2.2.2 Radiation Time, Dose, and Fractionation in the Treatment of Lung Cancer
Melenda D. Jeter, Ritsuko Komaki, and James D. Cox
M. D. Jeter, MD, MPH, Assistant Professor R. Komaki, MD, Professor
J. D. Cox, MD, Professor and Chairman
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
CONTENTS
2.2.2.1 Non-Small Cell Lung Cancer 67 2.2.2.1.1 Dose Escalation with
Standard Fractionation 68 2.2.2.1.2 Large-Dose Fractionation 68 2.2.2.1.3 Dose Escalation with
Hyperfractionation 68
2.2.2.1.4 Accelerated Fractionation 69 2.2.2.1.5 Reducing the Target Volume with
Three-Dimensional Conformal
Radiation Therapy 69
2.2.2.1.6 Intensity-Modulated Radiation Therapy 70 2.2.2.1.7 Accounting for Tumor Motion 70 2.2.2.1.8 Proton Therapy 70
2.2.2.1.9 Concurrent Chemotherapy 70 2.2.2.2 Small Cell Lung Cancer 71 2.2.2.2.1 Use of Combined Chemotherapy
and Thoracic Radiation Therapy 71 2.2.2.2.2 Concurrent Therapy 71
2.2.2.2.3 Radiation Dose to the Thorax 73
References 74
Radiation therapy has been an important compo- nent of potentially curative treatment of lung can- cer for four decades. The radiosensitivity of normal tissues in the thorax, especially normal lung and esophagus, has led investigators to seek ways of en- hancing the biological antitumor effects of radiation while reducing its acute and late effects on normal tissues. The focus in this chapter is on medically inoperable or locally advanced unresectable disease, specifi cally non-small cell lung cancer (NSCLC) classifi ed as stage IIIB (T4 or N3) or stage IIIA that is unresectable because of bulky tumors or fi xed N2 disease (according to the 1997 American Joint
Committee on Cancer staging system) and small cell lung cancer (SCLC) confi ned to one hemitho- rax and the ipsilateral supraclavicular lymph nodes.
Whether radiation therapy can be judged success- ful or unsuccessful depends on the endpoints used.
The traditional assumption has been that distant metastasis is the major cause of death from lung cancer; however, that cause is actually uncontrolled tumor in the chest. Improvements in thoracic com- puted tomography (CT) scanning and fi beroptic bronchoscopy that allow better visualization of lung tumors led to the recognition that lack of local con- trol is the main cause of treatment failure in lung cancer (Arriagada et al. 1991, 1997). Two inde- pendent randomized trials showed that improving local control, obtained by two different approaches, can affect overall survival rates in both SCLC and NSCLC (Saunders et al. 1997; Schaake-Koning et al. 1992).
The therapeutic ratio of radiation for the treat- ment of carcinoma of the lung can be improved by in- creasing the biological dose to maintain local control while protecting normal tissues. One way of doing so, and our emphasis in this chapter, is through the use of fractionation, i.e., manipulating the time interval and dose of irradiation to optimize the therapeutic ratio.
2.2.2.1.
Non-Small Cell Lung Cancer
Local control of NSCLC, like that of SCLC, is di- rectly related to survival. The ability to maintain local control of NSCLC has been far from satisfac- tory, and hence several attempts have been made to manipulate fractionation dose and schedule to escalate the biologically effective dose to the tumor and thus to improve outcome. Table 2.2.2.1 gives some definitions that are useful in reviewing the literature on time, dose, and fractionation in lung cancer.
2.2.2.1.1
Dose Escalation with Standard Fractionation
The single most infl uential study of dose escalation with standard fractionation was conducted by the Radiation Therapy Oncology Group (RTOG) (Perez et al. 1988). Patients were randomly assigned to one of four treatment groups. Three of these treatments involved standard fractionation (2.0 Gy per day given 5 days per week) to total doses of 40 Gy (in 20 fractions), 50 Gy (in 25 fractions), and 60 Gy (in 30 fractions); the fourth treatment used large-dose fractionation given in a split course (4 Gy per day for 5 days, followed by a 3-week interruption, and a second course of 4 Gy per day for 5 days) to a total dose of 40 Gy (in ten fractions over 5 weeks). The higher total radiation dose led to improved survival rates, but this effect came at the cost of some increase in toxicity. The RTOG investigators’ conclusion that 60 Gy in 30 fractions was the most effective treatment became a standard for the RTOG, for other coopera- tive groups, and for radiation oncologists throughout the United States.
2.2.2.1.2
Large-Dose Fractionation
Advocates of large-dose fractionation emphasize the usefulness of this form of treatment (also called hy- pofractionation) in lessening the overall number of treatments and the corresponding burden on health care facilities, decreasing the stress on patients to ad- here to a schedule of fi ve visits per week over a period of 6 weeks, and possibly in increasing the biologi- cal antitumor effect. Thames and colleagues (1983) documented in the early 1980s that use of large dose fractions was associated with increased late effects in
normal tissues; a comprehensive review of large-dose fractionation published 2 years later by Cox (1985) confi rmed the increase in late effects but also drew attention to the possibility that this practice also had adverse effects on tumor control because it allowed repopulation of tumor cells between fractions.
In a subsequent study involving large-dose frac- tionation, Uematso and others (2001) used CT- guided frameless stereotactic radiation therapy to treat 50 patients with stage I NSCLC. Most of the patients in this study were given 50–60 Gy in 5–10 fractions for 1–2 weeks, and 18 patients had also un- dergone conventional radiation therapy (40–60 Gy in 20–33 fractions) before the stereotactic procedure. At a median follow-up of 36 months, 47 patients (94%) showed no evidence of local progression on follow- up CT scans, and the 3-year overall survival rate was 66%. No adverse effects defi nitively related to the stereotactic radiation therapy were noted except for minor bone fractures (two patients) and temporary pleural pain (six patients). On the basis of these re- sults, the RTOG proposed a phase II trial (RTOG L- 0236) of extracranial stereotactic radioablation for medically inoperable stage I NSCLC. The proposed dose is 60 Gy, to be given in three 20-Gy fractions with no more than two fractions per week.
2.2.2.1.3
Dose Escalation with Hyperfractionation
The potential for hyperfractionation to improve the therapeutic ratio for radiation in many ma- lignant tumors was recognized in part from the failure of large-dose fractionation to improve lo- cal control and in part from the observation that use of smaller fractions was associated with fewer late effects in normal tissues. The RTOG conducted
Table 2.2.2.1. Fractionation defi nitions for lung cancera
Schedule Dose per fraction (Gy)
Number of fractions per week
Intervals between fractions (h)
Total number of fractions
Duration of treatment (weeks)
Total dose (Gy)
Standard 1.8-2.75 4-6 24 25–40 5–8 55–75
Hypo > 3.0 1–4 48–168b ? NC or ? NC or ?
Hyper 0.7-1.3 10-25 2–12 B (?) NC NC (B)
Rapid > 2.5 5 24 ? ? ?
Accelerated 1.5–2.5 10–21 4–12 ? ?? ?
a Numbers or symbols given assume a dose-rate of 2.0–6.0 Gy/min.
b Intervals longer than 168 h constitute a “split course.”
? or B indicate decreases or increases relative to values given for standard fractionation schedule.
a series of trials of hyperfractionated radiation therapy in which 1.2 Gy fractions were given twice daily and total doses were escalated (Diener-West et al. 1991). For cancer of the lung, the total doses ranged from 60 Gy (in 50 fractions over 5 weeks) to 79.2 Gy (in 66 fractions over 6.5 weeks). Improved survival rates were noted at a total dose of 69.6 Gy, given in 58 fractions, with no further improvement at higher doses. This dose fractionation regimen was subsequently investigated in a prospective trial in comparison with groups given either standard fractionation or induction chemotherapy followed by standard fractionation (Sause et al. 1995). In this trial, use of induction chemotherapy was associated with improved short-term survival but use of the hyperfractionated regimen was not.
2.2.2.1.4
Accelerated Fractionation
With its twice-daily doses of 1.2 Gy, the protocol in the RTOG study cited above (Diener-West et al.
1991) did involve some acceleration of treatment;
however, the most thorough investigation of a mark- edly accelerated course of radiation therapy was conducted at Mount Vernon Hospital in the United Kingdom by Saunders and colleagues (Saunders et al. 1997; Saunders 2000). Their investigation of continuous hyperfractionated accelerated radiation therapy (CHART) involved use of three 1.5-Gy frac- tions per day for a total of 12 consecutive treatment days, with no interruptions for weekends. The total dose for this regimen was 54 Gy, given in 36 fractions over 12 days.
After CHART was found to be promising in com- parison with the historical experience at Mount Vernon Hospital, a prospective randomized trial was undertaken to compare CHART (total dose of 54 Gy given in 36 fractions over 12 consecutive days) to standard fractionation (total dose of 60 Gy in 30 fractions, 5 days per week, for 6 weeks). The observed improvement in survival in the CHART group was considered to result largely from im- proved intrathoracic tumor control. A derivative benefi t of this local tumor control from CHART was the lesser incidence of distant metastasis in the CHART group than in the standard-fractionation group (Saunders 2000). This fi nding suggests that metastasis from locally advanced lung cancer, like that at other cancer sites, may arise through second- ary dissemination from residual local-regional tu- mor (Arriagada et al. 1995).
2.2.2.1.5
Reducing the Target Volume with Three- Dimensional Conformal Radiation Therapy
Some evidence exists to suggest that very high radiation doses (i.e., in excess of 70 Gy) for medically inoper- able stage I disease have shown acceptable results in terms of local control and survival (Qiao et al. 2003).
Such patients with small but inoperable tumors may be candidates for three-dimensional conformational radiation therapy, which can allow dose escalation if the high-dose radiation volume conforms closely to the size and shape of the tumor. The relationship between pulmonary toxicity, especially symptomatic toxicity, and the volume of irradiated lung is well established.
With regard to maximum tolerated doses, studies of fractionated irradiation delivered either to both lungs or to one lung at a time (Cox et al. 1972) suggested that the limit was approximately 20 Gy at 1.5 Gy per fraction.
With regard to the volume of lung subjected to radia- tion, Graham et al. (1995) used dose-volume histogram analysis to show that the percentage of normal lung volume receiving a total dose of 20 Gy (V20) or more, in standard daily fractions was strongly related to the risk of severe or life-threatening pulmonary toxicity.
That same group (Graham et al. 1995), among oth- ers (Bradley et al. 2003), led a prospective trial (RTOG 9311) of dose escalation with three-dimensional con- formal radiation therapy in patients with inoperable NSCLC (Bradley et al. 2003). The trial was designed to escalate doses given on a standard fractionation sched- ule based on V20; patients with V20 of less than 25%
were given doses of 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, or 90.3 Gy in 42 fractions. Toxic effects that occurred or persisted for more than 90 days after the start of radiation therapy were considered late effects. Estimated rates of grade 3 or higher late lung toxicity (according to the National Cancer Institute’s Common Toxicity Criteria; Cancer Therapy Evaluation Program 1998) at 18 months for the four dose levels were 7%, 16%, 0%, and 13%, re- spectively. Details on esophageal toxicity were not avail- able, although a fatal trachea-esophageal fi stula was re- ported in the 90.3-Gy group (Bradley et al. 2003).
A second group of patients in this study, those with a V20 of 25% to 37%, were given doses of 70.9 Gy in 33 fractions or 77.4 Gy in 36 fractions. Estimated rates of grade 3 pulmonary toxicity at 18 months for these pa- tients were 15% for both dose levels. Given these rela- tively high late toxicity rates (16% at 77.4 Gy for V20
<25% and a 15% at 70.9 Gy for V20 = 25%–37%), further dose escalation does not seem warranted, even with the use of three-dimensional conformal radiation therapy.
Other groups have attempted to reduce the vol- ume to be irradiated by avoiding elective nodal ir- radiation, even for patients with T3 tumors (Emami 1998; Belderbos et al. 2003). By avoiding elective nodal irradiation for locally advanced lung cancer, some investigators have been able to increase the ra- diation dose to the tumor above 80 Gy (Belderbos et al. 2003). Another approach to decreasing target volumes is to use simultaneous positron emission tomography and CT scanning to more precisely de- lineate tumor volume, position, and size. One such approach, intensity-modulated radiation therapy, is discussed further in the following paragraphs.
2.2.2.1.6
Intensity-Modulated Radiation Therapy
Development of sophisticated software programs, combined with improvements in diagnostic imaging and image reconstruction, have allowed tumors to be visualized and delineated more precisely, improving the delivery of three-dimensional radiation therapy and opening the door for intensity-modulated radia- tion therapy (IMRT). Two sources of error in IMRT that could prevent successful delivery of optimal con- formal treatment result from movement—movement of the patient, which can be addressed by careful immobilization, and the internal motion of thoracic tumors caused by respiration and heartbeat. Indeed, the main challenge in IMRT is to avoid increasing the integral dose to organs that lie in the path of the mul- tiple fi elds that are focused on the target volume. In practice, the question in treating for thoracic tumors is whether IMRT can reduce the V20 (the percentage of lung receiving 20 Gy or more). Preliminary fi nd- ings from Liu and colleagues (in press) suggest that IMRT is feasible but comes at the cost of exposing a much larger proportion of the lung to doses of 10 Gy or less. Furthermore, treatment with curative intent for thoracic tumors often involves concurrent chemotherapy, which can further increase the risk of normal tissue toxicity, especially pneumonitis, if large volumes of normal lung are exposed to low radiation doses.
2.2.2.1.7
Accounting for Tumor Motion
That intrathoracic tumors move in concert with re- spiratory and cardiac cycles has always been known, but the importance of accounting for this movement
has been magnifi ed with the advent of conformal and intensity-modulated radiation therapy. Lung tumors can move up to 15 mm in the inferior-su- perior directions with each breath (Seppenwoolde et al. 2002; Stevens et al. 2002). Motion in the an- terior and posterior directions can also be as great as that in the superior-inferior plane. Moreover, the location and size of the tumor can change over the course of radiation therapy that lasts several weeks.
The importance of recognizing and accounting for tumor motion over the course of radiation therapy is becoming increasingly apparent. Respiration-in- duced tumor motion changes during a course of radiation therapy can be more than 1 cm (Forster et al. 2003). Therefore, frequent monitoring of tu- mor motion and location may be required in order to insure that tumors remain within the high dose region throughout treatment.
2.2.2.1.8 Proton Therapy
At present, the best way of increasing the dose deliv- ered to tumors in the thorax without increasing the dose to critical normal tissues seems to be proton therapy. Treatment planning methods are being de- veloped that account for passive scattering (Moyers et al. 2001), and work has begun on the use of pen- cil beam scanning. Preliminary results suggest that good local control of small tumors can be achieved with little risk of acute or late toxicity (Shioyama et al. 2003). Clinical experience with proton beam ir- radiation is limited, particularly with regard to large tumors with lymph node involvement that would require high doses for control. Fractionation stud- ies in the context of proton therapy are currently in their infancy.
2.2.2.1.9
Concurrent Chemotherapy
The use of concurrent weekly or daily cisplatin with radiation therapy has been mainly based on the re- sults of a large randomized trial by the European Organization for Research and Treatment of Cancer (Schaake-Koning et al. 1992) that showed improved local control and overall survival from the use of concurrent chemotherapy and radiation. However, this trial was based on a fractionation scheme that may have been less than optimal in that 3-Gy frac- tions were given daily for 10 days, followed by an
interruption of 4 weeks and then daily 2.5-Gy frac- tions for 10 days. Randomized studies of fraction- ated radiation for locally advanced carcinomas of the upper respiratory and digestive tract (Fu et al.
2000) suggest that interruptions such as this quite likely permit proliferation of surviving clonogens, not only in normal tissues but also in the tumor.
Also, a recent meta-analysis based on individual patient data raised some doubts about the magni- tude of benefi t, if any (Auperin and Le Pechoux 2003), from concurrent chemotherapy and radiation therapy and suggested that more randomized evi- dence was needed to support use of the combined approach.
The most extensive experience with altered frac- tionation with concurrent chemotherapy for NSCLC comes from work at the M. D. Anderson Cancer Center and the RTOG. Results from randomized phase II trials of a fractionation scheme developed by the RTOG (58 twice-daily 1.2-Gy fractions for a total dose of 69.6 Gy) used with concurrent chemo- therapy seemed promising (Komaki et al. 1997).
However, the most favorable outcomes seemed to be associated with a learning curve; specifi cally, insti- tutions at which 5 or more patients received con- current chemotherapy and twice-daily irradiation showed signifi cantly better survival rates than in- stitutions with less experience in this form of treat- ment (Lee et al. 2002). At M. D. Anderson, long-term follow-up of patients given 1.2 Gy twice a day with concurrent cisplatin and etoposide showed the most favorable 5-year survival rates reported to date, 26%
(Liao et al. 2002).
2.2.2.2
Small Cell Lung Cancer
The current treatment strategy for limited-stage SCLC involves the use of chemotherapy, thoracic radiation therapy (Turrisi et al. 1999), and, for those who achieve a complete response, prophylac- tic cranial irradiation (PCI) (Auperin et al. 1999).
Comparisons of chemotherapy plus thoracic radia- tion therapy with chemotherapy alone have shown that use of combination therapy improves survival rates; other trials have shown that concurrent che- motherapy and thoracic radiation therapy is su- perior to sequential or alternating chemotherapy and thoracic radiation therapy with regard to lo- cal-regional control and survival in limited-stage SCLC.
2.2.2.2.1
Use of Combined Chemotherapy and Thoracic Radiation Therapy
Because even initially localized SCLC tends to metas- tasize early in the course of the disease, chemother- apy is an essential component of the treatment regi- men; intrathoracic failure becomes more important after distant metastases are controlled. Two separate meta-analyses have confi rmed the value of adding thoracic radiation therapy to chemotherapy for SCLC in terms of decreasing the rate of local recurrence and improving survival. Warde and Payne (1992) analyzed results from 11 prospective randomized trials of chemotherapy with or without thoracic ra- diation therapy for patients with limited-stage SCLC and found that the addition of thoracic radiation therapy conferred an absolute increase of 5.4% in overall survival rate at 2 years (from 15% to 20.4%) and an absolute increase of 25% in local control rate at 2 years (from 15% to 40%). Pignon and colleagues (1992), in their analysis of data from 2,140 patients in 13 randomized trials of chemotherapy alone versus chemotherapy plus thoracic radiation therapy, found an absolute increase of 5.4% in overall survival rate at 3 years.
2.2.2.2.2
Concurrent Therapy
Potential advantages of delivering chemotherapy and radiation therapy concurrently are the ability to apply both modalities early in the course of treat- ment; the possible induction of synergistic effects;
the enhanced accuracy of treatment planning ow- ing to the absence of induction chemotherapy that might obscure the original tumor volume; and the short overall treatment time (high dose intensity), which prevents proliferation of clonogens. Potential disadvantages of concurrent therapy are enhanced toxicity to normal tissues, which could necessitate dose modifi cation or treatment breaks; the inability to assess response to either modality; and possibly sensitization of normal tissues.
In 1990, McCracken and colleagues reported the results of a phase II trial of the Southwest Oncology Group in which two courses of cisplatin, etoposide, and vincristine were given concurrently with radia- tion therapy consisting of once-daily 1.8-Gy frac- tions given 5 days per week to a total dose of 45 Gy.
The concurrent therapy was followed by additional chemotherapy with vincristine, methotrexate, and
etoposide alternating with doxorubicin and cyclo- phosphamide for 12 weeks. This study evaluated 154 patients. With a minimum observation period of 3 years, the 2-year survival rate was 42% and the 4-year survival rate was 30%. An updated analysis (Janaki et al. 1994) after a longer observation period showed a 5-year survival rate of 26%.
In 1999, the RTOG and the Eastern Cooperative Oncology Group (ECOG) (Turrisi et al. 1999) re- ported the results of a US nationwide randomized study of limited-stage SCLC treated with concurrent chemotherapy (etoposide and cisplatin) and thoracic radiation therapy (45 Gy given in twice-daily 1.5-Gy fractions or once-daily 1.8-Gy fractions); radiation was started on the fi rst day of the chemotherapy cy- cle. The 2-year survival rate for the entire group was 44%. The 5-year survival rate was 16% for those given once-daily radiation and 26% for those given twice- daily radiation — a remarkable improvement over previously reported 5-year survival rates.
The Japanese Clinical Oncology Group (Goto et al.
1999) conducted a phase III study of concurrent ver- sus sequential thoracic radiotherapy, given in com- bination with cisplatin and etoposide chemotherapy, for patients with limited-stage SCLC. Chemotherapy was given in either a 28-day cycle (the concurrent group) or a 21-day cycle (the sequential group).
Thoracic radiation therapy was begun either on day 2 of the fi rst cycle of chemotherapy in the concurrent group or after the fourth cycle of chemotherapy in the sequential group. The radiation therapy consisted of 45 Gy delivered to the thorax in twice-daily 1.5- Gy fractions over 3 weeks. PCI was given to patients who showed a complete or a near-complete response;
the PCI consisted of 24 Gy given in twice-daily 1.5-Gy fractions given 5 days a week. The incidence of grade 3 or 4 leukopenia was signifi cantly higher in the con- current-therapy group (86.8% vs. 51.3%, p< 0.001), but the incidence of non-hematologic side effects was no different in the two groups. The 2- and 3-year survival rates in the sequential-therapy group were 35.4% and 20.7%, respectively, as compared with 55.3% and 30.9% in the concurrent-therapy group.
Overall survival seemed to be superior in the concur- rent group but this apparent trend was not statisti- cally signifi cant.
Arriagada and colleagues (1991) reported the results of two protocols involving 72 consecutive pa- tients with limited-stage SCLC. Patients were given two cycles of induction chemotherapy followed by three 2-week cycles of thoracic radiation therapy that included chemotherapy with the same regimen as that used for the induction. Cisplatin and etoposide
were used in the fi rst trial, and cisplatin, etoposide, cyclophosphamide, and doxorubicin were used in the second trial. The results of this trial are among the most favorable reported in terms of long-term sur- vival. The complete response rate was 87% and the overall survival rate was 26% at 3 years; the overall survival of patients who showed a complete response to the interdigitated therapy was 26% at 5 years.
Whether thoracic radiation therapy should be delivered early or late in the treatment course re- mains controversial. The National Cancer Institute of Canada Clinical Trials Group studied this issue in a randomized trial (Murray et al. 1993). In that trial, 308 patients were given six cycles of chemo- therapy with cyclophosphamide, doxorubicin, and vincristine alternating with etoposide and cisplatin.
Patients were randomly assigned to receive thoracic radiation therapy (40 Gy to the primary tumor site in 15 fractions over 3 weeks given concurrently with etoposide and cisplatin) beginning either at week 3 (the early group) or at week 15 (the late group). Those who showed a complete response were then given PCI (25 Gy in ten fractions over 2 weeks) after the completion of all chemotherapy and thoracic irradia- tion. Although the complete response rates were no different in the two groups, progression-free survival (p=0.036) and overall survival (p=0.008) were signif- icantly better in the early-radiation group. Patients in the late-radiation group also had a signifi cantly higher rate of brain metastasis (p=0.006). This study indicated that early use of thoracic radiation therapy with concurrent chemotherapy improved survival, possibly by eliminating the clonogens in the primary tumor.
Fractionation
The Intergroup study 0096 (Turrisi et al. 1999), conducted with the ECOG and RTOG, compared once-daily versus twice-daily radiation therapy in combination with concurrent cisplatin and etopo- side. All patients received four 21-day cycles of chemotherapy. The once-daily fractionation group received a single 1.8-Gy fraction each day, to a total dose of 45 Gy in 25 fractions over 5 weeks. The twice-daily fractionation group received two 1.5- Gy fractions each day, with a 4- to 6-h interval be- tween fractions, to a total dose of 45 Gy in 30 frac- tions over 3 weeks. Irradiation began during the first chemotherapy cycle. Patients who achieved a complete response then were offered PCI (ten 2.5-Gy fractions). Although accelerating the radia- tion improved median survival time (19 months
for the standard fractionation group to 23 months for the twice-daily group) and 2-year survival rates (41% vs. 47%), a statistically significant difference in survival was not apparent until 5 years (16% vs.
26%; p=0.04). The accelerated regimen also pro- duced acute grade 3 esophagitis in 27% of cases as compared with 11% of those in the once-daily fractionation group.
The Japanese Clinical Oncology Group (Ariyoshi et al. 1994) reported a multicenter phase II trial of concurrent cisplatin–etoposide chemotherapy and thoracic radiation therapy for limited-stage SCLC.
Thoracic irradiation was given in a split course, with 20 Gy given in ten 2-Gy fractions on days 2–12 of the first chemotherapy cycle and 30 Gy given in 15 2-Gy fractions delivered on days 29–47 of the second chemotherapy cycle. Some patients were then given a 10-Gy boost, bringing the total doses to 40–50 Gy over 7 weeks. PCI was given to those who showed a complete response. The split-course radiation therapy used in this study was not as ef- fective as that used in Intergroup 0096; the median response duration was 8.7 months, the median survival time was 14.8 months, and the 2-year sur- vival rate was 20%. The complete response rate was 40.7%.
2.2.2.2.3
Radiation Dose to the Thorax
Arriagada and colleagues (1990) at the Institut Gustave-Roussy conducted three consecutive tri- als of 173 patients with limited SCLC treated with different thoracic radiation doses. All thoracic ra- diation was given in split courses alternating with chemotherapy; the total doses given were 45 Gy (i.e., doses split 15-15-15), 55 Gy (20-20-15), and 65 Gy (20-20-25). The corresponding 3-year local control rates were 66% for the group given 45 Gy and 70%
for the two higher-dose groups; the 5-year survival rates were 16% for the 45-Gy group, 16% for the 55-Gy group, and 20% for the 65-Gy group. None of these apparent differences were statistically sig- nifi cant among the three groups. The overall inci- dence of lethal toxicity was 10%, and this rate was no different among any of the three radiation dose groups.
Choi and colleagues (1998) conducted a phase I study to determine the maximum tolerated dose of radiation in standard daily fractionation and hyperfractionated-accelerated twice-daily radia- tion schedules with concurrent chemotherapy for
limited-stage SCLC. The maximum tolerated dose of hyperfractionated radiation therapy was 45 Gy given in 30 fractions over 19 days. However, in daily fractionation, the maximum tolerated dose was not reached at 66 Gy given in 33 fractions over 45 days, and thus patients were accrued for a third group to receive 70 Gy in 35 fractions over 47 days. The tu- mor response rates varied from 78% to 100%, and no difference was found among dose levels. Doses above 40 Gy did not signifi cantly improve the local control rate. Esophagitis and granulocytopenia of grade 3 or higher were more common among pa- tients given hyperfractionated and accelerated-frac- tionation treatments.
To clarify the maximum tolerated dose of thoracic radiation (in terms of acute esophagitis and pneu- monitis) that could be given in combination with cisplatin and etoposide chemotherapy for patients with limited-stage SCLC, the RTOG conducted trial 9712 (Table 2.2.2.2) (Komaki et al. 2003). The fi nd- ings of this phase I trial indicated that doses could be escalated to 61.2 Gy over 5 weeks through the use of a concomitant boost technique without more than 40% of patients developing esophagitis of grade 3 or higher. This total dose was given as follows. Eleven 1.8-Gy fractions were given to large fi elds once daily for 5 days a week, followed by 4 days of twice-daily radiation therapy in which one 1.8-Gy fraction was given in the morning to large fi elds and another 1.8- Gy fraction was delivered to boost fi elds 6 h later;
for the fi nal 5 days, twice-daily 1.8-Gy fractions were given to the boost fi elds.
Acknowledgment: Supported in part by National Cancer Institute grants CA 16672 and 06294 and the Texas Tobacco Settlement.
Table 2.2.2.2. Intergroup Study 0096 versus RTOG 9712
Intergroup Group 1
Intergroup Group 2
RTOG 9712
Thoracic radiation dose 45 Gy 45 Gy 61.2 Gy Duration of radiation 5 weeks 3 weeks 5 weeks Median survival time 19 months 23 months — Survival rates
1 year 63% 67% —
2 years 44% 47% —
5 years 16% 26%a —
Local failure rate 52% 36% —
Incidence of grade 3 esophagitis
11% 27% <40%
a Signifi cantly different from Group 1 (p=0.01).
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