplatin (dose levels unknown). All but 1 patient (who

received 4 chemotherapy cycles) were given 3 cycles of

chemotherapy spaced at 3-weekly intervals and CRT,

which started 3 weeks after the 3rd cycle.

All patients received radiotherapy as planned. Af-

ter the start of radiotherapy, patients were seen weekly

for up to 9 weeks, subsequently at 3 months, every

3 months up to 2 years, twice yearly for up to 5 years,

and annually thereafter. During treatment and until

the acute reactions had settled, the severity of dyspha-

gia and the type of medication used were assessed by

using the Dische Dictionary scoring system, which is

summarized in Table 2.14 Two patients who had a pe-

ripheral presentation of the primary tumor were elimi-

nated from the analysis of esophageal damage and

analgesia, because the irradiation fields excluded the

mediastinum (both patients were in the radiation-

alone arm). The prevalence, incidence, and duration of

early adverse events at different levels of severity were

calculated for both dysphagia and analgesia.

Late radiation-induced adverse effects were as-

sessed initially every 3 months for up to 2 years, bi-

annually up to 5 years, and annually thereafter. At each

follow-up, a chest X-ray and/or CT scans were ob-

tained. Time-incidence curves and statistical compari-

sons were calculated by computing actuarial disease-

free intervals by using the product-limit (Kaplan–

Meier) method. Lung dysfunction was diagnosed by

both clinical and radiologic examination. Pneumonitis

was considered the transient, intermediate syndrome

that occurred during the first 6 months after the first

radiotherapy treatment, and late pulmonary toxicity

(lung fibrosis) as the syndrome evolving thereafter.

Locoregional control was attained if there was ei-

ther complete disappearance of all radiologic abnorm-

alities in the lung or when any residual abnormality

observed at 6 months remained stable for another 6

months or more. Patients who did not achieve this

were categorized as ‘‘never disease-free.’’ Overall sur-

FIGURE 1. These graphs illustrateacute dysphagia and the degree of

analgesia required. Top. The preva-

lence of Grade �2 (circles), Grade�3 (triangles), and Grade 4 (squares)dysphagia is illustrated on the left,

and the prevalence of Grade �1 (cir-cles), Grade �2 (triangles), and Grade3 (squares) analgesia is illustrated on

the right. Error bars 6 1 standard

deviation (SD). Bottom: The incidence

of Grade �2 (solid bars) and Grade�3 (open bars) dysphagia and anal-gesia are illustrated on the left, and

the duration of dysphagia and analge-

sia are illustrated on the right. SEM

indicates standard error of the mean.

1324 CANCER September 15, 2006 / Volume 107 / Number 6

vival was calculated as the time from the first radio-

therapy treatment to death; patients who remained

alive were censored at the last date they were seen. Dis-

ease-free survival was calculated as the time between

the commencement of CHARTWEL and the first evi-

dence of locoregional recurrence or distant metastases

or the date of death from any other cause. Survival fits

were obtained by using the product-limit (Kaplan–

Meier) method.

RESULTSChemotherapy, as planned, was received by 80% of

patients. Dose reductions and/or delays between

chemotherapy cycles and/or the start of radiotherapy

were caused primarily by neutropenia. Three patients

had severe neutropenia after the first or second cycle

of mitomycin C, ifosfamide, and cisplatin (MIC),

whereas another patient presented with severe to

life-threatening neutropenia after the first cycle of

paclitaxel/carboplatin therapy and was hospitalized

because of neutropenic sepsis. All these events were

managed and resolved with standard medical proce-

dures. The median time from the last chemotherapy

cycle and the start of radiotherapy was 33 days. Table 3

summarizes the mean values for hemoglobin concen-

trations, white blood cell counts, and platelet counts

throughout chemotherapy for 24 patients who received

either MIC (n ¼ 8 patients) or paclitaxel/carboplatin

(n ¼ 16 patients). There was a progressive reduction in

all 3 parameters that was significant for all compari-

sons except for hemoglobin in patients who received

MIC. Six patients were treated elsewhere and had no

toxicity data available. Severe nonhematologic morbid-

ity was not encountered in this series. There were 2

events of mild peripheral neuropathy (Patients 169

and 173), and there was 1 event of moderate neuropa-

thy (Patient 173): Both patients were receiving pacli-

taxel/carboplatin chemotherapy.

Figure 1 shows the prevalence of acute esophageal

reactions for 3 levels of severity (Grades �2, �3, and 4)

and of the type of medication (i.e., topical, nonnarco-

tic, narcotic) that was used to ameliorate the symp-

toms during the first 9 weeks after the start of 60-Gy

CHARTWEL in 40 patients who were treated with or

without adjuvant chemotherapy (2 patients were

excluded from the analysis). For moderate or worse

levels of dysphagia (i.e., Grade �2), the peak preva-

lence was observed at approximately 3 to 4 weeks after

the start of radiotherapy and was followed by a rapid

decline in the proportion of symptomatic patients, so

that, by 9 weeks, the prevalence of acute esophageal

reactions was <3%. For more severe levels of morbidity

(i.e., Grades �3 and 4), the response was shallower and

less time-dependent. Similar conclusions can be drawn

from the analysis of analgesia. The incidence and dura-

tion of Grade 2 or worse and Grade 3 or worse dyspha-

gia and the incidence and duration of Grade 2

analgesia (i.e., the use of nonnarcotic or worse analge-

sia) and Grade 3 analgesia (i.e., narcotic analgesia) also

are shown. Virtually 60% of patients had moderate-to-

severe dysphagia, but severe or worse dysphagia was

present in only 10% of patients during this 9-week ob-

servation period: All of these patients received narcotic

medication. On average, Grade 2 or worse reactions

lasted for 1.2 6 0.2 weeks (6 1 standard error of the

mean), whereas Grade 3 or worse reactions lasted for

1.4 6 0.1 days. At all times during follow-up, the preva-

lence, incidence, and duration of reactions in the

12 patients who received radiation alone were consid-

erably lower compared with those among the patients

who received chemotherapy, however, the differences

FIGURE 2. These charts illustrate the actuarial incidence of Grade �2(dashed lines) and Grade 3 (solid lines) early pneumonitis (top) and late lung

dysfunction (bottom).

3-D Conformal Radiochemotherapy in NSCLC/Rojas et al. 1325

were not significant, probably because of the small

number of patients in the radiation-alone arm (data

not shown).

The proportion of patients who were free of clini-

cal symptoms of pneumonitis and late lung dysfunc-

tion is shown in Figure 2. At 6 months, 29% of

patients had some sign and/or symptom of clinical

pneumonitis (i.e., Grade 1 or worse; curve not shown),

whereas moderate-to-severe pneumonitis was ob-

served in 10% of patients. Moreover, all patients were

free of severe complications (Grade 3) throughout this

time. The actuarial incidence of Grade 2 or worse late

lung morbidity was 3% at 1 year, rose to 10% at

2 years, and remained at that level for the remaining

time. Only 1 patient in this series presented with

severe pulmonary symptoms, which occurred 3 years

after treatment, yielding an actuarial Grade 3 morbid-

ity estimate of 7%.

The correlation between the percent volume of the

lung that receives �20 Gy (V20) or mean radiation dose

to the lung (MLD) and the severity of pneumonitis or

late lung dysfunction is shown in Figure 3. Within the

relatively narrow range of V20 (11–40%) and MLD (6.8–

21.7 Gy), the data show little indication of an increase

in the severity of damage with increasing parameter

values, particularly for pneumonitis. There was a good

correlation between V20 and MLD (r ¼ 0.75; P< .0001).

Treatment outcomes were assessed by means of

locoregional tumor control, disease-free survival, and

overall survival and are illustrated in Figure 4. The ac-

tuarial rates at 1 year, 2 years, and 3 years for locore-

gional tumor control, disease-free survival, and overall

survival were 76%, 61%, and 54% (locoregional con-

trol);, 74%, 48%, and 39% (disease-free survival), and

81%, 57%, and 45% (overall survival), respectively. To

date, no deaths have been attributable directly to

radiation-induced damage. Actuarial analyses of over-

all survival and metastases-free survival in patients

who did and did not attain control of their primary tu-

mor was carried out and also are shown in Figure 4.

Control of local disease had a significant impact on

survival: At 2 years, the overall survival rate was 67%

compared with 47% (P ¼ .05; log-rank test), and the

metastases-free survival rate was 67% compared with

43% (P ¼ .03; log-rank test) for patients who achieved

and did not achieve control of their primary tumor

site, respectively.

DISCUSSIONThe current data indicate that the dose-escalation sched-

ule of neoadjuvant chemotherapy with CHARTWEL to

60 Gy planned and delivered by using 3D-conformal

techniques is feasible and well tolerated. Compliance to

3 cycles of neoadjuvant chemotherapy (80%) was in the

lower range of that reported in other nonrandomized

trials of chemotherapy combined with 3D-CRT.15–17

Severe, radiation-induced, acute toxicity was mini-

mal and of short duration. The extent and duration

of all levels of early dysphagia was considerably less

FIGURE 3. The percent of lung vol-ume that received a radiation dose �20grays (Gy) (left graphs) and the mean

dose to the lung (right graphs) were

plotted against pneumonitis by grade

(top) or by late lung dysfunction (bottom).

Correlation coefficients (r) obtained from

the linear regression fits varied from

r ¼ 0.17 to r ¼ 0.43.

1326 CANCER September 15, 2006 / Volume 107 / Number 6

than that observed previously in patients who received

treatment in this center using nonconformal CHARTWEL

radiotherapy. Although there was no a priori intention

to spare the esophagus, the ability to delineate signifi-

cantly shorter superior-inferior lengths with conformal

techniques, relative to nonconformal delivery, for both

large and small volumes (P � .03) may explain the re-

duced mucositis. To date, there is no evidence of radia-

tion-induced, late damage to the esophagus. Likewise,

pulmonary morbidity was low. Moderate pneumonitis

(assessed during the first 6 months) developed in 10%

of patients, and severe pneumonitis developed in none

of the patients. The actuarial incidence of patients with

moderate or worse late lung dysfunction was 3% at 1

year and rose to 10% at 2 years. No events of severe

late symptoms were observed during that time. To

date, randomized comparisons of therapeutic gains

with CRT are not available. Bearing in mind all the

caveats associated with comparisons made using his-

toric controls from nonrandomized studies, our 3D-

CRT data relative to nonconformal techniques11 show

reduced incidence of adverse effects, particularly com-

pared with nonconformal CHARTWEL plus chemo-

therapy. These observations, namely, the reduced adverse

effects with CRT and their exacerbation by neoadjuvant

or concurrent chemotherapy, are well documented.8,18–20

Feasibility trials of 3D-CRT therapy that, like the

current trial, had the primary objective of evaluating

radiation adverse effects, are summarized in Table 4.

Because of differences in the scoring systems, methods

of analyses, variability in timing, and frequency of fol-

low-up, it is difficult to make valid cross-comparisons

between series. Comparing incidence rates of acute

morbidity may be straight forward enough. However,

such a comparison assumes that patients are scored at

the time during which peak reactions occur. Generally,

patients are seen once per week during radiotherapy, a

gap long enough for peak reactions to occur and even

resolve. Furthermore, this approach does not consider

the time spent at a particular reaction level. Determin-

ing this parameter or, equally, determining prevalence

over an appropriate observation period is akin to

defining an area under the curve; from it, the time of

onset of the reaction and, most important, the kinetics

of the recovery phase can be obtained and should be a

more reliable estimate of toxicity. In addition, it

enables the clinician to identify the patients who are at

risk of sustaining consequential damage. Two relatively

recent reviews discussed in detail the complexities

associated with normal tissue analyses and report-

ing.21,22 Because of the continually evolving nature of

radiation damage, late effects are far more difficult to

record and report, and many series suffer from paucity

of data and from suboptimal analytic methodology

FIGURE 4. Actuarial survival curves. Top: Locoregional (LRC) tumor control(solid line), disease-free survival (DFS) (dotted line), and overall survival

(dashed line) are illustrated. Middle: Overall survival is illustrated in patients

who maintained permanent tumor control (solid line) and in patients who

never attained or lost control of the primary tumor (dashed line) (log-rank

P ¼ .05). Bottom: Metastases-free survival is illustrated in patients whoattained permanent tumor control (solid line) and in patients who never

attained or lost control of the primary tumor (dashed line) (log-rank P ¼ .03).

3-D Conformal Radiochemotherapy in NSCLC/Rojas et al. 1327

and reporting.21,23 It is disconcerting that crude inci-

dence rates still are in use in an appreciable number of

reports. This can underestimate the real incidence sig-

nificantly, because it considers all patients included in

the study and not just those at risk from suffering the

event. Cumulative incidence is an improved method;

however, the actuarial analysis is considered the me-

thod of choice. Albeit and as shown in Table 4, our

results for early incidence of esophagitis and actuarial

estimates for late effects compare favorably with those

reported by others. Bearing in mind the extremely

accelerated nature of the CHARTWEL regimen, it is

noteworthy that a relatively low incidence of severe

esophageal toxicity was encountered, and late esopha-

geal complications were completely absent. Likewise,

there is no evidence of spinal cord or late normal tis-

sue complications in other organs at risk.

Both V20 and MLD have been proven to be useful

predictors of radiation-induced pneumonitis. In the

current study, no correlation was observed between the

severity of lung complications and either V20 or MLD.

However, the volumes of lung irradiated to �20 Gy var-

ied from 11% to 40%, and MLD did not exceed 22 Gy.

The upper limits for both parameters were lower than

those reported in other published series,.6,24,25 which

demonstrated that a threshold must be exceeded be-

fore the predictive value becomes apparent.

Because of the nonrandomized nature of the stu-

dies conducted to date and the small number of pa-

tients treated by most centers, estimates of treatment

outcome with 3D-CRTare not robust and, thus, should

be interpreted with caution. Tables 5 and 6 illustrate that

the 1-year, 2-year, and 3-year actuarial estimates of local

tumor control and overall survival for neoadjuvant

CHARTWEL are in good agreement with outcome esti-

mates from other studies. Although CHARTWEL delivers

a relatively low total radiation dose, it still achieves good

control of disease and survival. The precursor of

CHARTWEL (i.e., CHART, an even more accelerated

regimen up to 54 Gy in 12 days), in a randomized set-

ting, produced an absolute survival advantage of 9% at

TABLE 4Incidence of Severe Early and Late Esophageal and Pulmonary Complications in Trials of Conformal RadiotherapyAlone or Combined with Chemotherapy

No. of patients Dose, Gy Time, Weeks

Complications (% of patients)

Reference

Esophagus Lung

Early Late Early Late

45 52.2–72 6–8 2 0 9* Armstrong et al., 19977

55 60.8–87.8 6 0 0 6* Belderbos et al., 200328

177 70.9–90.3 7–8 0 �8 �9 �16 Bradley et al., 200530

91 73.6–80 11 3 Maguire et al., 199929

44 73.6–86.4 4–5 8–14 0–8 0 0–25 Marks et al., 200431

62 60–74 6–7.5 10 0 Rosennman et al., 200216

104 70.2–90 8–9 0–10 0 5–43 10–34 Rosenzweig et al., 200532

152 50–81 6–8 3 15* Sim et al., 200117

207 60–74 6–7 5 6 Singh et al., 200333

25 78–90 8–9 16 12 0 4 Socinski et al., 200434

62 60–74 6–8 8 0 0 0 Socinski et al., 200235

38 60 6 15 3 27 0 Willner et al., 200136

68 31–80 0–19 0–11 0–4 4 Wolski et al., 200537

Gy indicates grays.

* The report did not make it clear whether this was early or late lung morbidity.

TABLE 5Locoregional Control Rates in Trials of Conformal Radiotherapy Aloneor Combined with Neoadjuvant and/or Concurrent Chemotherapy

No. of

patients

CT (No. of

patients)

LCR (%)

Reference1 year 2 years 3 years

177 25 61–92 50–78 Bradley et al.,

200530

106 20 58 40 31 Kong et al., 200538

146 146 65 42 �39* Lee et al., 200315

104 16 27–84 Rosenzweig

et al., 200532

37 NS 62 23 23 Sibley et al., 199539

82 82 �77* 43 �38* Sim et al., 200117

70 0 �59* 35 �32* Sim et al., 200117

58y 41 77 41 26 Wolski et al., 200537

42 30 76 61 54 Current study

LCR indicates locoregional control; CT, chemotherapy; NS, not specified.

* Read off from graph.y Included only patients with Stage III disease.

1328 CANCER September 15, 2006 / Volume 107 / Number 6

2 years compared with 6 weeks of conventional radio-

therapy. The contention that a ‘‘tumorocidal effect’’ is

obtained by shortening the overall treatment time

(and, thus, minimizing compensatory proliferation) is

underpinned by the findings of Fowler and Chappell,

who showed that NSCLC tumors can repopulate dur-

ing treatment with a potential doubling time of ap-

proximately 3 days.26 A recent retrospective analysis of

3 prospective Radiation Therapy Oncology Group trials

showed that prolonged treatment time was associated

with poorer survival (P ¼ .02): Those authors reported

a 2% increase in the risk of death for each day that

treatment was prolonged.27

Despite advances in the treatment of locally ad-

vanced NSCLC, outcomes remain disappointing, and

local recurrence and distant metastases remain the

major causes of death. Previous studies have demon-

strated that patients with locally controlled disease

have a significant advantage in terms of overall survival

and metastases-free survival compared with patients

who either lost or never achieved control of the pri-

mary tumor.3,5 Perhaps the widely held view that con-

trol of primary disease is the prerequisite to improving

survival may be achieved with the use of CRT based on

the unproven assumption that dose escalation would

achieve improved locoregional control while maintain-

ing acceptable morbidity.

In general, concurrent radiochemotherapy appears

to achieve higher tumor control and survival rates than

neoadjuvant treatments10; therefore, future investiga-

tions at our center will combine neoadjuvant and

concomitant chemotherapy. Unfortunately, the clini-

cal results indicate that it is unlikely that any combina-

tion of radiotherapy with the drugs currently available

will lead to dramatic improvements in treatment out-

come. Furthermore, most studies have shown that

normal tissue affects are more severe with radioche-

motherapy schedules20 and reduce the therapeutic

benefit. The very low level of both early and late mor-

bidity encountered with CHARTWEL using conformal

delivery and the high regional control and survival

observed in these patients indicate that dose-escala-

tion protocols of conformal CHARTWEL radiotherapy

alone and combined with chemotherapy, coupled with

stratification of patients by known risk factors,24,28,29

warrant evaluation.

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TABLE 6Overall Survival Rates in Nonrandomized Trials of ConformalRadiotherapy Alone or Combined with Neoadjuvant and/orConcurrent Chemotherapy

No. of

patients

CT (No. of

patients)

OS rate (%)

Reference1 year 2 years 3 years

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200135

34 34 73 34 Willner et al., 200136

58y 41 44 27 12 Wolski et al., 200537

42 30 81 57 45 Current study

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1330 CANCER September 15, 2006 / Volume 107 / Number 6