Non-Small Cell Lung Cancer Treatment-Related Bone Marrow Toxicities

Non–Small Cell Lung Cancer Treatment-Related Bone Marrow Toxicities David S. Ettinger A major consequence of administering increasingly aggressive therapies (chemotherapy with or without radiation therapy) in the treatment of non–small cell lung cancer is the adverse effects on the bone marrow that may lead to neutropenia, thrombocytopenia, and/or anemia. Myelosuppression or bone marrow toxicity may also lead to dose reduction of chemotherapy and/or treatment delays in both chemotherapy and radiation therapy, diminishing the efficacy of therapy in the curative setting. In this setting, the use of hematopoietic growth factors may thus be beneficial. Semin Oncol 32(suppl 3):S81-S85 © 2005 Elsevier Inc. All rights reserved.

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major consequence of using more aggressive therapies (ie, chemotherapy and radiation therapy [RT]) in the treatment of non–small cell lung cancer (NSCLC) are their adverse effects on bone marrow, which may lead to neutropenia, thrombocytopenia, and/or anemia. These adverse effects can increase the risk of infection, bleeding, and fatigue, diminish quality of life, and reduce survival. Myelosuppression may also lead to dose reduction of chemotherapy and/or treatment delays in both chemotherapy and RT.

Chemotherapy When using chemotherapy alone in the palliative setting, neutropenia is a common side effect, while the occurrence of significant anemia and thrombocytopenia is less.1 The degree of hematopoietic toxicity is dependent on the chemotherapy regimen used. For example, in a comparison of four chemotherapy regimens (1) cisplatin plus paclitaxel (paclitaxel 135 mg/m2 over a 24-hour period on day 1, cisplatin 75 mg/m2 on day 2, 3-week cycle); (2) cisplatin plus gemcitabine (gemcitabine 1,000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 1, 4-week cycle); (3) cisplatin plus docetaxel (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD. Dr Ettinger has received research grant support from Aventis and Eli Lilly. He has served as a consultant to, received honoararium from, and served as a member of the speaker’s bureau for AstraZeneca, Aventis, BristolMyers Squibb, Eli Lilly, GlaxoSmithKline, Merck, MGI Pharma, and Pfizer. Address reprint requests to Davis S. Ettinger, MD, Alex Grass Professor of Oncology, Associate Director for Clinical Research, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room G88, Baltimore, MD 21231-1000.

0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.03.014

3-week cycle); and (4) carboplatin plus paclitaxel (paclitaxel 225 mg/m2 over a 3-hour period on day 1, carboplatin area under the concentration-time curve [AUC] 6.0 mg/mL/ minute on day 1, 3-week cycle) for the treatment of advanced NSCLC conducted by the Eastern Cooperative Oncology Group, grade 4 neutropenia, thrombocytopenia, and anemia ranged from 39% to 57%, 1% to 28%, and 1% to 2%, respectively.2 In general, except for the use of growth factors to treat chemotherapy-induced anemia, in the palliative setting, significant chemotherapy-induced neutropenia and thrombocytopenia are treated with a dose reduction of the chemotherapy rather than using growth factors.

Chemotherapy Plus Radiation Therapy In the treatment of locally advanced NSCLC, which is a potentially curable disease, sequential or concurrent chemotherapy and RT are frequently used. In this disease, every attempt should be made to complete the therapy in a timely fashion without dose modifications because of bone marrow toxicity. In a review of five Radiation Therapy Oncology Group trials using three different treatment strategies–(1) chemotherapy (CT) followed by standard RT; (2) combined sequential and concurrent CT/RT; or (3) concurrent CT and hyperfractionated RT–the grade 4 acute hematologic toxicity was similar between the three treatments, 47%, 51%, and 46%, respectively, with grade 5 hematologic toxicity occurring in 0%, 1%, and 2.5%, respectively.3 While hematologic toxicity during induction CT consisted primarily of grade 3 or 4 neutropenia, during concomitant CT/RT, the major hematoS81

D.S. Ettinger

S82 Table 1 Cancer and Leukemia Group B (CALGB) 9431 Grade 3/4 Adverse Events: Induction Chemotherapy Gemcitabine/Cisplatin (n ⴝ 62)

Paclitaxel/Cisplatin* (n ⴝ 58)

Vinorelbine/Cisplatin (n ⴝ 55)

15% 48% 31% 25% 18% 12%

12% 48% 39% 0 15% 12%

27% 55% 21% 2% 18% 16%

Leukopenia Granulocytopenia Lymphopenia Thrombocytopenia Nausea Vomiting

NOTE. Only grade 3/4 toxicities >15% for any arm are listed. *Two patients died of treatment-related causes (renal failure, infection).

logic toxicity consisted of thrombocytopenia and neutropenia. The severity of the myelosuppression, in part, is dependent on the chemotherapy regimens given as well as the doses of drug administered.4-8 In the Vokes et al study,4 patients received four cycles of cisplatin at 80 mg/m2 on days 1, 22, 43, and 64 with: arm 1, gemcitabine 1,250 mg/m2 on days 1, 8 , 22, and 29 and 600 mg/m2 on days 43, 50, 64, and 71; arm 2, paclitaxel 225 mg/m2 for 3 hours on days 1 and 22 and 135 mg/m2 on days 43 and 64; or arm 3, vinorelbine 25 mg/m2 on days 1, 8, 15, 22, and 29 and 15 mg/m2 on days 43, 50, 64, and 71. Radiation therapy was started on day 43 at 2 Gy/day (total dose, 66 Gy). Tables 1 and 2 list the grade 3 and 4 toxicities for white blood cell counts, platelets, granulocytes, and hemoglobin for induction chemotherapy plus concomitant chemotherapy and RT. In part, the hematologic toxicities are dependent on the regimen given. With the induction chemotherapy, approximately 50% of patients with all three regimens had grade 3 or 4 granulocytopenia. However, grade 3 or 4 thrombocytopenia was more severe with the gemcitabine regimen, 25% compared with 0% and 2% with the paclitaxel and vinorelbine regimens, respectively. Despite a dose reduction of the non-cisplatin drug given with concomitant RT, grade 3 and 4 granulocytopenia was significant. In addition, grade 3 or 4 thrombocytopenia and anemia were

present especially with the gemcitabine plus cisplatin chemotherapy. In the study by Furuse et al,5 patients received one of two regimens. Patients in the concurrent arm received CT/RT consisting of cisplatin (80 mg/m2 on days 1 and 29), vindesine (3 mg/m2 on days 1, 8, 29, and 36), and mitomycin (8 mg/m2 on days 1 and 29). RT began on day 2 at a dose of 28 Gy (2 Gy per fraction, 5 fractions per week for a total of 14 fractions) followed by a rest period and then repeated. In the sequential arm, patients received the same CT, with RT given after completion of the chemotherapy consisting of 56 Gy (2 Gy per fraction, 5 fractions per week for a total of 28 fractions). Table 3 compares the hematologic toxicity between the two treatment schedules. Myelosuppression (anemia, leukopenia, and thrombocytopenia) occurred more frequently in the patients receiving the concurrent therapy (P ⫽ .0001).

Hematopoietic Growth Factors The hematopoietic growth factors have changed the way we treat chemotherapy-induced anemia, neutropenia, and thrombocytopenia. The growth factors are erythropoietin (epoetin alfa, darbepoetin alfa), granulocyte colony-stimulating factor (filgrastim, pegfilgrastim), granulocyte-macro-

Table 2 Cancer and Leukemia Group B (CALGB) 9431 Grade 3/4 Adverse Events: Concomitant Chemotherapy Gemcitabine/Cisplatin (n ⴝ 53)

Paclitaxel/Cisplatin (n ⴝ 45)

Vinorelbine/Cisplatin (n ⴝ 43)

51% 79% 56% 32%

53% 79% 6% 4%

27% 65% 2% 19%

Granulocytopenia Lymphopenia Thrombocytopenia Anemia

NOTE. Only grade 3/4 toxicities >15% for any arm are listed.

Table 3 Hematologic Toxicity (WHO Grade) in Concurrent Versus Sequential RT and CT in NSCLC Concurrent Treatment (N ⴝ 156)

Sequential (N ⴝ 158)

WHO grade

1

2

3

4

1

2

3

4

P Value

Hemoglobulin Leukocyte Platelets

13 0 22

61 2 37

2 (1%) 35 (22%) 55 (35%)

14 (9%) 119 (76%) 27 (17%)

35 7 35

63 28 32

44 (28%) 82 (52%) 31 (20%)

8 39 (25%) 6 (4%)

<.0001 <.0001 <.0001

Abbreviations: CT, chemotherapy; NSCLC, non–small cell lung cancer; RT, radiation therapy; WHO, World Health Organization.

NSCLC treatment-related bone marrow toxicities

S83

Table 4 National Comprehensive Cancer Network (NCCN) Cancer and Treatment-Related Anemia Practice Guidelines Symptomatic Hb 10-11 g/dL Consider erythropoietic therapy Hb <10 g/dL Strongly consider erythropoietic therapy (category 1) Additional evaluation Iron studies Serum iron, TIBC, serum ferritin Initial response assessment Response (Hb 1 1 g/dL). Titrate dosage to maintain optimal Hb 12 g/dL No response (1 dose of agent) Abbreviations: Hb, hemoglobin; TIBC, total iron binding capacity. Data from Sabbatini et al.10

phage colony stimulating factor (sargramostim), and oprelvekin [interleukin-11]).

Treatment of Anemia Fatigue is the most prevalent symptom reported by NSCLC patients, and anemia, in part, contributes to it. Whether the anemia is caused by chemotherapy or the disease itself, it can be treated with erythropoietin. The American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH) and the National Compre-

hensive Cancer Network have developed practice guidelines for the use of epoetin and more recently darbepoetin in patients with cancer.9,10 In 2002, ASCO and ASH recommended the following9: 1. Epoetin is recommended for patients with chemotherapy-associated anemia and a hemoglobin concentration that has declined to a level of less than 10g/dL. Red blood cell transfusions should be considered depending on the severity of the anemia or clinical circumstances. 2. The use of epoetin for patients with less severe anemia (hemoglobin ⬍12g/dL to 10g/dL) should be based on the clinical situation. 3. Good evidence supported the use of subcutaneous epoetin three times a week (150 ␮/kg 3 times a week) for a minimum of 4 weeks. While an alternative weekly (40,000 ␮/wk) dosing schedule was used at the time of the guidelines report,11 the guideline panel did not recommend its use. 4. Continuing epoetin therapy beyond 6 to 8 weeks in the absence of response did not appear beneficial and was not recommended. 5. Once the hemoglobin level reached 12 g/dL, the dosage of epoetin should be titrated to maintain that level. The National Comprehensive Cancer Network guidelines are updated yearly.10 In general, they are similar to the ASCO

Table 5 Erythropoietic Therapy Initial Dosing Package insert dosing schedule Epoetin alfa 10,000 U TIW by SC injection

or Darbepoetin 2.25 ␮g/kg q week by SC injection

Commonly used regimens Epoetin alfa 40,000 U q week by SC injection11 or Darbepoetin 3 ␮g/kg every 2 weeks by SC injection12 or Darbepoetin 200 ␮g fixed-dose every 2 weeks by SC injection13

Titration for No Response

Titration for Response

1 Dose of epoetin alfa to 20,000 U TIW by SC injection

●

If Hb 1 by >1 g/dL in a 2-week period, dose should be 2 by 25%.

1 Darbepoetin to up to 4.5 ␮g every week by SC injection

●

If Hb is >12 g/dL, hold therapy. Re-initiate therapy if Hb falls to <12 g/dL at 25% dose reduction of the prior dose.

1 Dose of epoetin alfa to 60,000 U every week by SC injection 1 Darbepoetin to up to 5 ␮g/ kg every 2 weeks by SC injection12 1 Darbepoetin to up to 300 mcg fixed-dose every 2 weeks by SC injection13

New regimens being used in clinical trials Epoetin alfa 60,000 U loading dose SC then 120,000 U every 3 weeks maintenance SC14 Darbepoetin 4.5 ␮g/kg every week loading dose SC then 4.5 ␮g/kg every 3 weeks maintenance SC15 Abbreviations: Hb, hemoglobin; SC, subcutaneously; TIW, three times weekly; U, units. Data from Sabbatini et al.10

D.S. Ettinger

S84 Table 6 Colony-Stimulating Factor Therapy ● Filgrastim (Neupogen) 5 ␮g/kg/day ● Sargramostim (Leukine) 250 ␮g/m2/day G-CSF or GMCSF to begin between >24 hours subsequent to chemotherapy SC or IV until ANC >10,000/␮L ● Pegfilgrastim (Neulasta) 6 mg SC to start >24 hours post-chemotherapy Abbreviations: ANC, absolute neutrophil count; G-CSF, granulocytecolony stimulating factor; GM-CSF, granulocyte macrophage-colony stimulating factor; IV, intravenous; SC, subcutaneous.

and ASH practice guidelines (Table 4). However, in their recommendations for erythropoietic therapy (Table 5), darbepoetin alfa was an option.10-17

breast carcinoma, it is not routinely used in the treatment of lung cancer patients.25

Conclusion Bone marrow toxicity is one of the consequences associated with the use of chemotherapy with or without RT in the treatment of NSCLC. In the palliative setting, dose reduction of chemotherapeutic agents can reduce the anemia, neutropenia, and thrombocytopenia associated with its use. However, if the goal of treating the NSCLC patient is curative, dose reduction of the drugs or delays in the therapy may diminish its effectiveness. In this situation, the use of hematopoietic growth factors may be beneficial.

References

Treatment of Neutropenia In regard to neutropenia, in treating potentially curable locally advanced NSCLC patients with combined modality therapy, rather than reduce the dose of induction chemotherapy because of neutropenia, filgrastim, pegfilgrastim, and (less frequently) sargramostim are used (Table 6).18-20 In 2000, ASCO updated their 1994 practice guidelines for the use of hematopoietic colony-stimulating factors in patients receiving chemotherapy.21 They made, in part, the following recommendations: (1) The routine use of colony-stimulating factors for primary prophylaxis of febrile neutropenia in previously untreated patients is not recommended. (2) Patients with a prior episode of febrile neutropenia may benefit from colony-stimulating factor administration. A more recent development is the use of pegfilgrastim, a long-acting recombinant form of human granulocyte colonystimulating factor administered once per chemotherapy cycle as prophylaxis against chemotherapy-induced neutropenia.19,20 It is well tolerated and has the advantage of less frequent dosing and therefore less painful injections.

Treatment of Thrombocytopenia While thrombocytopenia remains a problem when treating a lung cancer patient with chemotherapy plus or minus RT, it is usually short lived and does not require platelet transfusions. Unless the patient has a bleeding episode, platelets are not used unless the platelet count falls below 10,000 cells/ ␮L.22,23 Usually, if a lung cancer patient becomes thrombocytopenic while receiving palliative chemotherapy, the dose of the drugs are reduced in subsequent cycles. Oprelvekin is a thrombopoietic growth factor that directly stimulates proliferation of hematopoietic stem cells and megakaryocyte progenitor cells. Oprelvekin was approved by the US Food and Drug Administration in 1997 to stimulate megakaryocyte thrombopoiesis.24 The recommended dose is 50 ␮g/kg given subcutaneously once daily usually starting 6 to 24 hours after the administration of chemotherapy for 10 to 21 days. While the use of oprelvekin may be indicated in patients receiving dose-intensive chemotherapy for cancers such as

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S85 19. Crawford J: Once-per-cycle pegfilgrastim (Neulasta) management of chemotherapy-induced neutropenia. Semin Oncol 30:24-30, 2003 (suppl 13) 20. Molineux G: The design and development of pegfilgrastim (PEG-rmetHuG-CSF). Curr Pharm Design 10:1235-1244, 2004 21. Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendation for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18:35583585, 2000 22. Goodnough LT, DiPersio JF: Issues in the management of cancer-related thrombocytopenia. Oncology 16:1558-1567, 2002 23. Schiffer CA, Anderson KC, Bennett CL, et al: Platelet transfusion for patients with cancer: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1519-1538, 2001 24. Kaye JA: FDA licensure of NEUMEGA to prevent severe chemotherapyinduced thrombocytopenia. Stem Cells 16:207-223, 1998 (suppl 2) 25. Issacs C, Robert NJ, Bailey FA, et al: Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapyinduced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin. J Clin Oncol 15: 3368-3377, 1997