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From conventionally fractionated radiation therapy to hyperfractionated radiation therapy alone and with concurrent chemotherapy in patients with early-stage nonsmall cell lung cancer
Article first published online: 2 JAN 2008
Copyright © 2008 American Cancer Society
Volume 112, Issue 4, pages 876–884, 15 February 2008
How to Cite
Jeremić, B. and Miličić, B. (2008), From conventionally fractionated radiation therapy to hyperfractionated radiation therapy alone and with concurrent chemotherapy in patients with early-stage nonsmall cell lung cancer. Cancer, 112: 876–884. doi: 10.1002/cncr.23240
- Issue published online: 1 FEB 2008
- Article first published online: 2 JAN 2008
- Manuscript Accepted: 5 SEP 2007
- Manuscript Revised: 4 SEP 2007
- Manuscript Received: 12 JUL 2007
- nonsmall cell lung cancer;
- early stage;
- radiation therapy;
The authors' single-institution experience in patients with early-stage (I and II) nonsmall cell lung cancer (NSCLC) who were treated between 1980 and 1998 with either conventionally fractionated (CF) radiation therapy (RT), or hyperfractionated (HFX) RT, or HFX RT with concurrent paclitaxel/carboplatin (HFX RT-Pac/C) was reviewed.
Seventy-eight patients received 60 grays (Gy) in 30 daily fractions (CF), 116 patients received 69.6 Gy (1.2 Gy twice daily), and 56 patients received 67.6 Gy (1.3 Gy twice daily) with concurrent, low-dose, daily C (25 mg/m2) and Pac (10 mg/m2). Biologically equivalent doses for the 3 groups were 72 Gy, 78 Gy, and 76 Gy, respectively, for acute effects (α/β = 10 Gy) and 120 Gy, 111 Gy, and 111 Gy, respectively, for late effects (α/β = 2 Gy).
For all 250 patients, the overall median survival was 27 months, the cause-specific survival was 27 months, the local progression-free survival was 32 months, and distant metastasis-free survival was not achieved; and the respective 5-year survival rates were 27%, 32%, 45%, and 68%. CF achieved significantly inferior survival than either HFX RT alone or HFX RT-Pac/C (P = .0332 and P = .0013, respectively), and no difference was observed between the 2 HFX RT regimens (P = .1934). Only acute hematologic high-grade toxicity (grade ≥3) was more frequent with HFX RT-Pac/C than with either RT alone, whereas other toxicities were similar between the 3 treatment groups.
HFX RT with or without concurrent chemotherapy may be better than CF in patients with early-stage NSCLC. The role of chemotherapy deserves further investigation, because the group that received chemotherapy in the current study had a higher incidence of acute high-grade hematologic toxicity. Cancer 2008. © 2008 American Cancer Society.
For the majority of patients with early-stage (I/II) nonsmall cell lung cancer (NSCLC), surgery remains the treatment of choice.1–3 For those with severe comorbidity, advanced age, or those who refuse surgery, however, traditional treatment has been radiation therapy (RT) alone. Numerous reports have indicated the effectiveness of RT in this disease.4–24 However, several questions regarding RT remained unanswered, including the “optimal” total dose and fractionation, the necessity for elective lymph node coverage, the establishment of known prognostic factors,25 or the addition of chemotherapy (CHT),26 mostly because there has been a lack of prospective studies addressing these questions. Also, the last decade witnessed wide introduction of novel technologies in the diagnosis and treatment of these tumors. Although it is expected that positron emission tomography (PET)27–30 will enable better detection of patients who fall in this group, stereotactic RT is enabling more precise treatment delivery to patients with stage I NSCLC with promising results.31–41
Since 1981, we have used RT to treat patients with technically resectable but medically inoperable, early-stage NSCLC. During the period from 1980 to 1987, we used conventionally fractionated (CF) radical doses of RT (60 grays [Gy]). To improve treatment outcome, hyperfractionated (HFX) RT was instituted, first alone (69.6 Gy; 1988–1993) and then at 67.6 Gy with concurrent, low-dose, daily CHT consisting of paclitaxel (Pac) and carboplatin (C) (HFX RT-Pac/C) (1996–1998). Although the results of the 2 latter approaches were published previously in detail,42–44 the objective of the current study was to summarize our single-institution experience in 250 patients who were available for analysis by focusing on the differences in treatment outcome and toxicity between the 3 treatment approaches.
MATERIALS AND METHODS
Adult patients (aged ≥18 years) with histologically or cytologically confirmed NSCLC classified as stage I or II according to the International System,1 a Karnofsky performance score (KPS) ≥70%, and no previous therapy have received RT at our institution since 1981. Excluded from this policy were patients with postoperative thoracic recurrence or a history of any prior or concurrent cancer (except for cancer of the skin), unless the patient had shown no evidence of disease for >5 years and malignant pleural effusion.
The pretreatment evaluation included medical history, physical examination, complete blood count, biochemical screening tests, chest radiography and computed tomography (CT) scans of the thorax and upper abdomen (the CT scans have been mandatory since 1988). Brain CT scanning and pulmonary function tests were performed whenever possible.
Treatment of Group 1 (CF) included radical CF RT (60 Gy); whereas, in Group 2 (HFX RT), treatment included a total dose of 69.6 Gy given in 58 fractions over 29 treatment days using 1.2 Gy twice-daily fractionation. Treatment in Group 3 (HFX RT-Pac/C) started on Day 1 (always on Monday), with patients receiving 30 mg/m2 of Pac during a 1-hour infusion. Premedication was not administered systematically but was prepared for patients who had any adverse effect and included dexamethasone, ranitidine, and dyphenilhydramine. Concurrent RT/CHT started from Day 2. HFX RT with 1.3 Gy twice daily up to a total dose of 67.6 Gy was administered with concurrent, intravenous CHT, which consisted of 25 mg/m2 C and 10 mg/m2 Pac on each RT day. The daily Pac dose was administered as a 1-hour infusion starting at least 2 hours before the first daily fraction, thus leaving a 1-hour gap between the end of the Pac infusion and the first daily RT fraction. C was administered as a short infusion (30 minutes) administered 3 to 4 hours after the first daily fraction (ie, 1.5–2 hours before the second fraction), as detailed in a previous report.44 The current study was performed after approval was obtained from the institutional ethics committee, and informed consent was obtained from all patients.
In all patients, RT was administered with 6- to 10-megavolt photons by using linear accelerators. The typical target volume included the primary tumor and ipsilateral hilum with a 2-cm margin (stage I); whereas, in patients with stage II disease, the target volume also included the ipsilateral mediastinum from the suprasternal notch to a level 6 cm below the carina (upper and middle lobe lesions) or to the diaphragm (lower lobe lesions). The initial target volume was treated with a minimum dose of 44 Gy (CF), or with 50.40 Gy (HFX RT), or with 49.4 Gy (HFX RT-Pac/C); then, the RT field was reduced to include all detectable tumor (total dose, 60 Gy for CF, 69.6 Gy for HFX RT, and 67.6 Gy for HFX RT-Pac/C). Doses were specified at mid-depth at the central axis for parallel-opposed fields or at the intersection of central axes for other techniques. For HFX RT treatments, 2 daily fractions of either 1.2 Gy or 1.3 Gy were administered 5 times per week with an interfraction interval of 4.5 to 6 hours, and 1.3 Gy twice a day was used to slightly accelerate the RT component, presumably bringing more cell-kill to a combined RT-CHT regimen. Two-dimensional (2D) treatment planning was done throughout the study, and it has been CT-based since 1988 (for studies of HFX RT and HFX RT-Pac/C)
Patients usually were examined first at the end of RT, then every month for 6 months after the completion of RT, then every 2 months for the next 2 years, and every 4 months thereafter. A medical history for the intervening period was obtained, and physical examination, complete blood count, biochemical tests, and chest radiography were performed at each visit. Symptomatic biopsies were not obtained routinely but were recommended if signs of tumor persistence or recurrence were present. Restaging at the time of any progression was performed mostly by using CT scans of the thorax, brain, and abdomen; bone scans; abdominal ultrasound images; and radiographs of the bones, whenever necessary, in addition to the previous procedures.
The radiation-induced effects on normal tissue were assessed as either acute or late phenomena according to criteria of the Radiation Therapy Oncology Group and the European Organization for the Research and Treatment of Cancer.45 Endpoints in this study included overall survival (OS) and relapse-free survival as well as toxicity. Survival and relapse-free survival rates were calculated from the first day of treatment by using the Kaplan-Meier method, and the differences were evaluated with the log-rank method. In calculating recurrence-free survival rates, patients who developed either type of failure were considered at risk for the other endpoint and were censored at the time of their last evaluation. Statistical analyses were carried out by one of the authors (B.M.) using the computer program SPSS. Statistical tests were based on a 2-sided significance level.
Between December 1980 and October 1998, 250 patients with NSCLC were treated either with RT alone or with RT and concurrent CHT. Between 1980 and 1987, all patients (n = 78) received CF RT; whereas, between 1988 and 1993, all patients received HFX RT alone (n = 116). Finally, between 1996 and 1998, 56 patients received HFX RT and concurrent, low-dose, daily Pac/C. Patient characteristics are listed in Table 1. There was no difference between the 3 treatment groups regarding KPS, tumor location, disease stage, or tumor classification. Although weight loss was always <5% in the HFX RT-Pac/C group, there was no difference between the CF and HFX RT groups regarding weight loss. Over the course of the study, we observed a statistically significant change in distribution according to sex, with women represented more frequently in recent years. In addition, although there were more patients aged >60 years in the early study period, the recent trend indicated that greater numbers of younger patients received RT. There also were progressively more patients with adenocarcinoma and large cell carcinoma over time. Finally, the reason for not undergoing surgery became significantly different over the period investigated. With time, more patients refused surgery than had refused it in earlier years.
|Characteristic||CF RT (n = 78)||HFX RT (n = 116)||HFX RT/Pac/C (n = 56)||P|
|Weight loss, %|
|Reason for not undergoing surgery|
The median survival for all 250 patients was 27 months, and the 1-year through 5-year survival rates were 78%, 54%, 37%, 28%, and 27%, respectively (Fig. 1). When cause-specific survival (CSS) was used as an endpoint, the median survival was 27 months, and the 1-year through 5-year CSS rates were 78%, 55%, 38%, 32%, and 32%, respectively (Fig. 1). The median time to local progression was 32 months, and the 1-year through 5-year local progression-free survival rates were 83%, 68%, 47%, 45%, and 45%, respectively (Fig. 2). The median time to distant metastasis was not achieved, and the 1-year through 5-year distant metastasis-free survival rates were 84%, 72%, 68%, 68%, and 68%, respectively (Fig. 2).
In a Kaplan-Meier survival analysis, the survival obtained by patients who received CF RT alone was significantly inferior to the survival obtained with either HFX RT alone or HFX RT-Pac/C (P = .0332 and P = .0013, respectively), and no difference was observed between the 2 HFX regimens (P = .1934; overall: P = .0064) (Fig. 3). The median survival was 20 months in the CF RT group, 29 months in the HFX RT group, and 35 months in the HFX RT-Pac/C group, and the 5-year survival rates were 17%, 29%, and 36%, respectively.
In a Kaplan-Meier survival analysis using CSS as an endpoint, treatment influenced CSS (P = .0016), again favoring HFX RT and HFX RT-Pac/C over CF (P = .0095 and P = .0009, respectively), and no difference was observed between the 2 HFX treatment groups (P = .1887). The median CSS was 20 months versus 29 months versus 39 months for the CF RT, HFX RT, and HFX RT-Pac/C groups, respectively; and the 5-year CSS rates were 20%, 35%, and 43%, respectively. When local progression-free survival (LPFS) was used as the endpoint, Kaplan-Meier analysis indicated a benefit for both HFX RT and HFX RT-Pac/C over CF (P = .0010 and P = .0099, respectively) (Fig. 4), with no difference observed between the 2 HFX groups (P = .8979). The median times to local progression were 22 months versus 39 months versus not achieved yet for the CF RT, HFX RT, and HFX RT-Pac/C groups, respectively; and the 5-year LPFS rates were 29%, 50%, and 54%, respectively. Finally, in a Kaplan-Meier analysis using distant metastasis-free survival (DMFS) as the endpoint, treatment did not influence DMFS (P = .60), because there was no difference between the 3 treatment groups (CF vs HFX RT, P = .9255; CF vs HFX RT-Pac/C, P = .5101; HFX RT vs HFX RT-Pac/C, P = .3340).
Acute high-grade (grade ≥3) toxicity observed during this study is listed in Table 2. No grade 5 toxicity was observed. When combined, acute high-grade (3 and 4) toxicity was increased in the HFX RT-Pac/C group compared with the RT alone groups. However, there was no increase in the incidence of high-grade acute toxicity with treatment intensification regarding either bronchopulmonary or esophageal toxicity, but there was an increase in the incidence of hematologic toxicity, that was attributable to the use of CHT. It is noteworthy that, in the HFX RT-Pac/C group, acute high-grade toxicity was observed in 10 of 44 patients (23%) who refused surgery but in only 10 of 12 patients (83%) with comorbid conditions/advanced age (P = .000). Late high-grade toxicity remained similar between the 3 treatment groups (Table 2).
|Toxicity||No. of patients (%)||P|
|Grade 3 + 4||CF RT, n = 78||HFX RT, n = 116||HFX RT/Pac/C, n = 56|
|Acute high-grade (≥3) toxicity|
|Bronchopulmonary||2 (3)||3 (3)||4 (7)||0.33|
|Esophageal||—||2 (3)||3 (3)||4 (7)||.33|
|Thrombocytopenia||—||0 (0)||0 (0)||6 (11)||.000|
|Leucopenia||—||0 (0)||0 (0)||6 (11)||.000|
|Late high-grade (≥3) toxicity|
|Bronchopulmonary||—||2 (3)||2 (2)||3 (6)||.40|
|Esophageal||—||2 (3)||3 (3)||3 (6)||.58|
|Osseous||—||0 (0)||1 (1)||0 (0)||.56|
In the last several decades, numerous studies have firmly established RT as the standard treatment approach in patients this disease.4–24, 42–44 Recent large reviews25, 46 have identified inherent biases in the earlier, mostly retrospective reports. Regardless of its shortcomings, RT alone is capable of producing a median survival up to 30 months and 5-year survival rates up to 30% (40% in patients with T1N0 disease13). Furthermore, in recent years, preliminary evidence also has been produced that high-precision RT, in the form of stereotactic radiosurgery31–33 or stereotactic fractionated RT,34–41 may lead to even better outcomes in these patients. In addition to the need for more prolonged follow-up data, this technique still is limited to a few institutions. Conversely, 2D or 3D planned and executed RT is practiced worldwide; therefore, the results of our current study may present a more appropriate picture of the use of RT in this setting.
The time span of >20 years, covering the study performance and follow-up periods, enabled us to gain an insight into contemporary trends in RT for early-stage NSCLC. It is noteworthy that more patients with early-stage NSCLC were referred for and received RT over time. Over the course of the study, fewer and fewer patients presented with existing comorbidities and/or advanced age; and more and more patients presented initially as surgical candidates, then refused surgery, and eventually received RT, a trend that was the backbone of the HFX RT-Pac/C study. Additional observation included that not only more women but also younger patients were referred for and received RT. Finally, similar to worldwide trends, we observed more adenocarcinoma histology, although SCC histology was the most frequently diagnosed. These observations may have influenced the study results favoring patients with a better prognosis (younger age, refusal) observed more frequently in 2 recent studies. During the whole study period, however, standard diagnostic procedures changed: CT scanning became mandatory only after 1988, and some patients who were treated between 1981 and 1987 did not have CT scans for diagnosis/staging and treatment planning, a clear disadvantage in interpreting the study results. An additional disadvantage of this study well may be the duration of follow-up, which was much longer in the CF RT group.
After frustrating results were obtained with CF RT, we moved into the HFX RT era based on radiobiologic calculations and assumptions that the use of HFX RT would produce better outcomes (survival and local control) because of total dose increases but that acceptable toxicity would be maintained. In our HFX RT studies,42, 43 these assumptions worked well. Compared with CF RT, HFX RT offered an improvement in OS and CSS, which was a consequence of an improvement in LRFS observed for HFX RT over CF RT. With concurrent Pac/C and an additional, slight HFX RT acceleration (1 week shorter), again, the approach was superior to CF RT in terms of OS, CSS, and LRFS. When HFX RT alone and HFX RT-Pac/C finally were compared, no difference between the 2 regimens was observed for any of the survival endpoints. The question remains, however, whether an increase in the total dose per se in both CF RT and HFX RT regimens (with or without CHT) also would lead to better outcomes that were not necessarily connected to HFX RT administration. This is an important issue in RT for lung cancer in which the dose response remains an achievable goal.
Another important endpoint was toxicity. In particular, acute high-grade toxicity may lead to treatment interruptions and poor outcomes, as we demonstrated successfully in our previous analysis.47 Although it was expected that the HFX RT regimens would bring more acute toxicity, there was no difference between the 2 RT alone groups in terms of toxicity. Concurrent Pac/C led only to significantly higher hematologic toxicity and not to bronchopulmonary or esophageal toxicity. In particular, the low incidence of acute high-grade pulmonary and esophageal toxicity was surprising despite the use of elective lymph node irradiation. We perhaps may attribute it to the use of either a small fraction size in the HFX RT regimen, small tumor sizes, and/or small patient numbers in the 3 groups. The incidence of late high-grade toxicity was similar between the 3 regimens. These results reconfirm another major premise of HFX RT: sparing of late-reacting, normal tissue. Finally, this study reconfirmed the low toxic potential (both hematologic and nonhematologic) of concurrent, low-dose, daily CHT in patients with lung cancer, a finding we observed consistently over the years in different lung cancer and head and neck cancer studies using concurrent RT and low-dose daily, CHT.44, 48–59
Although both HFX RT and HFX RT-;Pac/C demonstrated a clear advantage over CF RT alone, the major question from our analysis seems to focus on the comparison of HFX RT alone with HFX RT-Pac/C. We believe that this question should be answered from the standpoints of the observed therapeutic benefit and further optimization of RT in this setting. Simple comparison of various endpoints indicates that HFX RT-Pac/C had an insignificant advantage over HFX RT alone, possibly because of rather the low daily and/or total doses of both agents. In addition, the regimen of administration of both agents may not have been associated with the effect of RT sensitization. However, it brought significantly more hematologic toxicity. This clearly may disfavor HFX RT-Pac/C over HFX RT alone, especially because of better pretreatment patient-related characteristics in the HFX RT-Pac/C group, such as higher KPS and less pronounced weight loss. Conversely, we believe that the further optimization of RT may use an approach similar to that we used in the current study. The major issue in this setting is becoming the selection of patients for dose intensification. Although negative patient selection traditionally led to few intensification approaches in this patient population, patient refusal may be the most important issue, because more and more patients are refusing too undergo surgery and are requesting RT. These patients are surgical candidates without comorbidities or advanced age in whom the intensification of treatment should be sought. In addition, these patients are useful as a suitable group for meaningful (even if clinically staged) comparison of surgery versus RT, because they usually have no excessive toxicity or cancer-unrelated, intercurrent deaths, which traditionally dominated outcomes in RT series; thus, they are requested for analyses of other endpoints, such as CSS. It has been demonstrated that deaths unrelated to cancer are correlated directly with pre-existing comorbidity and/or advanced age11, 14–17, 19 and are correlated inversely with patient refusal to undergo surgery.5, 12, 42–44 Our study results seem to corroborate these correlations. High-grade acute toxicity in our HFX RT-Pac/C group was observed in 10 of 44 patients (23%) who refused surgery, whereas it was observed in 10 of 12 patients (83%) with comorbidity and/or advanced age (P = .000). Separating patients with early-stage NSCLC into subgroups, thus, may be useful for further optimization: Patients with comorbidities may be selected for less intensive treatments; and intensified treatments, such as concurrent RT/CHT, may be offered to patients who initially were considered surgical candidates but eventually refused surgery. It is worth noting that concurrent HFX RT-Pac/C did not lead to superior results compared with HFX RT alone. Possible explanations for this may include the finding that both HFX RT and HFX RT-Pac/C reached an LPFS plateau, with Pac/C demonstrating a lack of influence on DMFS. A possible solution for patients who are fit may include the administration of higher daily Pac/C doses and/or the administration of consolidation CHT.
The final question well may be the fate of the HFX RT-Pac/C regimen without its Pac/C component. HFX RT with 69.6 Gy and HFX RT with 67.6 Gy (without Pac/C) using 1.2 Gy and 1.3 Gy per fraction, respectively, yielded very similar biologically effective dose values for both acute effects (78 Gy and 76 Gy, respectively) and late effects (111 Gy for both). It also is likely that, without concurrent, low-dose Pac/C, the 2 HFX RT regimens would be very similar not only regarding nonhematologic toxicity (which already did not differ significantly) but also regarding hematologic toxicity, as illustrated in Table 2. Thus, with similar survival outcomes, using all endpoints, and presumably with similar toxicity profiles, the only difference that may favor HFX RT alone with 1.3 Gy twice daily would be the 1-week shorter treatment time, an additional convenience for both patients and hospitals.
In conclusion, the results of this retrospective, single-institution study with a large number of patients indicated that CF RT with 60 Gy should not be used in this patient population with early-stage NSCLC. Because of the lack of difference in the survival endpoint between the 2 HFX RT regimens, and because more hematologic toxicity was observed with the HFX RT-Pac/C regimen, it is unlikely that the latter regimen, although it produced the best overall results, may be suggested for indiscriminate use in this patient population. This is especially true because this regimen was particularly toxic in patients with existing comorbidities. Conversely, patients who refused surgery had less high-grade toxicity after HFX RT, with or without concurrent Pac/C. This patient subgroup represents the best prognostic subgroup in which further treatment intensification may be possible. Because of the low toxicity observed in the HFX RT-Pac/C group, further intensification of this approach may be attempted either through further RT (total dose) intensification (because of the low incidence of bronchopulmonary and esophageal toxicity) or, perhaps, CHT intensification (because of the low incidence of hematologic toxicity), which could be given, for example, as additional (adjuvant or consolidation) CHT and/or as targeted therapy. For patients who are not suitable for treatment intensification (ie, those with existing comorbidities), an option would include an accelerated RT regimen, like the HFX RT component that was used in HFX RT-Pac/C treatment, that is, the component using 67.6 Gy in 52 fractions in 26 treatment days, because it produced superior results compared with other regimens of shorter duration.9, 16, 18, 19, 22 However, the current results, which were obtained in a single-institution setting, call for confirmation in a prospective trials that tests these observations in different subgroups of patients with early-stage (I/II) NSCLC.
- 7Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys. 1992; 25: 3–9., , , et al.
- 20Radiation therapy for stage III epidermoid carcinoma of the lung. Lung Cancer. 1992; 8: 213–224., , , et al.