A Comparison of Grade 4 Lymphopenia With Proton Versus Photon Radiation Therapy for Esophageal Cancer

Abstract

PurposeGrade 4 lymphopenia (G4L) during radiation therapy (RT) is associated with higher rates of distant metastasis and decreased overall survival in a number of malignancies, including esophageal cancer (EC). Through a reduction in integral radiation dose, proton RT (PRT) may reduce G4L relative to photon RT (XRT). The purpose of this study was to compare G4L in patients with EC undergoing PRT versus XRT.Methods and materialsPatients receiving curative-intent RT and concurrent chemotherapy for EC were identified. Lymphocyte nadir was defined as the lowest lymphocyte count during RT. G4L was defined as absolute lymphocyte count <200/mm3. Univariate and multivariable logistic regression analyses (MVA) were performed to assess patient and treatment factors associated with lymphopenia. A propensity-matched (PM) cohort was created using logistic regression, including baseline covariates.ResultsA total of 144 patients met the inclusion criteria. The median age was 66 years (range, 32-85 years). Of these patients, 79 received XRT (27% 3-dimensional chemo-RT and 73% intensity modulated RT) and 65 received PRT (100% pencil-beam scanning). Chemotherapy consisted of weekly carboplatin and paclitaxel (99%). There were no significant differences in baseline characteristics between the groups, except for age (median 4 years older in the PRT cohort). G4L was significantly higher in patients who received XRT versus those who received PRT (56% vs 22%; P < .01). On MVA, XRT (odds ratio [OR]: 5.13; 95% confidence interval [CI], 2.35-11.18; P < .001) and stage III/IV (OR: 4.54; 95% CI, 1.87-11.00; P < .001) were associated with G4L. PM resulted in 50 PRT and 50 XRT patients. In the PM cohort, G4L occurred in 60% of patients who received XRT versus 24% of patients who received PRT. On MVA, XRT (OR: 5.28; 95% CI, 2.14-12.99; P < .001) and stage III/IV (OR: 3.77; 95% CI, 1.26-11.30; P = .02) were associated with G4L.ConclusionsXRT was associated with a significantly higher risk of G4L in comparison with PRT. Further work is needed to evaluate a potential association between RT modality and antitumor immunity as well as long-term outcomes.

Mono-institutional phase 2 study of innovative Stereotactic Body RadioTherapy targeting PArtial Tumor HYpoxic (SBRT-PATHY) clonogenic cells in unresectable bulky non-small cell lung cancer: profound non-targeted effects by sparing peri-tumoral immune microenvironment

“…Recent years brought renewed interest in the immuno-modulatory effects of RT, including AE [15], and the depletion of lymphocytes [16–24], both highlighting the importance of the anti-tumor immune system function. Radiation, by itself, can lead to increased antigen shedding and presentation of neo-antigens from the tumors leading to maturation and activation of antigen presenting cells (APCs), increased immuno-stimulatory cytokine production, increased CD-8 T cell and APC infiltration, and improved acquisition of immune stimulatory phenotype [37, 38].…”

“…The real value of the immunomodulatory effects of RT have yet to be defined. The potential beneficial immune stimulating properties of RT have been questioned by many scientists in the past and present, with a renewed focus on the immune-mediated abscopal effects (AE) [14] as well as on the depletion of lymphocytes [15, 16]. Recent studies have described an association between the RT-induced lymphopenia with poor oncologic outcome, with the thought that RT using larger volumes/multiple daily fractions can lead to global immunosuppression [17–20].…”

Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY)

“…Clinical data show that the conventional radiotherapy predominantly generates immune-suppressive effects [ 9 ]. Furthermore, it has been shown that irradiation of larger volumes in multiple daily fractions correlates with radiation-induced lymphopenia [ 10 , 11 ], leading to a global immunosuppression and consequent poor oncologic outcome [ 12 , 13 ]. These radiation-mediated immune-suppressive effects may negatively affect the therapeutic efficacy in many tumor types [ 14 , 15 ].…”

Abscopal Effect Following Proton Beam Radiotherapy in a Patient With Inoperable Metastatic Retroperitoneal Sarcoma

“…Radiation alone can induce volume-dependent lymphopenia via irradiation of lymphoid organs, bone marrow, and circulating lymphocytes (40). Radiation modality may also contribute to lymphopenia, as esophageal cancer patients treated with photons experienced more Grade 4 lymphopenia compared to those treated with protons, suggesting a dependence on total integral dose to lymphocyte-containing normal structures such as the vasculature (41). Lymphocytes are very radiosensitive, susceptible to apoptosis in response to doses as low as 1–2 Gy, with evidence indicating that activated T cells may be more radio-resistant (31, 32, 42).…”