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Pediatric Non-Hodgkin Lymphoma Treatment & Management

  • Author: J Martin Johnston, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
 
Updated: Mar 27, 2014
 

Approach Considerations

Proper care of non-Hodgkin lymphoma requires a referral to a comprehensive tertiary care center. The current intense treatment regimens, particularly those for advanced stages of the disease, necessitate inpatient administration of chemotherapy, as well as aggressive support by a team experienced in the care of children with immunosuppression.

Current treatment regimens for lymphoblastic lymphomas (T cell and B cell) are quite similar to protocols for their leukemic counterparts (T-cell ALL and B-cell ALL). In broad terms, these therapies are longer and less intensive (particularly with respect to the use of alkylating agents) than those for small noncleaved-cell lymphoma or LCL, which use relatively high doses of alkylating agents and antimetabolites.

Current survival rates for patients with advanced disease are 65-75% for T-cell lymphoblastic lymphomas and 80-90% for those with B-cell lymphomas.

Antibiotics

If present, fever simply may reflect the underlying malignancy. However, consider beginning empiric, broad-spectrum antibiotic coverage until sepsis or focal infection (eg, due to bowel perforation) is excluded.

Central venous access

For most patients, a central venous access device is necessary to manage chemotherapy. If feasible, multiple procedures (eg, line placement, biopsy, lumbar puncture, bone marrow aspiration) can be performed during one session of anesthesia.

As noted previously, patients with mediastinal disease must be treated cautiously if the use of general anesthesia is being considered. Unrecognized airway compression can lead to obstruction, with disastrous consequences.

Rapid progression

Non-Hodgkin lymphomas in children typically grow rapidly, in contrast to the more indolent lymphomas often observed in adults.

To prevent tumoral regrowth and to avoid increasing the short-term risk of complications, absolutely minimize any delay (eg, to allow healing after an abdominal procedure) between diagnosis and the start of chemotherapy.

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Tumor Lysis Syndrome Treatment

Before and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome, a condition that can result from the rapid destruction of a large number of neoplastic cells. This destruction causes intracellular ions and metabolic byproducts to be released into the systemic circulation, which can lead to the rapid development of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. (Renal involvement by lymphoma is an additional risk factor.)

Hyperuricemia or tubular obstruction may lead to acute renal failure, requiring dialysis. In general, this is not a contraindication to continuing chemotherapy. However, some protocols now include a preliminary phase of relatively gentle cytoreductive chemotherapy designed to avoid these metabolic complications.

With all patients, administer intravenous fluids at twice the maintenance rates, usually without potassium. Add sodium bicarbonate to the intravenous fluid to achieve moderate alkalinization of the urine (pH of approximately 7). This measure enhances the excretion of tumor metabolites. For example, the solubility of uric acid is 10-12 times higher at a pH of about 7 than it is at a pH of 5, and the solubility of xanthine is doubled. Avoid a urine pH higher than this to prevent crystallization of hypoxanthine or calcium phosphate.

Administer allopurinol to prevent or correct hyperuricemia. In high-risk situations (extreme elevations of lactate dehydrogenase [LDH] and/or uric acid or evidence of impaired renal function at presentation), consider administration of recombinant urate oxidase (rasburicase [Elitek]).[59]

Follow up the patient's laboratory values to monitor tumor lysis syndrome throughout initial therapy. Testing may be needed as often as 2-4 times per day. This follow-up is especially important during the first 48-72 hours of therapy in a patient with bulky disease.

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Chemotherapy for Lymphoblastic Lymphoma

The most successful treatment protocols for advanced-stage lymphoblastic lymphoma feature chemotherapy combinations designed to treat acute lymphoblastic leukemia (ALL).

LSA2L2 protocol

The LSA2 L2 protocol evolved from ALL protocols used at the Memorial Sloan-Kettering Cancer Center in the early 1960s. The LSA2 L2 protocol features 3 phases of therapy—namely, induction, consolidation, and repeated cycles of maintenance—given over a total of 2-3 years.[60] Methotrexate is administered intrathecally for CNS prophylaxis throughout treatment. When this protocol was first described, it included irradiation of sites of bulky disease; however, radiation is no longer routinely applied.

Children's Cancer Group protocol 552

Between 1986 and 1989, 143 subjects with lymphoblastic lymphoma (10% with localized disease) received treatment with a modified LSA2 L2 regimen in a Children's Cancer Group trial (see Table 1, below). Their 5-year event-free survival rate was 74%.[61]

Table 1. Modified LSA2 L2 Therapy in Children's Cancer Group Protocol 552 (Open Table in a new window)

Phase Drug Route
Induction Cyclophosphamide, vincristine, daunorubicin IV
Ara-C, methotrexate IT
Prednisone PO
Consolidation Ara-C IV or SC
6-thioguanine PO
Methotrexate IT
L-asparaginase IM
BCNU IV
Phase Cycle Drug Route
Maintenance* 1 6-thioguanine PO
Cyclophosphamide IV
2 Hydroxyurea PO
Daunorubicin IV
3 Methotrexate PO
BCNU IV
4 Ara-C IV or SC
Vincristine IV
Source: Children's Cancer Group



Ara-C = cytarabine; BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea, or carmustine; IM = intramuscular; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous



* A minimum of 5 repeated courses (total duration of therapy >18 mo) are noted. Each course of intrathecal methotrexate (day 0 of each course) consists of 4 cycles of rotating drug pairs that are administered every 2 weeks after blood counts have recovered.



German Berlin, Frankfurt, Muenster treatment protocol

The German Berlin, Frankfurt, Muenster (BFM) protocols have demonstrated excellent results in patients with ALL or lymphoblastic lymphoma. (See Table 2, below.)[62]

Unlike the LSA2 L2 protocol, the BFM regimen has a reinduction phase. It also features a less complicated and less intense maintenance phase. In its original report, the BFM protocol included prophylactic cranial irradiation during reinduction. Patients receiving this treatment had a 6-year event-free survival rate of 79%.

Table 2. Therapy for Stage III and IV Non–B-Cell Disease* According to BFM Protocol 86 (Open Table in a new window)

Phases Drug Route
Induction Prednisone, 6-mercaptopurine PO
Vincristine, daunorubicin, cyclophosphamide, Ara-C IV
L-asparaginase IM
Methotrexate IT
Consolidation 6-mercaptopurine PO
Methotrexate with leucovorin rescue IV
Methotrexate IT
Re-induction Dexamethasone, 6-thioguanine PO
Vincristine, doxorubicin, cyclophosphamide, Ara-C IV
L-asparaginase IM
Methotrexate IT
Maintenance 6-mercaptopurine, methotrexate PO
Source: Berlin-Frankfurt-Munster Group



Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous



* Diagnoses included lymphoblastic lymphoma of the T-cell or precursor B-cell type, immunoblastic T-cell lymphoma, and other peripheral T-cell lymphomas. Of note, patients with Ki-1+ anaplastic large cell lymphomas (LCLs) were not included.



Continued until 24 months after diagnosis.



Children's Oncology Group protocols

The most recent Children's Oncology Group phase 3 protocol (A5971) for children with advanced-stage T-cell lymphoblastic lymphoma featured a 4-way randomization between (1) BFM therapy, (2) a Children's Cancer Group modified version of BFM therapy (which did not include high-dose methotrexate/leucovorin during consolidation), and (3) intensified versions of these 2 protocols (with early introduction of daunomycin and cyclophosphamide). In patients with disseminated disease, there was no statistical difference in outcomes among the 4 groups, with 5-year event-free survival of approximately 81%. Age younger than 10 years and imaging response at 2 weeks were associated with better overall survival.[63]

The Children's Oncology Group is conducting specific protocols to treat T-lymphoblastic lymphoma and T-cell ALL. In particular, current clinical trials will examine the role of nelarabine (previously known as compound 506U78), a prodrug of the deoxyguanosine analog 9-beta-D-arabinofuranosylguanine (Ara-G) that has shown efficacy in T-cell malignancies.

Additional treatment details

For advanced-stage lymphoblastic lymphoma, as for ALL, relatively long intervals of treatment have been most successful. The maintenance phase typically lasts 18-30 months. Protocols shorter than this have also been investigated. For example, Children's Cancer Group protocol 5941 examined an aggressive, 11-month, multiagent regimen. In this trial, the 5-year event-free survival rate was 78% ± 4.5%, and the overall survival rate was 85% ± 3.9%. These results suggest that the experimental approach is safe and is just as effective as more prolonged regimens.[64]

When results from several series were combined, patients appeared to have an excellent prognosis. Long-term survival was approximately 80%.

Despite these findings, a consensus about optimal therapy for lymphoblastic lymphoma is lacking. Treatment options include the LSA2 L2 protocol and BFM protocol 86 for non-Hodgkin lymphoma (with the reinduction phase eliminated).

Localized lymphoblastic lymphoma is unusual. In the previously mentioned BFM study, 6 of 77 subjects with non–B-cell non-Hodgkin lymphoma had stage I or II disease. Patients with localized lymphoblastic lymphoma (n=60) were included in Children's Oncology Group protocol A5971; they received a Children's Cancer Group modified version of the BFM protocol (as described above) that included reinduction but had fewer doses of intrathecal chemotherapy during the maintenance phase. Interestingly, most patients (75%) had a B-precursor phenotype. At a median follow-up of 5.9 years, the 5-year event-free survival rate was 90% (95% confidence interval, 78-96%, with an overall survival rate of 96% [84-99%]). There were no relapses among the 15 T-cell lymphoblastic lymphoma subjects.[65]

Regimens simpler than these have demonstrated comparable results. For example, protocol 77-04 from the NCI included alternating cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and high-dose methotrexate (with leucovorin as rescue therapy). Aggressive intrathecal prophylaxis with cytarabine and methotrexate was included; local radiation therapy was not offered routinely. The total duration of therapy was 15 cycles (approximately 60 wk).

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Chemotherapy for Small Noncleaved Cell Lymphoma

Since the mid-1980s, survival rates for patients with Burkitt or Burkittlike lymphomas have increased dramatically. In general terms, the following lessons have been learned:

  • Long-term maintenance chemotherapy appears to have no role; therefore, chemotherapy can be short, with the typical duration being 2-6 cycles, each lasting 3-4 weeks (however, the intensity of treatment is high for most patients, and inpatient treatment is required)
  • When observed, relapses occur early, either during therapy or within 6-12 months of its completion; salvage rates for patients with relapse have been disappointing
  • Even patients with widely disseminated disease (eg, bone marrow involvement) have a long-term survival rate of 90%
  • Involvement of the CNS at diagnosis continues to be an adverse prognostic indicator

Treatment protocol from a Cooperative Group trial

Three cooperative groups conducted an international trial for patients with small noncleaved cell lymphoma (SNCCL); specifically, the French Society of Pediatric Oncology (SFOP), in France, Belgium, and the Netherlands; the Children's Cancer Group, in the United States, Canada, and Australia; and the United Kingdom Children's Cancer Study Group (UKCCSG), in the United Kingdom and Ireland.

Chemotherapy was based on the SFOP LMB-89 study, in which event-free survival rates ranged from 100% in group A to 87.5% in group C. Patients with B-cell acute lymphoblastic leukemia (ALL) were included in this protocol. Subjects were staged (as described above) and then were assigned to clinical risk groups. (See Tables 3, 4, 5, and 6, below.)

Table 3. Clinical Risk Groups in the International Trial for Patients With SNCCL (Children's Cancer Group study 5961) (Open Table in a new window)

Clinical Group Subjects,



Estimated %



Definition
A 10 All resected stage I or abdominal stage II tumors
B 65 Unresected stage I or II tumor, stage III, tumor, or stage IV tumor with no CNS involvement and < 25% marrow blasts
C 25 CNS involvement or >25% marrow blasts

Table 4. Standard Therapy in the International Trial for Patients With SNCCL, Group A* (Open Table in a new window)

Drug Route
Prednisone PO
Vincristine, cyclophosphamide, doxorubicin IV
Filgrastim (G-CSF), to enhance neutrophil recovery SC or IV
G-CSF = granulocyte colony-stimulating factor; IV = intravenous; PO = oral; SC = subcutaneous



* See Table 3 for the definition of group A. All subjects received 2 cycles.



With median follow-up of more than 4 years, the 4-year event-free survival rate for group A patients was 98.3%, and the overall survival rate was 99.2%.[66]

In this trial, patients with advanced disease (groups B and C) received an initial moderately intensive "reduction" phase of chemotherapy. This was intended to reduce the tumor burden with minimal risk of inducing or exacerbating tumor lysis syndrome. Patients in group B were randomized to 1 of 4 treatment arms: the 3 experimental treatment arms involved incremental decreases in the intensity and/or duration of chemotherapy.

For patients in group B with an "early response" to therapy (at least 20% tumor decrease after 7 days of treatment), outcomes with standard therapy were not superior to outcomes with any of the experimental (reduced therapy) arms. (See Table 5, below.)

The results indicated, therefore, that pediatric patients with intermediate-risk B non-Hodgkin lymphoma who have an early response and achieve a complete remission after the first consolidation course can be effectively treated using a 4-course regimen with a total dose of only 3.3 g/m2 cyclophosphamide and 120 mg/m2 doxorubicin.[67]

Table 5. Standard Therapy in the International Trial for Patients With SNCCL, Group B* (Open Table in a new window)

Phase Drug Route
Reduction Prednisone PO
  Vincristine, cyclophosphamide IV
  Methotrexate/hydrocortisone IT
Phase Cycles Drug Route
Induction 2, starting 7 days after reduction Prednisone PO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
Consolidation 2 Methotrexate with leucovorin rescue, Ara-C  
Methotrexate/hydrocortisone, Ara-C/hydrocortisone  
Filgrastim (G-CSF)  
Maintenance** 1 Prednisone PO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/hydrocortisone IT
Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous



* See Table 3 for the definition of group B.



** Based on published results from this trial, equivalent outcomes are expected with a reduced (50%) dose of cyclophosphamide in induction phase 2 and/or elimination of maintenance phase 1.

Group C patients in remission after 3 cycles were randomized to standard versus reduced-intensity therapy (omitting the last 3 cycles of maintenance). The 4-year event-free survival rate after randomization was 90% ± 3.1% versus 80% ± 4.2%, respectively, whereas the overall survival rate was 93% ± 2.7% versus 83% ± 4%, respectively. Patients with either combined marrow and CNS disease at diagnosis or a poor response to reduction therapy had significantly inferior event-free survival and overall survival.[68]

Therefore, decreasing therapy in this subgroup of patients appears unwise; standard-intensity therapy is recommended for children with high-risk B non-Hodgkin lymphoma. (See Table 6, below.)

Table 6. Standard Therapy in the International Trial for Patients With SNCCL, Group C* (Open Table in a new window)

Phase Drug Route
Reduction Prednisone PO
Vincristine, cyclophosphamide IV
Methotrexate/Ara-C/hydrocortisone IT
Induction, cycle 1 starting 7 days after reduction Prednisone PO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/Ara-C/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
Induction, cycle 2 Prednisone PO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/Ara-C/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
Consolidation, 2 cycles High-dose Ara-C, etoposide (VP-16) IV
Filgrastim (G-CSF), days 7-21 SC or IV
High-dose methotrexate with leucovorin rescue IV
Methotrexate/Ara-C/hydrocortisone IT
Maintenance 1 Prednisone PO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/Ara-C/hydrocortisone IT
Maintenance 2 Ara-C, etoposide (VP-16) IT
Maintenance 3 Prednisone PO
Vincristine, cyclophosphamide, doxorubicin IV
Maintenance 4 Ara-C, etoposide (VP-16) IV
Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous



* See Table 3 for the definition of group C.



For patients with CNS involvement, during consolidation cycle 1 only.



An alternative treatment approach has been developed over a series of randomized trials by the German Berlin, Frankfurt, Muenster (BFM) group.[69] In particular, the role of intermediate-dose or high-dose methotrexate has been investigated among the different clinical risk groups.

Pilot protocols for patients with B-cell non-Hodgkin lymphoma include monoclonal antibodies (eg, anti-CD20 rituximab) for children with high-risk disease (ie, patients with CNS disease at diagnosis or those with advanced-stage disease and elevated levels of lactate dehydrogenase).

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Chemotherapy for Large Cell Lymphoma

B cell ̶ derived LCLs

Patients with B cell ̶ derived large cell lymphomas (LCLs) are treated effectively using regimens for SNCCL.[70, 71, 72] Outcomes are similar between the groups.

An alternative therapy is the APO regimen, consisting of doxorubicin (Adriamycin), prednisone, and vincristine [Oncovin].[73] Methotrexate and 6-mercaptopurine have been added to this regimen.

A randomized study of children with LCLs (including B-cell LCLs) showed no advantage when cyclophosphamide was added to the APO regimen.[74] Therefore, this therapy has the advantage of avoiding exposure to an alkylating agent. However, the cumulative dose of doxorubicin is 450 mg/m2.

Anaplastic (T cell ̶ derived) LCLs

The therapy for anaplastic (T-cell) LCLs is somewhat controversial. Good results (event-free survival rates of 65-80%) have been reported with a number of protocols. Some were based on acute lymphoblastic leukemia (ALL) therapy, whereas others were similar or identical to those used to treat B-cell lymphomas.

The Berlin, Frankfurt, Muenster (BFM) group reported what may be the best results with treatment for Ki-1+ anaplastic LCLs.[75] The group administered a regimen for B-cell lymphomas that did not include local radiation therapy. Among 62 patients (none with bone marrow disease and 1 with CNS involvement), 4 did not achieve remission, 1 died from infection, and 7 had a relapse. At the time of the report, 50 patients remained in a continuous first episode of complete remission, and 56 were alive. The calculated event-free survival rate at 9 years was 83%.

Subsequent modifications have yielded the ALCL99 protocol as shown below and have further demonstrated that: (1) dosing methotrexate at 3 g/m2 over 4 hours appears to be at least as effective (and less toxic) when compared with a dose of 1 g/m2 over 24 hours with the addition of "triple" intrathecal chemotherapy and (2) the addition of vinblastine (both during chemotherapy and continuing weekly until 1 year from diagnosis) delayed but did not ultimately prevent relapses.[77, 78]

Table 7. Prephase Therapy for Ki-1+ Anaplastic LCLs According to the ALCL99 Protocol (Open Table in a new window)

Drug Route
Dexamethasone PO
Cyclophosphamide IV
Methotrexate/Ara-C/prednisolone IT
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.

Table 8. Subsequent Therapy for Ki-1+ Anaplastic LCLs According to the ALCL99 Protocol (alternating cycles, repeated 3times each) (Open Table in a new window)

Cycle Drug Route
A Dexamethasone PO
Methotrexate with leucovorin rescue, ifosfamide, etoposide (VP-16), Ara-C IV
B Dexamethasone PO
Methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.

Good results have been observed with the relatively uncomplicated APO regimen. In addition, a randomized study of children with LCL (including B-cell LCL and anaplastic LCL) showed no apparent advantage when intermediate-dose methotrexate and high-dose cytarabine were added to an APO backbone.[79]

A report from the SFOP described surprising efficacy for monotherapy with vinblastine for relapsing anaplastic LCL, even in patients who previously underwent myeloablative therapy with autologous bone marrow transplantation.[80]

The role of vinblastine in front-line therapy for anaplastic LCL was examined in a Children's Oncology Group protocol (A5941), which compared the standard APO regimen with an experimental therapy that included vinblastine. Myelosuppression was more significant than anticipated and the trial closed early; results have not been published.

The current Children's Oncology Group Phase 2 protocol for anaplastic LCLs uses the ALCL99 regimen (shown above) as a "backbone" and adds (in a randomized fashion) either brentuximab vedotin, an anti-CD30 monoclonal antibody, or crizotinib, a specific small-molecule inhibitor of the ALK pathway.[81]

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Radiation Therapy

In general, radiation therapy has a limited role in the treatment of pediatric non-Hodgkin lymphoma, and it is applied almost exclusively in situations deemed to be real or potential emergencies.

Mediastinal irradiation may be helpful in patients with impending airway obstruction, especially if the use of general anesthesia is being contemplated for biopsy or central line placement.

For patients with lymphoblastic lymphoma, low-dose radiation therapy is often used to treat neurologic involvement (eg, cranial nerve palsies, intracerebral extension of tumor, paraplegia).

Irradiation has minimal efficacy in patients with SNCCL, presumably because of the rapid growth of these cells. Although a dose of radiation may result in significant cell kill, rapid regrowth of surviving cells between doses largely negates the benefit. Hyperfractionated radiotherapy (ie, >1 dose daily) offers a theoretic advantage, as does low-dose continuous irradiation. However, the unfeasibility of the latter all but precludes its use.[82]

Finally, consider radiotherapy in any patient with documented residual disease after chemotherapy and in patients with bulky disease at the time of relapse.

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Treatment of Relapsed Disease

As front-line therapies for pediatric non-Hodgkin lymphoma continue to evolve and improve, treatment of relapses is becoming increasingly problematic.

Reinduction regimens use novel chemotherapy combinations, such as ifosfamide, carboplatin, and etoposide (ICE). Depending on the presence of certain cell-surface markers, monoclonal antibodies (eg, the anti-CD20 antibody rituximab) may be added to the regimen.[83, 84]

In most cases, myeloablative chemotherapy with either autologous stem-cell rescue or allogeneic bone marrow transplantation may offer the best option for curative consolidative therapy.

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Lymph Node Excision and Dissection

Even for patients with bulky non-Hodgkin lymphoma, debulking surgery is not crucial to effective therapy. For example, chemotherapy is effective in relieving partial airway or bowel obstruction. In rare instances, resection may be required for this purpose.

The chief role for surgery is obtaining tissue for diagnosis. Excision of an easily accessible lymph node (when present) is preferable to a thoracotomy or laparotomy, unless symptoms dictate otherwise. Even moderately aggressive surgery generally is not necessary or helpful.

One exception, and a potential therapeutic dilemma, involves abdominal B-cell non-Hodgkin lymphoma. The patient can be assigned to clinical group A (see Table 3) if the following conditions are met:

  • An intestinal primary lesion can be resected along with all involved adjacent lymph nodes
  • The marginal lymph nodes are free of disease
  • The patient has no evidence of further dissemination (eg, to the CNS or marrow)

In this situation, the prescribed chemotherapy regimen is far less toxic than it would be otherwise. Therefore, a surgeon treating a reasonably small abdominal non-Hodgkin lymphoma is advised to perform lymph node dissection and to try to excise all visible areas of tumor.

However, this surgery is performed only if it can be accomplished without causing clinically significant morbidity. Heroic attempts at resection are best avoided because unresected disease can still be cured in most patients. Furthermore, prolonged postoperative recovery may delay the start of chemotherapy and potentially compromise its effectiveness.

Second-look surgery may be helpful for assessing the viability of residual masses, although second-look procedures require highly individualized approaches. As an alternative, uptake of67 Ga or radiolabeled FDG suggests viability of residual masses in patients whose tumors are gallium or FDG avid.

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Consultations

Intensive care specialist

Patients with pediatric non-Hodgkin lymphoma frequently present in a tenuous condition because of airway compromise, metabolic derangements, and/or infection. In the initial stages of therapy, the patient's condition may be unstable or deteriorating. Therefore, the support of a pediatric intensive care unit is highly desirable.

If available, a pediatric intensivist should be made aware of the patient in the event that respiratory management or pressor support becomes necessary.

Radiation oncologist

Consider consultation with a radiation oncologist. As previously discussed, however, radiation therapy generally has a limited role in the treatment of pediatric non-Hodgkin lymphoma, and it is applied almost exclusively in situations deemed to be real or potential emergencies.

Nephrologist

Notify a nephrologist if the patient has substantial tumor lysis syndrome and if dialysis is under consideration.

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Contributor Information and Disclosures
Author

J Martin Johnston, MD Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Hematology/Oncology, The Children's Hospital at Memorial University Medical Center; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital

J Martin Johnston, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, International Society of Paediatric Oncology

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

Timothy P Cripe, MD, PhD Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office for Clinical and Translational Research, Cincinnati Children's Hospital Medical Center; Director of Pilot and Collaborative Clinical and Translational Studies Core, Center for Clinical and Translational Science and Training, University of Cincinnati College of Medicine

Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Kathleen M Sakamoto, MD, PhD Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Co-Associate Program Director of the Signal Transduction Program Area, Jonsson Comprehensive Cancer Center, California Nanosystems Institute and Molecular Biology Institute, University of California, Los Angeles, David Geffen School of Medicine

Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, International Society for Experimental Hematology, Society for Pediatric Research, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Massive mediastinal T-lymphoblastic lymphoma. Note compression of the left mainstem bronchus and the pulmonary atelectasis.
Non-Hodgkin lymphoma of the terminal ileum. Note the doughnut sign, ie, intraluminal contrast material surrounded by a grossly thickened bowel wall. This appearance is highly suggestive of small noncleaved cell lymphoma (Burkitt type).
Malignant pleural effusion. Non-Hodgkin lymphoma of the terminal ileum was diagnosed; the doughnut sign (ie, intraluminal contrast material surrounded by a grossly thickened bowel wall) was present. A diagnosis of stage 3 Burkitt lymphoma was established by means of pleurocentesis. (The bone marrow was normal.) The patient was treated successfully and never required an abdominal procedure.
Massive left pleural effusion as a complication of an upper anterior mediastinal T-lymphoblastic lymphoma. Note the atelectatic left lung. The diagnosis was established by means of thoracentesis. This patient had presented with bilateral parotid gland enlargement.
Table 1. Modified LSA 2 L 2 Therapy in Children's Cancer Group Protocol 552
Phase Drug Route
Induction Cyclophosphamide, vincristine, daunorubicin IV
Ara-C, methotrexate IT
Prednisone PO
Consolidation Ara-C IV or SC
6-thioguanine PO
Methotrexate IT
L-asparaginase IM
BCNU IV
Phase Cycle Drug Route
Maintenance* 1 6-thioguanine PO
Cyclophosphamide IV
2 Hydroxyurea PO
Daunorubicin IV
3 Methotrexate PO
BCNU IV
4 Ara-C IV or SC
Vincristine IV
Source: Children's Cancer Group



Ara-C = cytarabine; BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea, or carmustine; IM = intramuscular; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous



* A minimum of 5 repeated courses (total duration of therapy >18 mo) are noted. Each course of intrathecal methotrexate (day 0 of each course) consists of 4 cycles of rotating drug pairs that are administered every 2 weeks after blood counts have recovered.



Table 2. Therapy for Stage III and IV Non–B-Cell Disease * According to BFM Protocol 86
Phases Drug Route
Induction Prednisone, 6-mercaptopurine PO
Vincristine, daunorubicin, cyclophosphamide, Ara-C IV
L-asparaginase IM
Methotrexate IT
Consolidation 6-mercaptopurine PO
Methotrexate with leucovorin rescue IV
Methotrexate IT
Re-induction Dexamethasone, 6-thioguanine PO
Vincristine, doxorubicin, cyclophosphamide, Ara-C IV
L-asparaginase IM
Methotrexate IT
Maintenance 6-mercaptopurine, methotrexate PO
Source: Berlin-Frankfurt-Munster Group



Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous



* Diagnoses included lymphoblastic lymphoma of the T-cell or precursor B-cell type, immunoblastic T-cell lymphoma, and other peripheral T-cell lymphomas. Of note, patients with Ki-1+ anaplastic large cell lymphomas (LCLs) were not included.



Continued until 24 months after diagnosis.



Table 3. Clinical Risk Groups in the International Trial for Patients With SNCCL (Children's Cancer Group study 5961)
Clinical Group Subjects,



Estimated %



Definition
A 10 All resected stage I or abdominal stage II tumors
B 65 Unresected stage I or II tumor, stage III, tumor, or stage IV tumor with no CNS involvement and < 25% marrow blasts
C 25 CNS involvement or >25% marrow blasts
Table 4. Standard Therapy in the International Trial for Patients With SNCCL, Group A *
Drug Route
Prednisone PO
Vincristine, cyclophosphamide, doxorubicin IV
Filgrastim (G-CSF), to enhance neutrophil recovery SC or IV
G-CSF = granulocyte colony-stimulating factor; IV = intravenous; PO = oral; SC = subcutaneous



* See Table 3 for the definition of group A. All subjects received 2 cycles.



Table 5. Standard Therapy in the International Trial for Patients With SNCCL, Group B *
Phase Drug Route
Reduction Prednisone PO
  Vincristine, cyclophosphamide IV
  Methotrexate/hydrocortisone IT
Phase Cycles Drug Route
Induction 2, starting 7 days after reduction Prednisone PO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
Consolidation 2 Methotrexate with leucovorin rescue, Ara-C  
Methotrexate/hydrocortisone, Ara-C/hydrocortisone  
Filgrastim (G-CSF)  
Maintenance** 1 Prednisone PO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/hydrocortisone IT
Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous



* See Table 3 for the definition of group B.



Table 6. Standard Therapy in the International Trial for Patients With SNCCL, Group C *
Phase Drug Route
Reduction Prednisone PO
Vincristine, cyclophosphamide IV
Methotrexate/Ara-C/hydrocortisone IT
Induction, cycle 1 starting 7 days after reduction Prednisone PO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/Ara-C/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
Induction, cycle 2 Prednisone PO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/Ara-C/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
Consolidation, 2 cycles High-dose Ara-C, etoposide (VP-16) IV
Filgrastim (G-CSF), days 7-21 SC or IV
High-dose methotrexate with leucovorin rescue IV
Methotrexate/Ara-C/hydrocortisone IT
Maintenance 1 Prednisone PO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/Ara-C/hydrocortisone IT
Maintenance 2 Ara-C, etoposide (VP-16) IT
Maintenance 3 Prednisone PO
Vincristine, cyclophosphamide, doxorubicin IV
Maintenance 4 Ara-C, etoposide (VP-16) IV
Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous



* See Table 3 for the definition of group C.



For patients with CNS involvement, during consolidation cycle 1 only.



Table 7. Prephase Therapy for Ki-1+ Anaplastic LCLs According to the ALCL99 Protocol
Drug Route
Dexamethasone PO
Cyclophosphamide IV
Methotrexate/Ara-C/prednisolone IT
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.
Table 8. Subsequent Therapy for Ki-1+ Anaplastic LCLs According to the ALCL99 Protocol (alternating cycles, repeated 3times each)
Cycle Drug Route
A Dexamethasone PO
Methotrexate with leucovorin rescue, ifosfamide, etoposide (VP-16), Ara-C IV
B Dexamethasone PO
Methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.
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