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. Author manuscript; available in PMC: 2018 Jul 5.
Published in final edited form as: Pract Radiat Oncol. 2017 May 10;7(6):e401–e408. doi: 10.1016/j.prro.2017.05.002

Craniospinal irradiation prior to stem cell transplant for hematologic malignancies with CNS involvement: Effectiveness and toxicity after photon or proton treatment

Jillian R Gunther a, Ahmad R Rahman b, Wenli Dong c, Zeinab Abou Yehia a, Partow Kebriaei d, Gabriela Rondon d, Chelsea C Pinnix a, Sarah A Milgrom a, Pamela K Allen a, Bouthaina S Dabaja a, Grace L Smith a,*
PMCID: PMC6033267  NIHMSID: NIHMS978514  PMID: 28666906

Abstract

Purpose/Objective(s)

Craniospinal irradiation (CSI) improves local control of leukemia/lymphoma with central nervous system (CNS) involvement; however, for adult patients anticipating stem cell transplant (SCT), cumulative treatment toxicity is a major concern. We evaluated toxicities and outcomes for patients receiving proton or photon CSI before SCT.

Methods and materials

We identified 37 consecutive leukemia/lymphoma patients with CNS involvement who received CSI before SCT at our institution. Photon versus proton toxicities during CSI, transplant, and through 100 days posttransplant were compared using Fisher exact and Wilcoxon rank sum tests. Long-term neurotoxicity, disease response, and overall survival were analyzed.

Results

Thirty-seven patients (23 photon, 14 proton) underwent CSI for CNS involvement of acute lymphoblastic leukemia (49%), acute myeloblastic leukemia (22%), chronic lymphocytic leukemia (3%), chronic myelocytic leukemia (14%), lymphoma (11%), and myeloma (3%). CSI was used for consolidation (30 patients, 81%) and gross disease treatment (7 patients, 19%). Median radiation dose (interquartile range) was 24 Gy (23.4–24) for photons and 21.8 Gy (21.3–23.6) for protons (P = .03). Proton CSI was associated with lower rates of Radiation Therapy Oncology Group grade 1–3 mucositis during CSI (7% vs 44%, P = .03): 1 grade 3 with protons versus 5 grade 1, 3 grade 2, and 2 grade 3 with photons. During CSI, other toxicities (infection, gastrointestinal symptoms) did not differ. Allogeneic stem cell transplant (SCT) was used in 95% of patients, with 53% of patients in remission before SCT. Myeloablative conditioning was used for 76%. During SCT admission and 100 days post-SCT, toxicities did not differ by CSI technique. Successful engraftment occurred in 95% of patients (P = .67). Progression or death occurred for 47% of patients, with only 1 CNS relapse.

Conclusion

In our cohort, CSI offered excellent local control for CNS-involved hematologic malignancies in the pre-SCT setting. Acute mucositis occurred less frequently with proton CSI with comparable peritransplant/long-term toxicity profile, suggesting the need to further explore the benefit/toxicity profile of this technique.

Introduction

Radiation therapy is increasingly recognized as efficacious for the treatment of central nervous system (CNS) disease in hematologic malignancy patients, primarily leukemia.1 Although the natural history of leukemia/lymphoma has been known to include CNS disease,2,3 recent advances in therapy leading to overall improved hematologic malignancy outcomes have increased the rates of patients presenting with this therapeutic challenge, primarily from poor CNS penetrance of cytotoxic and targeted therapy agents.4,5 Although leukemia and lymphoma involving the CNS is generally associated with poor prognosis,4–6 a prior study demonstrated that whole brain or craniospinal irradiation (CSI) still conferred a 12-month CNS progression-free survival rate of 77% in patients affected with acute leukemia.1 With the continued discovery of novel chemotherapeutic and targeted regimens and improved survival rates for patients with hematologic malignancies, there is an increased focus on optimizing treatment toxicity profiles and patient quality of life, along with local and systemic disease control.7

The mainstay of up-front CNS-directed leukemia and lymphoma therapy includes systemic chemotherapies (eg, dexamethasone, high-dose methotrexate, cytosine arabinoside), and early intrathecal chemotherapy.7 In the setting of relapse, however, although alternative systemic agents are typically considered (eg, thiotepa, intrathecal liposomal cytarabine), CNS-directed radiation therapy also offers a local treatment alternative for patients who have not responded to or need to recover from systemic treatment.1 In the setting of stem cell transplant (SCT) for consolidation or salvage treatment, because standard conditioning regimens may also still not fully eradicate microscopic or gross disease across the blood brain barrier, CSI can play an especially important therapeutic role.

CSI fields are large, however, targeting the entire craniospinal axis and therefore risk considerable acute (mucositis, nausea, skin reaction, decrease blood counts) and late (endocrine dysfunction, secondary malignancy) side effects. Consideration of the possible toxicity risks and benefits of CSI is crucial for fragile populations, in which CSI could offer local control benefit. The potential relative benefit, however, must be carefully weighed against serious toxicities, especially with multimodality therapies, the potential benefits of alternative approaches (such as intrathecal therapy), and overall survival prognosis. In prior pediatric series, for example, recent investigations have even considered omission or reduction of radiation-based regimens.8,9 Adult hematologic patients anticipating SCT have typically undergone extensive prior systemic chemotherapy courses leading up to intense transplant conditioning regimens, which all carry a heavy cumulative acute toxicity profile. As a result, targeting the highest risk patients for local CNS relapse and minimizing treatment toxicity is of utmost importance in establishing a treatment paradigm that offers a beneficial therapeutic ratio.

In settings in which normal tissue toxicity limits effectiveness and delivery of radiation treatment, there is increasing interest in the implementation of proton therapy. Compared with photon therapy, protons treat the target while reducing exit dose to surrounding normal tissues.10 With the rarity of this disease presentation, as well as only recent emerging evidence for the effectiveness of CNS radiation in this group,1 the safety profile and possible benefit of proton CSI in adult hematologic malignancy patients with CNS involvement before SCT has not been established. We conducted a retrospective analysis to compare the toxicity profiles and disease outcomes in an institutional cohort of adult leukemia and lymphoma patients treated with photon versus proton CSI.

Methods and materials

Patients

After institutional review board approval, we retrospectively identified 87 consecutive patients (age >18 years) treated at our institution with CSI for hematologic malignancy with CNS involvement between 2011 and 2015. Patients must have had pathologically confirmed disease (including acute or chronic leukemia, lymphoma, or myeloma) classified by a hematopathologist at our institution. Of these, 37 patients received CSI before SCT using proton or photon technique and were therefore eligible for the analysis. Eight patients were treated with CSI as part of initial therapy at diagnosis; all others were treated at time of CNS relapse.

We confirmed the presence of CNS disease at presentation or relapse by 1 of the following: blast cells within the cerebrospinal fluid (CSF) (blood contamination was excluded for any patient with peripheral blood circulating blasts cells at time of lumbar puncture) according to criteria set for the European Organization for Research and Treatment of Cancer study 58881; computed tomography or magnetic resonance imaging evidence of leptomeningeal spread (documented by diagnostic radiologist); and/or new onset of neurologic deficits with hematologic malignancy, not attributable to other cause. For cases in which patients were suspected to have CNS disease observed through imaging/pathology, but imaging/pathology alone was not definitive, correlating clinical examination by an oncologic neurologist was used to determine and confirm correlation of the neurologic deficits in the physical examination with imaging/pathology findings and establish a clinical diagnosis of CNS involvement/relapse.

We abstracted demographic information, including age, sex, race, and date of diagnosis, from the electronic medical record. We also reviewed the medial record for treatment characteristics including radiation therapy type, dose, and delivery schedule; systemic chemotherapy history; intrathecal chemotherapy; and stem cell transplantation details.

Treatment

Photon CSI treatment was delivered with the patient in the prone position using a thermoplastic mask for immobilization. Two opposed 6 MV isocentric lateral beams were used to treat the whole brain and were matched to posteroanterior spine fields. Two to 3 spine fields were used, depending on the patient length, to include the spine and thecal sac. Field size and plan normalization was optimized to ensure full clinical target volume coverage with margin for setup uncertainty (spinal field width included vertebral body with 1 cm margin at each side). Field junctions were feathered using 2 0.5 cm junction shifts during the CSI course.11,12

Proton CSI was delivered with the patient in the supine position using a thermoplastic mask for immobilization. The target included the entire brain and spinal canal through the thecal sac without explicit anterior vertebral body sparing. All patients were treated using passive scatter proton therapy. A relative biological effectiveness correction of 1.1 was used for proton therapy planning. The treatment goal was targeting >95% CSF space with the 95% isodose line. Conventional junction shift and feathering techniques were used to avoid hot spots over the cord.11,13,14

Two patients had prior CNS radiation therapy: 1 received base of skull radiation approximately 2 months before CSI, and this previously treated area was blocked for a portion of the treatment course so that no area of the whole brain was treated to a cumulative excess of 36 Gy. One patient received stereotactic radiosurgery for a meningioma involving cranial nerve III 8 months before CSI; therefore, for this patient, only his spine was treated during CSI.

Patients typically received multiple salvage chemotherapy regimens before CSI. CSI was typically given weeks to months before transplantation. Hematopoietic cell transplantation standardly consisted of myeloablative chemotherapy conditioning regimen, followed by infusion of autologous or allogeneic peripheral blood or bone marrow stem cells. Patients received this treatment in the hospital and remained hospitalized until evidence of complete blood cell recovery and resolution of any medical complications requiring hospitalization.15–19 If total body irradiation (TBI) was part of the transplant conditioning regimen, there were 2 possibilities: reduced intensity conditioning regimen of 2 Gy TBI or myeloablative regimen of 12 Gy TBI. The 2 Gy TBI was given, as standard, regardless of previously delivered or planned CSI treatment. The 12 Gy TBI was given in conjunction with CSI. For example, if total CSI dose was planned for 24 Gy, an initial 12 Gy was given to target the craniospinal axis, followed immediately with 12 Gy TBI for a total of 24 Gy targeting the CNS.20

Study endpoints

Outcomes were compared by CSI technique and included toxicity and disease outcomes. Acute toxicity was determined during 3 time windows: during the course of CSI; during the course of SCT, and through 100 days post-SCT. Long-term outcomes were followed until patient death or last follow-up, including neurotoxicity, disease response, cause-specific survival, and overall survival.

Toxicities

Mucositis during CSI was graded according to the Radiation Therapy Oncology Group scale (eg, mucositis: grade 1, mild mucositis no treatment; grade 2, mucositis requiring analgesics; grade 3, mucositis requiring narcotic treatment; grade 4, ulceration, hemorrhage, necrosis).21 Mucositis during transplantation was graded according to World Health Organization toxicity grading (eg, mucositis: grade 1, oral soreness, erythema; grade 2, oral erythema, ulcers, solid diet tolerated; grade 3, oral ulcers, liquid diet only; grade 4, nothing by mouth).22 Viral and bacterial infections confirmed by clinical examination, laboratory analysis, or clinical imaging were recorded. The medical record was thoroughly abstracted for acute organ toxicities: gastrointestinal (GI) toxicity included nausea, vomiting, diarrhea, and bleeding. Pulmonary toxicity included pneumonia, cough, and pulmonary failure. CNS/neurotoxicity included neuropathy, headache, altered mental status, and any sensory or motor changes. Cardiovascular toxicities included arrhythmias, pericardial effusion, acute hypertension, abnormal ejection fraction, heart failure, and acute ischemic event.

Statistical analysis

Frequencies and percentages are reported for categorical variables; summary statistics are reported for continuous data. The χ2 test and Fisher exact test were used to evaluate the association between categorical variables and study group (photon vs proton). Wilcoxon rank sum test was used to compare the distributions of continuous variables (such as age and radiation dose) between the 2 study groups. Time to event was analyzed using the Kaplan-Meier method and the log rank test. All tests were 2-sided. P values < .05 were considered statistically significant. All analyses were conducted using SAS 9.3 (SAS, Cary, NC) software.

Results

Patient and treatment characteristics

Table 1 describes the pertinent clinical and treatment factors for this patient population. Baseline patient characteristics were similar for both photon and proton groups; differences in treatment characteristics including radiation dose, fraction number, and TBI receipt/dose are presented in Table 1. Of 37 patients, 23 (62%) received photon and 14 (38%) proton CSI. Diagnoses included acute lymphoblastic leukemia (49%), acute myeloblastic leukemia (22%), chronic lymphocytic leukemia (3%), chronic myelocytic leukemia (14%), lymphoma (11%), and myeloma (3%). Eight patients presented with neurologic deficits or symptoms including cranial nerve deficits (3), extremity weakness (2), pain (2), and headache (1). Four of these patients specifically reported improvement in these symptoms with radiation therapy.

Table 1.

Patient and treatment characteristics

Characteristic Photon
Proton
P
n = 23 n = 14
Age at CSI start (median, IQR) 39 (28–45) 37 (26–51) .91
Male (%) 15 (65) 8 (57) .62
Race (%)
 White 12 (52) 6 (43) .47
 Black 1 (4) 2 (14)
 Asian 1 (4) 2 (14)
 Mixed 9 (39) 4 (29)
Diagnosis
 ALL (%) 12 (52) 6 (43) .77
 AML (%) 4 (17) 4 (29)
 CLL (%) 1 (4) 0 (0)
 CML (%) 2 (9) 3 (21)
 Lymphoma 3 (13) 1 (7)
 Myeloma 1 (4) 0 (0)
Indication .22
Consolidation (%) 17 (74) 13 (93)
Gross (%) 6 (26) 1 (7)
ICU admission
 No (%) 16 (70) 11 (79) .71
 Yes (%) 7 (30) 3 (21)
RT dose (median, IQR) 24.0 (23.4–24) 21.8 (21.3–23.6) .03
Fractions (median, IQR) 12 (12–13) 13 (12–13) .06
TBI dose (median, IQR) 12.0 (4.0–12.0) 2.0 (2.0–2.0) .33
Days from end RT to SCT (median, IQR) 15 (7–47) 23 (9–44) .74
Days RT duration (median, IQR) 15 (10–20) 16 (15–18) .42
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ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelocytic leukemia; CSI, craniospinal irradiation; ICU, intensive care unit; IQR, interquartile range; RT, radiation therapy; TBI, total body irradiation; SCT, stem cell transplant.

CSI was used for consolidation in 30 patients (81%) and to treat gross CNS disease in 7 patients (19%) (P = .22). (Six of 7 patients with gross disease received photon treatment.) Median radiation dose (interquartile range [IQR]) was 24 Gy (23.4–24.0) for photons and 21.8 Gy (21.3–23.6) for protons (P = .03). Median time from the end of radiation therapy to SCT was 15 days for the photon group and 23 days for the proton group. Radiation therapy duration was similar (15 days, photon; 16 days, proton).

Allogeneic SCT was used in 95% of patients, with 53% of patients in first or second complete remission before SCT. Myeloablative conditioning was used for 76%. For patients receiving allogeneic transplants, donors were siblings (13 patients), parents (3 patients), or unrelated (19 patients). Twelve patients (34%) had a 10/10 match. Thirty-five patients (95%) successfully engrafted.

Toxicities during CSI

Table 2 describes toxicities experienced by patients during receipt of CSI. Proton CSI was associated with lower rates of Radiation Therapy Oncology Group grade 1–3 mucositis during CSI (7% vs 44%, P = .03). Only 1 proton patient experienced mucositis, which was grade 3 (confluent, severe pain requiring narcotics). In contrast, 10 photon patients experienced mucositis (5 grade 1, 3 grade 2, and 2 grade 3). During CSI, no other statistically significant differences in toxicities by CSI technique were found, including infection (16%) or GI (30%) toxicity. Of patients who did not receive TBI, proton CSI was associated with lower mucositis rates (48% in photon patients vs 8% in proton patients, P = .04).

Table 2.

Toxicity experienced during craniospinal irradiation for patients treated with photons vs protons

Photon
Proton
P
n = 23 (%) n = 14 (%)
Mucositis grade
 0 or unknown 13 (57) 13 (93) .10
 1 5 (22) 0 (0)
 2 3 (13) 0 (0)
 3 2 (9) 1 (7)
Any mucositis
 No 13 (57) 13 (93) .03
 Yes 10 (44) 1 (7)
Infection
 No 15 (65) 6 (43) .31
 Yes 8 (35) 8 (57)
GI toxicity
 No 16 (70) 10 (71) 1.00
 Yes 7 (30) 4 (29)
Any CNS toxicity
 No 20 (87) 11 (79) .65
 Yes 3 (13) 3 (21)
Any mucositis (patients without TBI) n = 15 (%) n = 13 (%)
 No 8 (53) 12 (92) .04
 Yes 7 (47) 1 (8)
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CNS, central nervous system; GI, gastrointestinal. Other abbreviation as in Table 1. Boldface text indicates statistical significance.

Toxicities during and after SCT

No toxicity differences by CSI technique were apparent during the window of SCT hospital admission (Table 3). Overall rates showed frequent toxicities with SCT regardless of radiation treatment approach, including mucositis (51%), infection (43%), and acute graft-versus-host disease (32%). Through a follow-up period of 100 days after admission for SCT, there were no differences in frequencies of any toxicity between the photon and proton groups.

Table 3.

Toxicities experienced during stem cell transplantation for photon and proton patients

Photon
Proton
P
n = 23 n = 14
Any mucositis
 No (%) 12 (52) 7 (50) .90
 Yes (%) 11 (48) 7 (50)
Infection
 No (%) 3 (13) 2 (14) 1.00
 Yes (%) 20 (87) 12 (86)
Neutropenic fever
 No (%) 10 (43) 10 (71) .17
 Yes (%) 13 (57) 4 (29)
GI toxicity
 No (%) 7 (30) 3 (21) .71
 Yes (%) 16 (70) 11 (79)
CNS toxicity
 No (%) 15 (65) 10 (71) 1.00
 Yes (%) 8 (35) 4 (29)
CV toxicity
 No (%) 16 (70) 10 (71) 1.00
 Yes (%) 7 (30) 4 (29)
Pulmonary toxicity
 No (%) 19 (83) 11 (79) 1.00
 Yes (%) 4 (17) 3 (21)
GVHD
 No (%) 17 (74) 8 (57) .29
 Yes (%) 6 (26) 6 (43)
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CNS, central nervous system; CV, cardiovascular; GI, gastrointestinal, GVHD, graft-versus-host disease.

No differences were found for admission length of stay of the transplant (median, 32 days; photon, 33, proton, 30.5; P = .39). Twenty-six percent of patients were admitted to the intensive care unit for reasons including hypotension (2 patients), diabetic ketoacidosis, acute respiratory failure (5 patients), and hyponatremia; this did not differ between photon and proton patients. Successful engraftment occurred in 95% of patients (P = .67).

Long-term toxicity

Over long-term follow-up, 1 patient, treated with proton CSI to 30 Gy (equivalent), experienced severe neurotoxicity characterized by diffuse demyelination and necrosis confirmed on magnetic resonance imaging, thought to be treatment-related with the combination of a history of multiple intrathecal chemotherapies and radiation. Clinically, this patient demonstrated neurocognitive impairment, lower extremity weakness, incontinence, and difficulty swallowing, which presented 10 months after radiation. This patient did not demonstrate evidence of CNS disease relapse. No long-term neurotoxicities were found in patients treated with photon CSI. Statistical comparison did not demonstrate a statistically significant difference in the occurrence of neurotoxicity for proton versus photon CSI (P = .38).

Survival and disease control

Median follow-up for all patients was 8 months (IQR, 6–17.5). Median follow-up for surviving patients was 16 months (IQR, 9–32), with a total of 17 patients (46%) who died. Primary causes of death included graft rejection or failure (1), infection (4), acute respiratory distress syndrome (1), acute graft-versus-host disease (1), recurrent disease (1), and liver failure (1). Actuarial 6-month survival after CSI was 69.6% for photons versus 78.6% for protons (P = .15) (Fig 1). Only 1 patient, treated with protons, had a CNS relapse with CSF positive for lymphoma cells 5 months after CSI. They also had concurrent systemic relapse and died from disease. There was no significant difference in CNS relapse risk for proton versus photon CSI (P = 1.00).

Figure 1.

Figure 1

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Kaplan-Meier (log-rank) comparison of survival of patients treated with photon versus proton craniospinal irradiation. Photon, solid line; proton, dotted line. RT, radiation therapy.

Discussion

Here, we evaluate the toxicity profiles and outcomes of hematologic malignancy patients who underwent photon or proton-based CSI before stem cell transplantation for CNS disease involvement. In this institutional series, we provide evidence for the effectiveness and safety of CSI, and even for this heavily chemotherapy pretreated population, found that pre-SCT CSI still allowed for successful engraftment rates. Results from our series suggested that proton CSI was associated with lower rates of mucositis in the acute peri-CSI period for these patients, although in the subsequent peritransplant period, frequency of mucositis was similar. Other toxicities, including infection rates and GI toxicity, were also similar between the groups at time of CSI, transplant, and 100 days posttransplant. Treatment decision-making for optimizing local control, salvage, and/or cure in this population is extraordinarily challenging given the rarity of disease and current lack of guiding evidence on risk/benefit ratios to optimize treatment approach, paradigm, and technique (including radiation technique).

Prior studies demonstrate that mucositis is a common side effect of radiation treatment, and can, depending on severity, result in decreased oral intake with subsequent need for intravenous fluid rehydration and even feeding tube placement.23–25 Because mucosal damage and neutropenia are the leading risk factors associated with development of infection in the preengraftment phase of transplant26 and many patients proceed to transplant within weeks of CSI completion, a step necessary to minimize the burden of disease at transplant, the minimization of mucositis severity for this patient population is an important priority to address both as a research question and in clinical practice. The clinical implications of optimizing the effectiveness and minimizing toxicity of CSI in this clinical setting are underscored by the unfortunately morbid natural history, prognosis, and challenges of treatment of CNS involvement in hematologic malignancies. Specifically, CNS involvement of adult hematologic malignancies are particularly challenging to treat, even in the setting of allogeneic SCT, because of the risk of inadequate chemotherapy CNS penetration and less graft-versus-leukemia effect in the CNS as a result of the blood-brain barrier. For similar underlying reasons, CNS relapses after allogeneic transplant are difficult to salvage. Nonetheless, improving local control or symptoms from CNS disease/relapse does not necessarily confer an overall survival benefit, and therefore, although optimal clearance of CNS disease before an allogeneic transplant is a priority for symptoms and quality of life, particularly in patients at high risk for CNS disease, using comprehensive CSI or other CNS-directed therapies must be carefully balanced with the potential toxicities that patients may experience.

The role of proton-based CSI is well-accepted in the pediatric population.27–32 The reduction in exit dose to normal tissues associated with proton radiation is particularly germane in the consideration of CSI because irradiation of the entire spinal axis risks cumulative exit dose over a large field. Although differences in acute toxicities are important, in children, there is also an important focus on long-term benefits of reducing exit dose to normal tissues. Specifically, incremental increases in dose to normal tissue can result in catastrophic long-term toxicities, including endocrine dysfunction, cardiopulmonary consequences, and secondary malignancies. As a result, proton CSI is an accepted CNS treatment option in children, in both the setting of hematologic CNS disease as well as primary brain malignancy.30,33 In adults, the comparative risk-benefits for proton versus photon treatment in many different anatomic and disease sites continues to be debated.34–37 The optimal role of proton-based CSI for adults has undergone investigation. Our institution has previously reported on a population of adult patients with medulloblastoma, a CNS malignancy in which CSI is the standard of care. This comparison of proton versus photon CSI revealed decreased gastrointestinal (nausea, vomiting, esophagitis) and hematologic toxicity for the patients who received proton therapy. Patients also had decreased weight loss in the proton cohort.13 The authors conclude that proton-based CSI used to reduce toxicity would likely benefit adult patients requiring CSI in this context.

Given that the role of CSI, regardless of radiation technique, for adult patients with hematologic malignancies is still emerging, there is a dearth of evidence to understand the potential relative benefits and harms for this patient population. Although the benefits of protons for acute mucositis risk were modest in our study, particular characteristics to consider when weighing the value of proton therapy in this patient population are (1) high risks for early death either from disease or from the toxicities of treatment (including secondary complications from high-dose chemotherapy conditioning regimens), weighed against (2) the cumulative toxicity already typically suffered by these patients, and (3) fragility and frequency of multiorgan toxicities in the acute transplant setting. Continued evaluation of the effectiveness and value of either proton or photon CSI may consider that these patients have often undergone chemotherapeutic regimens that are intensive and lengthy. The conditioning regimens are toxic and can lead to serious adverse events and nonrelapse mortality. For this reason, there is considerable interest in the development of reduced toxicity conditioning regimens for hematologic malignancy patients undergoing SCT.38,39 Future additional comprehensive and long-term data on outcomes after proton CSI will still be needed to continue establishing and testing the potential value of this approach.

A final consideration that requires exploration in future studies is the impact of radiation-associated mucositis on quality of life in this patient group. Such patients, at least half of whom ultimately experienced organ toxicity during radiation and transplant in our study, suffer substantial morbidity from treatment alone. Additional patient-centered outcomes would help to further inform the risk-benefit assessment and physician-patient discussions about offering proton versus photon CSI for this adult population.

Limitations of our study to consider include the retrospective nature of the analysis, the modest number of patients included, and some imbalances in the treatment characteristics between groups. As a result, possible differences in proton and photon mucositis profiles suggested by our results still require additional validation and, given the limitations of a small cohort, we caution against interpreting this association as definitively causal. Conversely, other small differences in toxicity frequencies for other outcomes may not be able to be ruled out. Notably, however, prospective and especially randomized data to address this question would be extremely difficult to obtain, given this relatively rare patient population. We did not address the outcomes profile of conformal methods of photon-based radiation delivery such as intensity-modulated photon therapy, as our institutional standard is to deliver 3-dimensional external beam photon radiation for CSI.

In conclusion, this study reports the local control outcomes and toxicity profile after a CSI plus SCT treatment paradigm for hematologic malignancy patients with CNS involvement. Because results from this series provided hypothesis-generating data that proton-based CSI technique could allow for decreased rates of acute CSI-associated mucositis with equivalent local control, results suggest a need for continued studies to develop this body of work. Such studies are needed to advance the understanding of the risk/benefit ratio of proton or photon CSI in this fragile but relatively rare clinical scenario.

Footnotes

Conflicts of interest: None.

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