This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haas, R.L.M. Articles by Bartelink, H. Search for Related Content PubMed PubMed Citation Articles by Haas, R.L.M. Articles by Bartelink, H. Social Bookmarking                            What's this?

High Response Rates and Lasting Remissions After Low-Dose Involved Field Radiotherapy in Indolent Lymphomas

From the Departments of Radiotherapy, Pathology, and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; the Department of Radiotherapy, Bernard Verbeeten Institute, Tilburg, The Netherlands; the Department of Haematology, The Academic Medical Hospital, Amsterdam, The Netherlands., On behalf of the Haemato-Oncology Group of Amsterdam (HORA-Group).

Address reprint requests to R.L.M. Haas, MD, The Netherlands Cancer Institute, Department of Radiotherapy, Plesmanlaan 121, 1066 CX Amsterdam; email: r.haas{at}nki.nl.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To study the response rates and duration of response after low-dose (4 Gy) involved field radiotherapy (LD-IF-RT) in patients with recurrent indolent lymphoma.

Patients and Methods: A total of 109 assessable patients (304 symptomatic sites) were irradiated (53 males and 56 females; median age, 62 years; range, 35 to 93), including 98 patients with follicular lymphoma (43 grade 1 and 55 grade 2), nine extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue-type and two patients with lymphoplasmacytoid lymphoma. Bulky disease (≥5 cm) was present in 52% of all patients. A median of two prior regimens (range, 0 to 11) preceded LD-IF-RT. The median time since diagnosis was 41 months (range, 2 to 358 months). Time to (local) progression was calculated according to the Kaplan-Meier method. Differences in response rates between treatments within the same patient were compared using the McNemar test.

Results: The overall response rate was 92%; complete response was reached in 67 patients (61%), partial response in 34 patients (31%), stable disease in six patients (6%), and progressive disease in two patients (2%). The median time to progression was 14 months. The median time to local progression was 25 months. The 67 patients with complete response showed a median time to progression of 25 months and a median time to local progression of 42 months. None of the factors studied (age, sex, follicular lymphoma grade, radiotherapy regimen, number of previous regimens and previous history, number of positive sites or largest lymphoma diameter) were found to be related to response rate.

Conclusion: LD-IF-RT is a valuable asset in the management of patients with follicular lymphoma and should be considered in patients with recurrent disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
OF ALL non-Hodgkin’s lymphomas (NHLs), 20% are follicular lymphoma (FL), and 80% of these patients present in (advanced) Ann Arbor stage III to IV. The incidence rises with age, and the incidence rates are estimated to rise annually in about 5% of patients.¹

The median survival time from the diagnosis of patients with advanced stage FL varies from 5 to 8 years. Over the past decades, overall survival time has not improved. Although FL is very sensitive to both chemotherapy and radiotherapy, no curative treatment is available.

The natural history of FL is characterized by multiple relapses and sometimes spontaneous remissions. The interval between subsequent relapses tends to shorten over time.^2–8

There is no consensus as to which first-line treatment should be provided to patients with advanced stage FL, although in general, either cyclophosphamide, vincristine, prednisone (CVP) polychemotherapy or chlorambucil single-agent therapy^9–22 are advised. These regimens are applied in recurrent disease as well.

FL is considered to be one of the most radiosensitive tumors. In early-stage FL, prolonged remissions are seen after radiotherapy to a dose of 36 to 40 Gy only. In advanced-stage FL, low-dose total-body irradiation (1.5 to 2.5 Gy in 10 to 15 cGy fractions) produces durable remissions as well.^23–32 In recurrent FL, low-dose (2 x 2 Gy) involved field radiotherapy (LD-IF-RT) has been studied. Girinsky et al³³ reported their series with a median follow-up of 3.3 years in 48 patients and found a response rate of 89%. A complete remission (CR; defined as the complete disappearance of all lymphoma activity within the radiation portals) was seen in 37%.^33,34 Two smaller series (Sawyer and Timothy³⁵ and Johansson et al^36,37) confirmed these results.

Chemotherapy (such as chlorambucil, CVP, cyclophosphamide, doxorubicin, vincristine, prednisone; and fludarabine) and immunotherapy (such as the anti-CD20 monoclonal antibody rituximab) for recurrent systemic disease has proven relatively effective in palliating symptoms. These regimens have several disadvantages, such as treatment duration (several months), side effects, and costs.

Until recently, patients referred for radiotherapy with recurrent disease were selected on the basis of having only one or at most a few active sites, after multiple relapses, with chemotherapy-refractory disease, or a combination of these. They were treated with fractionated regimens to a total dose of 20 to 36 Gy.

This article presents the results of LD-IF-RT (4 Gy) regimens tested in the Netherlands in the HORA-1 phase II study. We have treated 109 assessable patients with various types of recurrent indolent B-cell NHL. The main purpose was to evaluate the response rates, response duration, pattern of relapse, and toxicity of this regimen.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
From November 1997 to March 2002, we treated 111 patients. Patients were included if they had symptomatic recurrent B-cell indolent lymphomas. Patients with proven histologic transformation or concurrent use of any corticosteroid drug or chemotherapy were excluded. Of these 111 patients, two were not assessable, because of refusal of an evaluation computed tomographic scan (n = 1) and because of the prescription of inhalation corticosteroid medication to palliate an exacerbation of chronic pulmonary obstructive disease (n = 1). Before and after irradiation, all patients were staged by physical examination, ultrasonography of neck nodes, and contrast-enhanced computed tomographic scans of the chest and abdomen. If the last pathologic confirmation of the diagnosis were more than a year before, fine-needle aspiration cytology of the fastest-growing or most easily accessible node was performed.

A total of 109 patients, 53 males and 56 females (median age, 62 years; range, 35 to 93) were assessable for analysis. Pathology subtypes were: 98 patients with FL (43 grade 1 and 55 grade 2), nine with extranodal marginal-zone lymphomas of mucosa-associated lymphoid tissue-type, and two with lymphoplasmacytoid lymphomas.

Lymphoma-size data were available for 92 patients. (Table 1) In 48 patients (52%) bulky disease was present, defined as nodes ≥ 5 cm; 13% had nodes ≥ 10 cm.

Preirradiation Treatments
In 102 of these 109 patients, several lines of systemic treatment preceded LD-IF-RT. A median of two previous regimens (range, 1 to 11) were administered. More than six previous regimens preceded LD-IF-RT in nine patients. In seven patients, LD-IF-RT was offered as a first-line regimen for various reasons, usually older age. The median time since diagnosis was 41 months (range, 2 to 358). In 18 patients relapses of lymphoma had already persisted for longer than 10 years.

In 31 patients, radiotherapy was part of one or more previous regimens; total-body irradiation (2.5 Gy in 10 cGy) was administered to two of them. The median radiotherapy dose was 30 Gy (range, 2.5 to 40 Gy). The LD-IF-RT fields had been previously irradiated in four patients. In 18 of 102 patients, the last regimen was radiotherapy after a median interval of 34 months (range, 5 to 108 months). No patients received overlapping fields.

Radiotherapy Prescriptions
Patients received a dose of 4 Gy, either as 2 x 2 Gy, after an interval of 48 hours (n = 80), or as a single fraction of 4 Gy (n = 29). The target area could be either the entire lymph node area (eg, neck from mastoid to clavicles for a single node) or the node with a 1.5 cm margin. The choice was left to the discretion of the individual radiation oncologist. Megavoltage photon or electron beams (or both) of appropriate energy were used. Radiotherapy was only given to involved sites. A total of 13 patients were irradiated on six areas or more; six were treated by total nodal irradiation.

Supportive Care
To prevent nausea and vomiting when treating abdominal radiation fields, all registered antiemetic drugs were allowed except corticosteroids, such as dexamethasone. However, if in the best interest of the patient the radiation oncologist prescribed dexamethasone, either as a single agent or in combination with other antiemetics, this patient was taken off the study. The same rule was applied for the prescription of any corticosteroid medication for any other indication.

Additional Treatment
None of these patients were irradiated concurrently with chemotherapy. As soon as a patient received chemotherapy after low-dose irradiation, either because of local failure or because of distant relapse, the patient went off the study, and the treatment was counted as a (local) failure at that time point.

End Points
The main end point of the study was in-field lymphoma control. Therefore, in this study the definitions (complete remission [CR], partial remission [PR], stable disease [SD], and progressive disease [PD]) applied to the local lymphoma activity only. Patients were assigned to the best category found during follow-up. Nonresponders were patients with SD or PD. If patients were irradiated at more than one site and the response differed for each site (eg, CR in one site and PR in another) the disease was assigned to the worst category. Response assessment was performed 4 to 6 weeks after irradiation and then every 3 months.

Statistical Methods
Time to progression (TP) and time to local progression (TLP) were calculated according to the Kaplan-Meier method. The starting point for (local) time to progression was the first day of LD-IF-RT. For TP, the end point was either in-field or out-of-field progression (event) or end of follow-up for other reasons (censoring). For TLP the end point was in-field recurrence, either alone or synchronous with new lymphoma localizations; chemotherapy or corticosteroid medication, even for nonmalignant indications (eg, exacerbation of chronic obstructive pulmonary disease; event); or end of follow-up for other reasons (censoring). The median follow-up for patients still in remission was 7 months.

Differences in response rates between treatments within the same patient were compared using the McNemar test. Prognostic factors for response were tested for statistical significance by the ² test. The progression-free interval after LD-IF-RT and previous chemotherapy regimens was calculated from the start of treatment to any relapse. The statistical SSPS program version 10 was used for the calculations.

Relapsed Disease Management After LD-IF-RT
Treatment of relapsed disease (either in-field progression or out-of-field progression with ongoing local control) depended on the response to the first LD-IF-RT and the extent of the relapse. Patients who responded to the LD-IF-RT regimen, had chemotherapy-refractory disease, or preferred a second low-dose treatment were offered one. The second series could be either a re-treatment of the prior field(s) or an irradiation of a new area.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Response Rates
The overall response rate (RR) was 92%. The first low-dose irradiation (in 109 patients) resulted in a CR in 67 patients (61%) and in a PR in 34 patients (31%). SD was maintained in six patients (6%), and two patients (2%) had PD, resulting in eight nonresponders. CR lasted up to 77 months and was ongoing at the time of analysis. For PR patients, the response lasted up to 28 months and was ongoing as well. Of 304 irradiated sites, 203 reached a CR (66%), 90 reached a PR (30%), nine remained stable (3%), and progressive disease was seen in two (1%). There are no differences between the response rates or the CR rates on a patient-based analysis compared with the results on a site-based analysis in FL patients. Therefore, all further analyses are patient-based.

The onset of the response was usually rapid. At the time of first follow-up and response assessment (four to six weeks after LD-IF-RT), the response had been reached in all but two patients. These two patients showed slowly regressing masses over six months. Frequently, patients noticed a response within 10 days.

An LD-IF-RT re-treatment was given to 41 patients. Of course, this is a favorable group a priori, because they were selected based on a good response to a first LD-IF-RT. RR was 98%, which is not significantly better than for the first LD-IF-RT. A CR was achieved by 29 patients (71%) and a PR by 11 patients (27%); one patient’s disease progressed (Table 2). Fig 1 shows the progression-free and local progression-free curves for the group of patients receiving LD-IF-RT for the first time.

View larger version (17K): [in this window] [in a new window]   Fig 1. (A) Progression-free and (B) local progression-free curves after LD-IF-RT.

Radiotherapy Protocol Compliance
All 109 patients fulfilled the protocol radiotherapy prescriptions. None received elective irradiation of uninvolved adjacent regions. As mentioned above, one patient was excluded from the analysis because of corticosteroid medication after irradiation but before response assessment.

Time to Progression
For a first low-dose treatment in 109 patients, the median TP (either in-field or out-of-field) was 14 months, and the median TLP was 25 months (Table 2 and Fig 1). The patients achieving a CR on a first treatment showed a median TP of 25 months and a median TLP of 42 months. Because the first sign of progression in patients achieving a PR was usually in-field, in this group there was no difference between median TP and median TLP (nine v 10 months, respectively). The same pattern was seen in the nonresponding patients, in whom the median TP and median TLP were both two months.

Toxicity
Toxicity was virtually absent. Successful prophylactic noncorticosteroidal antiemetic medication was prescribed for upper abdominal fields. Transient alopecia was seen in one FL patient with upper neck nodes, and transient hyperpigmentation was seen in one FL patient in an inguinal nodal field. Patients with bulky disease usually received antihyperuricemic medication (allopurinol; dosage depending on renal function); no patients showed gout or tumor lysis syndrome.

Prognostic Factors
Prognostic factors for RR could not be distinguished in this group of patients. We tested for age, sex, FL grade, radiotherapy regimen, number and history of previous regimens, number of positive sites, and largest lymphoma diameter. Small P values were found for the difference in CR rate between patients having ≤two lymphoma sites and patients with more sites (P = .01), as well as between patients with lymphoma size ≤5 cm and patients with larger nodes (P = .006). However, in view of the large number of comparisons, the observed P values are still too large to allow definite conclusions. Other factors, such as serum levels of beta-2-microglobulin, lactate dehydrogenase, or the International Prognostic Index score were not found to be of prognostic value within this LD-IF-RT regimen, either for response or for CR. Beta-2-microglobulin was elevated above the upper limit of normal in four patients; lactate dehydrogenase was elevated in five patients.

Comparison of Low-Dose IF-RT to Previous Regimens
LD-IF-RT results were compared with the RR and response duration after each previous (usually chemotherapy) regimen in this same patient group. In Table 3, results are shown for all 109 patients. As stated above, for seven of these patients, LD-IF-RT was the first regimen; therefore, they had no other first or last previous regimen. For some patients the first treatment was also the last treatment—namely, those patients who were irradiated at first recurrence. The number of patients dropped to 17 patients receiving five previous regimens, the last subgroup to be analyzed. (Eight patients received six regimens, five patients received seven, two patients received eight, one patient received 10, and one patient received 11.)

The probability of having no progression 1 year (about 50%), 2 years (about 33%), 3 years (about 25%), and 5 years (about 10%) after LD-IF-RT is comparable to that after the best, namely the first, previous treatment. The observed percentages of being disease-free at any time point studied for any pretreatment line is lower than for the LD-IF-RT regimen, except for the first pretreatment (Table 3 and Fig 2).

View larger version (16K): [in this window] [in a new window]   Fig 2. Comparison of the progression-free curves between the LD-IF-RT group, the first regimen, and the last regimen before LD-IF-RT.

Malignant Transformation to Diffuse Large-B-Cell Lymphoma During Follow-Up
During follow-up, a total of 10 patients were diagnosed with a transformation to a diffuse large-B-cell lymphoma. Analyzing these 10 patients separately shows six CR patients (60%), three PR patients, (30%) and one PD patient(10%). These response rates are similar to those of nontransforming patients. However, the median TP of these 10 patients was only 3 months.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This series of low-dose involved field radiotherapy (LD-IF-RT) with a dose of 4 Gy in 109 patients with recurrent indolent lymphoma shows a 92% rate of inducing rapid and often lasting remissions without significant toxicity. Patients selected for a second low-dose treatment of an in-field or out-of-field progression show similar high RR as compared with the first LD-IF-RT. This is an attractive feature, and it is in contrast to standard chemotherapy regimens, because patients treated by a previous regimen usually have inferior results.

Watchful waiting is a widely accepted approach, both at diagnosis and in recurrent and advanced-stage asymptomatic patients. In the case of symptomatic disease, however, a regimen should be chosen that provides high response rates with a rapid onset of response, is of short treatment duration, and leaves the patient with a minimum of toxicity. The obvious choice for this systemic disease would be either chemotherapy (eg, chlorambucil; CVP; cyclophosphamide, doxorubicin, vincristine, prednisone; or fludarabine) or immunotherapy (rituximab). A local treatment such as the LD-IF-RT regimen could be considered as well, and weighted against treatment side effects and costs.

The results of this study are in agreement with data published previously.^33–37 However, this study is based on a considerably larger number of patients, and it compares the results with those of previous regimens. There are many striking similarities between the results of our study and the series by Girinsky et al,³³ which represents the most extensively analyzed series published up to now. Girinsky’s analysis is site-based (135 sites in 48 patients). Our findings in terms of RR, CR, two-year freedom from local progression and two-year freedom from local progression in CR patients and inferior results for bulky sites are in line with Girinsky et al’s data. Not all results are confirmative, however. In the Paris patient group, the two-year freedom from local progression in PR patients seems better (46%) than that of ours (10%). The Paris investigators found a higher response on LD-IF-RT if patients had less then one previous regimen (P < .01) or were ≤ 65 years of age (P = .003). In our series, neither CR nor overall RR was found to be associated with the number of previous regimens or age. Perhaps the differences can be explained by the relatively large number (18 patients, 38%) of stage I and II patients. These patients were not enrolled in our study. However, these differences between the two studies may also be due to chance.

We have seen transformation to diffuse large-B-cell lymphoma in 10 patients after LD-IF-RT. (This number is to be expected, given the number of patients and the duration of follow-up of this study³⁸). In these patients, RR on LD-IF-RT before transformation had been similar to that in the other 99 nontransformed patients. In parallel to this phase II study, another group of 25 patients (12 mantle-cell lymphoma, nine de novo diffuse large-B-cell lymphoma patients and four FL grade 3 patients) were treated by LD-IF-RT because of high age, chemotherapy refractory, or recurrent disease outside the protocol for palliative reasons. These patients showed a RR of 76%, a CR rate of 36%, a median TP of five months and a median TLP of 22 months. A third and last group of 14 patients small lymphocytic lymphoma/chronic lymphatic leukemia (in the WHO classification this is recognized as an indolent lymphoma as well) also received LD-IF-RT to palliate symptoms. These patients showed an RR of 86%, a CR rate of 43%, a median TP of 10 months, and a median TLP of 14 months; again, these results are comparable to the 109 indolent lymphoma patients analyzed in this article.

In general, cancer patients experience many problems that have a negative influence on their quality of life. These problems can be caused both by the disease itself, but also by treatment side effects. There are few data on quality-of-life issues for FL patients. Cole et al³⁹ showed that interferon alfa-2b was able to prolong progression-free survival after chemotherapy in FL, but at the cost of significant toxicity. The protracted course of disease may have serious negative effects on quality of life. Webster and Cella⁴⁰ showed that 141 lymphoma patients had significantly lower physical, emotional, and functional well-being, as well as lower total quality-of-life scores after treatment, as compared with baseline values. As far as quality of life is concerned, they advise treating these patients with the least aggressive approach possible. The lack of toxicity and the nonaggressive nature of this LD-IF-RT regimen may contribute to improve the quality of life of these patients.

Our present research on LD-IF-RT in these patients focuses on two issues. First, the high radiosensitivity in indolent lymphomas is poorly understood. It is known, however, that the lymphocyte is one of the most radiosensitive of all human cells. Basic biologic studies will be performed to explain these observations. Second, the high and often lasting RR in this and previous phase II studies has led to the design of a phase III trial: the HOVON 47/EORTC 20,013 Intergroup study (www.hovon.nl). This trial will compare 2 x 2 Gy IF-RT to chlorambucil chemotherapy in previously untreated FL patients. The main end points are progression-free survival and quality of life.

In conclusion, LD-IF-RT induces high RR in recurrent indolent lymphoma patients. RR was not found to be dependent on age, sex, histology, radiotherapy regimen, number of previous regimens, history, number of positive sites, and largest lymphoma diameter. LD-IF-RT can be administered without significant toxicity.

The results of LD-IF-RT at recurrent disease are comparable to the results of the first-line chemotherapy, especially in a time-without-treatment–based analysis. Low-dose re-treatment for a recurrence after a first LD-IF-RT regimen provides a similarly high RR. Therefore, this radiotherapy regimen, as a local treatment for a systemic disease, is a valuable asset in the management of FL patients and is an option for patients with recurrent disease.

	ACKNOWLEDGMENTS

 
We thank J.P. Baars, J.P. de Boer, A.E.G. Kr. von dem Borne, J.A.C. Brakenhoff, C.E.M. Hollak, J.M. Kerst, M.J. Kersten, G. de Klerk, J. van der Lelie, P.W.G. van der Linden, S. Lobatto, S.A. Luykx-de Bakker, J.H. Meerwaldt, S. Monasch, H.P. Muller, V. Lustig, F. Oldenburger, K.J. Roozendaal, M.J.H. Schweitzer, M. Soesan, K.D. van de Stadt, C.A.M. de Swart, L. Thomas, W.L.E. Vasmel, W.A. Veenhoven, T.A.M. Verschueren, and J.J. Zwaginga.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Cartwright R, Brincker H, Carli PM, et al: The rise in incidence of lymphomas in Europe 1985–1992. Eur J Cancer 35:627–633, 1999[CrossRef][Medline]

2. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329:987–994, 1993[Abstract/Free Full Text]

3. Portlock CS, Rosenberg SA, Glatstein E, et al: Management of low-grade non-Hodgkin’s lymphomas. Semin Oncol 17:51–59, 1990[Medline]

4. Lister TA, Cullen MH, Beard ME, et al: The management of follicular lymphoma. Ann Oncol 2:131–135, 1991[Free Full Text]

5. Kimby E, Bjorkholm M, Gahrton G, et al: Chlorambucil/prednisone vs. CHOP in symptomatic low-grade non-Hodgkin’s lymphomas: A randomized trial from the Lymphoma Group of Central Sweden. Ann Oncol 5:67–71, 1994

6. Mendenhall NP, Lynch W: The low-grade lymphomas. Semin Radiat Oncol 5:254–266, 1995[CrossRef][Medline]

7. Horning SJ: Treatment approaches to the low-grade lymphomas. Blood 83:881–884, 1994[Free Full Text]

8. Rohatiner AZS, Lister TA: New approaches to the treatment of follicular lymphoma. Br J Haematol 79:349–354, 1991[Medline]

9. Portlock CS, Rosenberg SA: Combination chemotherapy with cyclophosphamide, vincristine and prednisone in advanced non-Hodgkin’s lymphoma Cancer 37:1275–1280, 1976[CrossRef][Medline]

10. Bishop JF, Wiernik PH, Wesley MN, et al: A randomised trial of high dose cyclophosphamide, vincristine, and prednisone plus or minus doxorubicin (CVP versus CAVP) with long-term follow-up in advanced non-Hodgkin’s lymphoma. Leukaemia 1:508–513, 1987[Medline]

11. Steward WP, Crowther D, McWilliam LJ, et al: Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin’s lymphoma: A randomized prospective study with an assessment of prognostic factors. Cancer 61:441–447, 1988[CrossRef][Medline]

12. Morrison VA, Peterson BA: Combination chemotherapy in the treatment of follicular low-grade lymphoma. Leuk Lymphoma 10:29–33, 1993 (suppl)

13. Hagenbeek A, Carde P, Meerwaldt JH, et al: Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-Hodgkin’s lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 16:41–47, 1998[Abstract/Free Full Text]

14. Chisesi T, Congiu M, Contu A, et al: Randomized study of chlorambucil (CB) compared to interferon (alpha-2b) combined with CB in low-grade non-Hodgkin’s lymphoma: An interim report of a randomized study. Eur J Cancer 27:31–33, 1991[Medline]

15. Knospe WH, Loeb V Jr: Biweekly chlorambucil treatment of lymphocytic lymphoma. Cancer Clin Trials 3:329–336, 1980[Medline]

16. Gupta RK, Lister TA: Current management of follicular lymphoma. Curr Opin Oncol 8:360–365, 1996[Medline]

17. Stolzenbach G, Garbrecht M: Intermittent combination chemotherapy with chlorambucil and prednisone of low-grade malignant non-Hodgkin’s lymphomas according to the Kiel classification. J Cancer Res Clin Oncol 93:189–194, 1979[CrossRef][Medline]

18. Cadman E, Drislane F, Waldron JA Jr, et al: High-dose pulse chlorambucil: Effective therapy for rapid remission induction in nodular lymphocytic poorly differentiated lymphoma. Cancer 50:1037–1041, 1982[CrossRef][Medline]

19. Joseph G, Hadley T, Djulbegovic B, et al: High-dose chlorambucil and dexamethasone for relapsed non-Hodgkin’s lymphomas. Am J Clin Oncol 16:319–322, 1993[Medline]

20. Lister TA, Cullen MH, Beard ME, et al: Comparison of combined and single-agent chemotherapy in non-Hodgkin’s lymphoma of favourable histological type. BMJ 6112:533–537, 1979

21. Hayhoe FG: Chemotherapy in the management of stage III/IV grade I non-Hodgkin’s lymphomas (report no 17). Clin Radiol 32:547–552, 1981[CrossRef][Medline]

22. Portlock CS, Rosenberg SA, Glatstein E, et al: Treatment of advanced non-Hodgkin’s lymphomas with favourable histologies: Preliminary results of a prospective trial. Blood 47:747–756, 1976[Abstract/Free Full Text]

23. Delic J, Magdelenat H, Barbaroux C, et al: In vivo induction of apoptosis in human lymphocytes by therapeutic fractionated total body irradiation. Br J Radiol 68:997–1003, 1995[Abstract/Free Full Text]

24. Joiner MC, Lambin P, Malaise EP, et al: Hypersensitivity to very-low single radiation doses. Mutat Res 358:171–183, 1996[CrossRef][Medline]

25. Minehan KJ, Martenson JA Jr., Garrity JA, et al: Local control and complications after radiation therapy for primary orbital lymphoma: a case for low-dose treatment. Int J Radiat Oncol Biol Phys 20:791–796, 1991[Medline]

26. MacManus MP, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma? J Clin Oncol 14:1282–1290, 1996[Abstract/Free Full Text]

27. Meerwaldt JH, Carde P, Burgers JM, et al: Low-dose total body irradiation versus combination chemotherapy for lymphomas with follicular growth pattern. Int J Radiat Oncol Biol Phys 21:1167–1172, 1991[Medline]

28. De Neve WJ, Lybeert ML, Meerwaldt JH: Low-dose total body irradiation in non-Hodgkin lymphoma: Short and long term toxicity and prognostic factor. Am J Clin Oncol 13:280–284, 1990[Medline]

29. Lybeert ML, Meerwaldt JH, Deneve W: Long-term results of low dose total body irradiation for advanced non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 13:1167–1172, 1987[Medline]

30. Kaminski MS, Coleman CN, Colby TV, et al: Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy. Ann Intern Med 104:747–756, 1986[Abstract/Free Full Text]

31. Sutcliffe SB, Gospodarowicz MK, Bush RS, et al: Role of radiation therapy in localized non-Hodgkin’s lymphoma. Radiother Oncol 4:211–223, 1985[Medline]

32. Jacobs P, King HS: A randomized prospective comparison of chemotherapy to total body irradiation as initial treatment for the indolent lymphoproliferative diseases. Blood 69:1642–1646, 1987[Abstract/Free Full Text]

33. Girinsky T, Guillot-Vals D, Koscielny S, et al: A high and sustained response rate in refractory or relapsing low-grade lymphoma masses after low-dose radiation: analysis of predictive parameters of response to treatment. Int J Radiat Oncol Biol Phys 51:148–155, 2001[Medline]

34. Ganem G, Lambin P, Socie G, et al: Potential role for low dose limited-field radiation therapy (2 x 2 Grays) in advanced low-grade non-Hodgkin’s lymphomas. Hematol Oncol 12:1–8, 1994[Medline]

35. Sawyer EJ, Timothy AR: Low dose palliative radiotherapy in low grade non-Hodgkin’s lymphoma. Radiother Oncol 42:49–51, 1997[CrossRef][Medline]

36. Johansson J, Specht L, Meijer J, et al: Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin’s lymphoma (INHL) and chronic lymphocytic leukemia (CLL). Eur J Cancer 37:S93, 2001. (abstr)[CrossRef]

37. Johansson J, Specht L, Meijer J, et al: Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin’s lymphoma (INHL) and chronic lymphocytic leukemia (CLL). Int J Radiat Oncol Biol Phys 51:361–362, 2001. (abstr)

38. Lossos IS, Alizadeh AA, Diehn M, et al: Transformation of follicular lymphoma to diffuse large-cell lymphoma: Alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci U S A 99:8886–8891, 2002[Abstract/Free Full Text]

39. Cole BF, Solal-Celigny P, Gelber RD, et al: Quality-of-life-adjusted survival analysis of interferon alfa-2b treatment for advanced follicular lymphoma: An aid to clinical decision making. J Clin Oncol 16:2339–2344, 1998[Abstract]

40. Webster K, Cella D: Quality of life in patients with low-grade non-Hodgkin’s lymphoma. Oncology 12:697–714, 1998[Medline]

Submitted August 21, 2002; accepted February 24, 2003.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. K. Luthy, A. K. Ng, B. Silver, K. O. Degnan, D. C. Fisher, A. S. Freedman, and P. M. Mauch Response to low-dose involved-field radiotherapy in patients with non-Hodgkin's lymphoma Ann. Onc., December 1, 2008; 19(12): 2043 - 2047. [Abstract] [Full Text] [PDF]

				M. Bendandi Aiming at a Curative Strategy for Follicular Lymphoma CA Cancer J Clin, September 1, 2008; 58(5): 305 - 317. [Abstract] [Full Text] [PDF]

				L. Knoops, R. Haas, S. de Kemp, D. Majoor, A. Broeks, E. Eldering, J. P. de Boer, M. Verheij, C. van Ostrom, A. de Vries, et al. In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma Blood, August 15, 2007; 110(4): 1116 - 1122. [Abstract] [Full Text] [PDF]

				S. J. Horning, A. Younes, V. Jain, S. Kroll, J. Lucas, D. Podoloff, and M. Goris Efficacy and Safety of Tositumomab and Iodine-131 Tositumomab (Bexxar) in B-Cell Lymphoma, Progressive After Rituximab J. Clin. Oncol., February 1, 2005; 23(4): 712 - 719. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haas, R.L.M. Articles by Bartelink, H. Search for Related Content PubMed PubMed Citation Articles by Haas, R.L.M. Articles by Bartelink, H. Social Bookmarking                            What's this?