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Late course accelerated hyperfractionated radiotherapy plus concurrent chemotherapy for squamous cell carcinoma of the esophagus: A phase III randomized study
Int. J. Radiation Oncology Biol. Phys., Vol. 62, No. 4, pp. 1014 –1020, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/05/$–see front matter
doi:10.1016/j.ijrobp.2004.12.022
CLINICAL INVESTIGATION
Esophagus
LATE COURSE ACCELERATED HYPERFRACTIONATED RADIOTHERAPY PLUS CONCURRENT CHEMOTHERAPY FOR SQUAMOUS CELL CARCINOMA OF THE ESOPHAGUS: A PHASE III RANDOMIZED STUDY KUAI-LE ZHAO, M.D., XUE-HUI SHI, M.D., GUO-LIANG JIANG, M.D., WEI-QIANG YAO, M.D., XIAO-MAO GUO, M.D., GEN-DI WU, M.D., AND LONG-XIANG ZHU, M.D. Department of Radiation Oncology, Fudan University Cancer Hospital, Shanghai, China Purpose: Late course accelerated hyperfractionated (LCAF) radiotherapy (RT) is as effective as standard chemoradiotherapy for nonsurgical management of locally advanced esophageal squamous cell carcinoma (SCC). We have evaluated further the efficacy of concurrent LCAF RT and chemotherapy. Methods and Materials: In all, 111 eligible patients with esophageal SCC were randomized to receive LCAF alone (LCAF) or concurrent LCAF and chemotherapy (LCATⴙCT) between March 1998 and July 2000. All patients received conventional fractionation irradiation of 1.8 Gy per day, to a dose of 41.4 Gy/23 fractions in 4 –5 weeks, followed by accelerated hyperfractionated irradiation using reduced fields, 1.5 Gy/fractions twice a day, to a dose of 27 Gy in 18 days. Thus, the total dose was 68.4 Gy/41 fractions in 44 days. Fifty-four patients in the LCAFⴙCT arm had an additional four cycles of chemotherapy using cisplatin 25 mg/m2 daily and fluorouracil (5-FU) 600 mg/m2 daily on Days 1–3 every 4 weeks starting on the same day that LCAF was delivered. Results: The median survival was 23.9 months (95% confidence [CI], 20.1–27.7) for the LCAF arm and 30.8 months (95% CI, 17.6 – 44.1) for the LCAFⴙCT arm, respectively. Survival rates at 1, 3, and 5 years of the LCAF arm were 77%, 39%, and 28%, respectively, while those of the LCAFⴙCT arm were 67%, 44%, and 40%, respectively (p ⴝ 0.310). Grades 3 and 4 acute toxicities occurred in 46% and 25% of the patients in the LCAF arm and the LCAFⴙCT arm, respectively; 6% of the patients in the combined arm had Grade 5 acute toxicities, whereas none was noted in the LCAF alone arm. Conclusions: Late course accelerated hyperfractionation was effective for locally advanced esophageal SCC. There was a trend toward better survival among patients who received intensified treatment with concurrent chemotherapy. Further randomized studies with a larger number of patients should be carried out, but additional measures must be taken to reduce the higher mortality rate due to chemotherapy-related acute toxicities. © 2005 Elsevier Inc. Accelerated hyperfractionation, Chemotherapy, Esophageal carcinoma, Radiation.
The prognosis for patients with esophageal carcinoma treated with conventional radiotherapy alone remains discouraging despite the advances in radiotherapeutic techniques. Accelerated proliferation of tumor cells during the course of fractionated irradiation treatment is believed to be one of the causes of local failures in squamous cell carcinoma of the upper respiratory and digestive tracts (1–3). We have demonstrated marked improvement when late course accelerated hyperfractionation (LCAF) radiotherapy, which increased the probability of locoregional control by reducing the risk of tumor repopulation, was employed for locally advanced esophageal squamous-cell carcinoma (SCC) compared with the conventional fractionation radiation, with a 5-year survival and local control rate of 34% and 55%,
respectively, in our previous study (4). The results were also confirmed in the preliminary report of another similar large Phase III study where Han et al. (5, 6) reported 5-year survival rates of 32% and 14% after treatment with LCAF and conventional fractionation, respectively. Therefore, LCAF is widely accepted as standard treatment for locally advanced esophageal SCC in China. However, combined therapy by chemoradiation has been well established as a standard approach to locally advanced esophageal SCC, as demonstrated in the series of Radiation Therapy Oncology Group (RTOG) studies (7–12) that reported a 2-year local control rate of 55%, a 5-year survival rate of 25%, and a lower rate of distant metastases compared with radiation alone, 22% vs. 38% (p ⫽ 0.05). Thus, we initiated a prospective, randomized Phase III trial to see
Reprint request to: Guo-liang Jiang, M.D., Department of Radiation Oncology, Fudan University Cancer Hospital, Shanghai 200032, China. Tel: (⫹86) 21-64175590, ext. 1407; Fax: (⫹86) 21-64439052; E-mail: [email protected]
Acknowledgments—We thank Dr. Leaw Shiang Jiin for her assistance in editing the text in English. Received July 30, 2004, and in revised form Nov 16, 2004. Accepted for publication Dec 3, 2004.
INTRODUCTION
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Fig. 1. The treatment scheme for radiation therapy (RT) was 41.4 Gy (1.8 Gy/fraction, q.d.) using large fields, 27 Gy (1.5 Gy/fraction, b.i.d.) using reduced fields, total dose of 68.4 Gy/41 fractions in 44 days; 5-Fu,750 mg/m2 ⫻ 3 days; DDP, cisplatin, 25 mg/m2 ⫻ 3 days. The treatment scheme for LCAF was the same as for LCAF⫹CT except for chemotherapy.
whether the benefit of combination therapy seen in the RTOG series could translate into further improvement on the survival and locoregional control rate when LCAF plus concurrent chemotherapy was performed. Late course accelerated hyperfractionation alone was selected as the control treatment because it represented the most widely accepted modality for locally advanced esophageal SCC in China. METHODS AND MATERIALS Eligibility and study design The eligibility criteria were as follows: (1) confirmation of esophageal SCC by histology or cytology; (2) clinical stages of T1– 4, N0-1, M0 (International Union Against Cancer, 1997); (3) baseline laboratory tests, i.e., white blood cell count of ⬎4.0 ⫻ 109 /L, platelet count of ⬎100 ⫻ 109/L, adequate renal function (serum creatinine concentration ⬍1.5 mg/dL, blood urea nitrogen ⬍8 mmol/L, or creatinine clearance ⬎65 mL per minute); (4) Karnofsky performance status ⱖ70; (5) no prior therapy; (6) no previous malignancies; and (7) no serious medical conditions that would preclude safe administration of treatment. Exclusion criteria included the following: (1) evidence of esophageal perforation or deep ulceration to mediastinum; (2) complete obstruction of the esophageal lumen; (3) esophageal bleeding; (4) involvement of supraclavicular lymph nodes; and (5) distant metastases. All patients had the following pretreatment evaluations: complete history and physical examination; complete blood cell counts and serum biochemical assays; chest radiograph; chest computed tomography (CT) scan; esophageal barium examination; and ultrasonographic examination to rule out distant metastases in liver, kidney, spleen, and retroperitoneal lymph nodes. Patients or their legal representatives had understood and signed the written informed consent to participate in this trial.
Treatment arms and randomization The patients were randomized into two arms by random number table. The treatment scheme for both the study arm (LCAF⫹CT)
and control arm (LCAF) is shown in Fig. 1. In the LCAF⫹CT arm, radiation therapy began on Day 1, concurrently with the first cycle of chemotherapy. In the LCAF arm, patients received irradiation alone. The same fractionation scheme and total dose of radiotherapy was delivered to both arms.
Radiation therapy Details of LCAF have been published previously (4, 13). Briefly, the radiation was carried out by 6 MV or 18 MV X-ray using a two-phase irradiation schedule. The first phase was the conventional fractionated irradiation with the field arrangement as follows: (1) two anterior oblique fields with a pair of appropriate wedges for lesions localized in cervical region, and (2) a three-field approach with one anterior and a pair of posterior oblique portals for lesions in the thorax. Fields were designed on the basis of the lesions shown on CT and barium examinations, with 2–3 cm margins around the tumors to cover the primary tumor and metastatic mediastinal nodes, and 3–5 cm margins at the long axis of esophagus to sufficiently encompass the submucosal invasion of esophagus. The dose was prescribed to the isocenter without correction of inhomogeneity. Conventional fractionation was implemented by 1.8 Gy/fraction, five fractions a week, to 41.4 Gy/23 fractions in 4.6 weeks. The second phase irradiation was the accelerated hyperfractionated session, where the radiation fields were reduced over the superior and inferior ends of esophageal lesion with 2 cm margins, whereas the width of fields remained the same. The dose was delivered at 1.5 Gy/fraction, twice daily with a minimum interval of 6 hours, 10 fractions a week to 27 Gy/18 fractions in 1.8 weeks. The total dose of the two-phase irradiation would be 68.4 Gy/41 fractions in 6.2 weeks. No prophylactic irradiation was given to the supraclavicular regions.
Chemotherapy Patients in LCAF⫹CT received concurrent four cycles of chemotherapy besides LCAF. The chemotherapeutic regimen consisted of cisplatin 25 mg/m2/day and 5-FU 600 mg/m2/day i.v. from Day 1–3, every 4 weeks, with the first and second cycle given during irradiation sessions.
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Criteria to score toxicity Irradiation toxicity was scored by the RTOG criteria, which included acute reactions occurring within the first 90 days of treatment, or late reactions occurring after 90 days of treatment. Chemotherapy toxicity was scored by National Cancer Institute Common Toxicity Criteria (version 2.0) and tabulated continually over the course of treatment. The most severe reaction was taken as the toxicity score for the entire treatment.
Dose modifications Dose modifications were allowed based on the findings on the day of treatment as well as the toxicity between cycles, whichever was the greater. The dose of 5-FU and cisplatin was decreased by 50% if the white blood cell count was greater than 2.0 ⫻ 09/L but lower than 4.0 ⫻ 109/L, or the platelet count was greater than 75 ⫻ 109/L but lower than 100 ⫻ 109/L. If the white blood cell count was lower than 2.0 ⫻ 109/L, or the platelet count was lower than 75 ⫻ 109/L, both chemotherapy and radiation were stopped temporarily until the toxicity had abated. If the creatinine clearance was between 55 and 65 mL/min or the serum creatinine was between 1.6 and 2.0 mg/dL, the cisplatin dose was decreased by 50%. If the creatinine clearance was less than 55 mL/min, then both cisplatin and 5-FU were stopped until the toxicity disappeared, but the radiation therapy was continued. Any other Grade 3 or higher toxicity required a 1-week delay in the course of treatment. Treatment was resumed once the toxicity became Grade 2 or better. Patients with stomatitis Grade 3 or higher received no additional 5-FU for that cycle, and the dose was permanently reduced for all subsequent cycles. Stomatitis Grade 3 or higher occurring between cycles required a 25% permanent dose reduction. The radiation dose was not modified. However, radiation was also stopped for Grade 3 or higher toxicities until they disappeared. Patients who developed Grade 3 or higher toxicities unrelated to radiation (oral mucositis, genitourinary toxicity, and hand-foot syndrome) would stop the chemotherapy but the radiation therapy was continued.
Follow-up After treatment, patients were followed up every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter. Each visit included history, physical examination, complete blood count, chest X-ray, esophageal barium radiography, or chest CT. Biopsy of the primary tumor site was required once locoregional recurrence was suspected by X-ray or CT, or both.
Evaluation of efficacy and statistics The endpoints of this trial were overall survival, locoregional failure, and metastasis rate. Death from any cause was calculated from the date of radiotherapy until death or last follow-up evaluation. Patterns of failure evaluated were first failure (local, regional, or distant), time to any local failure, and time to any distant metastasis. If recurrences occurred within 60 days of each other, they were counted as simultaneous. All endpoints were observed from the first day of treatment until death or last follow-up time. All of the rates were estimated by the Kaplan-Meier model, and differences between rates were compared by the log–rank test, using SPSS (version 11.0; SPSS, Chicago, IL). In all analyses the significance level was specified at p ⬍ 0.05.
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Table 1. Patient clinical characteristics
No. of patients Gender, n (%) Male Female Age (y) Median (range) Chest pain, n (%) Yes No Karnofsky performance status, n (%) 70 80–100 Weight loss, n (%) Yes No Lesion location, n (%) Cervical Upper thorax Middle thorax Lower thorax Esophageal length, cm Median (range) Stage, n (%) T1–2N0M0 T3–4N0M0 T1–4N1M0
LCAF
LCAF⫹CT
57
54
36 (63) 21 (37) 61.0 (41–74)
42 (78) 12 (22) 54.5 (39–74)
p value
0.092 0.755
35 (61) 22 (39)
37 (69) 17 (31)
0.433
3 (5) 54 (95)
2 (4) 52 (96)
0.692
0 (0) 57 (100)
2 (4) 52 (96)
0.143
3 (5) 18 (32) 34 (60) 2 (3)
4 (7) 12 (22) 36 (67) 2 (4)
0.724
6.0 (1–10)
6.0 (2–9)
0.132
11 (19) 37 (65) 9 (16)
11 (20) 37 (69) 6 (11)
0.690
Abbreviations: CT ⫽ chemotherapy; LCAF ⫽ late course accelerated hyperfractionated.
RESULTS Patient characteristics Between March 1998 and July 2000, 111 patients were randomized to the study. The pretreatment characteristics of the 111 eligible and assessable patients are listed in Table 1. The two randomized arms were well balanced for gender, age, performance status, weight loss, primary tumor size, and clinical TNM stage; other factors were evaluated. All patients were followed up until death or the time of last follow-up evaluation. The median follow-up for the 38 surviving patients was 61.7 months (range, 47.6 –76.4 months). The median follow-up period for the 73 patients who had died of their disease was 15.7 months (range, 1.5–54.2 months).
Treatment finally given Ninety-five percent of patients in the LCAF⫹CT arm received more than two cycles of chemotherapy, whereas 43% completed all four cycles of chemotherapy. All patients in both arms received the full course of LCAF radiotherapy. The major reasons why they did not complete their chemotherapy included severe vomiting, radiation-induced esophagitis and pneumonitis, esophageal ulcer, and refusal of 17 patients after finishing irradiation.
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Table 2. Overall maximum toxicity per patient Acute toxicity LCAF (n ⫽ 57)
Late toxicity
LCAF ⫹ CT (n ⫽ 54)
LCAF (n ⫽ 57)
LCAF ⫹ CT (n ⫽ 54)
Treatment effect
3
4
5
3
4
5
3
4
5
3
4
5
Esophagus Lung/trachea Skin Neurologic Heart Nausea and vomiting WBCs Platelets Hemoglobin Others Maximum severity reported per patient
11 2 0 0 0 1 0 0 0 0 14 (25%)
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0
10 1 0 0 0 6 4 0 0 0 21 (40%)
2 0 0 0 0 0 1 0 0 0 3 (6%)
1 2 0 0 0 0 0 0 0 0 3 (6%)
6 7 0 0 0 0 0 0 0 0 13 (23%)
1 1 0 0 0 0 0 0 0 0 2 (4%)
0 2 0 0 0 0 0 0 0 0 2 (4%)
2 5 0 0 0 0 0 0 0 0 7 (13%)
1 1 0 0 0 0 0 0 0 0 1 (2%)
0 2 0 0 0 0 0 0 0 0 2 (4%)
Abbreviations: CT ⫽ chemotherapy; LCAF ⫽ late course accelerated hyperfractionated; WBCs ⫽ white blood cells.
Toxicity of treatment The incidence of Grade 3 or higher acute and late treatment-related toxicity is presented in Table 2. Acute toxicities were severe (Grades 3 and 4) in 46% and life-threatening (Grade 5) in 6% in the LCAF⫹CT group, whereas they were 25% and 0%, respectively, in the LCAF group. Acute toxicities occurring in the LCAF⫹CT arm were predominantly hematopoietic or oral and pharyngeal mucositis believed to be due to chemotherapy. The three treatmentrelated deaths in the LCAF⫹CT group were due to poor nutrition or inadequate supportive treatment with pulmonary infection or esophagitis: one death on completion of the second cycle of chemotherapy and two deaths after the third cycle. There were no significant differences of late complications between the two groups, as 2 patients died of treatment-related pulmonary toxicity without evidence of cancer recurrence in each arm. Six patients had Grade 3 esophageal stenosis, 7 had Grade 3 pulmonary fibrosis, and 1 had Grade 4 esophageal and pulmonary complications in the LCAF arm, and 2 patients suffered from Grade 3 esophageal stenosis, 5 from Grade 3 pulmonary toxicity, and 1 from Grade 4 esophageal complications in the LCAF⫹CT arm. Survival and patterns of failure The median survivals for the LCAF and LCAF⫹CT groups were, respectively, 23.9 months (95% confidence interval [CI], 20.1–27.7) and 30.8 months (95% CI, 17.6 – 44.1). The overall survivals are illustrated in Fig. 2. The survival rates at 1, 3, and 5 years were, respectively, 77%, 39%, and 28% for the LCAF arm; and 67%, 44%, and 40% for the LCAF⫹CT arm (p ⫽ 0.310). The patterns of first failure are listed in Table 3. Thirtysix percent (21/57) of the patients in the LCAF arm and 26% (14/54) in the LCAF⫹CT arm had locoregional disease presenting as the first failure. Of the patients who
underwent LCAF and LCAF⫹CT, distant metastases as the first failure occurred in 19% (11/57) and 24% (13/54), respectively. Twenty-five percent (14/57) of the patients in the LCAF arm and 39% (21/54) in the LCAF⫹CT arm remained disease free. Time to local recurrence is depicted in Fig. 3. The 1-, 3-, and 5-year local recurrence rates were 18%, 37%, and 41% for the LCAF arm and 16%, 26%, and 33% for the LCAF⫹CT arm, respectively (p ⫽ 0.305). Time to distant metastases is shown in Fig 4. The rates of distant metastases at 1, 3, and 5 years were, respectively, 9%, 35%, and 42%
Fig. 2. Kaplan-Meier plot of survival in patients treated with late course accelerated hyperfractionated (LCAF) alone or with LCAF and chemotherapy combined (LCAF⫹CT; n ⫽ 111).
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Table 3. Patterns of failure
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We have confirmed the efficacy of LCAF alone for locally advanced esophageal SCC in our present study, with 5-year survival and local control rates of 28% and 59%, respectively, which are comparable with previous series that reported 5-year survival rates ranging from 26 –33% and 5-year local control of 56% (4 – 6, 13–16). At the same time, our study confirmed the possibility of further improvement on overall survival than LCAF alone. There was a trend toward better survival in patients who received intensified treatment with concurrent chemotherapy. The 5-year sur-
vival rate of the 54 patients who received LCAF with concurrent chemotherapy was 40% with a median survival of 30.8 months. There was a trend toward better survival in patients who received LCAF plus concurrent combined treatment but the difference did not reach statistical significance. The small sample size could be one of the possible explanations, but the higher mortality rate due to chemotherapy-related acute toxicities most probably offset its benefit, being 46% severe (Grades 3 or 4) and 6% life threatening (Grade 5), whereas only 25% severe acute toxicities and no life-threatening acute toxicities were noted among patients who underwent LCAF alone. Our protocol was different in several ways from other studies focusing on concurrent chemoradiotherapy for esophageal cancer. A number of questions have been raised about the necessary components for optimal treatment of esophageal cancer. First, we used LCAF radiotherapy instead of conventional fractionation. Hyperfractionation (⬎1 fraction per day) allows a relative improvement in therapeutic ratio for late responding tissues such as bronchogenic and head-and-neck cancer by increasing the total dose of radiation but not the risk of long-term toxicity. Accelerated fractionation targets tumor proliferation during the therapy by shortening the overall treatment time, which may result in fewer late side effects to the mucus membranes and skins (17). Powell et al. (18) reported 54 patients with esophageal cancer treated by a CHART (continuously hyperfractionated accelerated radiation therapy) regimen in a Phase II pilot study in which radiation was given at 54 Gy in 36 fractions in 12 days with a 6-h interfraction interval. Fifteen patients received further chemotherapy with 15 mg/m2 mitomycin i.v. bolus and cisplatin 100 mg/m2 on Day 13, whereas another 11 patients received further intraluminal brachytherapy of 15 Gy at 1 cm. There were 10 histologic
Fig. 3. Kaplan-Meier plot of the time to a local recurrence in patients with esophageal carcinoma treated with late course accelerated hyperfractionated (LCAF) radiotherapy alone or with LCAF and chemotherapy combined (LCAF⫹CT; n ⫽ 111).
Fig. 4. Kaplan-Meier plot of the time to distant metastasis in patients treated with late course accelerated hyperfractionated (LCAF) alone or with LCAF and chemotherapy combined (LCAF⫹CT; n ⫽ 111).
LCAF (n ⫽ 57)
Alive/no failure Any failure Locoregional failure Distant metastasis Locoregional failure and distant metastasis Dead of acute complication Dead of late complication Second primary cancer Dead of disease
LCAF⫹CT (n ⫽ 54)
No.
%
No.
%
14 43 20 17 1
24.6 75.4 35.1 29.8 1.8
22 32 13 12 1
40.7 59.3 24.1 22.3 1.9
0
0
3
5.6
2
3.5
2
3.7
1 2
1.8 3.5
0 1
0 1.9
Abbreviations: CT ⫽ chemotherapy; LCAF ⫽ late course accelerated hyperfractionated.
for LCAF-only patients and 18%, 32%, and 32% for LCAF⫹CT patients (p ⫽ 0.736). DISCUSSION
Chemoradiotherapy for esophageal carcinoma
benign strictures compared with 11 unbiopsied strictures in the historical control group. Longer median survival time and lower local recurrence rate were noted in the treatment group. Jeremic et al. (19) reported a favorable median survival time of 26 months and a 5-year survival rate of 29% for 28 patients treated with HART (hyperfractionated accelerated radiation therapy) with 1.5 Gy twice daily to a total of 54 Gy, concurrently with 5-FU (300 mg/m2, Days 1–5) and cisplatin (10 mg/m2, Days 1–5) for four courses, but relatively higher incidences of acute toxicities were noted; the most frequent acute high-grade (Grades 3 or 4) toxicity was esophagitis and leukopenia, seen in 50% and 39% of the patients, respectively. However, we used LCAF radiotherapy instead of HART or other nonconventional radiotherapy. Late course accelerated hyperfractionated was preferred to HART in the treatment for locally advanced esophageal SCC because of easier application, better cost-effect ratio, less radiation toxicity, and improved treatment efficacy, as presented in our previous study (13). The HART group received RT at 1.5 Gy/fraction twice daily, 5 days a week, to a total dose of 66 Gy/44 fractions in 4.4 weeks that offered a full 2-week reduction in overall treatment time compared with LCAF without marked improvement on survival, 3-year-survivals being 41% in the LCAF group and 38% in the HART group (p ⫽ 0.576). However, the incidence of acute toxicities was significantly greater in the HART group: 8.2% vs. 3.8% and 61.2% vs. 9.6% for acute life-threatening bronchitis and esophagitis, respectively. Second, a smaller radiation therapy volume was employed in our treatment protocol: 41.4 Gy to the primary tumor with 3–5 cm proximal and distal margins followed by a cone down of 30 Gy to the primary tumor with 2-cm proximal and distal margins, instead of 30 Gy to the whole esophagus followed by a cone down of 20 Gy to the primary tumor with 5-cm proximal and distal margins as in the RTOG 85-01 study. Radiation therapy volume has not received much attention until recently. Upper abdominal radiation therapy for thoracic lesions has generally been avoided to potentially improve the tolerance for the treatment. Thus, sparing the supraclavicular nodes and the whole esophagus might also improve tolerance. However, the benefit of such measures as using smaller radiation therapy volume remains to be assessed in future trials. Finally, the RTOG 85-01 trial reported the rate of local recurrences, the main cause of failure, to be as high as 45%,
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whereas other series have shown that complete response, if confirmed histologically, lowers the rate of local recurrences and increases the likelihood of prolonged survival (20 –24). Thus, a higher dose of 68.4 Gy was delivered in our present study, and the locoregional recurrences documented were surprisingly few, with a 5-year local control rate of 68%. The insignificant difference in locoregional control and overall survival between the intensified group with higher radiation dose compared with the standard group with 50 Gy radiation dose demonstrated in the Intergroup INT 0122 (RTOG 90-12) (9, 10), prospective RTOG 92-07 (11), and randomized INT 0123 (RTOG 94-05) studies (12) could imply that the larger radiation volume might have offset the benefit of higher radiation dose and resulted in greater acute radiation toxicities and prolonged overall radiation time. We advocated the use of the combined modality in view of the poor prognosis of patients with locally advanced esophageal SCC if treated by a single modality only. However, the use of the same radiation dosage for both groups of patients in the present study could have accounted for the higher rate of acute toxicities. The treatment plan of four courses of chemotherapy with 5-FU/cisplatin and LCAF for the most suitable combination schedule and dosage could be designed in future trials to evaluate the maximal efficacy and minimal toxicities. Incorporating the use of newer radiation techniques such as three-dimensional conformal radiotherapy or intensity-modulated radiotherapy, newer chemotherapeutic regimens that include taxanes (25–29) and CPT-11 (29), and intensive supportive treatment could be explored to evaluate the possibilities for optimal locoregional control and overall survival for patients with locally advanced esophageal SCC. Moreover, the role of radioprotectors for normal tissue protection could be favorable for patients’ tolerability. In conclusion, LCAF was effective for locally advanced esophageal SCC. There was a trend toward better survival among patients who received the combined treatment but the difference did not reach statistical significance. The small sample size could be one of the possible explanations, but the higher mortality rate due to chemotherapy-related acute toxicities most probably has offset its benefit. Further randomized studies with larger accrual numbers should be carried out, but additional measures must be taken to avoid life-threatening acute toxicities.
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7. Herskovic A, Martz K, Al-sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with esophageal cancer. N Engl J Med 1992;326: 1593–1598. 8. Al-sarraf M, Martz K, Herskovic A, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer, an intergroup study. J Clin Oncol 1997;15:277–284. 9. Minsky BD, Neuberg D, Kelsen DP, et al. Neoadjuvant chemotherapy plus concurrent chemotherapy and high dose radiation for squamous cell carcinoma of the esophagus: A preliminary analysis of the Phase II Intergroup Trial 0122. J Clin Oncol 1996;14:149 –155. 10. Minsky BD, Neuberg D, Kelsen DP, et al. Final report of Intergroup Trial 0122 (ECOG PF-289, RTOG 90-12): Phase II trial of neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous-cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 1999;43:517– 523. 11. Gaspar LE, Winter K, Kocha WI, et al. A phase I/II study of external beam radiation, brachytherapy, and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group Study 9207). Cancer 2000;88:988 –995. 12. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT0123 (Radiation Therapy Oncology Group 94-05) Phase III trial of combinedmodality therapy for esophageal cancer: High-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20:1167–1174. 13. Wang Y, Shi XH, He SQ, et al. Comparison between continuous accelerated hyperfractionated and late-course accelerated hyperfractionated radiotherapy for esophageal carcinoma. Int J Radiat Oncol Biol Phys 2002;54:131–136. 14. Jiang JD, Dong SD. The analysis of esophageal cancer patients treated by late course hyperfractionation radiotherapy. Chin J Radiat Oncol 2001;10:236 –238. 15. Sheng XF, Mei BZ, Cai ML, et al. Late course accelerated hyperfractionation radiotherapy for middle esophageal carcinoma: Clinical phase III trial. Chin J Radiat Oncol 1998;7: 16 –18. 16. Gao XS, Qiao XY, Yang XR, et al. Late course accelerated hyperfractionation radiotherapy concomitant with cisplation in patients with esophageal carcinoma. Oncol Rep 2002;9: 767–772. 17. Poplin EA, Khanuja PS, Kraut MJ, et al. Chemoradiotherapy of esophageal carcinoma. Cancer 1994;15:1217–1224. 18. Powell MEB, Hoskin PJ, Sunders MI, et al. CHART in localized cancer of the esophagus. Int J Radiat Oncol Biol Phys 1997;38:133–136.
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19. Jeremic B, Shibamoto Y, Acimovic L, et al. Accelerated hyperfractionated radiation therapy and concurrent 5-fourouracil/cisplatin chemotherapy for locoregional squamous-cell carcinoma of the thoracic esophagus: A Phase II study. Int J Radiat Oncol Biol Phys 1998;40:1061–1066. 20. Le Prise E, Etienne PL, Meunier B, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994;73:1779 –1784. 21. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodality therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462– 467. 22. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337: 161–167. 23. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001; 19:305–313. 24. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003;185:538 –543. 25. Safran H, Gaissert H, Hesketh PJ, et al. Neoadjuvant paclitaxel, cisplatin and radiation for esophageal carcinoma: A phase II study [Abstract]. Proc Am Soc Clin Oncol 1997;16: 304a. 26. Blanke C, Chiappori A, Epstein B, et al. A phase II trial of neoadjuvant paclitaxel (T) and cisplatin (P) with radiotherapy followed by surgery (S) and postoperative T with 5-fluorouracil (F) and leucovorin (L) in patients (pts) with locally advanced esophageal cancer (LAEC) [Abstract]. Proc Am Soc Clin Oncol 1997;16:283a. 27. Urba S, Orringer M, Iannettoni M, et al. A phase II trial of preoperative cisplatin, paclitaxel, and radiation therapy (XRT) before trans-hiatal esophagectomy (THE) in patients (Pts) with loco-regional esophageal cancer (CA) [Abstract]. Proc Am Soc Clin Oncol 2000;19:248a. 28. Adelstein DJ, Rice TW, Rybicki LA, et al. Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy. J Clin Oncol 2000;18:2032–2036. 29. Ajani JA, Walsh G, Komaki R, et al. Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction. Cancer 2004;100:2347– 2354.
doi:10.1016/j.ijrobp.2004.12.022
CLINICAL INVESTIGATION
Esophagus
LATE COURSE ACCELERATED HYPERFRACTIONATED RADIOTHERAPY PLUS CONCURRENT CHEMOTHERAPY FOR SQUAMOUS CELL CARCINOMA OF THE ESOPHAGUS: A PHASE III RANDOMIZED STUDY KUAI-LE ZHAO, M.D., XUE-HUI SHI, M.D., GUO-LIANG JIANG, M.D., WEI-QIANG YAO, M.D., XIAO-MAO GUO, M.D., GEN-DI WU, M.D., AND LONG-XIANG ZHU, M.D. Department of Radiation Oncology, Fudan University Cancer Hospital, Shanghai, China Purpose: Late course accelerated hyperfractionated (LCAF) radiotherapy (RT) is as effective as standard chemoradiotherapy for nonsurgical management of locally advanced esophageal squamous cell carcinoma (SCC). We have evaluated further the efficacy of concurrent LCAF RT and chemotherapy. Methods and Materials: In all, 111 eligible patients with esophageal SCC were randomized to receive LCAF alone (LCAF) or concurrent LCAF and chemotherapy (LCATⴙCT) between March 1998 and July 2000. All patients received conventional fractionation irradiation of 1.8 Gy per day, to a dose of 41.4 Gy/23 fractions in 4 –5 weeks, followed by accelerated hyperfractionated irradiation using reduced fields, 1.5 Gy/fractions twice a day, to a dose of 27 Gy in 18 days. Thus, the total dose was 68.4 Gy/41 fractions in 44 days. Fifty-four patients in the LCAFⴙCT arm had an additional four cycles of chemotherapy using cisplatin 25 mg/m2 daily and fluorouracil (5-FU) 600 mg/m2 daily on Days 1–3 every 4 weeks starting on the same day that LCAF was delivered. Results: The median survival was 23.9 months (95% confidence [CI], 20.1–27.7) for the LCAF arm and 30.8 months (95% CI, 17.6 – 44.1) for the LCAFⴙCT arm, respectively. Survival rates at 1, 3, and 5 years of the LCAF arm were 77%, 39%, and 28%, respectively, while those of the LCAFⴙCT arm were 67%, 44%, and 40%, respectively (p ⴝ 0.310). Grades 3 and 4 acute toxicities occurred in 46% and 25% of the patients in the LCAF arm and the LCAFⴙCT arm, respectively; 6% of the patients in the combined arm had Grade 5 acute toxicities, whereas none was noted in the LCAF alone arm. Conclusions: Late course accelerated hyperfractionation was effective for locally advanced esophageal SCC. There was a trend toward better survival among patients who received intensified treatment with concurrent chemotherapy. Further randomized studies with a larger number of patients should be carried out, but additional measures must be taken to reduce the higher mortality rate due to chemotherapy-related acute toxicities. © 2005 Elsevier Inc. Accelerated hyperfractionation, Chemotherapy, Esophageal carcinoma, Radiation.
The prognosis for patients with esophageal carcinoma treated with conventional radiotherapy alone remains discouraging despite the advances in radiotherapeutic techniques. Accelerated proliferation of tumor cells during the course of fractionated irradiation treatment is believed to be one of the causes of local failures in squamous cell carcinoma of the upper respiratory and digestive tracts (1–3). We have demonstrated marked improvement when late course accelerated hyperfractionation (LCAF) radiotherapy, which increased the probability of locoregional control by reducing the risk of tumor repopulation, was employed for locally advanced esophageal squamous-cell carcinoma (SCC) compared with the conventional fractionation radiation, with a 5-year survival and local control rate of 34% and 55%,
respectively, in our previous study (4). The results were also confirmed in the preliminary report of another similar large Phase III study where Han et al. (5, 6) reported 5-year survival rates of 32% and 14% after treatment with LCAF and conventional fractionation, respectively. Therefore, LCAF is widely accepted as standard treatment for locally advanced esophageal SCC in China. However, combined therapy by chemoradiation has been well established as a standard approach to locally advanced esophageal SCC, as demonstrated in the series of Radiation Therapy Oncology Group (RTOG) studies (7–12) that reported a 2-year local control rate of 55%, a 5-year survival rate of 25%, and a lower rate of distant metastases compared with radiation alone, 22% vs. 38% (p ⫽ 0.05). Thus, we initiated a prospective, randomized Phase III trial to see
Reprint request to: Guo-liang Jiang, M.D., Department of Radiation Oncology, Fudan University Cancer Hospital, Shanghai 200032, China. Tel: (⫹86) 21-64175590, ext. 1407; Fax: (⫹86) 21-64439052; E-mail: [email protected]
Acknowledgments—We thank Dr. Leaw Shiang Jiin for her assistance in editing the text in English. Received July 30, 2004, and in revised form Nov 16, 2004. Accepted for publication Dec 3, 2004.
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Fig. 1. The treatment scheme for radiation therapy (RT) was 41.4 Gy (1.8 Gy/fraction, q.d.) using large fields, 27 Gy (1.5 Gy/fraction, b.i.d.) using reduced fields, total dose of 68.4 Gy/41 fractions in 44 days; 5-Fu,750 mg/m2 ⫻ 3 days; DDP, cisplatin, 25 mg/m2 ⫻ 3 days. The treatment scheme for LCAF was the same as for LCAF⫹CT except for chemotherapy.
whether the benefit of combination therapy seen in the RTOG series could translate into further improvement on the survival and locoregional control rate when LCAF plus concurrent chemotherapy was performed. Late course accelerated hyperfractionation alone was selected as the control treatment because it represented the most widely accepted modality for locally advanced esophageal SCC in China. METHODS AND MATERIALS Eligibility and study design The eligibility criteria were as follows: (1) confirmation of esophageal SCC by histology or cytology; (2) clinical stages of T1– 4, N0-1, M0 (International Union Against Cancer, 1997); (3) baseline laboratory tests, i.e., white blood cell count of ⬎4.0 ⫻ 109 /L, platelet count of ⬎100 ⫻ 109/L, adequate renal function (serum creatinine concentration ⬍1.5 mg/dL, blood urea nitrogen ⬍8 mmol/L, or creatinine clearance ⬎65 mL per minute); (4) Karnofsky performance status ⱖ70; (5) no prior therapy; (6) no previous malignancies; and (7) no serious medical conditions that would preclude safe administration of treatment. Exclusion criteria included the following: (1) evidence of esophageal perforation or deep ulceration to mediastinum; (2) complete obstruction of the esophageal lumen; (3) esophageal bleeding; (4) involvement of supraclavicular lymph nodes; and (5) distant metastases. All patients had the following pretreatment evaluations: complete history and physical examination; complete blood cell counts and serum biochemical assays; chest radiograph; chest computed tomography (CT) scan; esophageal barium examination; and ultrasonographic examination to rule out distant metastases in liver, kidney, spleen, and retroperitoneal lymph nodes. Patients or their legal representatives had understood and signed the written informed consent to participate in this trial.
Treatment arms and randomization The patients were randomized into two arms by random number table. The treatment scheme for both the study arm (LCAF⫹CT)
and control arm (LCAF) is shown in Fig. 1. In the LCAF⫹CT arm, radiation therapy began on Day 1, concurrently with the first cycle of chemotherapy. In the LCAF arm, patients received irradiation alone. The same fractionation scheme and total dose of radiotherapy was delivered to both arms.
Radiation therapy Details of LCAF have been published previously (4, 13). Briefly, the radiation was carried out by 6 MV or 18 MV X-ray using a two-phase irradiation schedule. The first phase was the conventional fractionated irradiation with the field arrangement as follows: (1) two anterior oblique fields with a pair of appropriate wedges for lesions localized in cervical region, and (2) a three-field approach with one anterior and a pair of posterior oblique portals for lesions in the thorax. Fields were designed on the basis of the lesions shown on CT and barium examinations, with 2–3 cm margins around the tumors to cover the primary tumor and metastatic mediastinal nodes, and 3–5 cm margins at the long axis of esophagus to sufficiently encompass the submucosal invasion of esophagus. The dose was prescribed to the isocenter without correction of inhomogeneity. Conventional fractionation was implemented by 1.8 Gy/fraction, five fractions a week, to 41.4 Gy/23 fractions in 4.6 weeks. The second phase irradiation was the accelerated hyperfractionated session, where the radiation fields were reduced over the superior and inferior ends of esophageal lesion with 2 cm margins, whereas the width of fields remained the same. The dose was delivered at 1.5 Gy/fraction, twice daily with a minimum interval of 6 hours, 10 fractions a week to 27 Gy/18 fractions in 1.8 weeks. The total dose of the two-phase irradiation would be 68.4 Gy/41 fractions in 6.2 weeks. No prophylactic irradiation was given to the supraclavicular regions.
Chemotherapy Patients in LCAF⫹CT received concurrent four cycles of chemotherapy besides LCAF. The chemotherapeutic regimen consisted of cisplatin 25 mg/m2/day and 5-FU 600 mg/m2/day i.v. from Day 1–3, every 4 weeks, with the first and second cycle given during irradiation sessions.
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Criteria to score toxicity Irradiation toxicity was scored by the RTOG criteria, which included acute reactions occurring within the first 90 days of treatment, or late reactions occurring after 90 days of treatment. Chemotherapy toxicity was scored by National Cancer Institute Common Toxicity Criteria (version 2.0) and tabulated continually over the course of treatment. The most severe reaction was taken as the toxicity score for the entire treatment.
Dose modifications Dose modifications were allowed based on the findings on the day of treatment as well as the toxicity between cycles, whichever was the greater. The dose of 5-FU and cisplatin was decreased by 50% if the white blood cell count was greater than 2.0 ⫻ 09/L but lower than 4.0 ⫻ 109/L, or the platelet count was greater than 75 ⫻ 109/L but lower than 100 ⫻ 109/L. If the white blood cell count was lower than 2.0 ⫻ 109/L, or the platelet count was lower than 75 ⫻ 109/L, both chemotherapy and radiation were stopped temporarily until the toxicity had abated. If the creatinine clearance was between 55 and 65 mL/min or the serum creatinine was between 1.6 and 2.0 mg/dL, the cisplatin dose was decreased by 50%. If the creatinine clearance was less than 55 mL/min, then both cisplatin and 5-FU were stopped until the toxicity disappeared, but the radiation therapy was continued. Any other Grade 3 or higher toxicity required a 1-week delay in the course of treatment. Treatment was resumed once the toxicity became Grade 2 or better. Patients with stomatitis Grade 3 or higher received no additional 5-FU for that cycle, and the dose was permanently reduced for all subsequent cycles. Stomatitis Grade 3 or higher occurring between cycles required a 25% permanent dose reduction. The radiation dose was not modified. However, radiation was also stopped for Grade 3 or higher toxicities until they disappeared. Patients who developed Grade 3 or higher toxicities unrelated to radiation (oral mucositis, genitourinary toxicity, and hand-foot syndrome) would stop the chemotherapy but the radiation therapy was continued.
Follow-up After treatment, patients were followed up every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter. Each visit included history, physical examination, complete blood count, chest X-ray, esophageal barium radiography, or chest CT. Biopsy of the primary tumor site was required once locoregional recurrence was suspected by X-ray or CT, or both.
Evaluation of efficacy and statistics The endpoints of this trial were overall survival, locoregional failure, and metastasis rate. Death from any cause was calculated from the date of radiotherapy until death or last follow-up evaluation. Patterns of failure evaluated were first failure (local, regional, or distant), time to any local failure, and time to any distant metastasis. If recurrences occurred within 60 days of each other, they were counted as simultaneous. All endpoints were observed from the first day of treatment until death or last follow-up time. All of the rates were estimated by the Kaplan-Meier model, and differences between rates were compared by the log–rank test, using SPSS (version 11.0; SPSS, Chicago, IL). In all analyses the significance level was specified at p ⬍ 0.05.
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Table 1. Patient clinical characteristics
No. of patients Gender, n (%) Male Female Age (y) Median (range) Chest pain, n (%) Yes No Karnofsky performance status, n (%) 70 80–100 Weight loss, n (%) Yes No Lesion location, n (%) Cervical Upper thorax Middle thorax Lower thorax Esophageal length, cm Median (range) Stage, n (%) T1–2N0M0 T3–4N0M0 T1–4N1M0
LCAF
LCAF⫹CT
57
54
36 (63) 21 (37) 61.0 (41–74)
42 (78) 12 (22) 54.5 (39–74)
p value
0.092 0.755
35 (61) 22 (39)
37 (69) 17 (31)
0.433
3 (5) 54 (95)
2 (4) 52 (96)
0.692
0 (0) 57 (100)
2 (4) 52 (96)
0.143
3 (5) 18 (32) 34 (60) 2 (3)
4 (7) 12 (22) 36 (67) 2 (4)
0.724
6.0 (1–10)
6.0 (2–9)
0.132
11 (19) 37 (65) 9 (16)
11 (20) 37 (69) 6 (11)
0.690
Abbreviations: CT ⫽ chemotherapy; LCAF ⫽ late course accelerated hyperfractionated.
RESULTS Patient characteristics Between March 1998 and July 2000, 111 patients were randomized to the study. The pretreatment characteristics of the 111 eligible and assessable patients are listed in Table 1. The two randomized arms were well balanced for gender, age, performance status, weight loss, primary tumor size, and clinical TNM stage; other factors were evaluated. All patients were followed up until death or the time of last follow-up evaluation. The median follow-up for the 38 surviving patients was 61.7 months (range, 47.6 –76.4 months). The median follow-up period for the 73 patients who had died of their disease was 15.7 months (range, 1.5–54.2 months).
Treatment finally given Ninety-five percent of patients in the LCAF⫹CT arm received more than two cycles of chemotherapy, whereas 43% completed all four cycles of chemotherapy. All patients in both arms received the full course of LCAF radiotherapy. The major reasons why they did not complete their chemotherapy included severe vomiting, radiation-induced esophagitis and pneumonitis, esophageal ulcer, and refusal of 17 patients after finishing irradiation.
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Table 2. Overall maximum toxicity per patient Acute toxicity LCAF (n ⫽ 57)
Late toxicity
LCAF ⫹ CT (n ⫽ 54)
LCAF (n ⫽ 57)
LCAF ⫹ CT (n ⫽ 54)
Treatment effect
3
4
5
3
4
5
3
4
5
3
4
5
Esophagus Lung/trachea Skin Neurologic Heart Nausea and vomiting WBCs Platelets Hemoglobin Others Maximum severity reported per patient
11 2 0 0 0 1 0 0 0 0 14 (25%)
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0
10 1 0 0 0 6 4 0 0 0 21 (40%)
2 0 0 0 0 0 1 0 0 0 3 (6%)
1 2 0 0 0 0 0 0 0 0 3 (6%)
6 7 0 0 0 0 0 0 0 0 13 (23%)
1 1 0 0 0 0 0 0 0 0 2 (4%)
0 2 0 0 0 0 0 0 0 0 2 (4%)
2 5 0 0 0 0 0 0 0 0 7 (13%)
1 1 0 0 0 0 0 0 0 0 1 (2%)
0 2 0 0 0 0 0 0 0 0 2 (4%)
Abbreviations: CT ⫽ chemotherapy; LCAF ⫽ late course accelerated hyperfractionated; WBCs ⫽ white blood cells.
Toxicity of treatment The incidence of Grade 3 or higher acute and late treatment-related toxicity is presented in Table 2. Acute toxicities were severe (Grades 3 and 4) in 46% and life-threatening (Grade 5) in 6% in the LCAF⫹CT group, whereas they were 25% and 0%, respectively, in the LCAF group. Acute toxicities occurring in the LCAF⫹CT arm were predominantly hematopoietic or oral and pharyngeal mucositis believed to be due to chemotherapy. The three treatmentrelated deaths in the LCAF⫹CT group were due to poor nutrition or inadequate supportive treatment with pulmonary infection or esophagitis: one death on completion of the second cycle of chemotherapy and two deaths after the third cycle. There were no significant differences of late complications between the two groups, as 2 patients died of treatment-related pulmonary toxicity without evidence of cancer recurrence in each arm. Six patients had Grade 3 esophageal stenosis, 7 had Grade 3 pulmonary fibrosis, and 1 had Grade 4 esophageal and pulmonary complications in the LCAF arm, and 2 patients suffered from Grade 3 esophageal stenosis, 5 from Grade 3 pulmonary toxicity, and 1 from Grade 4 esophageal complications in the LCAF⫹CT arm. Survival and patterns of failure The median survivals for the LCAF and LCAF⫹CT groups were, respectively, 23.9 months (95% confidence interval [CI], 20.1–27.7) and 30.8 months (95% CI, 17.6 – 44.1). The overall survivals are illustrated in Fig. 2. The survival rates at 1, 3, and 5 years were, respectively, 77%, 39%, and 28% for the LCAF arm; and 67%, 44%, and 40% for the LCAF⫹CT arm (p ⫽ 0.310). The patterns of first failure are listed in Table 3. Thirtysix percent (21/57) of the patients in the LCAF arm and 26% (14/54) in the LCAF⫹CT arm had locoregional disease presenting as the first failure. Of the patients who
underwent LCAF and LCAF⫹CT, distant metastases as the first failure occurred in 19% (11/57) and 24% (13/54), respectively. Twenty-five percent (14/57) of the patients in the LCAF arm and 39% (21/54) in the LCAF⫹CT arm remained disease free. Time to local recurrence is depicted in Fig. 3. The 1-, 3-, and 5-year local recurrence rates were 18%, 37%, and 41% for the LCAF arm and 16%, 26%, and 33% for the LCAF⫹CT arm, respectively (p ⫽ 0.305). Time to distant metastases is shown in Fig 4. The rates of distant metastases at 1, 3, and 5 years were, respectively, 9%, 35%, and 42%
Fig. 2. Kaplan-Meier plot of survival in patients treated with late course accelerated hyperfractionated (LCAF) alone or with LCAF and chemotherapy combined (LCAF⫹CT; n ⫽ 111).
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Table 3. Patterns of failure
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We have confirmed the efficacy of LCAF alone for locally advanced esophageal SCC in our present study, with 5-year survival and local control rates of 28% and 59%, respectively, which are comparable with previous series that reported 5-year survival rates ranging from 26 –33% and 5-year local control of 56% (4 – 6, 13–16). At the same time, our study confirmed the possibility of further improvement on overall survival than LCAF alone. There was a trend toward better survival in patients who received intensified treatment with concurrent chemotherapy. The 5-year sur-
vival rate of the 54 patients who received LCAF with concurrent chemotherapy was 40% with a median survival of 30.8 months. There was a trend toward better survival in patients who received LCAF plus concurrent combined treatment but the difference did not reach statistical significance. The small sample size could be one of the possible explanations, but the higher mortality rate due to chemotherapy-related acute toxicities most probably offset its benefit, being 46% severe (Grades 3 or 4) and 6% life threatening (Grade 5), whereas only 25% severe acute toxicities and no life-threatening acute toxicities were noted among patients who underwent LCAF alone. Our protocol was different in several ways from other studies focusing on concurrent chemoradiotherapy for esophageal cancer. A number of questions have been raised about the necessary components for optimal treatment of esophageal cancer. First, we used LCAF radiotherapy instead of conventional fractionation. Hyperfractionation (⬎1 fraction per day) allows a relative improvement in therapeutic ratio for late responding tissues such as bronchogenic and head-and-neck cancer by increasing the total dose of radiation but not the risk of long-term toxicity. Accelerated fractionation targets tumor proliferation during the therapy by shortening the overall treatment time, which may result in fewer late side effects to the mucus membranes and skins (17). Powell et al. (18) reported 54 patients with esophageal cancer treated by a CHART (continuously hyperfractionated accelerated radiation therapy) regimen in a Phase II pilot study in which radiation was given at 54 Gy in 36 fractions in 12 days with a 6-h interfraction interval. Fifteen patients received further chemotherapy with 15 mg/m2 mitomycin i.v. bolus and cisplatin 100 mg/m2 on Day 13, whereas another 11 patients received further intraluminal brachytherapy of 15 Gy at 1 cm. There were 10 histologic
Fig. 3. Kaplan-Meier plot of the time to a local recurrence in patients with esophageal carcinoma treated with late course accelerated hyperfractionated (LCAF) radiotherapy alone or with LCAF and chemotherapy combined (LCAF⫹CT; n ⫽ 111).
Fig. 4. Kaplan-Meier plot of the time to distant metastasis in patients treated with late course accelerated hyperfractionated (LCAF) alone or with LCAF and chemotherapy combined (LCAF⫹CT; n ⫽ 111).
LCAF (n ⫽ 57)
Alive/no failure Any failure Locoregional failure Distant metastasis Locoregional failure and distant metastasis Dead of acute complication Dead of late complication Second primary cancer Dead of disease
LCAF⫹CT (n ⫽ 54)
No.
%
No.
%
14 43 20 17 1
24.6 75.4 35.1 29.8 1.8
22 32 13 12 1
40.7 59.3 24.1 22.3 1.9
0
0
3
5.6
2
3.5
2
3.7
1 2
1.8 3.5
0 1
0 1.9
Abbreviations: CT ⫽ chemotherapy; LCAF ⫽ late course accelerated hyperfractionated.
for LCAF-only patients and 18%, 32%, and 32% for LCAF⫹CT patients (p ⫽ 0.736). DISCUSSION
Chemoradiotherapy for esophageal carcinoma
benign strictures compared with 11 unbiopsied strictures in the historical control group. Longer median survival time and lower local recurrence rate were noted in the treatment group. Jeremic et al. (19) reported a favorable median survival time of 26 months and a 5-year survival rate of 29% for 28 patients treated with HART (hyperfractionated accelerated radiation therapy) with 1.5 Gy twice daily to a total of 54 Gy, concurrently with 5-FU (300 mg/m2, Days 1–5) and cisplatin (10 mg/m2, Days 1–5) for four courses, but relatively higher incidences of acute toxicities were noted; the most frequent acute high-grade (Grades 3 or 4) toxicity was esophagitis and leukopenia, seen in 50% and 39% of the patients, respectively. However, we used LCAF radiotherapy instead of HART or other nonconventional radiotherapy. Late course accelerated hyperfractionated was preferred to HART in the treatment for locally advanced esophageal SCC because of easier application, better cost-effect ratio, less radiation toxicity, and improved treatment efficacy, as presented in our previous study (13). The HART group received RT at 1.5 Gy/fraction twice daily, 5 days a week, to a total dose of 66 Gy/44 fractions in 4.4 weeks that offered a full 2-week reduction in overall treatment time compared with LCAF without marked improvement on survival, 3-year-survivals being 41% in the LCAF group and 38% in the HART group (p ⫽ 0.576). However, the incidence of acute toxicities was significantly greater in the HART group: 8.2% vs. 3.8% and 61.2% vs. 9.6% for acute life-threatening bronchitis and esophagitis, respectively. Second, a smaller radiation therapy volume was employed in our treatment protocol: 41.4 Gy to the primary tumor with 3–5 cm proximal and distal margins followed by a cone down of 30 Gy to the primary tumor with 2-cm proximal and distal margins, instead of 30 Gy to the whole esophagus followed by a cone down of 20 Gy to the primary tumor with 5-cm proximal and distal margins as in the RTOG 85-01 study. Radiation therapy volume has not received much attention until recently. Upper abdominal radiation therapy for thoracic lesions has generally been avoided to potentially improve the tolerance for the treatment. Thus, sparing the supraclavicular nodes and the whole esophagus might also improve tolerance. However, the benefit of such measures as using smaller radiation therapy volume remains to be assessed in future trials. Finally, the RTOG 85-01 trial reported the rate of local recurrences, the main cause of failure, to be as high as 45%,
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whereas other series have shown that complete response, if confirmed histologically, lowers the rate of local recurrences and increases the likelihood of prolonged survival (20 –24). Thus, a higher dose of 68.4 Gy was delivered in our present study, and the locoregional recurrences documented were surprisingly few, with a 5-year local control rate of 68%. The insignificant difference in locoregional control and overall survival between the intensified group with higher radiation dose compared with the standard group with 50 Gy radiation dose demonstrated in the Intergroup INT 0122 (RTOG 90-12) (9, 10), prospective RTOG 92-07 (11), and randomized INT 0123 (RTOG 94-05) studies (12) could imply that the larger radiation volume might have offset the benefit of higher radiation dose and resulted in greater acute radiation toxicities and prolonged overall radiation time. We advocated the use of the combined modality in view of the poor prognosis of patients with locally advanced esophageal SCC if treated by a single modality only. However, the use of the same radiation dosage for both groups of patients in the present study could have accounted for the higher rate of acute toxicities. The treatment plan of four courses of chemotherapy with 5-FU/cisplatin and LCAF for the most suitable combination schedule and dosage could be designed in future trials to evaluate the maximal efficacy and minimal toxicities. Incorporating the use of newer radiation techniques such as three-dimensional conformal radiotherapy or intensity-modulated radiotherapy, newer chemotherapeutic regimens that include taxanes (25–29) and CPT-11 (29), and intensive supportive treatment could be explored to evaluate the possibilities for optimal locoregional control and overall survival for patients with locally advanced esophageal SCC. Moreover, the role of radioprotectors for normal tissue protection could be favorable for patients’ tolerability. In conclusion, LCAF was effective for locally advanced esophageal SCC. There was a trend toward better survival among patients who received the combined treatment but the difference did not reach statistical significance. The small sample size could be one of the possible explanations, but the higher mortality rate due to chemotherapy-related acute toxicities most probably has offset its benefit. Further randomized studies with larger accrual numbers should be carried out, but additional measures must be taken to avoid life-threatening acute toxicities.
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