Does the timing of adjuvant chemotherapy for gastric cancer influence patient outcome?

Validating QUANTEC recommendations into clinical practice for head and neck radiotherapy . Acta Oncol 2014 ; 53 : 1305 – 11 . Kerns SL , Ostrer H , Rosenstein BS . Radiogenomics: Using [3] genetics to identify cancer patients at risk for development of adverse effects following radiotherapy . Cancer Discov 2014 ; 4 : 155 – 65. Bentzen SM , Constine LS , Deasy JO , Eisbruch A , Jackson A , [4] Marks LB , et al . Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): An introduction to the scientifi c issues . Int J Radiat Oncol Biol Phys 2010 ; 76(3 Suppl) : S3 – 9 . Naqa IE , Deasy JO , Mu Y , Huang E , Hope AJ , Lindsay PE , [5] et al . Datamining approaches for modeling tumor control probability . Acta Oncol 2010 ; 49 : 1363 – 73 . Tucker SL , Dong L , Bosch WR , Michalski J , Winter K , [6] Mohan R , et al . Late rectal toxicity on RTOG 94-06: Analysis using a mixture Lyman model . Int J Radiat Oncol Biol Phys 2010 ; 78 : 1253 – 60 . Defraene G , Van den Bergh L , Al-Mamgani A , Haustermans [7] K , Heemsbergen W , Van den Heuvel F , et al . The benefi ts of including clinical factors in rectal normal tissue complication probability modeling after radiotherapy for prostate cancer . Int J Radiat Oncol Biol Phys 2012 ; 82 : 1233 – 42 . Tucker SL , Li M , Xu T , Gomez D , Yuan X , Yu J , et al . [8] Incorporating single-nucleotide polymorphisms into the Lyman model to improve prediction of radiation pneumonitis . Int J Radiat Oncol Biol Phys 2013 ; 85 : 251 – 7 .

To the Editor, Gastric cancer is the second most common cause of cancer-related deaths worldwide, despite a gradual decrease in incidence [1]. Although curative resection is the standard treatment for patients with locally advanced gastric cancer, it is associated with a high recurrence rate and poor survival [2]. Adjuvant chemotherapy has now become a standard therapy for patients with stage II/III gastric cancer, as demonstrated by the results of several meta-analyses and recent phase III trials [2 -5]. Nevertheless, there is no report about the optimal timing for starting adjuvant chemotherapy for gastric cancer after surgical resection.
According to population-based or cohort studies and meta-analyses of colorectal and breast cancer, a delay in the start of adjuvant chemotherapy is usually associated with poor cancer-specifi c and overall survival (OS) rates, indicating that early initiation of adjuvant therapy results in better outcomes [6 -12].
The criteria for eligibility were histologically proven gastric adenocarcinoma, curative resection [13], extended lymph node dissection (D2 dissection), and pathological stage II or III according to the 7th edition of American Joint Committee on Cancer (AJCC).
This research protocol was approved by the Institutional Review Board of Ajou University Hospital.

Adjuvant chemotherapy
In this study, data on all the patients who received FM-PSK chemotherapy with duration of 24 weeks were analyzed. Detailed protocols of chemotherapy and follow-up after treatment were previously described [14,15]. The chemotherapy was started according to the discretion of surgeons and medical oncologists.
The patients were divided into early or late initiation group using two predefi ned time points, median day from surgery to the start of chemotherapy and 28 days: time from surgery to chemotherapy before median day (early group), on and after median day (late group); time from surgery to chemotherapy before 28 days (group A), 28 days or longer (group B).

Statistical analysis
OS was calculated using the Kaplan-Meier method. OS was defi ned as the time from the day of operation to death. The differences between the survival curves were tested by using the log-rank test. The Fisher ' s exact test was used to compare different groups for categorical variables. The Cox proportional-hazards regression model was used to determine the joint effects of several variables on survival. Factors with p-values Ͻ 0.1 in the univariate analysis were included in the model. All statistical analyses were performed two-sided with SPSS for Windows 13.0 software.

Patient characteristics
A total 410 patients with stage II or III gastric cancer received FM-PSK adjuvant chemotherapy after curative resection between November 1996 and December 2004. The median time interval between surgery and chemotherapy was 21 days (7 -80 days). Twentyseven patients (6.6%) experienced re-admission or prolonged hospitalization before starting chemotherapy due to postoperative complications.
There were no signifi cant differences in baseline clinicopathological characteristics between the early and late group except a higher proportion of total gastrectomy (28.7% vs. 39.7%; p ϭ 0.022), and postoperative complications (0% vs. 11.6%; p Ͻ 0.0001) in the late group. The baseline characteristics were also well balanced between group A and B except for a higher proportion of postoperative complications in group B (Supplementary Table I

Overall survival
At the time of analysis, the median follow-up duration was 150 months (97 -195 months) for the survivors and no patient was lost to follow-up for survival status.

Discussion
In the present study period, adjuvant chemoimmunotherapy using 5-FU, MMC, and PSK was used for most stage II or III gastric cancer patients at our institution, based on a report by Nakazato et al., in which the addition of PSK to FM adjuvant chemotherapy improved OS compared with FM alone [16]. Furthermore, mitomycin-based adjuvant chemotherapy regimens demonstrated improved OS compared with surgery alone in several studies [3,17,18]. Therefore, the FM-PSK used in the present study could be considered as a reasonable regimen for adjuvant chemotherapy during the period when the study patients had been treated. The outcome of our study cohort is comparable to that of adjuvant treatment studies in other Korean institutions [19,20].
In breast and colorectal cancers, many studies have demonstrated poor outcome of patients when adjuvant chemotherapy was initiated later than 4 -12 weeks after surgery [6,8 -12]. However, in routine clinical practice, it is not always possible to start adjuvant chemotherapy according to a regular schedule for a number of reasons, such as unexpected operation-related complications, slow recovery of performance status, time period for pathological assessment of specimens, the place of residence, and the time for referral to oncologists [9,11]. In breast and colorectal cancers, previous studies revealed that adjuvant chemotherapy usually began 4 -7 weeks after surgery [6,7,10,11]. On the contrary, in the present study, the median time interval between surgery and the start of chemotherapy was 21 days, with a very low proportion of patients (2.9%) starting chemotherapy Ն 6 weeks after surgery. This relatively short interval from surgery to the initiation of chemotherapy can be explained by the practice pattern for gastric cancer treatment in Korea. First, gastric cancer surgery is usually performed in university hospitals, in which a patient is referred to a medical oncologist as soon as the pathology results are reported. Second, surgeons and medical oncologists have tended to start adjuvant chemotherapy as early as possible [21]. Third, postoperative complication rates are generally very low compared with Western countries because of advanced surgical techniques [2,21].
The present study revealed that patients who started adjuvant chemotherapy 28 days or more after surgery had a signifi cantly poor outcome. It is difficult to determine whether the association between the delay of chemotherapy initiation and poor outcome was attributable to the proliferation of micrometastasis resulting from the delay of chemotherapy or other patient-specifi c conditions related to the delay of chemotherapy. In the present study cohort, outcome-related factors, such as age, operation type, stage, and tumor size, did not differ signifi cantly between group A and B except for a higher proportion of postoperative complications in group B ( Ն 28 days after surgery). Moreover, the presence of postoperative complications itself was not associated with poor OS.
To our knowledge, this is the fi rst report about the effect of the interval between surgery and the initiation of adjuvant chemotherapy on OS in gastric cancer. In addition, our study cohort consisted of a relatively large, homogeneous study population treated with D2 dissection and a uniform chemotherapy regimen with a fairly long follow-up period for survival status, analyzing all patients eligible for the study.
However, the present study has several limitations. First, all the patients in the study were from single institution. Second, detailed investigation of several patient-related factors, such as socioeconomic status and the change of performance status after surgery, was almost impossible due to the retrospective nature of the study. Third, this study did not analyze patients treated with S1 or capecitabine/ oxaliplatin regimen currently established as the standard treatment after D2 dissection in Eastern Asian countries [4,5]. Finally, the number of patients who initiated chemotherapy after 28 days or more was relatively small (18.8%). However, implementation of randomized trials of the timing for adjuvant chemotherapy in gastric cancer would be almost impossible due to practical and ethical reasons. Therefore, to validate the results of the current study and to elucidate the exact cause of the association between the delay of chemotherapy and poor outcome, a retrospective study with a larger sample size or a prospective observational study using patient cohorts treated with S1 or capecitabine/oxaliplatin adjuvant chemotherapy is desirable.
Gastric cancer has different characteristics from other malignancies, such as breast cancer, in terms of the initiation of adjuvant chemotherapy. First, abdominal surgery requires a relatively long recovery period [8]. Second, it takes a longer time to resume a normal diet after gastric cancer surgery. Third, chemotherapy-induced nausea and vomiting may occur more frequently in gastrectomy patients. The results of the present study, especially the lack of benefi t of very early ( Յ 14 days after surgery) chemotherapy initiation, suggest that patients may be encouraged to have a suffi cient recovery time of 3 -4 weeks before initiating adjuvant chemotherapy in gastric cancer.
In conclusion, it does not seem to be necessary to initiate adjuvant chemotherapy too early after gastric cancer surgery. However, it is desirable to start treatment within four weeks after surgery if patients have fully recovered, especially in those with stage III.