Annals of Oncology Advance Access published online on July 22, 2008
Annals of Oncology, doi:10.1093/annonc/mdn529
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Response to low-dose involved-field radiotherapy in patients with non-Hodgkin's lymphoma
1 Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA
2 Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
* Correspondence to: Dr A. K. Ng, Department of Radiation Oncology, Brigham and Women's Hospital, 75 Francis Street, L2, Boston, MA 02115, USA. Tel: +1-617-732-6310; Fax: +1-617-264-5242; E-mail: ang{at}lroc.harvard.edu
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Abstract |
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Background: The purpose of this study was to analyze response to palliative low-dose involved-field radiotherapy (LD-IF-RT) (two 2-Gy fractions), explore factors predicting for response, and determine the time course to subsequent treatment.
Patients and methods: Thirty-three patients with advanced or recurrent indolent non-Hodgkin's lymphoma (NHL) received LD-IF-RT to 43 sites. Response was assessed by physical examination and radiographic studies. Median follow-up for individual sites was 14 months. Fisher's exact test was used to evaluate prognostic factors for response and in-field progression.
Results: Overall response was 95%. Thirty-six sites (84%) had a complete response (CR), five sites (12%) had a partial response, and two sites (5%) had progressive disease. The CR rate of head and neck sites was significantly higher than that of pelvic and/or inguinofemoral sites (95% versus 64%, P = 0.04). The CR rate was significantly higher for sites 
40 mm than for sites >40 mm (90% versus 56%, P = 0.04). Ten sites (23%) had in-field progression diagnosed at a median of 9 months. Sixteen patients (48%) received systemic treatment at a median of 8 months. Fourteen patients (42%) did not require additional treatment.
Conclusions: LD-IF-RT for selected NHL subtypes has excellent local CR and in-field control rates and may postpone the need for systemic therapy.
non-Hodgkin's lymphoma, palliation, radiation therapy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Indolent non-Hodgkin's lymphomas (NHL) are usually extensive (stage III/IV) at presentation, with a median age at presentation of 55–60 years [1]. With the exception of a minority of patients who present with localized disease in which radiation therapy alone may have a curative role [2–5], it is considered a largely incurable disease. Disease progression is characterized by multiple relapses with spontaneous remission and transformation to more aggressive lymphomas in some cases. Although generally not curable with conventional therapy, patients with indolent lymphoma have a relatively long life expectancy. Among patients with advanced-stage disease, the median survival ranges from 6 to 10 years [6]. The indication for initiating treatment is often symptomatic disease progression.
Chemotherapy and immunotherapy can be effective in achieving repeated remissions. Systemic therapy, however, can be associated with significant toxicity, especially in older patients with comorbid illnesses. The disease can also eventually become refractory to systemic treatment. Given the radiosensitivity of indolent lymphoma, local radiation therapy plays an important palliative role in these patients. Conventional-dose radiation therapy, depending on the sites of treatment, however, can have considerable side-effects affecting patients’ quality of life and ability to receive further systemic therapy. Examples include mucositis and xerostomia for treatment to head and neck sites, gastrointestinal toxicity for abdominal irradiation, and marrow toxicity with large pelvic fields.
The role of low-dose involved-field radiotherapy (LD-IF-RT) as palliative treatment for indolent lymphoma has been explored in several European studies [7–11]. These studies have consistently shown a high response rate with minimal treatment toxicity. In this study, we report our experience on palliative LD-IF-RT in patients with advanced-stage and/or refractory NHL.
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patients and methods |
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Institutional Review Board permission was granted to retrospectively review the records of all patients with a diagnosis of NHL who received palliative LD-IF-RT at our institution. Of these, 33 patients (19 male and 14 female) had pathologically confirmed advanced or recurrent NHL and therefore met the criteria for inclusion in this study. Patient characteristics are listed in Table 1. The median age at initial NHL diagnosis was 52 years (range 28–75). Median age at first LD-IF-RT treatment was 57 years (range 28–78) and the median interval between diagnosis and the start of LD-IF-RT was 43 months (range 2–217). Pathologic subtypes were follicular lymphoma (28 patients, 85%), extranodal marginal zone lymphoma (2, 6%), mantle cell lymphoma (2, 6%), and chronic lymphocytic leukemia (1, 3%). Before LD-IF-RT, 17 patients (52%) received systemic therapy, 15 (45%) received conventional-dose radiotherapy, and three (9%) underwent stem-cell transplant; nine (27%) received no prior treatment.
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Treatment consisted of a total dose of 4 Gy delivered in two fractions over two consecutive days. All treatments were delivered from April 2004 to July 2007. No other therapy was given concomitantly with LD-IF-RT. A total of 43 sites were treated (six patients received treatment to multiple sites). Twenty-one treatments (49%) were to the head and neck, 11 (26%) were to pelvic and/or inguinofemoral nodes, six (14%) to cutaneous sites, three (7%) to the axilla, one (2%) to a peripheral node, and one (2%) was to the breast. Data on the size of positive nodes were available for 38 sites (88%). The median size of the largest node per site was 35 mm (range 12–100).
Before and after LD-IF-RT, patients were evaluated by physical examination, computed tomography scanning, and positron emission tomography scanning. In assessing response, for patients with more than one node within the radiation treatment field and differing responses for each node, the response for that site was scored on the basis of the node with the worst response. In-field progression rates and time to in-field progression for each site were also analyzed. Median follow-up time for individual sites was 14 months (range 0–38). Fisher's exact test was used to evaluate prognostic factors for response and in-field progression.
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results |
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response to LD-IF-RT
The overall response rate was 95%. Thirty-six sites (84%) achieved a complete response (CR) (complete resolution of disease by physical examination or by radiographic findings), five (12%) achieved a partial response (PR), and two (5%) had progressive disease (PD). The onset of response was generally rapid. Patients often noted a response within 2 weeks of treatment. In all but two patients, the response had been achieved at the time of the first response assessment. Median time to first follow-up was 10 weeks (range 1–59 weeks). No treatment-related toxicity was observed.
factors predicting for response
The CR rate of the head and neck sites was significantly higher than that of the pelvic and/or inguinofemoral sites (95% versus 64%, P = 0.04). Responses by treatment sites are summarized in Table 2. Size and response data were available for 38 sites (88%). The CR rate was significantly higher for sites with disease 40 mm or smaller than for sites with disease >40 mm (90% versus 56%, P = 0.04). Responses by disease size are summarized in Table 3. We also analyzed the relationship between size and site of involvement. Size of disease was available for 20 of 21 head and neck sites and 10 of 11 pelvic and/or inguinofemoral sites. The median size of the largest head and neck node per site was 29 mm (range 12–50 mm) and that of the largest pelvic and/or inguinofemoral node per site was 42.5 mm (range 30–60). The difference between the sizes of the head and neck sites as compared with the pelvic and/or inguinofemoral sites was statistically significant (P < 0.001). Of the 20 head and neck sites, 19 (95%) had a CR and one had PD. Of the 10 pelvic and/or inguinofemoral sites, six (60%) had a CR, three had a PR, and one had PD. Data regarding the dimension of the largest node of each treatment area are summarized in Table 4.
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We did not find age to be predictive of CR rates. Eight of nine patients
50 years of age achieved a CR compared with 28 of 34 patients >50 (88% versus 82%, P = 1.0). Nineteen of 23 patients 60 achieved a CR compared with 17 of 20 patients >60 (83% versus 85%, P = 1.0). Twenty-four of 29 patients 65 achieved a CR compared with 12 of 14 patients >65 (83% versus 86%, P = 1.0). We also did not find receipt of prior treatment to be predictive of response to LD-IF-RT. Nine patients (13 sites) received no treatment before initiating LD-IF-RT. Twelve (92%) of these 13 sites achieved a CR; one (8%) achieved a PR. In comparison, 24 patients (30 sites) had received prior systemic and/or radiation therapy. Twenty-four (80%) of these sites achieved a CR, four (13%) achieved a PR, and two (7%) had PD. The difference in response rates between these two groups of patients were not statistically significant (P = 0.6).
recurrences
Nineteen patients (58%) had progression (in-field and/or out-of-field) after LD-IF-RT. Median time to progression was 4 months (range 0–16).
Ten sites (23%) had in-field progression, diagnosed at a median of 9 months (range 0–20) after LD-IF-RT. Of these sites, seven (70%) had initially achieved a CR, one (10%) achieved a PR, and two (20%) had PD. Of the 33 sites without in-field progression, 29 (88%) had an initial CR and four (12%) had a PR. Median follow-up time for these sites was 4 months (range 0–36). Initial CR to treatment did not significantly predict for in-field progression (70% versus 88%, P = 0.3).
Of the 10 sites with in-field progression, one was retreated with LD-IF-RT resulting in a PR. Five sites received conventional-dose RT, resulting in one PR and four CRs. One patient with PD to one treatment site is currently under observation only. Systemic therapy was also initiated in three patients, who received LD-IF-RT to a total of six different sites, at the time of in-field progression. In these three patients, PD requiring systemic treatment was only observed in one LD-IF-RT treatment site with or without PD outside of the original treatment field.
need for subsequent systemic treatment
Sixteen patients (48%) received systemic therapy at a median of 8 months (range 0–38) after LD-IF-RT. One patient who received systemic treatment <1 month after LD-IF-RT had been receiving rituximab-based systemic treatment before LD-IF-RT, but treatment was discontinued due to Hepatitis B viral loads. The patient resumed treatment after LD-IF-RT once viral loads were reduced.
Fourteen patients (42%) required no additional treatment. Median follow-up for these patients was 6 months (range 0–31).
other events
Seven patients (21%) had transformation of their NHL to more aggressive histologies. Four of these patients initially had a CR to LD-IF-RT, two had a PR, and one had PD. Median time to diagnosis of in-field or out-of-field progression in these seven patients was 2 months (range 0–9). One patient died 3 months after treatment due to treatment-related myelodysplasia, which was diagnosed before LD-IF-RT.
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discussion |
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This study of LD-IF-RT using 4 Gy in two fractions to 43 sites in 33 patients with indolent NHL shows an overall response rate of 95%, with a CR achieved in 84% of patients. Responses were often rapid and treatment-related toxicity was effectively absent. These results compare favorably with previously published data which are summarized in Table 5 [7–11].
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Other investigators have explored factors that predict for response. In the retrospective review by Girinsky et al. [8] on 48 patients with indolent lymphoma treated with LD-IF-RT, factors that were significantly associated with lack of response included bulky tumor (>5 cm), higher number of prior chemotherapy regimens, and age
65 years. Haas et al. reported their experience of 109 patients with recurrent indolent B-cell NHL treated with LD-IF-RT. Patients with only one or two lymphoma sites and disease size of 5 cm were significantly more likely to achieve a CR. In our study, we similarly found that the likelihood of achieving a CR is significantly influenced by disease size. We used a cut-off of 4 cm because of the limited number of patients with disease size >5 cm. The smaller disease bulk of patients included in our study may also explain the higher CR rate observed in our study in comparison with the others. We also explored CR rates on the basis of treatment sites, which have not been addressed by previous studies. Our finding of a significantly higher CR rate for head and neck sites than that for the pelvic and/or inguinofemoral sites may be explained by the difference in the sizes of the disease in the head and neck region versus the pelvic and/or inguinofemoral area. Nonetheless, this finding of a higher response rate in head and neck sites is encouraging as patients with symptomatic involvement in the head and neck region may particularly benefit from palliative LD-IF-RT because of the high toxicity of conventional-dose RT to the area.
Histology has also been shown to significantly influence response rates. Johannsson et al. [10] found that patients with chronic lymphocytic leukemia/small lymphocytic lymphoma were less likely to achieve a CR as compared with patients with follicular lymphoma (83% versus 17%). Most other studies, including our current study, however, predominantly consisted of patients with follicular lymphoma, rendering analysis by histology difficult. In a more recent report from The Netherlands Cancer Institute [12], which included only patients with nonfollicular lymphoma, comparable CR rates were observed between patients with indolent lymphoma (chronic lymphocytic leukemia and marginal zone lymphoma) and aggressive lymphoma (mantle cell lymphoma and diffuse large-cell lymphoma). However, the response rates of individual histologic subtypes were not reported. Additional data are needed on the effectiveness of palliative LD-IF-RT on different subtypes of NHL.
Two studies have demonstrated a relationship between initial response to LD-IF-RT and subsequent local progression. In the study by Girinsky et al. [8], the 2-year freedom from local progression rates in patients who had an initial CR and those with an initial PR were 76% and 46%, respectively (P = 0.04). Similarly, Haas et al. [9] showed that the median time to local progression for patients who had achieved an initial CR was 42 months as compared with 10 months in patients with a PR. In our study, we have not found an initial CR to LD-IF-RT to be predictive of in-field recurrence (P = 0.3). Our analysis may be limited by the relatively low number of patients who did not achieve a CR and the short follow-up time.
We observed a transformation rate of 21% among our patients, which is in line with the known histologic transformation rate of follicular lymphoma [13]. Haas et al. [9] reported 9% of their patients had transformation to diffuse large B-cell lymphoma. The difference may be due to the heterogeneity of underlying risk factors among patients included in the two studies and varying thresholds for work-up of potential transformation.
This first report of the United States experience with LD-IF-RT for NHL confirmed findings of European investigators, showing this approach to be an effective palliative treatment for selected patients with advanced-stage or recurrent NHL. In addition to providing a high response rate with negligible toxicity, the use of LD-IF-RT allowed the delay of further systemic therapy by at least 6–8 months in the majority of patients, most of whom had one or more sites of symptomatic local disease. In our clinical practice, we routinely recommend LD-IF-RT to patients with advanced-stage or recurrent indolent lymphoma who need local palliative therapy [14]. We reserve conventional-dose radiation therapy (30–36 Gy) for patients with early-stage disease for which the treatment intent is curative, and for patients with sites of involvement where durable local control is essential, including patients presenting with cord compression, nerve root compression, or cranial nerve involvement.
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This original article was presented in part at the 49th annual meeting of the American Society for Therapeutic Radiology and Oncology, Los Angeles, CA, 28 October 2007 to 1 November 2007.
Received for publication June 18, 2008. Accepted for publication June 20, 2008.
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