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Keywords:

  • continuous;
  • hyperfractionated;
  • accelerated radiotherapy week-end less;
  • early morbidity;
  • late morbidity;
  • neoadjuvant chemotherapy;
  • nonsmall-cell lung cancer;
  • 3-dimensional conformal radiotherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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, primarily 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. © 2006 American Cancer Society.

Analyses of patterns of treatment failure indicate that local recurrence is a major cause of death in patients with advanced nonsmall 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 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 radiotherapy dose planning and delivery6 has a serious risk of severe morbidity, has led to the design and evaluation 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 control from dose escalation while maintaining acceptable normal tissue effects.7, 8

Both treatment acceleration and radiochemotherapy, in particular concurrent, platinum-based regimens, can improve treatment outcomes for patients with NSCLC. For example, the continuous, hyperfractionated, accelerated radiotherapy (CHART) regimen produced a survival advantage of 9% at 2 years (equivalent 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 regimens 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 chemotherapy 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 radiation alone, but no signs of severe, late, clinical pulmonary fibrosis were observed. Relative to late adverse effects, the higher locoregional control rates observed with CHARTWEL plus neoadjuvant chemotherapy suggested 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 radiation dose escalation and/or the introduction of concurrent 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 advanced, 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 METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

From October 1999 to December 2003, 42 patients were entered into a nonrandomized prospective study of 3D-CRT CHARTWEL and neoadjuvant chemotherapy. Patients who were not suitable for treatment with chemotherapy because of comorbidity or who declined 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 Organization performance status of 0 or 1 were selected. Pretreatment 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 treatment, patients also had a chest X-ray, bronchoscopy, computed tomography (CT) scan of the chest, and histology or brush cytology. Serum urea and electrolyte levels, liver function tests, and ethylenediamine tetraacetic acid (EDTA) clearance were obtained prior to the first course of chemotherapy and subsequently if indicated. Full blood counts were obtained before each course of chemotherapy. The presence of liver metastases was assessed biochemically and by CT or 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 = 12 patients) or combined with chemotherapy (n = 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.

Table 1. Patient Demographics and Tumor Staging
ParameterValue
No. of patients42
Male:female ratio32:10
Age, y
 Range48–88
 Mean66.8
 Median68.1
Stage
 Stage IA3
 Stage IB10
 Stage IIB6
 Stage IIIA6
 Stage IIIB16
 Not known1

A diagnostic CT scan of the chest and upper abdomen was obtained to aid interpretation of the planning 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 Pinnacle™ 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 expanding of the gross tumor volume by 5 mm to allow for microscopic 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 tumor, 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 comprised 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 treated in a single Phase-2 technique. The esophagus generally was included in the Phase-1 volume and, if it was located close to disease, in the Phase-2 volume, particularly if there was aortal-pulmonary and subcarinal 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 esophageal 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 = [glomerular filtration rate + 25] mg/min), was given over 6 weeks before the start of 3D-CRT. Dose escalation with paclitaxel was from 150 mg/m2 (n = 5 patients), 175 mg/m2 (n = 5 patients), 200 mg/m2 (n = 6 patients), and 225 mg/m2 (n = 1 patient). Patients who had a history of previous malignancy, poor respiratory function, 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. After 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 dysphagia 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 peripheral presentation of the primary tumor were eliminated 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.

Table 2. Scoring Criteria for Early and Late Morbidity*
Morbidity scores01234
  • *

    Assessment according to the Dische Dictionary scoring system.

Acute
 DysphagiaNoneDiscomfort on swallowingSoft dietFluids onlySevere difficulty with fluids
 AnalgesiaNoneSurface medicineNonnarcotic medicinesNarcotic medicines 
Chronic
 Dysphagia (stricture)NoneCaused by tumorCaused by radiotherapyNot known 
 Lung (clinical)NoneSymptoms not interfering with lifestyleSymptoms requiring treatmentHospitalized/house bound 
 Spinal cordNoneL'HermittesIncomplete paraplegiaComplete paraplegia 

Late radiation-induced adverse effects were assessed initially every 3 months for up to 2 years, biannually up to 5 years, and annually thereafter. At each follow-up, a chest X-ray and/or CT scans were obtained. Time-incidence curves and statistical comparisons 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 either complete disappearance of all radiologic abnormalities 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 survival was calculated as the time from the first radiotherapy treatment to death; patients who remained alive were censored at the last date they were seen. Disease-free survival was calculated as the time between the commencement of CHARTWEL and the first evidence 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.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Chemotherapy, 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 tolife-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 procedures. The median time from the last chemotherapy cycle and the start of radiotherapy was 33 days. Table 3 summarizes the mean values for hemoglobin concentrations, white blood cell counts, and platelet counts throughout chemotherapy for 24 patients who received either MIC (n = 8 patients) or paclitaxel/carboplatin (n = 16 patients). There was a progressive reduction in all 3 parameters that was significant for all comparisons except for hemoglobin in patients who received MIC. Six patients were treated elsewhere and had no toxicity data available. Severe nonhematologic morbidity 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 neuropathy (Patient 173): Both patients were receiving paclitaxel/carboplatin chemotherapy.

Table 3. Hematologic Toxicity for Each of the 3 Cycles of Neoadjuvant Chemotherapy
Schedule (No. of patients)Mean ± SEM Hb concentration (g/dL)Mean ± SEM WBC count (× 109/L)Mean ± SEM platelet count (× 109/L)
  1. SEM indicates standard error of the mean; Hb, hemoglobin; WBC, white blood cell; MIC, mitomycin C, cisplatin, and ifosfamide; Tax/Cb, taxol plus carboplatin.

MIC (n = 8)
 Cycle 113.7 ± 0.87.9 ± 0.7356 ± 25
 Cycle 212.1 ± 0.45.1 ± 0.9278 ± 20
 Cycle 311.9 ± 0.64.5 ± 0.3235 ± 27
 P.06.002.002
Tax/Cb (n = 16)
 Cycle 113.8 ± 0.49.6 ± 0.8335 ± 23
 Cycle 213.0 ± 0.49.1±0.8312 ± 23
 Cycle 212.1 ± 0.46.9 ± 0.5232 ± 25
 P.01.01.003

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, nonnarcotic, narcotic) that was used to ameliorate the symptoms 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 prevalence 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 duration of Grade 2 or worse and Grade 3 or worse dysphagia and the incidence and duration of Grade 2 analgesia (i.e., the use of nonnarcotic or worse analgesia) 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 observation period: All of these patients received narcotic medication. On average, Grade 2 or worse reactions lasted for 1.2 ± 0.2 weeks (± 1 standard error of the mean), whereas Grade 3 or worse reactions lasted for 1.4 ± 0.1 days. At all times during follow-up, the prevalence, incidence, and duration of reactions in the 12 patients who received radiation alone were considerably lower compared with those among the patients who received chemotherapy, however, the differences were not significant, probably because of the small number of patients in the radiation-alone arm (data not shown).

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Figure 1. These graphs illustrate acute dysphagia and the degree of analgesia required. Top. The prevalence of Grade ≥2 (circles), Grade ≥3 (triangles), and Grade 4 (squares) dysphagia is illustrated on the left, and the prevalence of Grade ≥1 (circles), Grade ≥2 (triangles), and Grade 3 (squares) analgesia is illustrated on the right. Error bars ±1 standard deviation (SD). Bottom: The incidence of Grade ≥2 (solid bars) and Grade ≥3 (open bars) dysphagia and analgesia are illustrated on the left, and the duration of dysphagia and analgesia are illustrated on the right. SEM indicates standard error of the mean.

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The proportion of patients who were free of clinical symptoms of pneumonitis and late lung dysfunction 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 observed 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 morbidity estimate of 7%.

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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).

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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 = 0.75; P<.0001).

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Figure 3. The percent of lung volume that received a radiation dose ≥20 grays (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 = 0.17 to r = 0.43.

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Treatment outcomes were assessed by means of locoregional tumor control, disease-free survival, and overall survival and are illustrated in Figure 4. The actuarial rates at 1 year, 2 years, and 3 years for locoregional tumor control, disease-free survival, and overall survival were 76%, 61%, and 54% (locoregional control);, 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 overall survival and metastases-free survival in patients who did and did not attain control of their primary tumor 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 = .05; log-rank test), and the metastases-free survival rate was 67% compared with 43% (P = .03; log-rank test) for patients who achieved and did not achieve control of their primary tumor site, respectively.

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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 = .05). Bottom: Metastases-free survival is illustrated in patients who attained permanent tumor control (solid line) and in patients who never attained or lost control of the primary tumor (dashed line) (log-rank P = .03).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The current data indicate that the dose-escalation schedule 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 minimal and of short duration. The extent and duration of all levels of early dysphagia was considerably less 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 significantly shorter superior-inferior lengths with conformal techniques, relative to nonconformal delivery, for both large and small volumes (P ≤ .03) may explain the reduced mucositis. To date, there is no evidence of radiation-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 historic controls from nonrandomized studies, our 3D-CRT data relative to nonconformal techniques11 show reduced incidence of adverse effects, particularly compared 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 follow-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. Determining 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 reporting.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 and reporting.21, 23 It is disconcerting that crude incidence rates still are in use in an appreciable number of reports. This can underestimate the real incidence significantly, 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 method 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 esophageal complications were completely absent. Likewise, there is no evidence of spinal cord or late normal tissue complications in other organs at risk.

Table 4. Incidence of Severe Early and Late Esophageal and Pulmonary Complications in Trials of Conformal Radiotherapy Alone or Combined with Chemotherapy
No. of patientsDose, GyTime, WeeksComplications (% of patients)Reference
EsophagusLung
EarlyLateEarlyLate
  • Gy indicates grays.

  • *

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

4552.2–726–8209* Armstrong et al., 19977
5560.8–87.86006* Belderbos et al., 200328
17770.9–90.37–80≤8≤9≤16Bradley et al., 200530
9173.6–80 113  Maguire et al., 199929
4473.6–86.44–58–140–800–25Marks et al., 200431
6260–746–7.510 0 Rosennman et al., 200216
10470.2–908–90–1005–4310–34Rosenzweig et al., 200532
15250–816–83 15* Sim et al., 200117
20760–746–756  Singh et al., 200333
2578–908–9161204Socinski et al., 200434
6260–746–88000Socinski et al., 200235
38606153270Willner et al., 200136
6831–80 0–190–110–44Wolski et al., 200537

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 varied 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 before the predictive value becomes apparent.

Because of the nonrandomized nature of the studies conducted to date and the small number of patients treated by most centers, estimates of treatment outcome with 3D-CRT are 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 estimates 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 setting, produced an absolute survival advantage of 9% at 2 years compared with 6 weeks of conventional radiotherapy. 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 during treatment with a potential doubling time of approximately 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 = .02): Those authors reported a 2% increase in the risk of death for each day that treatment was prolonged.27

Table 5. Locoregional Control Rates in Trials of Conformal Radiotherapy Alone or Combined with Neoadjuvant and/or Concurrent Chemotherapy
No. of patientsCT (No. of patients)LCR (%)Reference
1 year2 years3 years
  • LCR indicates locoregional control; CT, chemotherapy; NS, not specified.

  • *

    Read off from graph.

  • Included only patients with Stage III disease.

1772561–9250–78 Bradley et al., 200530
10620584031Kong et al., 200538
1461466542∼39*Lee et al., 200315
10416 27–84 Rosenzweig et al., 200532
37NS622323Sibley et al., 199539
8282∼77*43∼38*Sim et al., 200117
700∼59*35∼32*Sim et al., 200117
5841774126Wolski et al., 200537
4230766154Current study
Table 6. Overall Survival Rates in Nonrandomized Trials of Conformal Radiotherapy Alone or Combined with Neoadjuvant and/or Concurrent Chemotherapy
No. of patientsCT (No. of patients)OS rate (%)Reference
1 year2 years3 years
  • OS indicates overall survival; CT, chemotherapy; NS, not specified.

  • *

    Read off from graph.

  • Included only patients with Stage III disease.

450 32 Armstrong et al., 19977
1772559–7520–50 Bradley et al., 200530
207955941 Bradley et al., 200240
10620613723Kong et al., 200538
1461465125∼18*Lee et al., 200315
4444 47 Marks et al., 200431
6262715038Rosennman et al., 200216
10416 21–71 Rosenzweig et al., 200532
37NS7537∼28*Sibley et al., 199539
8282∼75*∼31*∼25*Sim et al., 200117
700∼50*∼23*∼16*Sim et al., 200117
25256946 Socinski et al., 200434
6262715240Socinski et al., 200135
34347334 Willner et al., 200136
5841442712Wolski et al., 200537
4230815745Current study

Despite advances in the treatment of locally advanced NSCLC, outcomes remain disappointing, and local recurrence and distant metastases remain the major causes of death. Previous studies have demonstrated 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 primary tumor.3, 5 Perhaps the widely held view that control 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 maintaining acceptable morbidity.

In general, concurrent radiochemotherapy appears to achieve higher tumor control and survival rates than neoadjuvant treatments10; therefore, future investigations at our center will combine neoadjuvant and concomitant chemotherapy. Unfortunately, the clinical results indicate that it is unlikely that any combination of radiotherapy with the drugs currently available will lead to dramatic improvements in treatment outcome. Furthermore, most studies have shown that normal tissue affects are more severe with radiochemotherapy schedules20 and reduce the therapeutic benefit. The very low level of both early and late morbidity encountered with CHARTWEL using conformal delivery and the high regional control and survival observed in these patients indicate that dose-escalation protocols of conformal CHARTWEL radiotherapy alone and combined with chemotherapy, coupled with stratification of patients by known risk factors,24, 28, 29 warrant evaluation.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Arriagada R, Le Chevalier T, Quoix E, et al. ASTRO (American Society for Therapeutic Radiology and Oncology) plenary: effect of chemotherapy on locally advanced non-small cell lung carcinoma: a randomized study of 353 patients. GETCB (Groupe d'Etude et Traitement des Cancers Bronchiques), FNCLCC (Federation Nationale des Centres de Lutte Contre le Cancer) and the CEBI trialists. Int J Radiat Oncol Biol Phys. 1991; 20: 11831190.
  • 2
    Cox JD, Yesner RA. Causes of treatment failure and death in carcinoma of the lung. Yale J Biol Med. 1981; 54: 201207.
  • 3
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