ORIGINAL ARTICLE

A Phase II Study of Concurrent Chemoradiotherapy With Paclitaxel and Cisplatin for Inoperable Esophageal Squamous Cell Carcinoma Hua-Rong Tang, MD,*w Hai-Feng Ma, BSc,*z Shi-Min An, MSc,y Harun Badakhshi, MD,8 Jia-Ying Deng,*z Jun-Hua Zhang, MD,*z Yun Chen, MSc,*z Zhen Zhang, MD,*z Xiao-Mao Guo, MD,*z Guo-Liang Jiang, MD,*z and Kuai-Le Zhao, MD*z

Objectives: A phase II study was performed to investigate the efficacy and the safety of a 3-week schedule of paclitaxel (PTX) plus cisplatin (DDP) combined with concurrent radiotherapy for esophageal squamous cell cancer. Patients and Methods: Patients with newly diagnosed esophageal squamous cell cancer who had histologic proof of local-regional carcinoma of the esophagus, a Karnofsky performance status of 80 or greater, and normal liver, renal, and bone marrow functions were enrolled in the phase II trial. Chemotherapy consisted of DDP (25 mg/ m2/d) for 3 days plus PTX (175 mg/m2) given for 3 hours, every 3 weeks for 4 cycles. The total dose of concurrent radiation with 68.4 Gy/44 Fx (late course–accelerated radiotherapy) or 61.2 Gy/34 Fx (conventional radiotherapy) was given at the first day of chemotherapy. Results: Between July 2008 and November 2011, 76 patients were enrolled in this trial. The median age was 58 years (range, 37 to 74 y). The stages were stage II (21 patients), stage III (27 patients), and stage IV (28 patients). A total of 89.5% (68/76) and 63.2% (48/76) patients completed Z2 cycles and all 4 cycles of chemotherapy, respectively. With the median follow-up of 36 months, the overall median survival time was 28.5 months and the progression-free survival time was 14.7 months. One- and 3-year survival rates were 75% and 41%, respectively. Neutropenia grade 3 and 4 occurred in 30.3% and 31.6% of the patients, respectively. Conclusions: Radiotherapy concurrent with a 3-week schedule of PTX and DDP resulted in an encouraging overall survival rate, but a relatively higher hematological toxicity. Key Words: concurrent chemoradiotherapy (CCRT), paclitaxel (PTX), cisplatin (DDP), esophageal squamous cell carcinoma (ESCC)

(Am J Clin Oncol 2014;00:000–000)

From the *Department of Radiation Oncology, Fudan University, Shanghai Cancer Center; yDepartment of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine; zDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai; wDepartment of Radiation Oncology, The First People’s Hospital of Zhenjiang, Jiangsu Provence; zDepartment of Radiation Oncology, Dongyang People’s Hospital, Zhejiang Province, China; and 8Department of Radiation Oncology, Charite´ School of Medicine and Centre for Cancer Medicine, Berlin, Germany. H.-R.T. and H.-F.M. contributed equally. Supported by the National Natural Science Foundation of China Research, China (grant number 21172043). The authors declare no conflicts of interest. Reprints: Kuai-Le Zhao, MD, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong’An Road, Shanghai 200032, China. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000069

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sophageal cancer is the eighth most common cancer in the world, and about 50% of cases occur in China.1,2 Although definitive concurrent chemoradiation has been proposed as the standard care for locally advanced unresectable and inoperable esophageal cancers, the outcome is not satisfactory, with a 5-year survival of 20% to 30% and a locoregional control rate of 45%.3,4 A combination of fluorouracil (5-FU) and cisplatin (DDP) has been a standard radiosensitizing regimen for several decades. However, the efficacy is only about 25% to 35%, and the median survival time is merely 16 months in advancedstage patients.1–4 Thus, it is necessary to look for potent radiosensitizers and more effective drugs. Paclitaxel (PTX) is a promising agent against esophageal cancer; its single activity reaches 32% when administrated alone.5 PTX and DDP regimens have achieved better efficacy in a neoadjuvant and definitive setting for advanced esophageal cancer: the effective rate is about 50% to 60%.6 On the basis of these considerations, we initiated a prospective phase II trial to evaluate the efficacy and tolerability of the definitive concurrent chemoradiation with PTX and DDP combination in patients with locally advanced esophageal squamous cell cancer (ESCC).

PATIENTS AND METHODS Eligibility The eligibility criteria were as follows: (1) newly diagnosed patients with histologically confirmed ESCC; (2) age less than 75 years; (3) Karnofsky Performance status Z80; (4) clinical stages of II-IVa and stage IVb without viscera metastasis according to the International Union against Cancer (UICC 6th); (5) presence of adequate bone marrow function (neutrophil count Z1.5 109/L, leukocyte count Z3 109/L, hemoglobin Z90 g/L, and platelet count Z100109/L), adequate liver function (serum bilirubin 1.5 mg/dL and transaminase level r2.5 the upper limit of normal), adequate serum creatinine (r1.2 mg/dL) and blood urea nitrogen (r25 mg/dL), and an expected survival time Z3 months. Patients with complete obstruction, tracheoesophageal fistula, and viscera metastasis were not eligible for this study.

Evaluation Before Treatment Before treatment, all patients underwent the following evaluations: physical examination, esophageal barium examination, upper digestive endoscopy, chest/abdominal computed tomography (CT) scanning, and ultrasonographic examination to rule out distant metastasis in the liver, the kidney, the spleen, and retroperitoneal lymph nodes. In addition, complete blood cell count, liver/renal function, and ECG were obtained

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in all patients. Patients or representatives had understood and signed the written informed consent to participate in this trial.

Treatment Schedule Chemotherapy was started on day 1 of radiotherapy: PTX 175 mg/m2, i.v., lasting for 3 hours, day 1; DDP 25 mg/m2, i.v., days 1 to 3. Cycles were repeated every 21 days, for 4 courses totally. Pretreatment before PTX treatment: 27 tablets of dexamethasone administered orally (0.75 mg/tablets) at 12 and 6 hours before PTX treatment, respectively, and 600 mg climetidine i.v. and 25 mg phenergan i.m. given at 0.5 hours before PTX treatment. If grade 3 or higher hematological toxicity occurred or a nadir granulocyte count 2 dose reductions.

Radiotherapeutic Technique Radiation therapy was administered using the 3-dimensional planning technique or intensity-modulated radiation therapy. Megavoltage photon energy of 6 MV was used. Computerized imaging was used to define the gross tumor volume (GTV). GTV included the primary tumor and metastatic lymph nodes (the diameter of the lymph node local in the trachea esophagus groove Z5 mm, in the mediastinum Z1 cm, and biopsy-proven metastatic superficial lymph nodes); CTV was defined as having a 2- to 3-cm cephalad and caudad margin beyond GTV. The planning target volume, defined by the margin around the CTV, was established. The planning target volume (PTV) included a 1-cm margin around the CTV. No prophylactic irradiation was given for all patients. In this study, 2 fractionation regimens of radiation were used. At the beginning, the radiation regimen was late course– accelerated radiotherapy (LCAF). Details of the LCAF regimen were as follows: the first phase of radiation was conventional fractionation: 1.8 Gy/fraction, 5 fractions a week, to 41.4 Gy/23 fractions in 4.6 weeks. The second phase of irradiation was the accelerated hyperfractionated session: 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 2-phase irradiation would be 68.4 Gy/41 fractions in 6.2 weeks. Whereas 16 patients completed the regimens, radiation twice daily for each patient was impossible because the number of radiotherapeutic patients increased and radiation machines were limited in our hospital. Hence, the radiation regimen was changed into conventional radiotherapy (CF) of 1.8 Gy/fraction, 5 fractions a week, to 61.2 Gy/34 fractions in 6.8 weeks. Plan optimization was based on the dose-volume histogram as follows: (1) the prescribed isodose curve covered 95% of the PTV; (2) the 95% isodose curve covered 99% of the PTV; (3) the maximum dose within the PTV was not allowed to exceed 110% of the prescribed dose; and (4) inhomogeneity corrections were carried out. Dose constraints to the organs at risk were as follows: (1) the mean lung dose wasr16 Gy, and the V20 (ie, percentage of the total lung volume receiving Z20 Gy) was r30%; (2) the mean heart dose was r40 Gy; and (3) the maximum spinal cord dose was r45 Gy.

Follow-up Evaluations During the treatment, the blood cell count was examined twice weekly. Other related symptoms were assessed daily. Toxicity of the treatment was evaluated according to the

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National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 3.0). After completion of therapy, the patients were then observed every 3 months during the first year and then every 6 months for 2 additional years and then on an yearly basis. All patients underwent the following evaluations: complete history and physical examination, CBC, blood, liver/renal function, ECG, a barium swallow study, CT scanning on the chest, and ultrasonographic examination or CT scanning on the abdomen. Biopsy of the primary tumor site was required once locoregional recurrence was suspected by image examination. The median follow-up time was 36 months (range, 16 to 58 mo).

Ethical Considerations This prospective phase II study was carried out with strict adherence to the Declaration of Helsinki. The study protocol was reviewed and approved by the Ethics Committee of Cancer Hospital Affiliated to Fudan University. Written informed consent was obtained from all participants.

Statistical Analysis Primary endpoints of this study were the overall survival (OS) and the progression-free survival (PFS). Secondary endpoints were the evaluation of toxicity and patterns of treatment failure. All of the rates were estimated by the Kaplan-Meier model, and differences between rates were compared by a logrank test, using SPSS (version 11.0; SPSS, Chicago, IL). All endpoints were observed from the first day of treatment until death or last follow-up time. Patterns of failure evaluated were first failure (local, regional, or distant). If recurrences occurred within 60 days of each other, they were counted as simultaneous. TABLE 1. Patient Characteristics (N = 76)

Characteristics

No. of Patients (n [%])

Age (y) Median Sex Male Female Tumor size (cm) Median Tumor location Cervical Upper thoracic Middle thoracic Lower thoracic Synchronous multiple primary Stage* II III IVa + IVb Fractionation regimen LCAF CF Cycles of chemotherapy 1 cycle only 2 cycle only 3 cycle only 4 cycle

58 (37-74) 63 (82.9) 13 (17.1) 5.5 (1-20) 12 31 23 8 2

(15.8) (40.8) (30.3) (10.5) (2.6)

21 (27.6) 27 (35.5) 14 + 14 (36.8) 16 (21.1) 60 (78.9) 8 13 7 48

(10.5) (17.1) (9.2) (63.2)

*UICC 6th. CF indicates conventional fractionation; LCAF, late course–accelerated fractionation.

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metastases without viscera metastasis. Of all 76 patients, 2.6% (2/76) are synchronous with multiple primary ESCC.

TABLE 2. Patterns of First Treatment Failure (N = 76)

First Failure

N (%)

No failure Failure Locoregional only Distant only Locoregional/distant Others

25 51 15 25 6 5

(32.9) (67.1) (19.7) (32.9) (7.9) (6.6)

RESULTS Demographic Variables of the Patients Between July 2008 and November 2011, we enrolled 76 patients to this study. Their demographic variables at study entry are presented in Table 1. Of all patients, 27.6% (21/76) were stage II, 35.5% (27/76) were stage III, 18.4% (14/76) were stage IVa, and 18.4% (14/76) were stage IVb. All 14 patients of stage IVb had nonlocoregional lymph-node

A 1.0

CCRT With Paclitaxel and Cisplatin for ESCC

Feasibility Among all patients, 1.3% (1/76) had interruptions 9 days during the radiotherapy period because of grade 3 esophagitis, and 5.2% (4/76) have not finished radiotherapy. One patient’s radiation dose was 9 Gy/5 Fx because of the severe toxicity of herpes zoster. One patient’s radiation dose was 52.2 Gy/29 Fx because of the severe toxicity of fatigue; 1 patient’s radiation dose was 59.4 Gy/35 Fx because of his own decision. One patient’s radiation dose was 57.6 Gy/32 Fx because of grade 3 esophagitis. Among all patients, 8 patients completed only 1 cycle of chemotherapy, 13 patients finished 2 cycles of chemotherapy, 7 patients finished 3 cycles of chemotherapy, and 48 patients finished 4 cycles of chemotherapy.

OS and PFS Rates As of May 8, 2013, 29 patients were alive, 25 with no evidence of disease progression. Of 51 patients with treatment failure, 15 patients had local/regional recurrence only,

A

Overall Survival

Stage II+III vs Stage IV

1.0 0.8

0.6

Survival Rate

Survival Rate

0.8

0.4

Stage II+III 0.6

0.4

Stage IV

0.2 0.2 0.0 0.0 0.00

12.00

24.00

36.00

48.00

60.00 0.00

Time (months)

12.00

24.00

36.00

48.00

60.00

48.00

60.00

Time (months)

B

B

Progression - free Survival

1.0

LCAF vs CF

1.0 0.8

0.6

Survival Rate

Survival Rate

0.8

0.4

LCAF

0.6 CF 0.4

0.2 0.2 0.0 0.00

12.00

24.00

36.00

48.00

60.00

Time (months)

FIGURE 1. OS (A) and PFS (B) curves for all patients. The 1-, 2-, 3-, and 4-year OS rates were 75%, 54%, 41%, and 29%, respectively. The 1-, 2-, 3-, and 4-year PFS rates were 55%, 38%, 28%, and 24%, respectively. OS indicates overall survival; PFS, progression-free survival. r

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0.0 0.00

12.00

24.00

36.00

Time (months)

FIGURE 2. The overall survival rate curves of stage II + III versus stage IV and LCAF versus CF (A, stage II + III vs. stage IV, P = 0.006; B, LCAF vs. CF, P = 0.649). CF indicates conventional radiotherapy; LCAF, late course–accelerated radiotherapy.

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the esophagus and the lung/trachea were 5/76 and 4/76, respectively. No Zgrade 4 late toxicity was observed.

25 patients had distant metastasis only, 6 patients had concurrent local/regional/distant failure, and 5 patients failed as a result of other reasons including second primary cancers (3 patients), second primary cancer’s progression (1 patient), and heart failure (1 patient who had cardiac insufficiency before chemoradiation) (Table 2). The number of patients at stages IIIII and stage IV who had treatment failure were 29/48 and 22/24, respectively; among them, those who failed because of distant metastases were 12 and 19 patients, respectively. The median OS time was 28.5 months (95% confidence interval [CI], 16.280-40.653). The 1-, 2-, 3-, and 4-year OS rates were 75%, 54%, 41%, and 29%, respectively. The 1-, 2-, 3-, and 4-year PFS rates were 55%, 38%, 28%, and 24%, respectively (Fig. 1). We compared the survival rate difference between the LCAF group and the CF group, and the result showed no statistic significance (P = 0.649), which implicated that the fractionation regimen (LCAF and CF) had no significant impact on the general survival rate (Fig. 2). We also compared the survival between stages II + III and stage IV: the median survival time was 38.6 months (95% CI, 26.715-50.418) versus 15.4 months (95% CI, 12.309-18.557) (P = 0.006) (Fig. 2).

DISCUSSION Previous phase II trials showed that PTX has therapeutic efficacy in esophageal cancer, and it was widely used in neoadjuvant concurrent chemoradiation.7–14 However, few studies revealing valid data on PTX involvement in definitive chemoradiation for locoregionally advanced esophageal cancer have yet been published. Thus, we carried out the study to observe the efficacy and toxicity of concurrent chemoradiation with PTX and DDP (TP regimen) in unresectable or inoperative local advanced esophageal cancer. In this study, we observed that concurrent chemoradiation with a TP regimen showed better survival rates, with 1-, 2-, 3-, and 4-year survival rates of 75%, 54%, 41%, and 29%, respectively. The median survival time was 28.5 months (95% CI, 16.280-40.653). This OS rate seems better than that of RTOG9405 and equal to the result of RTOG0113.4,15 In the RTOG9405 phase III trial, treated with 50.4 Gy radiotherapy with 5-FU + DDP, the median survival time was 18.1 months; 1- and 2-year survival rates were only 66% and 40%, respectively. In the RTOG0113 phase II clinical study, treated with 5FU + PTX with 50.4 Gy of radiation, the median survival time was 28.8 months, with 1- and 2-year survival rates of only 76% and 56%, respectively. In the present trial, all patients were inoperable, with 55/76 patients in stages III + IV. In the RTOG9405 and the RTOG0113 studies, all participants were localized esophageal cancer patients. In the RTOG9405 trials, there were 10/109 T4 patients and 18/108 N1 patients. In the RTOG0113 group, T4 accounts for only 6/100 and N1 for only 27/100 cases. Adverse effects were tolerable in general. In the study, 94.7% patients finished all courses of radiotherapy, 89.5% patients finished Z2 courses of chemotherapy along with a full course of radiotherapy, and 63.2% patients finished all 4 courses of chemotherapy. The main toxicities were grade 3 and 4 leukopenia and neutropenia. Grade 3 and 4 leukopenia occurred in 43.4% and 14.5% of the cases, respectively. Grade 3 and 4 neutropenia occurred in 30.3% and 31.6% of the cases, respectively. In the RTOG0113 study, which is a nonsurgery radical concurrent

Adverse Events Acute toxicities are summarized in Table 3. The most frequent acute adverse events were grade 3 and 4 neutropenia (47/76) and leukopenia (44/76). Thrombocytopenia and anemia occurred in 7/76 and 2/76 cases, respectively. Nonhematological adverse events were mild. Common adverse events included grade 2 fatigue (15/76), neurotoxicity (14/76), pneumonitis (13/ 76), nausea/vomiting (12/76), esophagitis (9/76), and muscular soreness (6/76). Percentages of the adverse events listed above that reached grades 3 and 4 were 6/76, 3/76, 0/76, 6/76, 2/76, and 1/76, respectively. Fatigue and nausea/vomiting are 2 common adverse events of chemotherapy, whereas peripheral neurotoxicity and muscular soreness are 2 common adverse events of PTX treatment. Neurotoxicity usually appears at 24 hours after PTX infusion, with a median lasting time of 6 months. Radiotherapy-related adverse events included mainly esophagitis and pneumonitis. There was no relevant toxicity for the liver, the kidney, and the heart recorded. In late toxicities, grade 2 and 3 in TABLE 3. Acute Treatment Toxicity (N = 76)

LCAF (N = 16) (n [%]) Hematological toxicity Leukopenia Neutropenia Anemia Thrombocytopenia Nonhematological toxicity Fatigue Neurotoxicity Pneumonitis Nausea/vomiting Esophagitis Muscular soreness Skin Weight lost Fever Diarrhea Allergy

CF (N = 60) (n [%])

Total Patients (N = 76) (n [%])

Grade 3

Grade 4

Grade 3

Grade 4

Grade 3

Grade 4

10 (62.5) 7 (43.8) 0 1 (6.3)

0 6 (37.5) 0 0

23 16 1 6

11 (18.3) 18 (30.0) 1 (1.7) 0

33 23 1 7

11 (14.5) 24 (31.6) 1 (1.3) 0

1 (6.3) 0 0 0 2 (12.5) 1 (6.3) 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

(38.3) (26.7) (1.7) (10.0)

5 (8.3) 3 (8.0) 0 2 (3.3) 0 0 0 1 (1.7) 0 0 0

0 0 0 4 (6.7) 0 0 0 0 0 0 0

(43.4) (30.3) (1.3) (9.2)

6 (7.9) 3 (3.9) 0 2 (2.6) 2 (2.6) 1 (1.3) 0 1 (1.3) 0 0 0

0 0 0 4 (5.3) 0 0 0 0 0 0 0

CF indicates conventional fractionation; LCAF, late course–accelerated fractionation.

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chemoradiation regimen, 1 group also adopted PTX + DDP, in which the dose of radiotherapy was 50.4 Gy/28 Fx, and grade 3 and 4 adverse reactions occurred in 43% and 40% of the cases, respectively. The death rate related to treatment was 6%. However, another group with PTX + 5-FU showed lower toxicity and better efficacy than PTX + DDP. Other phase II clinical studies showed strong grade 3/4 neutrophils in concurrent chemoradiation with PTX and DDP.16,17 These results implied that the PTX + DDP regimen may have a strong impact on neutrophils. Possible factors causing the hematological toxicity in our study are as follows: (a) a high dose of radiotherapy (60 to 70 Gy) was given; (b) the dose of chemotherapy was kept unchanged when radiotherapy proceeded; (c) chemotherapy was repeated every 3 weeks. Compared with our 3-week schedule of PTX with DDP/carboplatin, the weekly schedule of TP showed a milder hematological toxicity.6,10,18 However, which effect is better of the 2 schedules of TP meanwhile remains unknown. Next, we will conduct a prospective clinic trial to study the results of a weekly schedule of TP on a large patient sample. Nonhematological toxicity was mild. Grade 3 neurotoxicity occurred in only 3/76 cases, and most of the patients with neurotoxicity tend to recover in the following several months. Grade 3 and 4 nausea/vomiting occurred in 2/76 and 4/76 cases, respectively. Grade 3 esophagitis occurred in only 2/76 cases. No grade 4 esophagitis or grade 3 and 4 radiation-induced pneumonitis were observed. We also observed no treatmentrelated death. The reason we chose the 3-week schedule of chemotherapy was to reduce the rate of distant metastasis and also provide radiosensitization. In the present trial, the rate of distant metastasis remained the first reason of failure: 60.8% (31/51), which is higher than other reports.6,19 The reason for this high rate is that more patients with stage IV were enrolled in this trial. The rate of distant metastasis for patients with stages II-III and IV were 41.4% and 86.4%, respectively.

CONCLUSIONS Radiotherapy concurrent with a 3-week schedule of PTX and DDP resulted in an encouraging OS rate, but a relatively higher hematological toxicity.

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A Phase II Study of Concurrent Chemoradiotherapy With Paclitaxel and Cisplatin for Inoperable Esophageal Squamous Cell Carcinoma.

A phase II study was performed to investigate the efficacy and the safety of a 3-week schedule of paclitaxel (PTX) plus cisplatin (DDP) combined with ...
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