Capecitabine and Cisplatin Chemotherapy (XP)

Jpn J Clin Oncol 2007;37(11)829–835 doi:10.1093/jjco/hym117

Capecitabine and Cisplatin Chemotherapy (XP) Alone or Sequentially Combined Chemoradiotherapy Containing XP Regimen in Patients with Three Different Settings of Stage IV Esophageal Cancer Sung Sook Lee, Sung-Bae Kim, Seung-Il Park, Yong Hee Kim, Jin-Sook Ryu, Ho-Yong Song, Ji Hoon Shin, Hwoon Yong Jung, Gin Hyug Lee, Kee Don Choi, Kyung-Ja Cho and Jong Hoon Kim Department of Medicine, Thoracic Surgery, Radiation Oncology, Diagnostic Radiology, Pathology, ECSG (Esophageal Cancer Study Group), Asan Medical Center, Seoul, Korea Received January 25, 2007; accepted July 29, 2007; published online October 19, 2007

For reprints and all correspondence: Dr Sung-Bae Kim, Division of Oncology, Department of Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-ku, Seoul 138-736, South Korea. E-mail: [email protected]

# 2007 Foundation for Promotion of Cancer Research

Downloaded from http://jjco.oxfordjournals.org/ by guest on June 7, 2013

Background: The 1997 staging system for esophageal carcinoma subdivided distant metastatic disease (M1) into nonregional lymph node metastases (M1a) and other metastases (M1b). To determine the relevance of this classification system, we investigated the efficacy and toxicity of capecitabine/cisplatin (XP) chemotherapy alone or in combination with radiotherapy. Methods: We identified 74 patients with M1 disease treated at Asan Medical Center from January 2003 to December 2005. Of these patients, 19 (25.7%) were classified as M1a, 29 (39.2%) as M1b (nonvisceral lymph node metastases), and 26 (35.1%) as M1b (visceral metastases). All patients were treated with first two cycles of XP induction chemotherapy, consisting of capecitabine 1000 mg/m2 twice daily on days 1 – 14, and i.v. cisplatin 60 mg/m2 on day 1, every 3 weeks. Patients classified as M1a and M1b (nonvisceral lymph node metastases) were treated with 54 Gy of radiotherapy, concurrently with weekly capecitabine 800 mg/m2 twice daily on days 1 – 5 and i.v. cisplatin 30 mg/m2 on day 1 during radiation. Patients classified as M1b (visceral metastases) were treated with chemotherapy only until disease progression or intolerance to chemotherapy. Results: In response to the first two cycles of chemotherapy, 3/18 (16.7%) M1a nonregional lymph node (LN), 4/27 (14.8%) M1b nonvisceral LN metastases and 5/25 (20%) M1b visceral metastases patients attained partial responses. After definitive chemoradiation in the setting of M1a, M1b nonvisceral LN metastases and maximum cycles of chemotherapy in the M1b visceral metastases setting, the response rates were 77.8, 62.9 and 36.0% respectively. With median follow-up of 12.5 months (range 0.5 – 22.8), 50 of 74 patients (67.5%) died. The median time to progression (TTP) was 7.8 months (95% CI, 6.0 – 9.5 months) and the median overall survival (OS) was 12.0 months (95% CI, 9.0 – 15.0 months). Median TTP in the M1a, M1b nonvisceral LN metastases and M1b visceral metastases were 10.3, 6.5 and 5.9 months, respectively (P ¼ 0.087), whereas median OS in these groups was 13.8, 13.8, and 8.2 months, respectively (P ¼ 0.134). Median TTP was 8.4 months (95% CI, 5.5 –11.3 months) in the 48 patients with M1a and M1b nonvisceral LN metastases and 5.9 months (95% CI, 2.7 – 9.0 months) in the 26 patients with M1b visceral metastases (P ¼ 0.03), and median OS in these two groups was 13.8 months (95% CI, 10.4 –17.3 months) and 8.2 months (95% CI, 5.7–10.7 months), respectively (P ¼ 0.04). Conclusion: The similar OS in patients with M1a and M1b nonvisceral LN metastases suggests that concurrent chemoradiotherapy might contribute in the latter. Our findings

830

XP alone or sequentially combined chemoradiotherapy

indicate that sequentially combined chemoradiotherapy containing XP regimen was active and well tolerated as first-line treatment for M1a as well as M1b esophageal cancer. Key words: capecitabine – cisplatin – esophageal cancer

PATIENTS AND METHODS

The 2002 AJCC staging classified M1a and M1b for stage IV, therefore, the cervical and celiac lymph node (LN) metastases are defined as distant metastasis (M1 LYM) by TNM classification (1). Moreover, there was no significant correlation between the tumor location and sites of M1 LYM; even upper thoracic tumor could frequently metastasize to the celiac nodes, whereas lower tumor could metastasize to the cervical nodes. Thus, in clinical practice setting, stage IV esophageal cancer can be subclassified into three different settings of M1a nonregional LN metastases, M1b nonvisceral LN metastases, and M1b visceral metastases. Treatment of stage IV metastatic esophageal cancer consists of chemotherapy alone or palliation, with definitive chemoradiotherapy in selected cases. The combination of 5fluorouracil (5-FU) and cisplatin has become a standard regimen, due to clinical outcome, synergism between these two agents and their radiosensitizing effects (2 – 5). The oral fluoropyrimidine capecitabine (Xelodaw ) was designed to generate 5-FU preferentially in tumor tissues and to mimic continuously infused 5-FU (6,7). The convenience of administration and the tolerable toxicity profile have made concurrent capecitabine and radiation therapy an attractive option in the treatment of metastatic esophageal cancer (8– 10). The combination of capecitabine (X) and cisplatin (P) has been tested in several malignancies, including gastric, biliary and esophageal cancers (11 – 15). A phase II trial reported on 20 patients who received twice daily capecitabine 1250 mg/m2 on days 1 – 14 and cisplatin 60 mg/m2 on day 1 of every 21 day cycle as first-line chemotherapy in metastatic or recurrent esophageal cell carcinoma (16). The results of these trials suggest that capecitabine and cisplatin showed a very promising preliminary anti-tumor activity and was well tolerated with convenient administration as a firstline treatment. We therefore divided these patients into three groups: those with M1a distant, nonregional LN metastases, M1b nonvisceral LN metastases at other sites and M1b visceral metastases. Those with M1b visceral metastases were treated with XP chemotherapy alone, whereas the other two groups were treated with induction followed by concurrent chemoradiation containing XP. We investigated the efficacy and toxicity of treatment regimens of XP chemotherapy alone or the combination of radiotherapy with weekly XP in patients with three different settings of stage IV esophageal cancer.

PATIENTS Prospectively obtained clinical data from patients with metastatic or unresectable esophageal cancer were analyzed retrospectively. Patients eligible for this study were those with histologically determined carcinoma of the esophagus, clinically or biopsy-determined M1 LN/visceral metastases, as defined by the criteria of the American Joint Committee on Cancer (17), and without prior treatment. Patients with histologically determined small-cell carcinoma were excluded. All patients were 18 years old, with an Eastern Cooperative Oncology Group Performance status of 0 – 2, a white blood cells (WBC) count 3000/mL, a platelet count 100 000/mL, aspartate transferase (AST) and alanine transferase (ALT) levels within three times the normal upper limit, serum bilirubin level 2.0 mg/dl, and creatinine clearance 50 ml/min. Patients with serious complications, a history of ischemic heart disease or active carcinoma at another site were also excluded. We identified 74 patients with M1 esophageal cancer who had received first-line XP chemotherapy between January 2003 and December 2005.

TREATMENT SCHEDULE

AND

TOXICITY ASSESSMENT

Capecitabine was administered orally at a dose of 1000 mg/m2 twice a day according to the standard intermittent schedule (14 days of treatment followed by a 7-day rest period, every 3 weeks). Cisplatin was administered intravenously on day 1 (before the first dose of capecitabine) at a dose of 60 mg/m 2 for 1 h with hydration, and repeated every 3 weeks. Following two cycles of chemotherapy alone, patients classified as M1a and M1b nonvisceral metastases disease received 54 Gy of radiotherapy, delivered concurrently with oral capecitabine 800 mg/m2 twice daily on 5 days a week and weekly i.v. cisplatin 30 mg/m2 on day 1, during radiation. Patients classified as M1b visceral metastasis were treated with chemotherapy only until disease progression or intolerance to chemotherapy. Treatment continued until disease progression or unacceptable toxicity, or if the patient chose to discontinue treatment. Toxicity was assessed before starting each 3-week cycle using the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0.


INTRODUCTION

Jpn J Clin Oncol 2007;37(11)

PRETREATMENT, FOLLOW-UP AND RESPONSE EVALUATION

RESULTS

Physical examination, chest X-rays, complete blood counts and biochemical tests were performed before each chemotherapy cycle. Response evaluation was performed by computed tomography (CT) scan every two to three cycles until the tumor progressed. Tumor response was classified on the basis of the response evaluation criteria defined by RECIST guidelines.

PATIENT CHARACTERISTICS

STATISTICS

Table 1. Patient characteristics (n ¼ 74) Age

63 (44-83)

Gender Male Female

Histology Squamous

71 (95.9%)

Adeno

72 (97.3%) 2 (2.7%)

3 (4.1%)

ECOG PS

Differentiation

0

3 (4.1%)

1

69 (93.2%)

2

2 (2.7%)

Well

8 (11.3%)

Moderated

47 (66.2%)

Poor

16 (22.5%)

The characteristics of the 74 patients are summarized in Table 1. Their median age was 63 years (range 44 – 83 years). Of the 74 patients, 71 (95.9%) were male and 72 (97.3%) had a good performance status (ECOG performance status 0 or 1). Primary tumors were distributed throughout the upper, middle and lower esophagus. Histologically, 72 tumors (97.3%) were squamous cell carcinomas and two (2.7%) were adenocarcinomas. The most common metastatic site was the cervical lymph nodes (56.8%), and the most common visceral metastatic organ was the lungs (18.9%). Of the 74 patients, 25 received XP chemotherapy alone and 49 received XP chemotherapy followed by chemoradiotherapy. The median number of chemotherapy cycles in patients receiving chemotherapy alone was 2 (range 1 – 8). TUMOR ACTIVITY When excluding patients lost to follow-up after the first cycle of treatment, there were 70 patients with measurable disease, 18 classified as M1a, 27 as M1b nonvisceral LN metastases and 25 as M1b visceral metastases. Of these, 3/18 (16.7%), 4/27 (14.8%) and 5/25 (20.0%), respectively, had partial responses to the first two cycles of XP chemotherapy (Table 2). Following two cycles of chemotherapy alone, each patient classified with M1a and M1b nonvisceral LN metastases disease received a total of 54 Gy of radiotherapy, delivered concurrently with oral capecitabine 800 mg/m2 twice daily 5 days per week and weekly i.v. cisplatin 30 mg/m2 on day 1. The first-course treatment field, which included the supraclavicular region LN, received

Table 2. Antitumor activity of the first two cycles of chemotherapy Location of Primary tumor

Metastatic sites Response

M1b nonvisceral LN metastases, n ¼ 27

M1b visceral metastases, n ¼ 25

Upper

19 (25.7%)

Liver

Middle

27 (36.5%)

Peritoneum

2 (2.7%)

CR

0

0

0

Lower

24 (32.4%)

Lung

14 (18.9%)

PR

3

4

5

Cervical LN

42 (56.8%)

SD

10

14

12

PD

0

1

5

GE junction involved Diffuse

3 (4.1%) 1 (1.4%)

Intraabdominal LN Bone

10 (13.5%)

M1a, n ¼ 18

22 (29.7%) 7 (9.5%)

NA ORR

Treatment Modality

5 16.7%

8 14.8%

3 20.0%

No. of metastases

Combined CRTx

49 (66.2%)

1

47 (63.5%)

Only CTx

25 (33.8%)

2

27 (36.5%)

LN, lymph nodes; ECOG PS, Eastern Cooperative Oncology Group performance status; CRTx, preoperative chemoradiotherapy; CTx, preoperative chemotherapy.

M1a: metastasis in cervical lymph nodes of the upper thoracic esophagus; not applicable to the mid thoracic esophagus; metastasis in celiac lymph nodes of the lower thoracic esophagus. M1b (nonvisceral LN metastases): metastasis in celiac lymph nodes of the upper thoracic esophagus; cervical/celiac lymph nodes of the mid thoracic esophagus; metastasis in cervical lymph nodes of the lower thoracic esophagus. M1b (visceral metastases): distant visceral metastasis. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not assessable; ORR, overall response rate.


Time to progression (TTP) and overall survival (OS) were estimated using the Kaplan – Meier method. In patients with measurable disease, the duration of response was defined as the interval from the onset of complete response (CR) or partial response (PR) until first evidence of disease progression. If death occurred before progression was documented, the date of death was assumed to be the date of progression. TTP was calculated from the date of entry to the date of progression, and OS was measured from the date of entry to the date of last follow-up or death.

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Table 3. Antitumor activity after completion of concurrent chemoradiotherapy or chemotherapy alone Response

M1a, n ¼ 18

M1b nonvisceral LN metastases, n ¼ 27

M1b visceral metastases, n ¼ 25

CR

9

9

0

PR

5

8

9

SD

2

7

8

PD

1

1

5

NA

1

2

3

ORR

77.8%

62.9%

36.0%

SURVIVAL OUTCOMES After a median follow-up of 12.5 months (range 0.5 – 22.8), the median overall TTP was 7.8 months (95% CI, 6.0 – 9.5 months) and the median OS was 12.0 months (95% CI, 9.0 – 15.0 months; Fig. 1). Median TTP in the M1a, M1b nonvisceral LN metastases and M1b visceral metastases patients was 10.3, 6.5 and 5.9 months, respectively (P ¼ 0.087), whereas median OS in these groups was 13.8, 13.8 and 8.2 months, respectively (P ¼ 0.134, Fig. 2). When the 74 patients were divided into subgroups of 48 with M1a and M1b nonvisceral LN metastases and 26 with M1b visceral metastases, median TTP was 8.4 months (95% CI, 5.5 – 11.3 months) and 5.9

ADVERSE EVENTS Of the 74 patients, three were lost to follow-up without toxicity evaluation, and 71 (95.9%) were assessed for safety during the first two cycles of chemotherapy. The highestgrade toxicities and their frequencies throughout treatment, including those of treatment-related hematological and nonhematological adverse events, are shown in Table 4. During the first two cycles of chemotherapy, the most common treatment-related hematological adverse events were grade 1/2 anemia and neutropenia. The most important major toxicities throughout the concurrent chemoradiotherapy/chemotherapy alone treatment period included myelosuppression and esophagitis. Hematological adverse events included anemia (93%), neutropenia (64.8%) and thrombocytopenia (40.8%), with grade 3/4 intensity rates of 1.4, 23.9 and 12.7%, respectively. Hand – foot syndrome and diarrhea were rare. The rate of esophagitis was 72.1%, and two patients (2.9%) developed treatment-related perforation of the esophageal wall.

DISCUSSION Patients with inoperable metastatic disease but in good general condition are candidates for palliative chemotherapy. A combination of fluorouracil (5-FU) and cisplatin has become a standard regimen, not only because of its clinical outcome, but also because of the synergism between the two

Figure 1. Time to progression (TTP) and overall survival (OS) for all patients (n ¼ 74); median follow-up, 12.5 months (range 0.5–22.8 months).


44 Gy, administered via an anterior:posterior (AP) approach. The boost field included the tumor with 5 cm cranial and caudal margins, delivered via a three-field approach consisting of an AP and two posterior obliques. The response rates following completion of concurrent chemoradiotherapy or chemotherapy alone were 77.8% (14/18), 62.9% (17/27) and 36% (9/25), respectively (P ¼ 0.014; Table 3). The median response duration was 5.0 months (range 0.1– 21.1 months).

months (95% CI, 2.7 – 9.0 months), respectively (P ¼ 0.03), and median OS was 13.8 months (95% CI, 10.4 – 17.3 months) and 8.2 months (95% CI, 5.7 – 10.7 months), respectively (P ¼ 0.04, Fig. 3). Fifty of the 74 patients (67.5%) died, making the 2-year survival rates 18.6% in patients with M1a and M1b nonvisceral LN metastases, and 0% in patients with M1b visceral metastases M1b, respectively.


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Figure 2. Time to progression and overall survival according to nonregional lymph node metastases (M1a) (black solid line), nonvisceral lymph nodes metastases (M1b) (black dotted line) and visceral metastases (M1b) (gray dotted line).

location of the primary lesion. Stage IV esophageal cancer may be subdivided into three categories: M1a, consisting of metastases in the cervical lymph nodes of the upper thoracic esophagus or the celiac lymph nodes of the lower thoracic esophagus, but not applicable in the mid thoracic esophagus; M1b nonvisceral LN metastases, metastases in the celiac lymph nodes of the upper thoracic esophagus, the cervical/ celiac lymph nodes of the mid thoracic esophagus or the cervical lymph nodes of the lower thoracic esophagus; and M1b visceral metastases, consisting of distant visceral metastasis. We observed similar response rates and overall survival in patients with M1a and M1b nonvisceral LN metastases, with both decreased significantly in patients with M1b visceral metastases. The TNM classification defines cervical and celiac lymph node metastases as distant metastases. Moreover, tumor location did not show significant correlation with sites of M1 LYM, in that upper thoracic tumors

Figure 3. Time to progression and overall survival according to M1a and M1b nonvisceral LN metastases (black solid line) and M1b visceral metastases (gray solid line).


agents and their radiosensitizing effects. The combination of cisplatin and 5-FU is one of the most widely used palliative regimens, with a response rate of about 35% and a median survival of 6 – 8 months (18). Chemoradiotherapy might have curative potential even in patients with locally advanced carcinoma of the esophagus. In the study by Ohtsu et al. (19), where patients were divided into subgroups of 32 with M1 lymph node and 22 without M1 lymph node, the 3-year survival rate was 27 and 21%, respectively. The combination of capecitabine and cisplatin has been tested in several malignancies, including gastric cancer (11 – 13). In this study, we sought to determine whether capecitabine and cisplatin combination therapy, alone or in combination with radiation therapy, was effective and safe in stage IV esophageal cancer patients. The current TNM staging system divides nonregional and distant nodal involvement into M1a and M1b categories according to the

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Table 4. Treatment-related adverse events during first two cycles of chemotherapy and sequential induction chemotherapy followed by concurrent chemoradiation or chemotherapy alone by NCI CTC V.2.0 Toxicity

Grade 3– 4 (% of patients)

Anemia

0% (1.4)

Neutropenia

Grade 1– 4 (% of patients) 82.9% (93)

14.3% (23.9)

51.4% (64.8)

Febrile neutropenia

1.4% (2.8)

1.4% (2.8)

Thrombocytopenia

2.9% (12.7)

15.7% (40.8)

Hypoalbuminemia

1.4% (2.8)

18.6% (31)

Hand– foot syndrome Diarrhea Esophagitis

0% (0)

8.5% (8.5)

1.4% (2.8)

4.3% (5.7)

0% (16.1)

52.2% (72.1)

NCICTC, National Cancer Institute Common Toxicity Criteria.

Conflict of interest statement None declared.


could metastasize to the celiac nodes, whereas lower tumors could metastasize to the cervical nodes. It has also been proposed that this entity should be classified as N2 disease, since some nonregional lymph node metastases may be resectable and some patients with M1a disease may have long-term survival after resection (20 – 22). Some patients with M1 LYM have been found to survive longer after extended esophagectomy with three-field extensive lymph node dissection (23 – 26). In our M1 LYM patients, increased response rate and similar overall survival in the M1a and M1b nonvisceral metastases suggested that sequentially combined chemoradiotherapy might be equally beneficial in the M1a and M1b nonvisceral metastases to improve the prognosis. However, in another study, subclassification of M1 into M1a and M1b did not provide distinctive prognostic information because survival rates are relatively homogeneous (27), whereas other studies showed significant differences in survival of patients with M1a and M1b in that median and 5-year Kaplan – Meier survival estimates are 11 months and 6% for patients with M1a disease and 5 months and 2% for those with M1b disease (28). 5-FU þ cisplatin remains as the standard treatment for metastatic esophageal carcinoma, producing response rates of 20 – 35% in the phase II trials. In a phase II trial of 20 patients with metastatic or recurrent esophageal cell carcinoma who received twice daily capecitabine 1250 mg/m2 on days 1 – 14 and cisplatin 60 mg/m2 on day 1 of every 21 day cycle as first-line chemotherapy, the objective response rate was 47.1% (16). Similarly, in our 26 patients with M1b visceral metastases who received twice daily capecitabine 1000 mg/m2 on days 1 – 14 and cisplatin 60 mg/m2 on day 1 of every 21 day cycle as first-line chemotherapy, the response rate was 36.0%, suggesting that XP chemotherapy is not inferior to 5-FU/cisplatin (FP) in the treatment of metastatic esophageal cancer. In a phase III evaluation of XP vs continuous infusion of FP as first-line therapy in patients with advanced gastric cancer, XP had a significantly

higher response rate and a similar PFS rate, with similar safety (11). Moreover, the combination of capecitabine and oxaliplatin demonstrated activity in metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia (29), and three times weekly docetaxel (T) plus capecitabine (X) as first- and second-line treatments in metastatic esophageal cancer demonstrated a 46% response rate (30). The median number of cycles was 6, alone or in combination with radiation therapy. The most common overall treatment-related hematological adverse events were myelosuppression and esophagitis. Hand – foot syndrome and diarrhea were rare. The convenience of administration and the tolerable toxicity profile have made concurrent XP and radiation therapy an attractive option in the treatment of metastatic esophageal cancer of M1 LYM. At first glance, the use of oral chemotherapy in patients with esophageal cancer may seem counterintuitive, since dysphagia may preclude capecitabine administration. However, a previous NCCTG study showed that, while dysphagia is prevalent, most patients who remain eligible for chemotherapy do not suffer from severe dysphagia to the point that it interferes with their ability to take pills (31). This study had several limitations. First, we observed a response rate of 36% in M1b visceral metastases. However, we may have underestimated the response rate, because we did not routinely perform follow-up imaging studies every two cycles in some patients. Second, so far, no comparative data of modalities approaches have been published in M1a and M1b nonvisceral LN metastases. We treated M1a and M1b nonvisceral LN metastases patients with induction chemotherapy followed by chemoradiotherapy instead of concurrent XP containing chemoradiotherapy from the beginning. We found that patients classified as having M1a and M1b nonvisceral LN metastases have somewhat better long-term survival compared with patients with M1b visceral metastases. We also found that patients with M1a and M1b nonvisceral LN metastases may benefit from concurrent chemoradiotherapy. Several factors may have contributed to these results. It was predetermined that the patients with M1a and M1b nonvisceral LN metastases were treated with sequential XP chemotherapy and concurrent chemoradiotherapy. Thus, selection bias was unavoidable. However, this study reports exploratory results of XP chemotherapy alone or sequentially combined radio-chemotherapy in patients with three different settings of stage IV esophageal cancer. In summary, the similar OS observed in patients with M1a and M1b nonvisceral LN metastases suggests that sequentially combined chemoradiotherapy containing XP regimen was active and well tolerated as first line treatment for M1a as well as M1b esophageal cancer, as long as tumor site was covered by a single radiation port.


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