ABSTRACTBackground and purpose

The role of stereotactic radiosurgery (SRS) alone for gastrointestinal (GI) cancer patients has yet to be established based on a large patient series. We analyzed post-SRS treatment results and reappraised weather either the GI Graded Prognostic Assessment (GPA) system or Modified-Recursive Partitioning Assessment (M-RPA) system is applicable to our 802 SRS-treated GI cancer patients with brain metastases.

Materials and methods

This was an institutional review board-approved, retrospective cohort study two database comprising 802 GI cancer patients treated with gamma knife SRS by two experienced neurosurgeons during the 1998-2018 period. The Kaplan-Meier method was applied to determine post-SRS survival times and competing risk analyses were used to estimate cumulative incidences of the secondary endpoints.

Results

The median survival time (MST, months) after SRS was 5.7. With the GI GPA system, MSTs were 3.5/6.1/7.7/11.0 in the four subgroups, i.e., 0-1.0/1.5-2.0/2.5-3.0/3.5-4.0, respectively (stratified p<0.0001). However, there was no significant MST difference between two of the subgroups, GI-GPA 1.5-2.0 and 2.5-3.0 (p=0.073). In contrast, using the M-RPA system, three plot lines corresponding to the three subgroups showed no overlap and the MST differences between the subgroups with M-RPA 1+2a vs 2b (p<0.0001) and 2b vs 2c+3 (p<0.0001). Better KPS score, solitary tumor, well controlled primary cancer and the absence of extra-cerebral metastases were shown by multivariable analysis to be significant predictors of longer survival. The crude and cumulative incidences of neurological death, neurological deterioration, local recurrence, salvage WBRT and SRS-related complications did not differ significantly between the two patient groups, with upper and lower GI cancers.

Conclusions

This study clearly demonstrated the usefulness of the GI GPA. Patients with GI GPA 1.5-2.0 or better or M-RPA 2b or better are considered to be favorable candidates for SRS alone treatment.

INTRODUCTIONGastrointestinal (GI) cancer rarely metastasizes to the brain. Particularly, brain metastases (BMs) from esophageal and gastric cancers are much less common than colorectal cancer BMs [1Trifiletti DM Patel N Lee CC et al.Stereotactic radiosurgery in the treatment of brain metastases from gastrointestinal primaries., 2Ghidini M1 Petrelli F Hahne JC et al.Clinical outcome and molecular characterization of brain metastases from esophageal and gastric cancer: a systematic review., 3Lin L Zhao CH Ge FJ et al.Patients with brain metastases derived from gastrointestinal cancer: clinical characteristics and prognostic factors., 4Page BR Wang EC White L et al.Gamma Knife radiosurgery for brain metastases from gastrointestinal primary., 5Sanghvi SM Lischalk JW Cai L et al.Clinical outcomes of gastrointestinal brain metastases treated with radiotherapy.]. However, due to the currently widespread use of magnetic resonance (MR) imaging with gadolinium enhancement, BMs are being detected ever more frequently. Even in recently published studies, the outcomes of patients with GI cancer BMs were poor, i.e., median survival times (MST) from diagnosis of BMs were reportedly 6 months or slightly more [[1]Trifiletti DM Patel N Lee CC et al.Stereotactic radiosurgery in the treatment of brain metastases from gastrointestinal primaries., [2]Ghidini M1 Petrelli F Hahne JC et al.Clinical outcome and molecular characterization of brain metastases from esophageal and gastric cancer: a systematic review., [4]Page BR Wang EC White L et al.Gamma Knife radiosurgery for brain metastases from gastrointestinal primary., [5]Sanghvi SM Lischalk JW Cai L et al.Clinical outcomes of gastrointestinal brain metastases treated with radiotherapy.]. A general consensus regarding the optimal treatment is, however, currently lacking, i.e., there are no specific recommendations for treating BMs from GI cancers. Therefore, steroid therapy, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), surgical removal, or various combinations of these four approaches are selected on a case-by-case basis. Very recently, Lin et al reported that MST after diagnosis of BM from GI cancers was 4.1 months for all patients and 1.2 months for patients who received only steroids, 4.0 months for those undergoing WBRT, 11.1 months for those given gamma-knife SRS alone or/and WBRT, and 13.7 months for patients receiving both surgery and radiotherapy (P [3]Lin L Zhao CH Ge FJ et al.Patients with brain metastases derived from gastrointestinal cancer: clinical characteristics and prognostic factors.]. Several retrospective studies on SRS treatment for BMs from GI cancer have been reported. However, patient numbers in these reports were relatively small [[1]Trifiletti DM Patel N Lee CC et al.Stereotactic radiosurgery in the treatment of brain metastases from gastrointestinal primaries., [2]Ghidini M1 Petrelli F Hahne JC et al.Clinical outcome and molecular characterization of brain metastases from esophageal and gastric cancer: a systematic review., [4]Page BR Wang EC White L et al.Gamma Knife radiosurgery for brain metastases from gastrointestinal primary., [5]Sanghvi SM Lischalk JW Cai L et al.Clinical outcomes of gastrointestinal brain metastases treated with radiotherapy.].

Patient heterogeneity is the main source of the ongoing debate among clinical oncologists, regarding how best to treat patients with BM from GI cancers. Several clinical and demographic factors impact the outcomes of BM patients. Clinicians are thus often uncertain as to the best approach to selecting a treatment strategy. An improved prognostic index would lead to resolution of certain issues complicating treatment decisions as well as guiding future research in this field.

Historically, the Recursive Partitioning Analysis (RPA) system was generally used. This system divides patients into three subclasses based on age, Karnofsky Performance Status (KPS), primary tumor status and extracranial metastases [[6]Gaspar L Scott C Rotman M et al.Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials.]. The RPA index was found to be applicable to BM patients undergoing SRS alone, as described in our earlier report [[7]Gaspar L Scott C Rotman M et al.Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials.]. However, in our BM patients who underwent SRS alone, there were large discrepancies in patient numbers among subgroups, with 85.3% of all patients being class II and only 6.2% being class III, yielding rates of 13.7 and 1.0, respectively.Sperduto et al undertook careful reevaluation and updating of the RPA system, which resulted in development of the Graded Prognostic Assessment (GPA) index [[8]Sperduto PW Berkey B Gaspar LE et al.A new prognostic index and comparison to three other indices for patients with brain metastases: An analysis of 1,960 patients in the RTOG database.]. However, marked differences in oncological and clinical features as well as responses to treatment, among a broad range of primary tumor types, are well recognized. Sperduto et al thus modified their original GPA system and devised a new index, termed the Diagnosis-Specific GPA (DS-GPA) [[9]Sperduto PW Kased N Roberge D et al.The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer.]. Unfortunately, this system was found to be overly simple for GI malignancies because patients are categorized into four subgroups based solely on their KPS scores. Higher DS-GPA scores are associated with longer MST, as we reported elsewhere [[10]Sperduto PW Kased N Roberge D et al.The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer.]. Furthermore, in GI cancer categories, the survival difference based on the four-subgroup stratification is statistically significant (pTable 2.

Table. 1Outline of reported grading indexes for patients with brain metastases (BMs)

Table. 2Summary of clinical characteristics of 7355 metastasis patients treated with stereotactic radiosurgery*

NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; GI, Gastro-intestinal, KPS; Karnofsky Performance Status, WBRT; whole brain radiotherapy

*Values are presented as the number of patients (%).

**32 patients (12/NSCLC, 12/SCLC, 6/breast, 4/GI 1/kidney and 2/others) were excluded because the day of primary cancer diagnosis was not available.

Very recently, Sperduto et al again updated their DS-GPA system, focusing exclusively on GI cancer patients, thereby devising the GI-GPA index [[11]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).]. The present retrospective analysis aimed to reappraise the applicability of the GI-GPA system to our patients who underwent SRS for BMs. We also analyzed treatment results of 802 GI cancer patients with BM given SRS alone.METHODS Patient Population

This retrospective cohort study employed our prospectively accumulated database, which was comprised of 7355 consecutive patients who received gamma knife (GK) SRS alone, i.e. without WBRT, for BMs during the period of 20 years from 1998 through 2018. Among the 7355 patients, 3558 were treated by the first author (–) and the other 3797 by the second author (–). The Institutional Review Boards of —— University (No. 0000-00) and —— Clinic (No. 0000-00) approved this study. Among the 7355 patients, we selected a total of 802 patients (10.9%) with GI-tract primary tumors (265 females, 537 males, median age; 67 [range; 25-94] years) for this study.

Prior to referral to us for SRS, most of the patient selections had been made by the patients’ primary physicians because our clinic is equipped only for GK SRS. It should be noted that patient selection criteria may have differed among the referring doctors. Therefore, the second author (–) decided whether or not the patient could be treated with SRS in each case. We did not perform SRS on patients with low Karnofsky Performance Status (KPS) scores due to systemic diseases (<70%), a non-cooperative state due to poor neurocognitive function, meningeal dissemination, or an anticipated survival period of three months or less.

 Radiosurgical techniques and follow-upOur radiosurgical techniques have already been reported in detailed [[8]Sperduto PW Berkey B Gaspar LE et al.A new prognostic index and comparison to three other indices for patients with brain metastases: An analysis of 1,960 patients in the RTOG database.,[12]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).]. Briefly, we performed standard, single-session GK SRS with frame placement for all patients. Selected doses for delivery to the tumor periphery were in the 8.0 Gy to 25.0 Gy range (median; 20.0, inter-quartile range [IQR]; 18.00, 21.00). Most patients required only one session but a two- or three-stage treatment regimen was applied to 113 cases because they had one or a few relatively large BMs. Multi-stage treatments were also deemed to be necessary even if a tumor was small, located at or near the optic chiasma, hypothalamus, internal auditory canal, or other very critical anatomical structures [[13]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).,[14]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).]. Among these 113 patients, 53 underwent two-stage treatment, with peripheral doses of 14 Gy being delivered at a three-week interval, while the other 58 received 3-stage treatment with peripheral doses of 9-10 Gy being administered at a two-week interval.

Post-SRS, all patients were routinely managed by their referring physicians and were recommended to have clinical and neuro-imaging examinations at an interval of approximately 2-3 months. The local recurrence criteria generally applied were increased size of an enhanced area on post-gadolinium T1-weighted MR images and enlarged tumor core on T2-weighted MR images. However, in cases in which MR imaging alone was not sufficient to confirm recurrence, positron emission tomography with 11C methionine was used to distinguish tumor recurrence from necrotic lesions. Neurological death was defined as death caused by any intracranial disease, i.e., tumor recurrence, carcinomatous meningitis, cerebral dissemination, and progression of other untreated intracranial tumors.

 Statistical AnalysisThe primary outcome examined was overall survival. The secondary outcomes were neurological death, neurological deterioration (defined as KPS score decrease ≥20% from baseline in the —–series and as KPS score decrease to less than 70% in the ——series), SRS-related complications, local recurrence and the necessity of salvage SRS and/or WBRT. Major complications were those judged to be Radiation Therapy Oncology Group (RTOG) neurotoxicity grades of 2 or more severe. The Kaplan-Meier method was used to assess overall survival, while we employed competing risk analysis for time-to-event outcome analyses of all secondary endpoints [[15]A Proportional Hazards Model for the Subdistribution of a Competing Risk.,[16]Gooley TA Leisenring W Crowley J et al.Estimation of failure probabilities in the presence of competing risks: New representations of old estimators.]. The Cox proportional hazards model was employed for the multivariable analyses assessing survival duration. Also, the Fine and Gray proportional subdistribution hazards model was used to account for competing risk of death [[12]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).,[13]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).]. An experienced statistician (–), using SAS software version 9.4 (SAS Institute, Cary, NC, USA), carried out all statistical analyses, prior to which the full database had been cleaned by another co-author (–). These two authors had no involvement in either the SRS treatments or any aspects of patient follow-up.RESULTSDistributions of pre-SRS clinical characteristics are listed along with primary cancer categories in Table 2. Proportions of patients with KPS 70% or lower, Modified Recursive Partitioning Analysis (M-RPA) class 2c+3, DS-GPA 0-1.0 class, being neurologically symptomatic, metachronous presentation, cumulative tumor volume ≤10.0 cc and the largest tumor volume ≥5.0 cc were higher among those with primary GI cancers than in patients with NSCLC, SCLC, breast cancer or kidney cancer. Proportions of patients with metachronous presentation and latency period to BM ≥18 months were larger among those with GI cancer than among those with lung cancers, while the proportions were similar to those in patients with breast or kidney cancers. Survival period

Median post-SRS follow-up for 65 censored observations (8.1%) was 6.8 (IQR; 1.4-17.0) months, and 737 patients (91.9%) were confirmed to be deceased as of June 30, 2019. MST after SRS was 5.7 (95% CI; 5.0-6.0) months. The proportions for actuarial post-SRS survival were 46.3%, 21.9%, 8.7%, 4.1%, 2.8% and 1.9% at the 6th,12th, 24th, 36th, 48th and 60th post-SRS months, respectively. Among the 737 deceased patients, the causes of death were unknown in 12, but were confirmed in the other 725 to be non-brain diseases in 646 (89.1%) and brain diseases in 79 (10.9%). Among the 802 patients in total, repeat SRS was required in 415 (51.7%), generally for newly-appearing lesions (313 patients, 39.0%) but also, though much less commonly, for recurrence at the site of a treated lesion (102 patients, 12.7%). Salvage WBRT was performed for meningeal dissemination or numerous cerebral metastases in 13 (1.6% of the 802) patients. The cumulative incidences of neurological death, which were obtained using competing risk analyses, were 4.8%, 7.3%, 9.3% and 10.7% at the 6th, 12th (No. at risk: 159), 24th (56) and 36th (24) post-SRS month, respectively.

Table 3 presents the latency periods to BM and post-SRS survival periods according to the primary cancer sites. The latency periods to BM were significantly longer in patients with lower GI cancer (mean/median; 40.1/32.5 months) than in those with upper GI cancer (24.2/17.0, p

Table 3Time to brain mestatization and median survival time after stereotactic radiosurgery (SRS).

*Based on 798 patients in whom the day of primary cancer diagnosis was available (4 patients in whom the day of primary cancer diagnosis was not available were excluded).

 Overall Survival Difference Based on GI-GPA and M-RPAFig. 1-A presents the Kaplan-Meier plots of the four subgroups of the GI-GPA, i.e., 0-1.0, 1.5-2.0. 2.5-3.0 and 3.5-4.0 [[8]Sperduto PW Berkey B Gaspar LE et al.A new prognostic index and comparison to three other indices for patients with brain metastases: An analysis of 1,960 patients in the RTOG database.,[14]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).]. The stratified p-value was Fig. 1B) [[7]Gaspar L Scott C Rotman M et al.Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials.,[10]Sperduto PW Kased N Roberge D et al.The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer.].Fig. 1Overall survival according to A; Gastrointestinal-Graded Prognostic Assessment (GI-GPA) [[11]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).] and B; Modified Recursive Partitioning Analysis (M-RPA). MST; median survival time, CI; confidence interval, HR; hazard ratio, SRS; stereotactic radiosurgery, mos; months Factors impacting longer survival periodSeveral pre-SRS clinical factors, as listed in Table 4, were examined. Multivariable analysis showed better KPS score, solitary tumor, controlled primary cancer and absence of extra-cerebral metastases to significantly predict longer survival for the entire cohort as well as for both upper and lower GI tumor groups. Lack of pre-SRS WBRT was shown to significantly favor longer survival in patients with upper GI cancers, while showing no effect on the survival of those with lower GI cancers.

Table. 4Multivariable analyses of survival after stereotactic radiosurgery (SRS)

GI; gastro-intestinal, HR; hazard ratio, 95% CI;95% confidence intervals, KPS; Karnofsky Performance Status, METs; metastases, WBRT; whole brain radiotherapy

 Secondary OutcomesThe crude and cumulative incidences of the secondary outcomes, i.e., neurological death, neurological deterioration, local recurrence, salvage WBRT and SRS-related complications, did not differ significantly between the two patient groups, with upper and lower GI cancers (Table 5). Cumulative incidences of repeat SRS were significantly lower in the group with upper GI cancer than in that with lower GI cancer. However, the upper 95% CI of the HR was 1.000 and the p-value was 0.049. Furthermore, the crude incidences of repeat SRS did not differ significantly between these two groups (p=0.061). Crude incidences of repeat SRS differed significantly among the six primary cancer categories, while those of the other secondary endpoints differed minimally among these categories (Table 6).

Table 5Crude and cumulative incidences after stereotactic radiosurgery (SRS).

HR; hazard ratio, CI; confidence interval, GI; gastro-intestine

*Based on 725 patients who were confirmed to have died and whose cause of death was determined (either 65 patients who were confirmed to be alive and, among the 737 deceased patients, 12 in whom the cause of death had not been determined, were excluded).

**see text.

***Based on 659 patients in whom post-SRS imaging examination was available (143 patients in whom follow-up imaging examinations were not performed were excluded).

Table 6Crude incidences of neurological death, neurological deterioration, local recurrence, repeat salvage stereotactic radiosurgery (SRS), salvage whole brain radiotherapy (WBRT) and complications

p value; Pearson p-value was used.

* 65 patients who were confirmed to be alive and, among the 737 deceased patients, 12 in whom the cause of death had not been determined were excluded.

**143 patients without follow-up imaging examinations results were excluded.

Cumulative incidences of re-GK SRS, which were obtained using competing risk analyses, were 34.4%, 45.8%, 51.3% and 53.4% at the 6th, 12th (No. at risk: 98), 24th (30) and 36th (12) post-SRS month, respectively. Multivariable analyses showed female gender, synchronous presentation, non-symptomatic, single BM, cumulative tumor volume <10.0 cc, peripheral dose <20.00 Gy, well-controlled original cancers and having prior WBRT to be clinical factors associated with decreased incidence of neurological death.

DISCUSSION

To our knowledge, this is the first effort, based on a large patient series, 802 GI cancer patients in whom GK SRS alone for BMs was performed by two highly experienced neurosurgeons (– and –), to analyze treatment results of SRS alone and to perform a validity test of the GI-GPA. Also, this is the first study to demonstrate cumulative incidences of neurological death, neurological deterioration, local recurrence, repeat SRS, salvage WBRT and SRS-related complications determined using a competing risk analysis. Furthermore, this is the first investigation to clarify which pre-SRS clinical factors significantly impact improved survival based on a patient number large enough to provide adequate statistical power.

As noted above, proportions of patients with metachronous presentation and latency period to BM ≥18 months were larger among those with GI cancer than among those with lung cancers, while the proportions were similar to those in patients with breast or kidney cancers. This reflects the recent trend that lung cancer patients are periodically assessed by MR imaging even if asymptomatic. In contrast, MR imaging has usually been performed after BMs become symptomatic in patients with GI, breast or kidney cancers. In particular, common symptoms in GI cancer patients, nausea and vomiting, generally develop in BM patients as intracranial pressure increases. Thus, physicians initially consider nausea and vomiting to be caused by GI cancers, thereby delaying the BM diagnosis.

One of the major motivations to perform this retrospective study was to test whether the GI-GPA system is applicable to GI patients with BMs being treated by SRS only [[11]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).]. As shown in Fig 1-A, MST differences among the four subgroups reached statistical significance (stratified p-value was [7]Gaspar L Scott C Rotman M et al.Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials., [10]Sperduto PW Kased N Roberge D et al.The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer.], there were significant differences in survival periods not only according to cohort (stratified p-value was Trifiletti et al reported, based on 86 GI cancer patients, that MST was improved with a higher performance score and luminal primary location on multivariable analyses (p=0.002 and 0.015, respectively) [[1]Trifiletti DM Patel N Lee CC et al.Stereotactic radiosurgery in the treatment of brain metastases from gastrointestinal primaries.]. Tumor histology, WBRT, targeted therapies, and antineoplastic therapies were not associated with improved overall survival. Page et al. reported, based on 62 GI cancer patients, that multivariate analysis revealed craniotomy for resection of BMs (HR = 2.63, P [4]Page BR Wang EC White L et al.Gamma Knife radiosurgery for brain metastases from gastrointestinal primary.]. As stated above, statistical power was not considered to be sufficient in these two studies. In the present study, multivariable analyses demonstrated better KPS score, being free of neurological symptoms, solitary tumor, maximum dose of ≥36 Gy, good control of the primary malignancy and no extra-cerebral metastases to be significantly predictive factors of longer survival for the full cohort (Table 4). As described above, lack of pre-SRS WBRT was shown to significantly favor longer survival in patients with upper GI cancers, while having no effect on the survival of those with lower GI cancers. In our view, patients with prior WBRT harbor more malignant tumor cells and, therefore, longer survival cannot be expected. However, unfortunately, we obtained no convincing evidence to explain this difference between upper and lower GI cancer patients.As described above, a relatively small proportion of patients, 113, underwent two- or three-stage treatment. The respective MSTs and local recurrence rates were reportedly 7.0-11.8 months and 7.0-15.0% [[13]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).]. —— et al recently reported that there were no significant differences in survival or incidences of neurological death, tumor progression or SRS-related complications, between patients receiving two- and three-stage treatments [[14]Sperduto PW Fang P Li J et al.Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).].We acknowledge the retrospective design of this study as a major weakness. Another possible weakness is the lack of both original cancer phenotypes (positive or negative for HER-2, KRAS and so on) and information on whether systemic anti-cancer agents had been administered, factors which have both been suggested to correlate with patient survival though controversy persists regarding the impacts of these factors. [[2]Ghidini M1 Petrelli F Hahne JC et al.Clinical outcome and molecular characterization of brain metastases from esophageal and gastric cancer: a systematic review.,[18]Koo T Kim K Park HJ et al.Prognostic factors for survival in colorectal cancer patients with brain metastases undergoing whole brain radiotherapy: multicenter retrospective study.,[19]Koo T Kim K Park HJ et al.Prognostic factors for survival in colorectal cancer patients with brain metastases undergoing whole brain radiotherapy: multicenter retrospective study.]. Another possible weakness, since the data accumulation period was rather long, almost 20 years, is that changes in patient selection criteria, as well as progress in technical factors and surveillance method quality, may have influenced our observations. However, at the