8.1 Hematologic Toxicity in Lung Cancer Francesc Casas

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8.1 Hematologic Toxicity in Lung Cancer

Francesc Casas and Núria Viñolas

F. Casas, MD; N. Viñolas, MD

Radiation and Medical Oncology Departments (ICMHO), Hospital Clínic i Universitari, Villarroel 170, 08036 Barcelona, Spain

CONTENTS

8.1.1 Introduction 339

8.1.2 Toxicity in Chemotherapy 340 8.1.3 Toxicity in Radiotherapy 342 8.1.4 Hematologic Toxicity After Combined

Chemo- and Radiotherapy 343 8.1.5 Preventive or Support Treatment of

Hematologic Toxicity in Lung Cancer 345 References 348

8.1.1

Introduction

Hematologic toxicity in non-surgical treatment of lung cancer generally depends on the type of treatment administered, whether chemo- and/or radiotherapy. This chapter will describe the normal physiology of bone marrow followed by a synthesis of the current knowledge of the toxicity of these two treatments either alone or in combination. Lastly, support treatments and the management of these secondary effects is proposed.

The toxicity of tumor cells after chemo- and radiotherapy, administered either alone or in combination is dose-dependent. Aggression to the bone marrow, which is expressed by a reduction in circulating blood cells, is often the main dose-limiting toxicity because of the risks of anemia, bleeding and infection. Strategies aimed at protecting the hematopoietic cells or the stroma of the bone marrow from death induced by the treatment, the acceleration of hematopoiesis after treatment, may theoretically allow more intensive treatments in lung cancer without the above mentioned associated risks. To know the true impact of individual or combined, sequential or concurrent treatment to thereby act accordingly, it is necessary to know the structure and function of the bone mar-

row as an organ. Thus, the pluripotent stem cells rep- licate and differentiate in lymphoid or myeloid lines through a complex process regulated by a network of hematopoietic growth factors as well as by cellular in- teractions. The cascade through myeloid differentiation leads to the erythrocytes, platelets, granulocytes and macrophages, while the lymphoid differentiation leads to T and B cells. Families of growth factors (or cytokines) which control these processes of replication and differentiation have been identiﬁ ed. The hematopoietic progenitor cells and their daughter cells are enveloped in a stroma of endothelial cells, adventitial cells, ﬁ broblasts, macrophages and fat cells in the sinus of the bone marrow. This micro- scopic medium is a physical support and director of the development of the replication process. In addition, the geographic distribution of the bone marrow is particularly relevant to know the possible local effects of radiotherapy in the treatment of lung cancer.

The most functional and important localizations are the pelvis, the vertebrae (these two represent 60% of the total of the bone marrow), as well as the ribs, the sternum, the cranium, the scapula and the proximal portions of the femur and humeral bones. It should also be remembered that hematopoietic stem cells are also found in the spleen and circulate in the blood.

Bone marrow dysfunction in neoplastic processes may be due to different etiologies:

1 Depletion or direct lesions of the hematopoietic stem cells

2 Functional or structural damage of the stroma or the microcirculation

3 Lesion of other collaborator cells which have a regulator function or hemostasis

The consequences of the aggression of cytotoxic and radiotherapeutic treatment to the bone marrow should, therefore, be understood within the context of the previously described mechanisms. Nonetheless, it may be difﬁ cult to elucidate the most important vari- ables due to the limitations in the evaluation of both the structure and bone marrow function. The peripheral determination of the blood cells fails to demon-

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strate the true extension of bone marrow suppression or its capacity to tolerate additional cytotoxic therapy mainly because of the capacity of the bone marrow to transitorily compensate the aggression. To evalu- ate several quantitative and functional aspects of the bone marrow cultures of progenitor cells, histopatho- logic studies (bone marrow aspirate and biopsy), and determined radioisotopes or stromal cell cultures may be used, although to a limited extent.

8.1.2

Toxicity in Chemotherapy

The myelosuppression directly caused by chemotherapy depends not only on the agent used but also on patient-dependent factors, such as age and general status. Important factors in relation to the type of chemotherapy administered are the doses, the interval of the doses, the route of administration or the use of a single or several antitumoral agents. On the other hand, the site of action of the antineoplastic drug within the cellular cycle also appears to inﬂ u- ence myelosuppression (Howard and Pelc 1951).

It is known that the S phase represents DNA synthesis and M the period of mitosis. G1 and G2, respectively, represent the gaps between mitosis and the beginning of DNA replication and between the end of replication and the beginning of mitosis. Some cells have very prolonged G1 periods and may be considered as rest- ing cells which are said to be in the G0 phase.

Most of the cells maturing in the bone marrow are actively dividing. This means that cytostatic drugs which act in a speciﬁ c phase of the cycle, for example in the S phase of synthesis, cause a rapid, early and reversible reduction in the number of granulocytes.

Thus, for agents which act on the cell cycle and which are phase-specifi c, the length of exposure determines the toxicity in relation to the greater number of cells exposed during continuous infusion compared to bolus administration. Other classes of agents, mainly the cell-cycle agents that are not specifi cally phase- selective (such as anthracyclines and certain alkyl- ators, i.e. busulfan) may cause slightly more delayed suppression of bone marrow and longer recovery than phase-specifi c agents.

On the other hand, many hematopoietic stem cells are not in a cycle and may only be altered by agents which act in the G0 phase. These chemotherapeutic agents act on the DNA bridges provoking cell death.

If a particular agent predominantly affects the stem cells rather than cells in speciﬁ c phases of the cell

cycle, then all the cell lines are suppressed. Very few cytostatics selectively depress the stem cell (i.e. nitro- soureas, streptozotocin) and none are used at present in the treatment of lung cancer.

The damage results from a depletion in the total number of stem cells (the stem cell pool) with a late myelosuppression pattern which takes place when the peripheral blood cells die and cannot be replaced. That is to say that myelotoxicity by chemotherapy agents produces a decrease in the production of blood cells more than an immediate elimination of the peripheral cells (Ratain et al. 1990).

Because of differences in the peripheral blood half life, drugs that induce myelosuppression ﬁ rst result in leukopenia followed by thrombocytopenia with the former generally being more severe than the latter. Thus, the nadir for neutrophils and platelets is normally between 7 and 15 days after drug administration. For most of the compounds, neutropenia and thrombocytopenia are reversible and not accumulative. In addition to the direct cytotoxicity at the level of the progenitor cells, at an erythrocytic level, blood cells with a more prolonged half life, the mechanisms involved may be direct hemolysis of the red blood cells after the administration of, for example, mitomycin (Vervey et al. 1987) or a decrease in the production of endogenous erythropoietin due to chronic renal insufﬁ ciency by cisplatin (Pivot et al.

2000). The pluripotent stem cells are protected from the toxic effects of chemotherapy because of their slow proliferation.

The biological differences among different patients affects the degree of bone marrow damage for a determined chemotherapy agent, although they may also reﬂ ect differences in bone marrow cellularity before treatment. Advanced age is associated with a reduction in bone marrow cellularity and a lower tolerance to chemotherapy which may be related to pharmacokinetic alterations of drugs in the elderly in whom drug clearing may be decreased. The nutri- tional status may also be an important factor in patients with a negative balance of nitrogen and weight loss is also associated since it has been found that it provokes lower tolerance to chemotherapy (Dewys et al. 1980). It is also known that anything which in- terferes with the route of activation, metabolism or excretion of a chemotherapy drug may exacerbate myelosuppression. Other possible causes include effects in cell regulation (that is, an alteration in growth factor secretion) or cell interaction. For example, it appears that chemotherapy may affect the response of endogenous erythropoietin to anemia causing a dysregulation in the normal control of red blood

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cells (Miller et al. 1990). One of the main factors of toxicity for a given chemotherapy agent is the phar- macodynamic interaction between the drug and the combination of other anticancer drugs. Thus, one of the general principles for combining different drugs is that they should have a different limiting toxicity, although a sum of these effects is normally produced in relation to myelotoxicity. There is, however, an ex- ception to this rule in the case of the combination of paclitaxel-carboplatin: paclitaxel decreases the platelet toxicity of carboplatin in relation to a non-pharmacokinetic mechanism (Calvert et al. 1999).

Patients who have undergone previous chemotherapy present a greater susceptibility of hematologic toxicity with new treatment. This observation has even led to the consideration of different doses of carboplatin in patients who have been previously treated (Albers and Dorr 1998). Previous irradiation may also decrease the tolerance to chemotherapy agents and vice versa. Finally, circadian variations have been reported in the pharmacokinetics of some drugs. Since cell division of hematopoietic cells has a circadian variation, the time of administration may inﬂ uence hematologic toxicity (Kerr et al. 1990).

Chemotherapy is the standard treatment in patients with stage IIIB non-small cell lung cancer (NSCLC) with pleural effusion and stage IV. The aim of this treatment is palliative and attempts to improve the quality of life and prolong survival. It has also been demonstrated to have a role in stage III NSCLC as neoadjuvant therapy to surgery in stage IIIA with or without radiotherapy and in combination with the latter in patients with stage IIIB and good performance status. The role of chemotherapy in early stages as a neoadjuvant or complementary therapy to surgery is still under study.

The most frequent schedules of chemotherapy currently used in NSCLC include combinations of cisplatin or carboplatin with some of the new drugs (gemcitabine, vinorelbine, paclitaxel, docetaxel). All have been shown to be similar in regard to efﬁ cacy in stage IV although the toxicities observed, including hematologic toxicity, differs (Schiller et al. 2002).

These combinations of chemotherapy cause grade 3 and 4 neutropenia which varies from 40% to 70%

with febrile neutropenia in less than 10%. Some of the randomized studies comparing these different schedules have shown that the combination of cisplatin and vinorelbine causes grade 3 and 4 neutropenia in a greater percentage of patients, although in the study by Fosella et al. (2003), which compared this schedule with docetaxel in addition to platin drugs, did not ﬁ nd differences in regard to neutro-

penia. Grade 3 and 4 platelet toxicity was observed in 1%–55% of the patients, with a schedule combining cisplatin and gemcitabine showing a greater percentage of thrombocytopenias (Cardenal et al. 1999).

No serious hemorrhagic events were reported with these different schemes. In the study by Scagliotti et al. (2002) in which patients were randomized to receive three different chemotherapy schedules (cisplatin-gemcitabine, carboplatin-paclitaxel and cisplatin-vinorelbine) the percentages of patients who received platelet transfusions for each arm was 8%, 2%

and 8%, respectively, and were not consistent with the respective percentages reported for grade 3/4 thrombocytopenia. In regard to anemia, the percentages varied from 10% to 30%, with the schedules based on cisplatin and gemcitabine or vinorelbine being those producing the greater percentage of patients with anemia (Kelly et al. 2001; Schiller 2002).

Continuous infusion of paclitaxel leads to an increase in neutropenia without greater efﬁ cacy, thus, this drug is currently administered in shorter infu- sions of 1 or 3 h. The sequence of administration is also very important since an increase in myelotoxicity has been observed when cisplatin is administered before paclitaxel. Platelet toxicity is not of note in schemes including paclitaxel combined with carboplatin suggesting that paclitaxel protects against the thrombopenia associated with carboplatin.

To improve the effectiveness and/or reduce the toxicity of chemotherapy schedules based on cisplatin, different randomized studies have been carried out with schemes based on cisplatin and combination therapy without this drug. In a randomized study by Georgoulias et al. (2001), patients with advanced NSCLC received treatment with cisplatin and docetaxel versus gemcitabine-docetaxel and although no differences were observed in the effectiveness of both schedules, a better toxicity proﬁ le was found with the latter scheme including less neutropenia.

With respect to small-cell lung cancer (SCLC) the most commonly used schedules which show greater effectiveness are those based on cyclophosphamide and adriamycin combined with vincristine (CAV) or etoposide (CAE) or those based on a combination of platin and etoposide derivatives. The combination of cisplatin and etoposide produces less neutropenia than the CAV and CAE schemes although with more anemia (Fukuoka et al. 1991). The proﬁ le of hematologic toxicity with the combination of etoposide and carboplatin is similar to that found with the schedule of cisplatin except with a greater percentage of thrombocytopenia (Ettinger 1988).

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The beneﬁ ts of palliative treatment with chemotherapy in advanced lung cancer are basically achieved in patients with a good functional status.

It was traditionally believed that patients with performance status 2 (PS 2) presented greater toxicity with chemotherapy, thereby reducing the possible beneﬁ cial effect. Retrospective analysis of prospective studies in patients with NSCLC receiving treatment based on cisplatin demonstrated that the subgroup of patients with PS 2 presented a much lower median survival than patients with a better general status. In this way the group of ECOG (Sweeney et al. 2001) has recently published the results of a subgroup of patients receiving chemotherapy with cisplatin and paclitaxel versus three experi- mental arms (cisplatin and gemcitabine, cisplatin and docetaxel and carboplatin and docetaxel).

This study conﬁ rmed that patients with PS 2 have a greater incidence of grades 3 and 4 hematologic toxicity. Nonetheless, analysis of the cause of death during treatment demonstrated that most of the deaths were associated with the disease and that the poor survival was due to the disease more than to treatment-associated toxicity.

It is diffi cult to know whether this subgroup of patients with a short survival and greater possibili- ties of treatment-associated toxicity benefi ts from chemotherapy treatment. The study of Billingham and Cullen (Billingham 2001) suggested that PS 2 patients had no survival benefi t from chemotherapy but in contrast these patients experienced the gratest improvement in quality of life during the fi rst cycle of chemotherapy. Subgroup analysis from several randomised trials seems to demonstrate that several new generation cytotoxic drugs are superior to supportive care alone in patients with PS 2 (Elvis 1999; Ransom 2000). In the analysis of PS 2 patients in CALGB 9739 study comparing pladitaxel plus carboplatin versus pladitaxel, median survival in the combination chemotherapy was signifi cantly longer than with pladitaxel alone although it should be noted that combination produced a statistically signifi cant higher incidence of several hematological and non hematological toxicities. (Lilenbaum 2002). The preliminary results of a randomized, prospective study comparing carboplatin plus paclitaxel versus cisplatin plus gemcitabine in patients with PS 2 showed greater response for patients in the latter group but with greater thrombopenia (Langer et al.

2003). Chemotherapy appears justiﬁ ed to patients with advanced NSCLC and PS 2 although it is not clear the best regimen taking into account the ef- ﬁ cacy and toxicity.

In elderly patients or those with concomitant diseases, trials with monotherapy or combined therapy without cisplatin have demonstrated to be active and well tolerated. One clinical trial compared monotherapy with vinorelbine versus the best support treatment in patients over 70 years of age, 25% of whom had PS 2. Greater palliation, time to progression, survival and quality of life were observed in the patients treated with vinorelbine (ELVIS 1999). In a similar population of patients (Frasci et al. 2000) combined treatment with gemcitabine plus vinorelbine was compared with monotherapy with vinorelbine and found better survival and quality of life with the combined treatment without differences in toxicity. These results disagree with those by Gridelli et al. (2003) who did not ﬁ nd better results and observed greater toxicity in the patients receiving combined therapy.

The combination produced a greater percentage of anemia and neutropenia in relation to gemcitabine and platelet toxicity related to vinorelbine.

Isolated administration of gemcitabine has con- ﬁ rmed its activity as well as its tolerable toxicity pro- ﬁ le in elderly patients with NSCLC, although with a greater proportion of patients with grades 3 and 4 anemia (Shepherd et al. 1997).

The administration of combinations with cisplatin and the new cytostatic drugs have not shown notable differences between patients older or younger than 70 years of age, with a tolerable toxicity proﬁ le and the main toxicity being hematologic (Booton et al. 2003).

Elderly patients with advanced stage NSCLC pre- senting an acceptable general status should receive chemotherapy treatment (Langer et al. 2002).

To date two randomized studied have compared standard endovenous treatment with doses at the lower limit with oral treatment with etoposide alone in fragile, elderly patients with SCLC. Both studies showed that combination therapy was superior in regard to response to treatment and survival than monotherapy and had less hematologic toxicity (Souhami et al. 1997; Thatcher 1996).

8.1.3

Toxicity in Radiotherapy

In the case of irradiation in lung cancer, acute toxicity of the bone marrow depends on the volume irradiated, the doses of radiation and its rate. Although the compensatory mechanisms are mainly relevant for the knowledge of long term effects, some effects are acute. Thus when volumes limited to the bone mar-

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row are irradiated, such as, for example 10%–15%, the remaining bone marrow responds by increasing the population of progenitor cells. This is why the bone marrow, as an organ as a whole, is able to regenerate the previously irradiated zone by a compensatory process to satisfy the needs of hematopoiesis and acute toxicity is not observed. This compensatory phenomenon may be observed by factors (CSFs) from the cell stroma suggesting the implication of a humoral mechanism (Croizat et al. 1976).

It has been shown that there is a extensive com- munication and compensation network in the bone marrow after aggression with radiation and this may be summarized as follows:

1 Regeneration within the ﬁ eld of irradiation 2 Hyperactivity in non-irradiated regions

3 Extension of the function of bone marrow production in previously dormant zones (Tubiana et al. 1979)

This reparation or compensatory capacity of the bone marrow makes the bone marrow toxicity secondary to exclusive radiotherapy treatment in lung cancer difﬁ cult to observe clinically. Nonetheless, this exclusive irradiation using standard fractionation leads to subclinical, but quantiﬁ able, hematologic toxicity which we will describe more in depth later when we go into combined treatment (chemo- and radiotherapy) and compare the resulting myelotoxicity using references from randomized studies related to radiotherapy alone.

8.1.4

Hematologic Toxicity

After Combined Chemo- and Radiotherapy The combined effects of chemotherapy and radiotherapy on the bone marrow are complex (Kovacs et al. 1988). The selective action of the chemotherapy agents for different populations of hematopoietic cells determine the temporary consequences of the tolerance of the bone marrow to radiation after chemotherapy. In addition, when wide ﬁ elds are used, before chemotherapy, the tolerance expected is poor.

This may be due not only to the suppression or ab- lation of determined segments or portions of the bone marrow, but also because of the increase in the sensitivity of non exposed zones of the bone marrow which, at that time, are in a period of hyperactivity.

This is produced in the case of sequential treatments further complicating the question when referring to combined treatments of radio- and chemotherapy. In

the case of SCLC, the study by Abrams et al. (1985) is of note. These authors randomized 42 patients to receive either chemotherapy alone or in combination with thoracic irradiation. In the group receiving combined treatment an increase was observed in both hematopoietic toxicity and the circulating number of progenitor cells suggesting that the toxicity of concurrent treatment is additive. It was found that:

1 The combination of chemotherapy and thoracic radiotherapy produces somewhat more hematologic toxicity than when chemotherapy is administered alone.

2 This increase may be explained by a generally subclinical, although measurable, toxicity of the thoracic radiotherapy when administered alone.

3 The potential of hematopoietic toxicity by irradiation by itself may vary in relation to the timing, the volume of treatment, to the region irradiated and the treatment ﬁ elds used. That is, that the greater the volume treated and the greater the quantity of the cardiac circuit and bone marrow involved in the irradiated ﬁ elds, the greater the toxicity.

The third point of this study introduces the con- cepts that not only irradiation of the bone marrow may cause hematologic toxicity but blood irradiation within the cardiac circuit may also play a role that should be taken into account in this toxicity. Turrisi et al. (1993) have also shown this in the sense that the great vessels are in the irradiated ﬁ elds, the cardiac output is probably irradiated twice– once from the pulmonary circuit and then again in the systemic circuit.

In recent years the contribution of not only the importance of the timing of the administration (early or late) in concurrent combined treatment, but also the alterations of the fractionation (accelerated hy- perfractionation versus standard fractionation) in patients with SCLC conditioned changes in hematologic toxicity. Thus, Murray et al. (1993) randomized a group of patients into two arms of early concurrent irradiation (in the third week) versus late (in the ﬁ f- teenth week) and found that although the differences between neutropenia and thrombocytopenia greater than or equal to grade 3 were not statistically signiﬁ - cant for either of the treatment arms, they were so in relation to grade 3 anemia which was greater in the late administration (p<0.03).

In a study by Jeremic et al. (1997), 107 patients were randomized to receive either chemotherapy plus early hyperfractionated radiotherapy (weeks 1–4) with concurrent chemotherapy versus late administration (weeks 6–9) and did not ﬁ nd statisti-

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cally signiﬁ cant differences in hematologic toxicity.

In the same year the group of the EORTC (Gregor et al. 1997) published another randomized study in patients with limited stage SCLC comparing sequential chemoradiotherapy versus alternating treatment and reported that the latter schedule was as effective as the sequential administration but caused greater grades 3 and 4 hematologic toxicity.

Turrisi et al. (1999) carried out a randomized study comparing concurrent chemotherapy with hyperfractionated radiotherapy versus the same chemotherapy with standard fractionated radiotherapy and found greater toxicity in the treatment with hyperfractionated radiotherapy. Lastly, Takada et al. (2002) randomized concurrent versus sequential chemoradiotherapy and observed greater hematologic toxicity in the ﬁ rst treatment arm (Table 8.1.1).

At the beginning of the 1990s a series of randomized studies in NSCLC were performed which evaluated both the effectiveness and the toxicity of concurrent or sequential chemoradiotherapy versus irradiation alone (Table 8.1.2). Firstly, the study by Le Chevalier et al. (1991) was of note. In this study 353 patients

were randomized to receive 65 Gy of irradiation alone versus the same irradiation preceded by three cycles of vindesine, lomustine, cisplatin and cyclophosphamide. The group receiving irradiation alone showed three-fold less hematologic toxicity than the group administered combined therapy. In 1990, Dillman et al.

(1990) randomized 155 patients to receive two cycles of cisplatin and vinblastine followed by 60 Gy of irradiation versus radiotherapy alone at the same doses.

Although the hematologic toxicity in this study was not correctly explained, it was of note that neutropenic infection was more prevalent in the patients receiving chemotherapy with double the number of admissions due to severe infections versus the patients administered irradiation alone.

In a study by Trovó et al. (1992) 173 stage III patients were randomized to receive 45 Gy versus the same irradiation administered concurrently with a daily dose of 6 mg/m2 of cisplatin. The hematologic toxicity of the combined treatment was only slightly superior to that of radiotherapy alone. Schaake- Koning et al. (1992) randomized 331 patients to receive 56 Gy administered by split-course or the same radiotherapy plus 30 mg/m2 of cisplatin administered each week of irradiation versus the same total doses of irradiation administered continuously with a daily doses of 6 mg/m2 of cisplatin during irradiation. It was found that grades 3–4 hematologic toxicity was four- fold greater in the group with concurrent administration with weekly cisplatin compared to radiotherapy alone and was double in the concurrent treatment with daily versus weekly chemotherapy.

In 1995, Sause et al. (1995) published a randomized study on whether patients receiving chemotherapy followed by irradiation showed longer survival than hyperfractionated radiotherapy or irradiation

Leukopenia Thrombo- cytopenia

Anemia

Grade % Grade % Grade %

Jeremic et al.

(1995)

3 4

21 11

3 4

25 13

3 4

11 2 Turrisi et al.

(1999)

3 4

38 44

3 4

13 8

3 4

23 5 Takada et al.

(2002)

3 4

51 38

3 4

23 5

3 4

54 – Table 8.1.1. Hematologic toxicity in randomized concurrent hyperfractionated arms on SCLC

Table 8.1.2. Hematologic toxicity in randomized trials on NSCLC Hematologic

toxic effect

RT Group CH + RT Group (monthly CH)

CH + RT Group (daily CH) Le Chevalier et al.

(1991) (sequential)

Grade 2–5 1.4% 4.2% –

Trovo et al.

(1992) (concurrent)

Hemoglobin (grade 1–2) Leukopenia

1.7%

1.1%

– –

2.3%

1.7%

Schaake-Koning et al.

(1992) (concurrent)

Leukopenia (grade 3–4) Thrombopenia (grade 3–4)

3.3%

0.6%

6.6% (weekly CH) 0.9% (weekly CH)

14.5%

1.8%

Dillman et al.

(1990) (sequential)

Neutropenia (infection)

3% 7% –

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with standard fractionation in patients with stage III NSCLC. Hematologic toxicity greater than grade 3 in the white cells was presented in 50% of the patients with combined treatment and was null in the other two treatment arms. Jeremic et al. (1995) randomized 169 patients to receive hyperfractionated radiotherapy at 1.2 Gy/twice per day up to a total dose of 64.8 Gy versus the same doses of irradiation plus 100 mg of carboplatin on days 1 and 2 and 100 mg of etoposide days 1 and 3 of each week of irradiation versus a third group in which the same radiotherapy was administered plus 200 mg of carboplatin administered days 1 and 2 and 100 mg of VP-16 on days 1 and 5 of the ﬁ rst, third and ﬁ fth week of irradiation.

Likewise, the toxicity was greater in the combined treatment, especially in the second group.

On demonstration of the greater effectiveness, but with more hematologic toxicity, of sequential treatment versus exclusive irradiation, the next step was to demonstrate that concurrent administration was better than sequential. This was corrobo- rated by Furuse et al. (1999) in a study in which 320 stage III NSCLC patients were randomized to receive concurrent treatment with cisplatin, vindesine and mitomycin and 56 Gy administered by split-course versus the same chemotherapy and one continuous dose of 56 Gy. Greater immunosuppression was also observed in the concurrent treatment arm. Another study which demonstrated greater survival with concurrent treatment was that by RTOG 9410 published only in abstract form and thus, the toxicity cannot by completely presented.

A new combination of treatment has been investi- gated. In a randomized phase II study the effectiveness and tolerance of two cycles of induction chemotherapy (with the so-called new chemotherapy drugs) followed by two additional cycles of the same chemotherapy plus concurrent radiotherapy have been studied. The chemotherapy used was doublets of cisplatin with gemcitabine, vinorelbine and paclitaxel (Vokes et al. 2002)

and in this study hematologic toxicity was presented separately in the induction and also in the concurrent treatment (Table 8.1.3). In the ﬁ rst part grade 3–4 gran- ulocytopenia was of note in 50% of the patients in the three treatment arms presented, and in the arm with gemcitabine 25% of the patients also presented grades 3 and 4 thrombocytopenia. In regard to the toxicity observed with concurrent treatment it was of note that notable differences were found in the three treatment arms of the study. Thus, while in the groups treated with gemcitabine and paclitaxel grades 3 and 4 granulocy- topenia were observed in 51% and 53%, respectively, in the group receiving vinorelbine this hematologic toxicity was seen in 27% of the patients. Platelet toxicity was also found to be greater (50%) in the group with concurrent treatment with gemcitabine.

Finally, a new strategy used in inoperable stage III patients is of note in which initial plus consolidation chemotherapy was administered (Gandara et al.

2000). This strategy is also part of a phase III study published only in abstract form (Choy et al. 2002) which evaluates induction chemotherapy followed by irradiation alone, induction chemotherapy followed by concomitant chemoradiotherapy and lastly, concomitant chemoradiotherapy followed by consolidation. Deﬁ nitive publication of these studies, together with other ongoing studies such as the randomized trial of CALGB 3981 and the Hoosier Oncology Group will aid in determining whether complete doses of chemotherapy before or after chemoradiotherapy increase survival and with what toxicity.

8.1.5

Preventive or Support Treatment of Hematologic Toxicity in Lung Cancer

In the last 20 years the knowledge of the physiology of hematopoiesis has been broadened and has led to

Table 8.1.3. Hematologic toxicity of Vokes’s scheme on induction chemotherapy and concurrent chemoradiotherapy on NSCLC

Hematologic toxic effect

Gemcitabine/cisplatin Paclitaxel/cisplatin Vinorelbine/cisplatin Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Vokes et al.

(2002) induction

Platelets Granulocytes Lymphocytes

18%

23%

26%

7%

25%

5%

0%

25%

27%

0%

23%

12%

0%

32%

14%

2%

23%

7%

Vokes et al.

(2002) concurrent

Platelets Hemoglobin Granulocytes Lymphocytes

33%

30%

33%

17%

23%

2%

18%

62%

2%

4%

29%

12%

4%

0%

24%

67%

0%

19%

21%

2%

0%

8%

44%

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the use of the so-called hematopoietic growth factors in the treatment of bone marrow toxicity. These factors are glycoproteins which stimulate the myeloid progenitor cells and produce mature myeloid ele- ments. Their objective is to reduce the length and intensity of neutropenia associated with chemotherapy, allow the administration of this treatment at the doses initially planned, increase the doses of chemotherapy and/or reduce the time interval between each treatment cycle. A systematic review of the literature of 12 randomized studies including 2107 patients evaluated the effectiveness of the colony stimulating factors (of granulocytes or G-CSF and granulocytes- macrophages or GM-CSF), in the treatment of SCLC with regard to survival, the rate of response, toxicity and frequency of infection or neutropenic fever. This review concluded that the administration of G-CSF or GM-CSF to maintain or increase the dose intensity of planned chemotherapy has not been demonstrated to be effective in terms of a greater rate of response and survival. Moreover, a harmful effect has been observed with the use of this cytokine in patients with an intrathoracic stage who had been treated con- comitantly with chemo- and radiotherapy, as well as in extrathoracic stages treated with high dose chemotherapy (Berghmans et al. 2002). Other studies along the same line have coincided in that more studies on the use of CSF as a support treatment or as primary or secondary prophylaxis in patients with SCLC are required (Adams et al. 2002). In 1996, the American Society of Clinical Oncology (ASCO) recommended that the use of CSF should be avoided in patients who had received concomitant chemo-radiotherapy, and 4 years later speciﬁ ed that its use should be avoided in patients with radiochemotherapy if the mediastinum had been irradiated (Ozer et al. 2000) as in the case of lung cancer.

In relation to the preventive use of antibiotics to reduce the febrile leukopenia observed in patients with lung cancer, a randomized study of the EORTC on the prophylactic use of ciproﬂ oxacin and roxithromycin during chemotherapy administration is of note (Tjan-Heijnen et al. 2001). These antibiotics reduced the incidence of leukopenic fever, the number of infections, and the use of antibiotics and hos- pitalizations due to this fever by 50%, as well as death caused by infection.

The clinical studies do not advise the routine use of CSF as a treatment added to antibiotics in the treatment of patients with uncomplicated febrile neutropenia.

The efﬁ cacy of most of the antibiotic regimens, the good results obtained even with wide spectrum anti-

biotics in patients who may present rapid neutrophil recovery without the administration of CSF makes its routine use in all patients with neutropenic fever inadvisable. Nonetheless, in certain high risk patients with clear predictive factors of worse outcome (for example in sepsis, pneumonia, fungal infections, etc.) the use of CSF together with antibiotics may be justi- ﬁ ed (Bennet et al. 1999).

In relation to anemia, another known effect of bone marrow toxicity, it should be remembered that its etiology is multifactorial and includes an inappro- priate production of erythropoietin in response to the alteration of the normal hemoglobin levels (Miller et al. 1990). This abnormality in the production of erythropoietin is also exacerbated by chemotherapy (Schapira et al. 1990). On the other hand, recombinant human erythropoietin (r-Hu-EPO) has been used to improve the anemia observed in patients with cancer with an increase being observed in the number of erythroid progenitors in both the bone marrow and peripheral blood (Ludwig et al. 1990). One of the ﬁ rst studies on the possibility of achieving the prevention or reduction of anemia by the administration of r-Hu- EPO in patients with lung cancer was by de Campos et al. (1995). Later studies have shown that the use of r-Hu-EPO in lung cancer not only does not produce adverse effects, but also decreases both the degree of anemia as well as the blood transfusion needs in patients who have been treated with schemes including cisplatin (Zaragoulidis et al. 1997; Thatcher et al. 1999). On the other hand, in addition to studying anemia within the context of bone marrow toxicity, it has also been correlated with the probability of tu- moral control and survival in some types of cancer (Henke et al. 1999). To this effect, a metaanalysis by Caro et al. (2000) should be pointed out. The aim of these authors was to determine whether anemia was an independent prognostic factor of survival in patients with different neoplasms. In relation to anemic patients with lung cancer it was concluded that the relative risk of death increased by a factor of 1.9.

A study by Casas et al. (2003) also studied the impact of the use of r-Hu-EPO in the maintenance of Karnofsky and the hemoglobin levels in patients with lung cancer receiving concurrent treatment of chemoradiotherapy after induction therapy (11 limited small cell and 40 non-small cell lung cancers). In addition to fi nding a benefi cial and signifi cant impact of the administration of r-Hu-EPO at the level of general status and hemoglobin levels, it was also found to be a signifi cant prognostic factor of survival on mul- tivariate analysis, together with classical factors such as weight loss and fi nal improvement in hemoglobin,

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the histology of SCLC and ﬁ nally, hemoglobin levels greater than 10 g/dl prior to concurrent chemoradiotherapy. MacRae et al. (2002) analyzed the impact of the hemoglobin levels of groups of patients with lung cancer treated with different protocol of the RTOG and also described a relationship between hemoglobin levels and survival. Lastly, a study by Robnett et al. (2002) showed a signiﬁ cant relation between hemoglobin levels in patients who had received concurrent treatments of induction chemoradiotherapy and histologic response with regard to the pathological tissue.

The ASCO has made recommendations with an evidence level of II concerning the treatment of this anemia with r-Hu-EPO (Rizzo et al. 2002) in treatment with chemotherapy and anemia with hemoglobin concentrations close to 10 g/dl. It has also made recommendations with the same level of evidence II for patients with baseline hemoglobin levels between 10 and 12 g/dl based on the clinical judgment or the premise that patients with speciﬁ c comorbid- ity have a greater absolute probability of anemia or a greater risk of adverse effects related to this grade of anemia than other patients with the same hemoglobin concentrations. As an example the ASCO has in- dicated patients who may be considered for the use of r-Hu-EPO in levels close to 12 g/dl, among others, including elderly individuals with limited cardio- pulmonary reserves or patients with symptomatic coronary disease and angina. These recommendations have been made because although the patients over the age of 70 years present similar rates of response and survival than younger patients to combined treatments for lung cancer, they show a greater grade of hematologic toxicity, and thus, elderly patients with a good general status should probably be selected (Yuen et al. 2000). This greater hematologic toxicity may be due to the fact that the concentration of pluripotent hematopoietic stem cells seems to reduce with age, since a reduction has been observed in this concentration in the bone marrow of subjects with anemia over the age of 65 years. Other clinical ﬁ ndings such as an increase in the incidence and prevalence of anemia with age, a reduction in reticulocyte response in elderly anemic patients, an increase in death due to infection and a reduction in hematopoietic tissue concentration with age, indicate a decrease in the reserves of pluripotent hematopoietic stem cells (Baraldi-Junkins et al. 2000). On the other hand, as reported by Balducci and Hardy (1998), anemia is considered to be an important pa- rameter since it is associated with a decrease in the quality of life and the levels of energy in the patient.

These levels appear to be optimum with hemoglobin concentrations from 11 to 13 g/dl since they allow greater autonomy for elderly patients. This is why the use of growth factors is recommended to prevent the early mortality observed in elderly patients who are treated with schedules with a doses toxicity similar to CHOP and also to maintain the hemoglobin levels at approximately 12 g/dl with the aim of preventing the complications of anemia and ﬁ nally, to carry out the adjustment of the doses of the cytostatic drugs for the renal excretion of these patients (Balducci et al. 2000).

From our point of view, objective clinical data which patients with lung cancer present such as smoking-related diseases and comorbid pulmonary and cardiac disease, and concurrent or sequential chemotherapy or chemoradiotherapy should also make up part of the group of patients in whom the use of r-Hu-EPO with hemoglobin levels of 12 g/dl should be considered similar to what has been recommended by ASCO.

In relation to thrombopenia, thrombopoietin, the synthesized factor for the stimulation of this series based on preventing hemorrhagic problems after myelosuppressive chemotherapy is still under evaluation and clinical implementation (Vadhan-Raj 2001).

In addition to the development of speciﬁ c cytokines for the production and secretion of different hematologic cells, trials with medications such as glutation are currently ongoing on different meth- ods of prevention of bone marrow toxicity. Glutation has been shown to be an effective chemoprotector against toxicity induced by cisplatin. Although the main experience is in ovarian cancer, randomized studies in other types of tumors such as the lung and the head and neck have demonstrated lower hematologic toxicity in patients receiving glutation compared with the control group (Schmidinger et al. 2000). Other drugs such as amifostine, have also shown a signiﬁ cant reduction in hematologic toxicity in randomized studies including patients with lung cancer undergoing concurrent chemoradiotherapy (Antonadou et al. 2003; Komaki et al.

2002).

There is a new pathway to reduce bone marrow toxicity secondary to radiotherapy alone or associated with chemotherapy. Radiotherapy modulated by doses intensity (IMRT) in different locations have been demonstrated to be useful to signiﬁ cantly reduce the doses of radiotherapy in critical tissues.

Studies in gynecologic tumors have shown that this type of irradiation reduces the volume of bone

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marrow in the pelvis irradiated compared with con- formed radiotherapy, with a probable secondary decrease in hematologic toxicity although prospective studies are necessary to know the true clinical impact of this partial bone marrow protection at a hematologic level (Lujan et al. 2003).

With IMRT planning it may be possible to reduce both bone marrow volume at a thoracic level and cardiac circulation thereby avoiding blood cells to be irradiated with radiotherapy alone or in combination.

Prospective studies aimed at achieving a reduction in hematologic toxicity by this way should be under- taken.

Finally, it is currently possible to prospectively monitor or even predict bone marrow toxicity after chemotherapy (Lyman et al. 1995) or radiotherapy.

A recent article demonstrated that the variations of the cytokine called Glt-3 ligand in plasma directly reﬂ ect the damage induced by radiotherapy in the bone marrow during fractionated radiotherapy, even when this damage is maintained at subclinical levels (Huchet et al. 2003). This may be very useful for the preventive monitoring of hematologic toxicity in determined groups of patients with lung cancer receiving chemo- or radiotherapy.

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