Abstract
Background
Although treatment‐related lymphopenia (TRL) is common and associated with poorer survival in multiple solid malignancies, few data exist for anal cancer. We evaluated TRL and its association with survival in patients with anal cancer treated with chemoradiation (CRT).
Materials and Methods
A retrospective analysis of 140 patients with nonmetastatic anal squamous cell carcinoma (SCC) treated with definitive CRT was performed. Total lymphocyte counts (TLC) at baseline and monthly intervals up to 12 months after initiating CRT were analyzed. Multivariable Cox regression analysis was performed to evaluate the association between overall survival (OS) and TRL, dichotomized by grade (G)4 TRL (<0.2k/μL) 2 months after initiating CRT. Kaplan‐Meier and log‐rank tests were used to compare OS between patients with versus without G4 TRL.
Results
Median time of follow‐up was 55 months. Prior to CRT, 95% of patients had a normal TLC (>1k/μL). Two months after initiating CRT, there was a median of 71% reduction in TLC from baseline and 84% of patients had TRL: 11% G1, 31% G2, 34% G3, and 8% G4. On multivariable Cox model, G4 TRL at two months was associated with a 3.7‐fold increased risk of death. On log‐rank test, the 5‐year OS rate was 32% in the cohort with G4 TRL versus 86% in the cohort without G4 TRL.
Conclusion
TRL is common and may be another prognostic marker of OS in anal cancer patients treated with CRT. The association between TRL and OS suggests an important role of the host immunity in anal cancer outcomes.
Implications for Practice
This is the first detailed report demonstrating that standard chemoradiation (CRT) commonly results in treatment‐related lymphopenia (TRL), which may be associated with a poorer overall survival (OS) in patients with anal squamous cell carcinoma. The association between TRL and worse OS observed in this study supports the importance of host immunity in survival among patients with anal cancer. These findings encourage larger, prospective studies to further investigate TRL, its predictors, and its relationship with survival outcomes. Furthermore, the results of this study support ongoing efforts of clinical trials to investigate the potential role of immunotherapy in anal cancer.
Keywords: Anal neoplasms, Squamous cell carcinoma, Lymphopenia, Chemoradiotherapy, Survival
Short abstract
Considering the association between treatment‐related lymphopenia and worse survival and data supporting the importance of immune response in patients with anal cancer, this study focused on whether treatment‐related lymphopenia would negatively affect survival outcomes in patients with anal cancer treated with chemoradiation.
Introduction
Lymphocytes are key mediators of the host antitumor immune response, which helps suppress cancer growth [1]. Clinical studies have identified total lymphocyte counts (TLCs) and tumor‐infiltrating lymphocytes (TILs) as prognostic factors for multiple solid tumors [2, 3, 4]. Although chemoradiation (CRT) is a common treatment modality for solid malignancies, it frequently results in lymphopenia from depletion of the circulating lymphocytes and/or bone marrow suppression [5, 6]. Treatment‐related lymphopenia (TRL) has been associated with worse survival outcomes in malignant tumors of the brain, head and neck, lung, esophagus, pancreas, and cervix [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17].
In patients with anal cancer, the standard treatment is definitive CRT [18, 19, 20], and acute hematological toxicities associated with pelvic irradiation and concurrent chemotherapy have been described [21, 22]. However, to date, TRL has not been well described or correlated with clinical outcomes. Given other hematological toxicities observed with CRT in anal cancer, at least a subset of patients is expected to develop TRL and likely have reduced antitumor immune response. Antitumor immunity is hypothesized to play an important role in anal cancer outcomes, as 90% of cases are human papillomavirus (HPV)‐driven, which is thought to render tumors to be more immunogenic [23]. HPV positivity is associated with improved survival outcomes hypothesized to be secondary to the viral antigens eliciting a host immune response against the tumor cells [23, 24, 25]. A study by Gilbert et al. demonstrated the importance of TILs in the prognosis of anal cancer as patients with absent or low TIL had a lower relapse‐free survival rate of 63% compared with 92% in patients with high levels of TILs [4]. Another study showed that 56% of patients with anal cancer (HPV positive or negative) express the immune checkpoint protein programmed death‐ligand (PD‐L1), a mechanism by which cancer cells attempt to evade immune surveillance [26]. The KEYNOTE‐028 [27] and phase II NCI9673 trial [28] reported antitumor activity of programmed cell death protein‐1 (PD‐1) inhibitors in treatment‐refractory advanced anal cancers expressing PD‐L1, further suggesting a role of the immune system in disease control among patients with anal cancer.
Given the association between TRL and worse survival in other solid malignancies as well as data supporting an important function of the immune response in patients with anal cancer, we hypothesized that TRL will negatively affect survival outcomes in patients with anal cancer treated with CRT. The objectives of this study were two‐fold: (a) to characterize TRL in patients with anal cancer undergoing definitive CRT and (b) to investigate the relationship between TRL and survival outcomes in the patient population.
Materials and Methods
Patient Population
Institutional review board approval was obtained for the retrospective chart review study. Between November 2005 and April 2019, 140 patients with anal cancer who met the following inclusion criteria were identified: (a) biopsy proven anal squamous cell carcinoma (SCC), (b) CRT delivered at our institution, and (c) complete blood count (CBC) with differential available prior to and 2 months after initiating CRT. Patients were excluded if they had metastatic disease at the time of diagnosis. Patient and disease characteristics including age, race, sex, performance status, smoking history, immunosuppression, HPV status, histologic grade, and staging information were collected.
Treatment
All patients underwent concurrent CRT. For radiotherapy (RT), clinical target volume (CTV) was assigned for the primary tumor, involved nodal, and elective nodal areas. Planning target volume (PTV) was defined as a 7‐mm expansion from the CTV. In general, dose was prescribed per RTOG 0529 guidelines [19]. Nine percent of patients received proton beam therapy, and 91% received x‐ray therapy. Median duration of RT was 43 days. All patients received concurrent chemotherapy, with the majority (81%) receiving two cycles of 5‐fluorouracil (5FU)/mitomycin‐C (MMC) at a median dose of 10mg/m2. At the discretion of the treating oncologist, on a case‐by‐case basis, granulocyte‐colony stimulating factor (G‐CSF) was administered to 16% of patients during and 3% after CRT, respectively. During G‐CSF administration, RT was held and resumed until absolute neutrophil count (ANC) was at least 0.5k/μL.
Complete Blood Counts
White blood cell (WBC), hemoglobin (HGB), platelet (PLT), and TLC prior to and monthly after initiating CRT up to 12 months were recorded. Available blood counts closest (within 2 weeks) to the exact monthly interval date were recorded. Lymphopenia was classified according to the CTCAE version 5.0: [29] grade (G) 1 for TLC 0.8–1k/μL, G2 for 0.5–0.8 k/μL, G3 for 0.2–0.5k/μL, and G4 for less than 0.2k/μL.
Statistical Analysis
Characteristics of patients, disease, and treatments were summarized using descriptive statistics. The primary study variable was TRL, dichotomized by G4 TRL 2 months after initiating CRT. TLC cutoff of less than 0.2k/μL and the 2‐month time point were chosen based on previous studies reporting these measures of TRL as predictors of worse survival. G4 lymphopenia [7, 8, 9, 10] and persistent lymphopenia at 2 months after initiating CRT [13, 14, 15, 16, 17] have been correlated with poorer survival in other solid malignancies. Characteristics of patients with versus without G4 TRL at 2 months were compared using the Kruskal‐Wallis test for continuous variables and Fisher's exact test statistics for categorical variables. The primary endpoint of the study was overall survival (OS), assessed from the date of initial diagnosis to death of any cause or time of last follow‐up. To identify significant predictors of OS, univariable Cox regression analysis was performed, followed by multivariable Cox regression analysis adjusted with significant variables identified in the univariable analysis. The Kaplan‐Meier method was used to estimate survival probabilities and the log‐rank test was used to compare OS rates between patients with versus without G4 TRL at 2 months. For all analyses, statistical significance was defined as a two‐sided p value < .05. All statistical analyses were conducted using Stata (StataCorp, College Station, TX).
Results
Patient Characteristics
Characteristics of patients are summarized in Table 1. For the entire patient cohort, median age was 61. The majority were female (67%) and white (94%). Ninety‐four percent had Eastern Cooperative Oncology Group performance status ≤1. At diagnosis, 19% were immunosuppressed, with 9% having HIV. Among 53% of patients with a known HPV status, 91% had HPV‐positive disease. Thirty‐eight percent had T3–T4, and 36% had node‐positive disease. In this study cohort, 8% of patients had G4 TRL, and 92% had TLC greater than 0.2k/μL 2 months after initiating CRT. Patients in the G4 TRL group were more likely to be female (p = .016), had a lower baseline TLC (p = .002), were more likely to have received only one cycle of MMC (p = .032), and had a longer RT duration (p = .004) compared with the group without G4 TRL.
Table 1.
Characteristics of patients, disease, and treatment
| Characteristics | All patients (n = 140) | 2m TLC <0.2k/μl a (n = 11) | 2m TLC ≥0.2k/μl a (n = 129) | p value |
|---|---|---|---|---|
| Patient characteristics | ||||
| Age, median (range) | 61 (15–92) | 63 (15–73) | 60 (40–92) | .520 |
| Sex, n (%) | .016 | |||
| Female | 94 (67.1) | 11 (100) | 83 (64.3) | |
| Male | 46 (32.9) | 0 (0) | 46 (35.7) | |
| Race, n (%) | .038 | |||
| White | 130 (93.5) | 9 (81.8) | 121 (94.5) | |
| African American | 4 (2.9) | 0 (0) | 4 (3.1) | |
| Hispanic | 2 (1.4) | 0 (0) | 2 (1.6) | |
| Asian | 2 (1.4) | 2 (18.2) | 0 (0) | |
| Native American | 1 (0.7) | 0 (0) | 1 (0.8) | |
| Unknown | 1 | 0 | 1 | |
| ECOG PS, n (%) | .108 | |||
| 0 | 84 (60.0) | 4 (36.4) | 80 (62.0) | |
| 1 | 48 (34.3) | 5 (45.5) | 43 (33.3) | |
| 2 | 7 (5.0) | 2 (18.2) | 5 (3.9) | |
| 3 | 1 (0.7) | 0 (0) | 1 (0.8) | |
| Smoking, n (%) | .782 | |||
| Never | 59 (42.1) | 6 (54.5) | 53 (41.1) | |
| Former | 52 (37.1) | 3 (27.3) | 49 (38.0) | |
| Current | 29 (20.7) | 2 (18.2) | 27 (20.9) | |
| Immunosuppression, n (%) | .133 | |||
| HIV | 13 (9.3) | 0 (0) | 13 (10.1) | |
| Prior transplant | 9 (6.4) | 2 (18.2) | 7 (5.4) | |
| Other | 5 (3.6) | 1 (9.1) | 4 (3.1) | |
| Baseline CBC, median (IQR) | ||||
| WBC, k/μL | 7.4 (6.1–8.8) | 7.3 (4.8–8.5) | 7.4 (6.2–8.8) | .337 |
| HGB, g/dL | 13.2 (11.8–14.2) | 12.3 (11.5–13.5) | 13.3 (11.9–14.4) | .102 |
| PLT, k/μL | 260 (209–314) | 233 (200–286) | 260 (210–319) | .446 |
| TLC, k/μL | 1.8 (1.4–2.2) | 1.3 (1.2–1.5) | 1.9 (1.4–2.3) | .002 |
| <1, n (%) | 7 (5.0) | 1 (9.1) | 6 (4.7) | .443 |
| Disease characteristics | ||||
| HPV, n (%) | .587 | |||
| Positive | 67 (90.5) | 9 (100.0) | 58 (89.2) | |
| Negative | 7 (9.5) | 0 (0) | 7 (10.8) | |
| Unknown | 66 | 2 | 64 | |
| Grade, n (%) | .740 | |||
| 1 | 11 (10.6) | 0 (0) | 11 (11.6) | |
| 2 | 73 (70.2) | 7 (77.8) | 66 (69.5) | |
| 3 | 20 (19.2) | 2 (22.2) | 18 (18.9) | |
| NA | 36 | 2 | 34 | |
| T‐stage, n (%) | .859 | |||
| 1 | 30 (21.4) | 2 (18.2) | 28 (21.7) | |
| 2 | 57 (40.7) | 4 (36.4) | 53 (41.1) | |
| 3 | 37 (26.4) | 3 (27.3) | 34 (26.4) | |
| 4 | 16 (11.4) | 2 (18.2) | 14 (10.9) | |
| Node‐positive, n (%) | 50 (35.7) | 5 (45.5) | 45 (34.9) | .522 |
| Clinical stage, n (%) | .843 | |||
| I | 24 (17.1) | 1 (9.1) | 23 (17.8) | |
| II | 60 (42.9) | 5 (45.5) | 55 (42.6) | |
| III | 56 (40.0) | 5 (45.5) | 51 (39.5) | |
| Treatment characteristics | ||||
| Concurrent chemo regimen, n (%) | .032 | |||
| 1 cycle of 5FU/MMC | 15 (10.7) | 4 (36.4) | 11 (8.5) | |
| 2 cycles of 5FU/MMC | 114 (81.4) | 7 (63.6) | 107 (82.9) | |
| Other b | 11 (7.9) | 0 (0) | 11 (8.5) | |
| Receipt of G‐CSF | .691 | |||
| Yes | 27 (19.3) | 1 (9.1) | 26 (20.2) | |
| No | 113 (80.7) | 10 (90.9) | 103 (79.8) | |
| Radiation modality, n (%) | >.999 | |||
| Photon | 127 (90.7) | 10 (90.9) | 117 (90.7) | |
| Proton | 13 (9.3) | 1 (9.1) | 12 (9.3) | |
| RT duration, d | ||||
| Median (IQR) | 43 (39–47) | 50 (44–53) | 42 (39–46) | .004 |
| >53 days, n (%) | 3 (2.1) | 2 (18.2) | 1 (0.8) | .016 |
| Total RT dose, median (IQR), Gy | ||||
| Primary tumor | 54.0 (50.4–54.0) | 54.0 (52.2–54.0) | 54.0 (50.4–54.0) | .129 |
| >50.4Gy, n (%) | 79 (56.4) | 8 (72.7) | 71 (55.0) | .348 |
| Elective nodes | 45.0 (42.0–45.0) | 45.0 (42.0–45.0) | 45.0 (42.0–45.0) | .604 |
| Fraction, median (IQR) | 30 (28–30) | 30 (29–30) | 30 (28–30) | |
| CTV (cc), median (IQR) | ||||
| Primary tumor | 309 (215–428) | 329 (286–349) | 305 (212–435) | >.999 |
| Elective nodes | 851 (681–1032) | 813 (773–1047) | 853 (681–1026) | .970 |
Lymphopenia threshold was defined around G4 (total lymphocyte count <0.2k/μl) lymphopenia.
Other chemotherapy regimen includes 5FU/cisplatin, 5FU, or capecitabine alone.
Abbreviations: 2m TLC, total lymphocyte count 2 months after initiation of chemoradiation; 5FU, 5‐fluorouracil; CBC, complete blood count; CTV, clinical target volume ECOG PS, Eastern Cooperative Oncology Group performance status; G‐CSF, granulocyte‐colony stimulating factor; HGB, hemoglobin; HIV, human immunodeficiency virus; HPV, human papilloma virus; IQR, interquartile range; MMC, mitomycin‐C; NA, not available; PLT, platelet; RT, radiotherapy; T, tumor; WBC, white blood cell.
Lymphocyte Counts
Lymphocyte counts at baseline and over 12 months since initiating CRT are presented in Figure 1. Prior to CRT, 95% of patients had a normal baseline TLC of greater than 1k/μL. Two months after initiating CRT, there was a median of 71% reduction of TLC from baseline, and TRL was found in 84% of patients: G1 in 11%, G2 in 31%, G3 in 34%, and G4 in 8%. Fifty‐six percent of patients had a TLC nadir of less than 0.2k/μL within 6 months of CRT. The median TLC nadir was 0.18k/μL at a median of 38 days since beginning CRT. Following TLC nadir, lymphocyte counts gradually recovered but the median TLC remained below 1k/μL during the 12‐month observation period. Forty‐five percent of patients had TLC returned to baseline by 12 months, whereas 55% either had persistent lymphopenia beyond 12 months or at the time of last follow‐up.
Figure 1.
Box plot. Total lymphocyte counts at baseline and over time up to 12 months after initiation of chemoradiation (n = 140).
Association Between Lymphopenia and Survival
Median follow‐up was 55 months. At the time of the study, 83% of patients were alive, whereas 17% were dead. The 5‐year OS rate was 32% in the cohort with G4 TRL versus 86% (p < .001 by log‐rank) in the cohort with TLC at least 0.2k/μL 2 months after initiating CRT (Fig 2). Table 2 shows the results of the univariable and multivariable Cox regression analysis. On univariable analysis, G4 TRL at 2 months was significantly associated with increased risk of death (hazard ratio [HR], 5.33; p = .001). In addition, lower baseline HGB (HR, 1.34; p = .008) and dose to the primary tumor greater than 50.4Gy (HR, 2.63; p = .034) were significantly associated with increased risk of death on univariable analysis. No statistically significant association with OS was observed for variables including sex, performance status, immunosuppression; smoking; stage; RT modality; RT duration; CTV; chemotherapy regimen; baseline WBC, PLT, and TLC; and WBC, PLT, and HGB at 2 months since initiating CRT. On multivariable analysis, G4 TRL at 2 months remained significantly associated with a 3.7‐fold increase in risk of death (p = .013). Baseline HGB and primary tumor dose were no longer significantly associated with OS in the multivariable model.
Figure 2.
Kaplan‐Meier estimates. Overall survival (OS) in patients with anal cancer treated by chemoradiation (CRT), grouped by total lymphocyte count (TLC) <0.2k/μL versus TLC ≥0.2k/μL at 2 months since initiating CRT. The 5‐year OS rate was 32% for the cohort with TLC <0.2k/μL versus 86% for the cohort with TLC ≥0.2k/μL (p < .001 by log‐rank)
Table 2.
Univariable and multivariable predictors of overall survival
| Variables | OS HR (95% CI) | p value |
|---|---|---|
| Univariable analysis | ||
| Older age (cont) | 1.03 (0.99–1.07) | .114 |
| Male sex | 1.32 (0.58–3.02) | .508 |
| ECOG PS >1 | 2.65 (0.61–11.48) | .193 |
| Immunosuppression | 0.92 (0.34–2.50) | .875 |
| Ever smoking | 0.75 (0.34–1.66) | .476 |
| Stage (I as reference) | ||
| II | 4.75 (0.62–36.61) | .135 |
| III | 5.62 (0.72–43.62) | .099 |
| Higher BL WBC (cont) | 1.02 (0.86–1.21) | .835 |
| Higher BL HGB (cont) | 0.75 (0.60–0.93) | .008 |
| Higher BL PLT (cont) | 1.00 (1.00–1.01) | .056 |
| Higher BL TLC (cont) | 0.66 (0.33–1.33) | .250 |
| Photon vs proton | 1.86 (0.25–13.99) | .546 |
| RT duration >53 d | 1.19 (0.16–9.11) | .864 |
| RT dose to primary >50.4Gy | 2.63 (1.07–6.43) | .034 |
| Larger CTV of primary tumor | 1.00 (1.00–1.00) | .136 |
| Larger CTV of elective nodes | 1.00 (1.00–1.00) | .663 |
| 5FU/MMC | 0.50 (0.12–2.15) | .351 |
| Higher 2m WBC (cont) | 1.00 (0.87–1.15) | .970 |
| Higher 2m HGB (cont) | 0.94 (0.71–1.24) | .659 |
| Higher 2m PLT (cont) | 1.00 (1.00–1.01) | .392 |
| 2m TLC <0.2k/μL | 5.33 (1.95–14.59) | .001 |
| Multivariable analysis | ||
| RT dose to primary >50.4Gy | 1.87 (0.74–4.74) | .185 |
| Higher BL HGB (cont) | 0.81 (0.64–1.02) | .071 |
| 2m TLC <0.2k/μL | 3.73 (1.33–10.47) | .013 |
Abbreviations: 2m, 2 months since initiation of chemoradiation; 5FU, 5‐fluorouracil; BL, baseline; CI, confidence interval; cont, continuous; CTV, clinical target volume; ECOG PS, Eastern Cooperative Oncology Group performance status; HGB, hemoglobin; HR, hazard ratio; MMC, mitomycin‐C; OS, overall survival; PLT, platelet; RT, radiotherapy; TLC, total lymphocyte count; WBC, white blood cell.
Discussion
To our knowledge, this is the first detailed report characterizing TRL and its association with survival in anal cancer. The present study demonstrates that TRL is common among patients with anal cancer treated with standard CRT and may be a new prognostic marker for OS.
Prior to treatment, 95% of patients had a normal baseline TLC, which fell by a median of 71% by 2 months after initiating CRT. After 2 months, TRL was present in 84% of patients, with 34% having G3 and 8% having G4 lymphopenia. The median TLC of the entire cohort remained below 1k/μL over 12 months. The magnitude and timing of TRL observed in our study aligns with published data in other solid malignancies, in which a 51%–73% reduction in TLC and a 45%–61% incidence of G3–4 lymphopenia were observed 2 months after initiating CRT with lymphopenia also persisting over 1 year in some patients [12, 13, 14, 15, 16, 30].
Although multiple factors likely contribute to TRL, similar findings of TRL observed across tumors of diverse anatomic sites treated with varying concurrent chemotherapy regimens suggest RT may be the main driver of lymphocyte depletion. Circulating lymphocytes are radiosensitive, and a relatively low dose of 2Gy and 3Gy can result in 50% and 90% reduction of the lymphocyte population, respectively [5]. Higher RT dose, greater target volume, and photon therapy (which generally leads to a higher mean body dose compared with proton therapy) have been associated with worse TRL in other solid tumors [9, 10, 11]. In the present study, small sample size precluded a formal statistical evaluation for predictors of G4 TRL at 2 months since CRT. However, between two cohorts with versus without G4 TRL, there were no significant differences in RT modality, target dose, and CTV. Furthermore, no significant correlation was observed between CTV of primary tumor and TLC at 2 months (supplemental online Fig. 1). However, the cohort with G4 TRL at 2 months had a longer duration of RT compared with the cohort without G4 TRL (p = .004). Other variables such as age, smoking history, immunosuppression (i.e., HIV), HPV status, histologic grade, stage, chemotherapy regimen, and baseline WBC, HGB, and PLT did not differ significantly between the two cohorts. However, the cohort with G4 TRL had a lower baseline TLC compared with the cohort without G4 TRL (p = .002), although there was no significant difference in the proportion of patients with baseline lymphopenia (p = .443). Interestingly, all patients in the G4 TRL cohort were female. Although greater hematological toxicity has been reported with two cycles compared with one cycle of MMC in anal cancer [31], patients who developed G4 TRL in our study were more likely to have received only one cycle of MMC (p = .032), likely as they developed severe TRL during CRT and second cycle of MMC was subsequently held.
Consistent with prior studies reporting association of TRL with worse outcomes in various solid tumors, our study shows that TRL is associated with poorer survival in anal cancer. Patients with G4 TRL had a lower 5‐year OS of 32% compared with 86% (p < .001 by log‐rank) in the cohort without G4 TRL at 2 months because initiating CRT. G4 TRL at 2 months was an independent predictor of death with a 3.7‐fold higher risk (p = .013) according to the multivariable model. Similar to our findings, G4 TRL has been correlated with poorer survival outcomes among patients with glioblastoma, esophageal, and cervical cancer [7, 8, 9, 10]. Persistent lymphopenia at 2 months since initiating CRT, which is commonly the first follow‐up time point after RT completion, has also been associated with higher hazards of death among patients with glioblastoma, non‐small cell lung cancer, pancreatic adenocarcinoma, and cervical cancer [13, 14, 15, 16, 17].
Although the exact mechanism by which TRL correlates with worse OS is yet unclear, it can be hypothesized to be related to inferior disease control secondary to the loss of the antitumor activity of lymphocytes. Lymphocytes are thought to play an important role in disease control for anal cancer, as 90% of cases are HPV related, in which viral antigens are thought to elicit a host immune response against tumor cells [23, 24, 25]. Higher TILs have also been correlated with better disease control in anal cancer [4], and immunotherapy trials of immune checkpoint inhibitors such as PD‐1 inhibitors showing promising results among patients with anal cancer further support a role of the immune system in disease control [27, 28]. Alternatively, TRL may lead to inferior OS because of lymphopenia‐related complications such as infection, although studies in glioblastoma and pancreatic cancer showed infection was not a significant cause of death among patients with lymphopenia [14, 32]. In contrast, lymphopenia has also been thought to reflect bone marrow suppression secondary to the depletion of intestinal microbiota from prolonged antibiotic use [33]. In such case, lymphopenia may merely be another prognostic factor, as prolonged antibiotic use likely occurs in patients with recurrent infections and thus poorer overall prognosis. Elucidating the exact mechanism by which TRL correlates with inferior OS is crucial, as it will impact the management of patients with TRL. If TRL is simply another prognostic marker, then patients with TRL may need to be monitored more closely given their poorer expected prognosis. In contrast, if TRL directly contributes to worse OS as a result of reduced TILs and thus poorer disease control, then identifying and employing chemoradiotherapeutic approaches to minimize TRL will be important. Potential approaches to minimizing the severity of TRL may include closer observation of blood counts for high‐risk patients (i.e., immunosuppressed, low baseline blood count), limiting radiation dose to pelvic bone marrow and chemotherapy dose adjustment for patients with TRL.
Aside from TRL, lower baseline HGB and dose to the primary tumor of over 50.4Gy were identified as adverse prognostic factors in the univariable analysis, although they did not remain statistically significant in the multivariable model. The 2‐month interval values of other hematological lines including WBC, HGB, and PLT were not significantly associated with OS, suggesting that TRL is not simply a reflection of overall bone marrow suppression which could affect survival.
The results of our study should be considered keeping in mind several limitations of the study. Given its retrospective nature, the recorded monthly lab values were plus or minus 2 weeks from the exact time point and not all patients had monthly follow‐up lab data available after the 2‐month time point. Although the majority of our patient cohort underwent standard CRT per RTOG 0529 with concurrent 5FU/MMC, additional and/or salvage treatments post‐CRT varied among patients, limiting the interpretation of our results. Furthermore, an accurate and robust evaluation of the association between TRL and OS is likely limited by a relatively small number of patients having G4 TRL at 2 months given modest sample size of the study. We also observed a relatively small number of deaths as anal cancer patients treated with CRT generally have a good prognosis; therefore, our multivariable model may be overfit. Despite these limitations, our results are still hypothesis generating.
Conclusion
In summary, definitive CRT in patients with anal cancer commonly results in TRL, which may be a new prognostic factor for OS. The association between TRL and OS supports the important role of host immunity in survival among patients with anal cancer. Larger, prospective studies are needed to further establish the relationship between TRL and survival outcomes. Various predictors of TRL and corresponding chemoradiotherapeutic approaches to minimize TRL will need to be investigated. Meanwhile, the results of our study support ongoing efforts of clinical trials to investigate the potential role of immunotherapy in anal cancer.
Author Contributions
Conception/design: Grace Lee, Jennifer Y. Wo
Provision of study material or patients: Christine E. Eyler, Theodore S. Hong, Lorraine C. Drapek, Jill N. Allen, Lawrence S. Blaszkowsky, Bruce Giantonio, Aparna R. Parikh, David P. Ryan, Jeffrey W. Clark, Jennifer Y. Wo
Collection and/or assembly of data: Grace Lee, Devarati Mitra
Data analysis and interpretation: Daniel W. Kim, Vinayak Muralidhar, Nora K. Horick,
Manuscript writing: Grace Lee, Daniel W. Kim, Vinayak Muralidhar, Devarati Mitra, Nora K. Horick, Christine E. Eyler, Theodore S. Hong, Lorraine C. Drapek, Jill N. Allen, Lawrence S. Blaszkowsky, Bruce Giantonio, Aparna R. Parikh, David P. Ryan, Jeffrey W. Clark, Jennifer Y. Wo,
Final approval of manuscript: Grace Lee, Daniel W. Kim, Vinayak Muralidhar, c Devarati Mitra, Nora K. Horick, Christine E. Eyler, Theodore S. Hong, Lorraine C. Drapek, Jill N. Allen, Lawrence S. Blaszkowsky, Bruce Giantonio, Aparna R. Parikh, David P. Ryan, Jeffrey W. Clark, Jennifer Y. Wo
Disclosures
Theodore Hong: Synthetic Biologics, Novocure (C/A), Taiho, Astra‐Zenaca, Tesaro, IntraOp, Bristol‐Myers Squibb (RF), Merck (SAB); Aparna Parikh: Foundation Medicine, Puretech (SAB); David P. Ryan: MPM Capital, Acworth Pharmaceuticals, Thrive Earlier Detection (OI), MPM Capital, Oncorus, Gritstone Oncology, Maverick Therapeutics, 28/7 Therapeutics (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Supplemental Figure
Disclosures of potential conflicts of interest may be found at the end of this article.
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Footnotes
For Further Reading: Xi‐Lei Zhou, Wei‐Guo Zhu, Zhi‐Jian Zhu et al. Lymphopenia in Esophageal Squamous Cell Carcinoma: Relationship to Malnutrition, Various Disease Parameters, and Response to Concurrent Chemoradiotherapy. The Oncologist 2019;24:e677–e686.
Implications for Practice: A total of 286 patients with locally advanced esophageal squamous cell carcinoma were treated with concurrent chemoradiotherapy (CCRT), and treatment‐related lymphopenia occurred in 31% of patients within 6 weeks from the start of CCRT. Treatment‐related lymphopenia was significantly associated with lack of treatment response, and older age, lower tumor location, greater tumor length, and larger planning target volume were independent predictors of treatment‐related lymphopenia. Lymphocyte count is an inexpensive biomarker that may be easily used by clinicians to identify patients who are most likely to benefit from CCRT.
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