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GI CANCER: ORIGINAL ARTICLE
Year : 2020  |  Volume : 57  |  Issue : 2  |  Page : 158-163
 

An analysis of adjuvant treatment strategies in operated pancreatic cancer patients: An Izmir oncology group study


1 Department of Medical Oncology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
2 Department of Internal Medicine, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
3 Department of Radiation Oncology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
4 Department of Oncology Clinic, Manisa Government Hospital, Manisa, Turkey
5 Department of Institute of Oncology, Dokuz Eylul University, Izmir, Turkey

Date of Submission22-May-2018
Date of Decision09-Jun-2019
Date of Acceptance11-Jun-2019
Date of Web Publication17-May-2020

Correspondence Address:
Ahmet Alacacioglu
Department of Medical Oncology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_318_18

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 » Abstract 


Background: Adjuvant treatment is necessary in pancreatic cancer patients, but the optimal approach is not clear yet. Our aim was to explore the effectiveness of adjuvant treatment modalities in patients with operated pancreatic cancer.
Methods: There were five groups of patients operated for primary pancreas adenocarcinoma. The first two groups included patients who were treated with only adjuvant chemotherapy or radiotherapy. The patients in third group had received combination chemotherapy and radiotherapy either sequentially or concomitantly. The fourth group was composed of patients who were treated with adjuvant chemotherapy after concurrent chemoradiotherapy, whereas the patients in the fifth group were only observed after surgery without any adjuvant treatment.
Results: There were 83 operated pancreatic cancer patients available for analysis. Median age of the patients was 63 years (range, 40–82 years). There were 55 patients who had local disease recurrence (n = 14) or metastasis (n = 41) during or after adjuvant treatment. The median overall survival for all patients was 14 months. When we compared the median survival of patients who had any adjuvant treatment with the patients treated without any adjuvant therapy, we found a significant statistical difference between the groups (32.4 vs 6.5 months; P = 0.000). In addition, survival of each treatment group was also compared with each other but we did not find any significant statistical difference.
Conclusions: Our result suggests that any adjuvant therapy in the treatment of pancreatic cancer patients is important. However, we could not find any superiority between adjuvant treatment modalities.


Keywords: Adjuvant, pancreatic cancer, treatment


How to cite this article:
Varol U, Uzum Y, Sengul A, Korkmaz UB, Parvizi M, Akyol M, Taskaynatan H, Salman T, Oflazoglu U, Yildiz Y, Alacacioglu A, Kucukzeybek Y, Tarhan MO. An analysis of adjuvant treatment strategies in operated pancreatic cancer patients: An Izmir oncology group study. Indian J Cancer 2020;57:158-63

How to cite this URL:
Varol U, Uzum Y, Sengul A, Korkmaz UB, Parvizi M, Akyol M, Taskaynatan H, Salman T, Oflazoglu U, Yildiz Y, Alacacioglu A, Kucukzeybek Y, Tarhan MO. An analysis of adjuvant treatment strategies in operated pancreatic cancer patients: An Izmir oncology group study. Indian J Cancer [serial online] 2020 [cited 2020 May 28];57:158-63. Available from: http://www.indianjcancer.com/text.asp?2020/57/2/158/284471





 » Introduction Top


Most of the patients with pancreatic cancer are diagnosed at advanced or metastatic stage and only about 15% of them have a chance of potential surgical resection.[1],[2] However, prognosis is poor for pancreatic cancer patients, even after undergoing complete resection. Not only systemic recurrence but also local recurrence rate is very high after surgery alone. For this reason, systemic chemotherapy, radiation therapy (RT), or chemoradiotherapy (CRT) have been used in the adjuvant and neoadjuvant setting in an effort to improve cure rates.[3],[4],[5],[6]

Adjuvant chemotherapy is recommended for all patients with operated pancreatic cancer, including stage 1 disease as postoperative chemotherapy has been shown to prolong survival.[2],[7] On the other hand, the role of adjuvant RT, neoadjuvant chemotherapy, and RT remains controversial.[8],[9],[10],[11] The addition of radiotherapy or radiotherapy plus chemotherapy to postoperative chemotherapy has been investigated in several randomized trials.[12],[13],[14] While some randomized trials have demonstrated improvements in local control and survival with the use of concurrent chemoradiotherapy, other studies have failed to show an outcome benefit from the addition of RT to chemotherapy. Although controversial, the advantage of adding RT to local control seems to be effective especially in surgical margin–positive and peripancreatic lymph node–positive patients.[15],[16],[17],[18]

In pancreatic cancer patients who have no metastases after radiological evaluation at diagnosis, primary surgical resection may not be sufficient and the adjuvant treatment, although the appropriate approach is not definitive yet, may provide an opportunity for a long-term survival. The purpose of this study was to evaluate the efficiency of adjuvant treatment modalities in pancreatic cancer patients with primary surgical resection.


 » Methods Top


Patient eligibility criteria

Patients with operated primary pancreas adenocarcinoma were included. Patients had received adjuvant chemotherapy, radiotherapy, or both of the treatment modalities, or no treatment (only surveillance) following surgical resection. Adjuvant treatment with combination chemotherapy and radiotherapy was sequential or concomitant. Patients were excluded if they were found to have M1 disease or R2 resection margins at the time of operation. Patients were not eligible for the study if they had previously received any preoperative treatment. Patients diagnosed with carcinoma-in-situ; neuroendocrine tumors; and billiary tract cancers such as ampullary carcinoma, periampullary carcinoma, and cholangiocarcinoma were also excluded. The study was approved by the local ethics committee and patients have given their informed written consent.

Treatment details

There are five groups of pancreatic cancer patients included for the analyses. The first and second groups were composed of patients who were treated with only adjuvant chemotherapy or radiotherapy. The third group of patients had received combination chemotherapy and radiotherapy either sequentially or concomitantly, whereas the fourth group of patients were treated with adjuvant chemotherapy after concurrent chemoradiotherapy. The patients in the fifth group had no adjuvant treatment and they were only observed after surgery. The decision for the adjuvant treatment of patients after resection of the tumor was done by the multidisciplinary medical council according to patients' performance status, doctors' preferences, and tumor characteristics.

Treatment endpoints

Disease-free survival was the investigated primary endpoint, which was defined as the time from the date of surgery to the first documentation of progression. First documentation of progressive disease (PD) was based on the definition of PD in the RECIST (Response Evaluation Criteria in Solid Tumors 1.1) guidelines,[19] death as a result of any cause in the absence of previously documented PD and the investigator's clinical judgment of PD. We censored the last clinical visit data for patients that died without known progression.

Statistical analysis

Quantitative data are presented as the means, standard errors, medians, minimums, and maximums; the results of qualitative analyses are presented as frequencies and percentages. The survival analysis and curves were established according to the Kaplan–Meier method and compared with the log-rank test. SPSS for Windows version 18.0 (SPSS Inc., Chicago, IL, USA) was employed for the data analysis.


 » Results Top


From June 2002 to December 2017, all pancreatic cancer patients were retrospectively evaluated. There were 83 patients found to be operated for pancreatic cancer. The sample comprised 51 males (61.4%) and 32 females (38.6%). Median age of the patients was 63 years (range, 40–82 years). Nearly all of them (95%) had undergone pancreaticoduodenectomy, and only four patients had distal pancreatectomy. Twenty-five patients had no jaundice at the time of diagnosis, whereas the other patients (n = 58) had. Surgical margins of 30 patients were positive for malignancy. Lymphovascular and perineural invasion was positive in about half of the patients (57% and 63%, respectively). Most of the patients had grade 2 disease (n = 51, 61.4%). The stages of the patients were stage I in 13 (15.7%), II in 56 (67.4%), and III in 14 (16.9%) patients. Baseline CEA and CA 19-9 data were available for 56 and 61 patients and the median CEA level was 5.85 U/mL (5.85 ± 12.8) and CA 19-9 level was 852 U/mL (852.8 ± 1922.6). Patient characteristics were shown in [Table 1].
Table 1: Patient characteristics

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There were five groups of patients (adjuvant chemotherapy only, adjuvant radiotherapy only, adjuvant chemoradiotherapy only, adjuvant chemotherapy following chemoradiotherapy, and no adjuvant treatment) and each of 11, 7, 14, 27, and 24, respectively. There was a total of 44 patients (53%) who had received adjuvant chemotherapy either alone or after RT or after chemoradiotherapy. The most common adjuvant regimen used was single agent gemcitabine (n = 29) followed by gemcitabine plus cisplatine (n = 8) and gemcitabine plus capecitabine or 5-fluorouracil (n = 7). Median number of adjuvant chemotherapy cycle was 4 (range, 1–8). Twenty-three patients had received gemcitabine and 12 patients had received capecitabine or 5-fluorouracil in combination with RT with a total number of 35 (42.1%).

There were 55 patients who had disease recurrence (n = 14) or metastasis (hepatic metastasis n = 20, peritoneal metastasis n = 14, pulmonary metastasis n = 7) during or after adjuvant treatment. Median overall survival for the 55 patients was 15 months (95% CI, 12.1–17.8). Only 24 of them had received first-line chemotherapy which was either gemcitabine-based (n = 14) or capecitabine/5-fluorouracil-based (n = 10) regimens. Nine of 24 patients were able to receive second-line treatment. Only two patients had partial response to first-line chemotherapy and stable response was obtained in three patients in the first- and second-line treatments. The mortality rate was found to be high in the first 2 months following surgery (n = 9; 10.8%). All the early deaths except one were in the observation arm. One patient died after the end of adjuvant radiotherapy. Nineteen patients (22.8%) were dead at the time of data analysis. When we compared the median survival of patients who had first-line chemotherapy (n = 24) with the patients who did not have first-line chemotherapy (n = 31), a significant statistical difference was found (19 months; 95% CI, 14.1–23.4 vs. 11 months; 95% CI, 5.9–16; P = 0.000).

We analyzed the OS time for all patients, from the time of diagnosis and we found it to be 14 months (95% CI, 10.8–17.8). The OS time of the patients with respect to stage was as follows: 17 months for stage I, 15 months for stage II, and 11 months for stage III. The survival of patients for R0 (n = 53) and R1 (n = 30) resection margins were 15 and 13 months, respectively (P = 0.04), and 14 months for both lymph node-positive (n = 47) and -negative (n = 36) group of patients (P = 0.651). When we compared the median survival of patients who had no adjuvant treatment with the patients treated with any adjuvant therapy, we found a significant statistical difference between the groups (4 months; 95% CI, 0.5–7.4 vs. 17 months; 95% CI, 12.7–21.2; P = 0.000) [Table 2]. Median survival of all the treatment group was compared one by one with the group of patients without any adjuvant treatment and all were statistically significant (P = 0.000). Additionally, survival of each treatment group was also compared with each other, but we did not find any statistically significant difference. Then, 18 patients treated with adjuvant monotherapy (chemotherapy only or radiotherapy only) compared with the patients treated with combined modality therapies (n = 41) and we did not find any statistical significance (15 vs. 19 months; P = 0.795).
Table 2: Median survival of patient groups

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 » Discussion Top


Chemotherapy, radiation therapy, combined chemotherapy and radiation therapy, and chemotherapy following chemoradiotherapy are treatment modalities used in the adjuvant treatment of our patients. When we compared the median survival of patients treated with any adjuvant treatment and the patients with no adjuvant treatment, we found a significant statistical difference between the groups which means that adjuvant therapy improves outcomes in patients with resected pancreatic cancer. However, we could not find any benefit for adjuvant combination treatments when compared with chemotherapy alone. Our results were correlated with those of the previously reported phase III studies investigating the efficiency of adjuvant chemotherapy just like CONKO-001 trial.[12]

For pancreatic cancer, the role of adjuvant radiotherapy either alone or in combination with chemotherapy is still questionable.[20],[21],[22] In Europe, standard adjuvant therapy for pancreatic cancer is the combination of florouracil and gemcitabine.[12] In the United States, CRT is proposed based on GITSG trial which compared the outcome of patients who only had pancreatic cancer surgery with patients treated with adjuvant CRT. The median survival was significantly longer in the adjuvant-treatment group than in the surgery-only group (median OS 10.9 vs. 21.0 months, P = 0.04).[23] The role of adjuvant radiotherapy for operated pancreatic cancer patients remains controversial and randomized trials comparing CRT with chemotherapy alone is limited. GITSG, EORTC, and ESPAC-1, those multicenter randomized trials had conflicting results in terms of adjuvant RT requirement and shaped opinion regarding the benefit of adjuvant chemoradiation for resected pancreatic cancer.[14],[23],[24] GITSG, a small sized randomized trial has been extensively criticized because of its limited number of patients and exclusion of lymph node-negative patients. The randomized EORTC trial investigated the effect of adjuvant radiotherapy in combination with five cycles of fluorouracil after surgery but did not demonstrate a significant survival benefit with the use of adjuvant chemoradiotherapy. One such study is ESPAC-1, a phase III randomized control trial, that investigated the survival contribution of radiation therapy by comparing adjuvant chemotherapy and CRT in 289 patients with operated pancreatic cancer.[14] ESPAC-1 trial showed a survival benefit for adjuvant chemotherapy in comparison to concurrent CRT, 20.1 versus 15.9 months, respectively. Thus, while this study confirmed the benefits of adjuvant chemotherapy, it did not demonstrate any benefit from the addition of RT in the adjuvant setting.[14] In summary, although the GITSG trial demonstrated improved survival with adjuvant chemoradiation, the EORTC failed to demonstrate a statistically significant survival benefit for adjuvant chemoradiation, and the ESPAC-1 trial suggested a detrimental effect of radiation.

The importance of resection margin positivity on survival was investigated in many studies. It is suggested that patients with microscopic residual disease after resection are benefited from the addition of RT. The area of resection is thought to be sterilized by the addition of adjuvant RT and thus local recurrences are prevented.[25] In a meta-analysis with five randomized controlled trials of adjuvant treatment of pancreatic cancer, it was found that chemotherapy is an effective adjuvant treatment and R0 operated pancreatic cancer patients did not particularly appear to benefit from chemoradiotherapy. This meta-analysis revealed a possible beneficial effect for chemoradiotherapy within the R1 subgroup, whereas chemotherapy was less effective in patients with positive resection margins.[26] When RTOG 9704 study results were analyzed in terms of locoregional control rate, the results were not different from the results of other studies in which adjuvant chemotherapy was given alone. According to RTOG 9704, the addition of CRT does not seem to have a greater impact on local control when compared with the effects of full dose systemic therapy.[17] In many studies, the presence of lymph node involvement in pancreatic cancer was found to be a poor prognostic factor.[12],[27],[28] In an analyses from a SEER database, 3,314 patients with nonmetastatic pancreas carcinoma were evaluated and 1,597 of them received adjuvant RT. In patients who received adjuvant RT, OS significance was only persistent for lymph node-positive patients.[27] In a multi-institutional retrospective study, it was suggested that patients with lymph node involvement demonstrated a clinical benefit from adjuvant CRT, whereas the effects of chemoradiotherapy on patients with lymph node -negative disease may be limited.[28] In our study, because of the limited number of patients, we could not analyze the efficiency of adjuvant treatments in our resection margin and lymph node-positive patients.

The proportion of patients receiving adjuvant chemotherapy varied apparently between oncology centers. The differences in the probability to receive adjuvant chemotherapy may be due to various factors.[29] For example, elderly and fragile patients with early stage disease were less likely to undergo adjuvant chemotherapy. Therefore, the most important determinate for deciding adjuvant treatment seems to be performance status. In our study, 55 patients had adjuvant treatment with a median survival of 17 months and median survival of the patients who had no adjuvant treatment was only 4 months. This poor outcome can be explained by the high postoperative 2-month mortality rate (10.8%). Additionally, there are also many differences from center to center in the type of adjuvant chemotherapy regimen. After ESPAC-4 trial, in the adjuvant setting, the combination of two drugs including gemcitabine and capecitabine were mostly used. Single agents (gemcitabine or fluorouracil plus folinic acid) were generally chosen in patients with poor performance status.[14] The optimal timing and duration of adjuvant treatment is also not established yet. Guidelines usually recommend adjuvant systemic chemotherapy for about 6 months starting within 8–12 weeks postoperatively, although there are no randomized trials evaluating the impact of delayed adjuvant therapy initiation on survival outcomes or the effect of a longer treatment duration.[30]

In nonmetastatic pancreatic cancer, after pancreatoduodenectomy, adjuvant treatment is currently considered standard of care, because survival analyses of many randomized trials revealed that the addition of adjuvant chemotherapy was associated with prolonged survival. This study also confirmed that adjuvant chemotherapy is mandatory for resected pancreatic cancer, whereas we could not find any additive effect of radiotherapy. Thus, further research needs to be conducted in order to find out more refined indications and timing of radiotherapy either alone or in combination with chemotherapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2]



 

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