Toxicity of small cell lung cancer treatment

Hematol Oncol Clin N Am 18 (2004) 461 – 481

Toxicity of small cell lung cancer treatment Francesc Casas, MD, PhDa,*, Nu´ria Vin˜olas, MD, PhDb a

Department of Radiation Oncology, Institut Clı´nic de Malalties Oncohematolo`giques, Hospital Clı´nic i Universitari, Villarroel 170, 08034 Barcelona, Spain b Department of Medical Oncology, Institut Clı´nic de Malalties Oncohematolo`giques, Hospital Clı´nic i Universitari, Villarroel 170, 08034 Barcelona, Spain

The main objective of all oncologic treatment is to eradicate local and systemic neoplastic disease without severely compromising the quality of life of the patient. The optimum combination of chemotherapy and radiotherapy is based on the equilibrium between their antitumoral effectiveness and the morbidity that the normal neighboring tissue may undergo. Chemotherapy also acts against micrometastasis outside the field of radiotherapy and increases the effect of the latter, with greater control at a local level. In contrast, radiation acts exclusively at a locoregional level. During the course of radiotherapy, the target volume and the disposal of the treatment rays are designed with the aim of achieving the maximum dose in the tumor while maintaining the minimum dose possible in the neighboring tissues. In the treatment of lung cancer, the dose-limiting factors or organs (also called critical organs) are those within the surrounding area, such as the normal lung itself, the esophagus, and less commonly, the heart. Similarly, the maximum dose tolerated in chemotherapy is related to the recovery capacity of the healthy tissue (especially bone marrow) in relation to the rate of growth or tumoral recovery. Some drugs such as the cisplatin analogs may cause a certain increase in the toxicity of normal tissue (as in the case of esophagitis) when used concomitantly with thoracic irradiation. This toxicity may be acute or deferred over time and may even cause late esophageal stenosis. Thus, the aggressivity of treatment may only be determined through knowledge of the acute tolerance of the normal tissue and the involvement that may appear later. With the current use of combined treatments, toxicity may present in patients who receive doses of both treatments considered as ‘‘safe.’’ Reactions also may unforeseeably occur after an undetermined period of time. The variety of the possible interactions between radiotherapy and chemotherapy may appear over a wide spectrum of potential morbidities. The inherent difficulties in understanding these interactions may be complicated by the number * Corresponding author. E-mail address: [email protected] (F. Casas). 0889-8588/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.hoc.2003.12.007

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of chemotherapeutic agents used and combined in treatment protocols and the use of unconventional irradiation techniques (ie, hyperfractionation). Although there are experimental models that evaluate the effects caused by each chemotherapy agent and irradiation in normal tissue, no dose-response data are available. Thus, most of the data reported is derived from clinical observations.

Definitions of acute and chronic morbidity The acute, early complications observed are those that may appear during or within the first days after treatment. On occasion, the complications that appear during treatment may be reduced by treatment modification or with adequate support therapy. This topic will be covered in another section on possible alternatives to reduce the toxicity of chemoradiotherapy treatment in small-cell lung cancer (SCLC). Late or chronic complications are sequelae that appear months or even years after termination of treatment. This definition, in itself, implies that all therapeutic decisions made to obviate these effects may only be based on the probability and not the certainty of the appearance of these events. The relationship between acute lesions and late effects is unforeseeable. Although it is reasonable to suppose that every therapy that is sufficiently intense to cause acute morbidity may subsequently cause chronic effects, the structural characteristics of some tissues are such that this sequence may not occur. In fact, the absence of any acute complication does not mean that long-term toxic effects will not occur. The relationship between acute and late effects and the role that combined treatment plays in their development may be analyzed by evaluating the differences between clinical and subclinical reactions. Nonetheless, these reactions must take place in a subclinical alteration for adequate observation. The administration of chemotherapy or radiotherapy causes cellular lesions that are difficult to totally repair. Residual damage depends on the severity of the initial lesion (based on the radiation dose or the type and dose of chemotherapy used) in an organ or tissue. This subclinical lesion may not be appreciable until the administration of the following dose of another treatment. In this respect, it should not be forgotten that although acute morbidity may limit the complete and correct administration of combined treatment, late morbidity may also lead to an important alteration in the quality of life of the patient, as in the case of pulmonary fibrosis after pneumonitis secondary to combined treatment in a patient with SCLC with previous respiratory problems. Although the morphologic changes produced in a wide variety of tissues after the administration of a determined therapy may not be detected, we should not have the false impression that the immediate cellular and ultrastructural changes are only temporary and reversible. Only when these tissues receive additional treatment will the persistent residual effects be clinically demonstrable. Efforts have been made not only to define but also to quantify the toxic effects of the combined treatment of chemoradiotherapy. Organs and tissues have been

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subclassified in radiation oncology based on the dose of tolerance (TD). TD 5/5 and TD 50/5 have a probability of 5% and 50%, respectively, for a determined dose to produce complications in the 5 years after treatment. Thus, doses under TD 5/5 are considered as safe, although this is in relation to the relative volume of the irradiated organ or tissue [1]. The dose-volume histogram may be very useful at the time of weighing the volume factor when predicting whether a dose is safe, without, however, assuming the action of other competitive treatments such as chemotherapy. Attempts have also been made to quantify the chemotherapy doses that may be related to determined toxicities; the doses have been elaborated as accumulated doses administered at a determined time period. The combined effect of chemotherapy and radiotherapy on normal tissues in relation to a doseeffect factor (DEF) has also been quantified [2]. The following formula describes this potentiation measured with the DEF: DEF ¼

biologic effect related to the dose of radiation without chemotherapy biologic effect related to the dose of radiation with chemotherapy

This formula may be applied to the clinical response at a tumoral level. Thus, for tumors, a DEF > 1 is required (the mortality of the tumoral cells is produced at lower doses of radiation with chemotherapy than without). To the contrary, in relation to normal tissues, the DEF should be lower than that for tumors. This relative difference between the two DEF values is known as gain or therapeutic index, whereby the combination of chemotherapy and radiotherapy has a greater relative effect at a tumoral level than in the normal tissue versus when either of the two treatments is administered alone. Considering the potential of therapeutic gain from the addition of one type of treatment or another, it is important to remember that an increase in cell death is only important if it is not accompanied by an equivalent or greater toxicity of normal tissue. The variables related to the reactions of normal tissue include factors related to the patient, the treatment, and the tumor itself. One additional therapeutic variable that is specifically relevant in the interaction of chemotherapy and radiotherapy is the timing related to the administration of each, with concurrent administration presenting the greatest acute toxicity.

Early concurrent chemoradiotherapy in small cell lung cancer: efficacy and toxicity The benefits of combined chemoradiotherapy in SCLC are unquestionable. The combination of thoracic radiotherapy with chemotherapy, mainly based on the use of cyclophosphamide and adriamycin, was initiated more than 25 years ago, but the benefits attributable to this limited irradiation were demonstrated in a meta-analysis at the beginning of the 1990s [3]. Until a relatively short time ago, the optimum time of administration was controversial and was only administered as consolidation therapy. Thus, in 1993, the National Cancer Institute of Canada published the results of a randomized study that compared early versus late

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thoracic irradiation. This study showed a significant improvement in survival in the patients receiving combined treatment in whom early irradiation was administered [4]. Later, the randomized studies by Jeremic et al [5], Turrisi et al [6], and Takada et al [7] that used hyperfractionated early radiotherapy showed for the first time a 5-year survival rate of close to 30%. Early concurrent chemotherapy, probably with hyperfractionated radiotherapy, became in the new standard treatment of the limited-disease (LD) form of SCLC. In most of these studies, chemotherapy was based on cisplatin (Jeremic et al [5] used carboplatin) in association with VP-16. In contrast to the chemotherapeutic agents used in previous schemes based on cyclophosphamide and adriamycin, these agents have not demonstrated important toxicity at a cardiac, esophageal, or pulmonary level, making them appear ideal for combined use with irradiation. Cisplatin not only has a radiosensitizing effect but also reduces the repair of sublethal lesions after irradiation, and its combination with etoposide has shown synergy [8]. In a metaanalysis of 1579 patients with SCLC treated with cisplatin versus without cisplatin, it was concluded that the combinations that included cisplatin achieved a greater rate of response and probability of survival with respect to other regimens without increasing the risk of toxic death [9]. In another systematic review of the role of VP-16 and cisplatin in the treatment of SCLC, survival was found to be longer in schedules including etoposide alone or in combination with cisplatin [10]. Although there does not appear to be a sum of added toxicity with radiotherapy with the use of the chemotherapeutic agents, in practice, chemoradiotherapy causes greater toxicity than chemotherapy alone. This increase in toxicity is mainly produced at a hematologic, esophageal, and pulmonary level (without forgetting the impact on the general status, appetite, and even quality of life of the patient), especially in the case of the LD form based on mechanisms that are discussed in depth to propose mechanisms of action or support. In the extensive-disease (ED) form, the toxicity is usually hematologic and, thus, it will not be approached separately. Because the toxicity of combined treatment at the level of the bone marrow, esophagus, and lung are limiting, the authors specifically discuss these without going into other types of toxicity such as neurotoxicity or nephrotoxicity secondary to chemotherapy. The control of toxicity by active measures or support treatment are important not only to improve the quality of life of the patients but also to avoid interruptions that may cause a reduction in survival [11].

Hematologic toxicity Myelosuppression is the most frequent toxicity observed and is often the main dose-limiting toxicity due to the risks of infection involved. Among the strategies aimed at protecting blood cell hematopoiesis or the stroma of the bone marrow from treatment-induced death, acceleration of hematopoiesis after treatment theoretically allows the use of more intensive treatment without the associated risks mentioned previously.

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Acute toxicity to chemotherapy with bone marrow suppression is a wellknown and expected effect. The degree of toxicity varies in relation to the type and the dose administered. The use of cisplatin and etoposide, currently the base of SCLC treatment, normally shows a medium level of myelosuppression, with a nadir of 7 to 14 days and an approximate recovery of 21 days. The bone marrow, however, is also extremely radiosensitive according to the dose of radiation, its rate, and the volume of treatment. The interactions observed are not completely understood. The complexity of these interactions were first studied by Kovacs et al [12] who placed emphasis on the study of alterations of hematopoietic reserves following the administration of radiotherapy and different chemotherapy agents. The selection of drugs for different hematopoietic cell populations determines the temporal consequences of the tolerance of the bone marrow to radiation after chemotherapy. Additional considerations should also be taken into account in relation to the kinetics of cell replacement after cytotoxic treatment. Thus, small volumes of radiation after chemotherapy are better tolerated probably because the nonirradiated areas act to compensate for this deficit with an in cell production. In summary, the toxicity of concurrent chemoradiotherapy in the treatment of SCLC causes several grades of leukopenia, anemia, and thrombocytopenia, the incidence of which may be determined by analysis of hematologic toxicity published in the previously cited studies (Table 1). The last 2 decades have shown advances in the knowledge of the physiology of hematopoiesis that led to factors of hematopoietic growth being used in the treatment of bone marrow toxicity. At the level of the white cells, glycoproteins stimulate the production of myeloid progenitor cells and produce mature myeloid elements to reduce the duration and intensity of neutropenia, allow the administration of the scheduled chemotherapy, increase the doses of chemotherapy, or reduce the time interval between each treatment cycle. They have been used in randomized studies for support or for increasing the intensity of the doses in

Table 1 Incidence of acute toxicity in early concurrent hyperfractionated arm

Toxic effect/grade Leukopenia Grade 3 Grade 4 Thrombocytopenia Grade 3 Grade 4 Anemia Grade 3 Grade 4

Jeremic et al [5]

Turrisi et al [6]

Takada et al [7]

No. of patients (%)

No. of patients (%)

No. of patients (%)

52

206

112

11 (21) 6 (11)

79 (38) 90 (44)

57 (51) 42 (38)

13 (25) 7 (13)

27 (13) 16 (8)

33 (29) 8 (7)

6 (11) 1 (2)

47 (23) 10 (5)

60 (54) —

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chemotherapy schedules. The systematic review of 12 randomized studies that included 2107 patients to evaluate the effectiveness of granulocyte and granulocyte macrophage colony-stimulating factors in the treatment of SCLC concerning survival, the rate of response, toxicity, and frequency of infection or neutropenic fever concluded that their effectiveness was not demonstrated in terms of a better rate of response or survival. Moreover, a harmful effect of the use of this cytokine before chemotherapy was observed in patients with LD who had received concomitant treatment with chemotherapy and radiotherapy. This effect was also found in patients with ED treated with high-dose chemotherapy who presented with leukopenia and thrombocytopenia associated with chemotherapy [13]. Other studies have concluded that there is insufficient evidence for the use of colony-stimulating factors as support treatment of primary or secondary prophylaxis in patients with SCLC [14]. In 1996, the American Society of Clinical Oncology (ASCO) recommended that the use of colony-stimulating factors should be avoided in patients who were receiving concomitant chemotherapy and radiotherapy, further indicating the risk of the administration of chemoradiotherapy on the mediastinum [15], as pointed out later in the year 2000. The impact of the prophylactic use of antibiotics to avoid or reduce leukopenic fever in patients with SCLC has also been studied. The conclusion was that the prophylactic use of ciprofloxacin plus roxitromycin during chemotherapy [16] reduced the incidence of leukopenic fever, the number of infections, the use of antibiotics, and hospitalizations due to this fever by 50%, in addition to reducing infection-related mortality. It should be remembered that anemia often complicates the evolution of neoplastic disease. Its etiology is multifactorial and leads to inadequate production of erythropoietin in response to the alteration of normal hemoglobin levels [17]. This alteration is further exacerbated by chemotherapy [18]. Recombinant human erythropoietin (r-HuEPO [Eprex or Procrit]), however, has been satisfactorily used to improve anemia in patients with cancer, showing an increase in the number of erythroid progenitors in the bone marrow and in peripheral blood in patients who have received it together with chemotherapy [19]. de Campos et al [20] performed one of the first studies of the possibility of achieving the prevention or reduction of anemia by the administration of r-HuEPO specifically in patients with SCLC. One-third of the patients treated had ED, and thoracic and cranial irradiation were administered in single doses of greater than 10 Gy each. Later studies demonstrated that in addition to not producing adverse effects, the use of r-HuEPO decreases the degree of anemia and the need for blood transfusion in patients with SCLC [21,22]. It seems, however, that the rate of tumoral recurrence at a locoregional level increases in anemic patients and that after their correction, local control of the tumor and survival may improve [23]. In experimental studies, it has also been demonstrated that the administration of r-HuEPO restores tumoral radiosensitivity, which is reduced in anemia [24]. In recent years, different articles have reported the impact of hemoglobin levels in local control and survival. A recent meta-analysis determined whether anemia was an independent prognostic factor of survival in cancer patients. In

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those with lung cancer and anemia, the relative risk of death increased 1.9-fold [25]. The administration of r-HuEPO was therefore recommended by the clinical guidelines of the ASCO [26] with an evidence level of II in patients with anemia secondary to chemotherapy and hemoglobin concentrations close to 10 g/dL. At the same evidence level II, the administration of r-HuEPO also has been considered in patients with basal hemoglobin levels between 10 and 12 g/dL, particularly in elderly patients with limited cardiopulmonary reserves or patients with coronary disease and symptomatic angina. From the authors’ point of view, there are sufficient objective clinical data to include patients with lung cancer, smoking-related diseases, and comorbid pulmonary and cardiac disease who are receiving intensive chemoradiotherapy treatments, as in the specific case of SCLC in this group. In a group of patients with lung cancer undergoing concurrent chemoradiotherapy after induction chemotherapy (11 LD SCLC and 40 non-SCLC [NSCLC]), Casas et al [27] studied the impact of the use of r-HuEPO in the maintenance of the Karnofsky performance scale index and hemoglobin levels. They found a significant, beneficial effect in the general status of the patients and in hemoglobin levels. On multivariate analysis, they also found hemoglobin levels greater than 10 g/dL before concurrent chemoradiotherapy and the final improvement in hemoglobin levels to be a significant prognostic factor of survival (Fig. 1). In another study [28] that analyzed the impact of hemoglobin levels in groups of patients with lung cancer treated with Radiation Therapy Oncology Group protocols, a relationship was also found between hemoglobin levels and survival. Lastly, Robnett et al [29] showed a significant relationship between hemoglobin levels in patients who had received concurrent induction chemoradiotherapy and the histologic response in surgical specimens. It should be pointed out, however, that in the last two studies, the patients had NSCLC. At present, several randomized prospective studies are

Fig. 1. Survival by hemoglobin improvement after chemoradiotherapy. Hb, hemoglobin. KaplanMeier method.

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ongoing. One of these studies is in patients with LD SCLC, with the impact on local control and survival of the maintenance of normal hemoglobin levels with the administration of r-HuEPO being evaluated during concomitant treatment. In relation to the recommendations of the ASCO on the need for the administration of r-HuEPO in elderly patients (this topic is addressed in depth in another article in this issue), it should be pointed out that in an analysis on patients with SCLC over the age of 70 years treated in the Intergroup Trial 0096, it was found that although these patients presented similar response and survival rates to those of younger patients, a greater grade of hematologic toxicity was observed [30]. This result may be explained by the apparent reduction in pluripotent hematopoietic stem cells with age. Less concentration of hematopoietic stem cells has been observed in bone marrow in subjects over 65 years in age with anemia, whereas this has not been found in younger patients. Certain clinical findings such as an increase in the incidence and prevelance of anemia with age, a reduction in reticulocyte response in elderly anemic patients, an increase in mortality by infection, and a reduction in the concentration of hematopoiteic tissue with age indicate a decrease in the reserves of pluripotent hematopoietic stem cells [31]. Balducci et al [32] indicated, however, that at present, anemia is considered to be a parameter of maximum importance because of its association with a decrease in the quality of life and energy levels. These levels appear to be optimum with hemoglobin concentrations between 11 and 13 g/dL because these levels allow greater autonomy in elderly patients. Thus, anemia in this subgroup of patients produces not only a loss of independence and quality of life but may also cause limitations regarding the possibility of receiving other treatments. Because of all these indications, Balducci et al [33] noted the need for the prophylactic use of growth factors to prevent the early mortality observed in elderly patients treated with regimens with a toxicity of doses similar to cyclophosphamide, adryamicin, vincristine, prednisone and to maintain hemoglobin levels at approximately 12 g/dL to prevent the complications related to anemia and neutropenia. In relation to thrombocytopenia, to avoid hemorrhagic problems after myelosuppressive chemotherapy, thrombopoietin (the synthesized platelet-stimulating factor) is still under evaluation and clinical implementation [34]. Nonetheless, severe thrombocytopenia secondary to chemoradiotherapy does not constitute a problem in the clinical management of these patients. In addition to the development of specific cytokines for the production and secretion of the different hematologic cells, different forms of prevention against toxicity are currently being studied in SCLC in bone marrow with the administration of cytoprotectors such as amiphostine (Ethyol). Nonetheless, significant results remain to be found [35]. Moreover, the use of drugs such as glutation has demonstrated effective cytoprotection against toxicity induced by cisplatin. Although the main experience has been in ovarian cancer, lower hematologic toxicity has been found in randomized studies in a limited number of patients with other types of tumors such as lung and head and neck cancer with glutation compared with a control group [36].

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Esophageal toxicity The esophagus is normally within the field of irradiation in patients with lung cancer, and acute damage to the mucosa may be observed within a few days after irradiation. Rapid cell replacement of the mucosa cells in a normal esophagus makes this organ particularly sensitive to radiation-induced damage that at first appears to be an inflammatory response. If the rate of repopulation of the basal epithelial cell layer undergoes important after this aggression, denudation is produced, leading to an atrophy and ulceration of the mucosa [37]. Among these patients, the endoscopic findings produced are erythema of the mucosa, edema, and on occasion, the esophageal mucosa becomes friable. Microscopically, the epithelial layer of the esophagus demonstrates acantosis, atrophy, dimunition in basal mitotic activity, keratosis, parakeratosis, dysplasia, and cytoplasmatic vacuolization. Nonetheless, Jatoi and Thomas [38] reported that although some patients present symptoms of esophagitis and dysphagia, not all demonstrate endoscopic or histologic findings suggestive of esophagitis. On administration of isolated fractionated radiotherapy, a certain degree of acute esophagitis may be observed with symptoms that resolve easily within 7 to 10 days and that are rarely severe with less than 50 Gy. Depending on the size of esophagus irradiated, severe esophagitis may appear after 60 Gy, which may evolve occasionally to stenosis. It should also be taken into account that chronic problems or stenosis may appear when using lower doses than indicated in accelerated irradiation schedules. Chemotherapy agents may significantly alter the tolerance of the irradiated esophageal tissue, and the incidence of severe esophagitis may increase up to 50% [39]. Specifically, in combined treatment in LD SCLC, reference studies have reported grade 3 and 4 esophagitis in a significant proportion of patients, and even (exceptionally) stenosis has been observed (Table 2). In the case of SCLC in which chemotherapy together with hyperfractionated ratiotherapy appears to be the treatment of choice, the management of esophagitis is a challenge for clinicians, not only for achieving the administration of all treatment schedules but also for maintaining the quality of life of the patient during treatment. Different studies have evaluated the incidence, severity, and predictive factors of acute and chronic esophageal toxicity in

Table 2 Incidence of esophageal toxicity

Toxicity grade Acute toxicity Grade 3 Grade 4 Late toxicity Grade 3 a

Grade 3.

Jeremic et al [5]

Turrisi et al [6]

Takada et al [7]

No. of patients (%)

No. of patients (%)

No. of patients (%)

52

206

112

13 (25) 2 (4)

56 (27) 11 (5)

1 (2)

0 (0)

10a (9)

—

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patients with SCLC and NSCLC receiving combined chemoradiotherapy treatments. One of these studies in 105 patients with lung cancer undergoing concomitant chemotherapy and irradiation is of note. In this study, the patients demonstrated a greater grade and duration of esophagitis [40]. Other studies have also described the percentage of volume of the esophagus treated with more than 50 Gy as a predictive factor of late toxicity [41], whereas other studies indicated chemotherapy together with hyperfractionated radiotherapy as the most important factors for acute esophagitis and its length [41]. The last two studies were in agreement that the length of the esophagus included in the treatment field was not a predictive factor of acute toxicity. Although the proportion of SCLC was limited in both studies, their results, especially those of the second article, coincide with the grade of esophagitis reported by Turrisi et al [6] in the arm of concurrent hyperfractionated radiotherapy. In a phase I study of dose escalation in SCLC, Choi et al [42] demonstrated that the grade of esophagitis is dose dependent and is more frequent in hyperfractionated treatment, mainly due to the expected increase in inactivation of the cells in tissues of acute response, as in the case of the esophagus. In the authors’ experience with concurrent and hyperfractionated treatment of SCLC (F. Casas, N. Vin˜olas, unpublished data, 2001), the grade and the duration of esophagitis greater than or equal to grade 3 are related to the leukopenia by a diminution in mucosa repair in the esophagus. Thus, 15 of 50 patients who were treated presented with esophagitis of grade 3 or greater in the context or as the first symptom of intense leukopenia or aplasia. This same correlation was reported by Choi et al [43] in studies of stage III NSCLC submitted to preoperative induction treatment with concurrent hyperfractionated chemoradiotherapy schedules. These researchers observed grade 4 esophagitis in 14% of the patients who presented with marked leukopenia shortly after chemotherapy, followed by resolution of the leukopenia and then recovery of the dysphagia. One possible route of action or prophylaxis against esophagitis in SCLC may be the use of amiphostine. Nonetheless, in a recent phase II study in 34 patients with SCLC treated with amiphostine and with the aforementioned combined treatment, no benefits were observed in the control of esophageal toxicity [44], contrary to the positive results reported in NSCLC [45,46]. These negative results, however, refer to a phase II study in a limited number of patients. Nonetheless, this study reproduced the results of previous publications on local control and survival, thereby demonstrating that amiphostine does not appear to have a possible tumor protector effect. From the authors’ point of view, in addition to continuing the investigation of radio- and chemoprotectors and the prognostic factors of esophagitis, a prophylactic or symptomatic treatment of this toxicity should be considered because in addition to altering the patient’s quality of life, it produces a reduction in ingestion and weight loss that weakens patients and worsens their general status. Some investigators [43] defend the prophylactic use of antacids, especially in patients with a history of gastric ulcer and hiatus hernia because gastroesophageal reflux may aggravate an incipient subclinical esophagitis. For many years, the

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authors have administered transdermic fentanyl (Durogesic) at a dose of 25 mg/ 72 hours in patients with grade 2 and 3 esophagitis (F. Casas, N. Vin˜olas, unpublished data, 2001) in addition to the use of antacids, anti-inflammatory drugs, or antifungal drugs in cases of superinfection by these pathogenic agents. This treatment allows palliation of the pain and continuation of modified but sufficient food intake while closely monitoring the clinical evolution and leukocyte values to detect severe leukopenia that would require hospitalization.

Pulmonary toxicity The tolerance of normal lung tissue imposes limitations for combined treatment in SCLC because considerable areas of the lung must be irradiated at relatively high doses, which may cause long-term sequelae. In clinical practice, certain structural damage, whether pneumonitis or fibrosis due to the wide capacity of functional pulmonary reserve, is accepted. That is, pulmonary function is not altered despite damage to a small part of the lung. At this level, morbidity is determined by many factors including the damage caused in the tissue, the impact of the damage on organ function, and finally, the impact of lesions on the quality of life of the patient. This dissociation between damage and morbidity at a pulmonary level is a reflection of the particular organization of the anatomic units responsible for pulmonary function. Functional damage, reflected by total lung function, is shown only when a determined number of acines is destroyed. In clinical practice, thoracic radiotherapy is associated with significant alterations in pulmonary function (measured with pulmonary function tests) [47]. Residual pulmonary function is a determining factor of the functional state of the patient after treatment, especially in patients with lung cancer in whom the lung is often compromised before treatment secondary to the neoplasm and previous coexistent pulmonary diseases. Greater levels of alteration have been reported in pulmonary function tests following combined radiotherapy and chemotherapy treatment compared with radiotherapy alone [48], and regimens of concurrent chemoradiotherapy have been found to be more toxic than sequential therapy. Normal lung is a tissue with slow response (the damage is not observed until weeks or years after completion of treatment), in contrast to tissues of acute response. In an analysis of experimental studies with acute- or late-response types of tissues, the latter tissues, as in the lung, showed that greater doses of the radiation fraction are more toxic [49]. The physiopathologic mechanism of pneumonitis following irradiation may occur because radiotherapy particularly affects endothelial capillary cells and type I epithelial cells so that acute histologic changes are characterized by alterations in small vessels, with the subsequent development of vascular congestion and an increase in permeability. An exudate rich in fibrin is produced in the alveolar spaces, leading to hyaline membranes. In the chronic phase of fibrosis, an increase in the thickness of the alveolar walls is found as fibrosis of the subintimal layer of the vessels, with their consequent stenosis.

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Several studies have been performed on the possible predictive factors of pulmonary toxicity following irradiation. One study in which the risk of pneumonitis varied in relation to the zone irradiated is of note. In a group of 60 patients with lung cancer treated with sequential or concurrent chemoradiotherapy, the area of irradiation was evaluated. When the risk of pneumonitis in relation to the zone irradiated was analyzed, it was found that when the base of the lung was irradiated, the incidence of pneumonitis significantly increased compared with other localizations [50]. Some investigators have attributed this fact to the differences in the quantity of DNA in pulmonary cells at the base or in the apex of the lung [51]. One of the most recent studies on the effects of radiotherapy and chemotherapy on pulmonary function was published by the M.D. Anderson Cancer Center Group [52]. Although this study was exclusively based on NSCLC, homogeneous groups of patients who participated in different Radiation Therapy Oncology Group studies were included. The patients were treated with radiotherapy alone (19 patients), sequential chemotherapy and standard radiotherapy (24 patients), concurrent chemotherapy and classical fractionated radiotherapy (7 patients), and concurrent chemotherapy and hyperfractionated radiotherapy (27 patients), allowing analogs of toxicity in SCLC to be made. Factors such as total lung capacity and the diffusion capacity for carbon monoxide (DLCO) were studied, and it was concluded that the addition of chemotherapy to radiotherapy significantly increases the decrease in total lung capacity and DLCO produced after radiotherapy alone, with a greater reduction in DLCO being observed in patients receiving concurrent chemoradiotherapy. The advent of three-dimensional radiotherapy totally modified the distribution of doses in pulmonary schedules. Dose-volume histograms reflect the impact of the changes in pulmonary function and structure. Later, these dose-volume histograms may be used to develop mathematic models aimed at predicting the probability of complications in normal tissue. The use of these models requires posterior clinical confirmation in many patients, complicating the joint administration of chemotherapy. In a Dutch study in 382 patients with breast cancer, lymphoma, and NSCLC irradiated in two different centers, different models of the probability of complications in normal tissue were compared to predict the incidence of pneumonitis based on the distribution of the dose in the lung. The mean lung dose was a predictive factor of pneumonitis of greater importance than the volume of the lung that received more than one determined dose [53]. Nonetheless, this volume, specifically the V20, defined as the percentage of lung irradiated at more than 20 Gy, also is a predictive factor for pneumonitis after chemoradiotherapy. This finding was also shown in a Japanese study in 71 patients with lung cancer in whom a V20 <25% was associated with a low incidence of grade 2 or greater pneumonitis, whereas a V20 >30% was significantly associated with a higher incidence of grade 2 or greater pneumonitis [54]. A close correlation between V20 and the mean lung dose was also reported [55]. A recent analysis of 32 patients with NSCLC treated with continuous hyperfractionated accelerated radiotherapy after induction chemotherapy is also of note. This study concluded

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that this type of hyperfractionation appears to show a greater therapeutic index than conventional radiotherapy in relation to pulmonary toxicity. Likewise, V20 and the mean pulmonary dose were suggested to be useful predictive factors for the risk of pneumonitis [56]. In contrast to the previous Japanese study that calculated the V20, excluding the volume of the trachea, bronchi, and gross tumor volume, this study [57] not only excluded the airways from the pulmonary contour to determine the V20 but also excluded the planning target volume. To calculate the V30, another group subtracted the pulmonary contour, trachea, bronchi, gross tumor volume, and the diaphragm [57]. This difference in the calculation of this variable may explain certain differences in the results reported. It has been demonstrated in experimental animals that although some animals developed only acute toxicty (ie, pneumonitis) after radiation, others developed more chronic toxicity that presented with fibrosis. In other words, there appears to be a certain intrinsic susceptibility in the group of animals after the same radiation [58]. At a clinical level, the study of 56 patients with LD SCLC treated in two studies of chemoradiotherapy with conventional radiotherapy (45 Gy administered in 25 sessions over 5 weeks) or hyperfractionated accelerated radiotherapy (45 Gy in 30 sessions, twice a day, administered over 3 weeks) showed that the risk and severity of fibrosis, analyzed with CT scan, increases with total dose with the accelerated treatment and also in relation to the intrinsic heterogenicity of the patients. This last variable suggests that the risk of fibrosis is closely correlated with the inherent factors of the patient that may vary widely from person to person [59]. This fact may also explain the difference in acute and late pulmonary toxicity presented in different studies (Table 3). This variability in the response of normal tissue may be used to individualize treatment strategies. To this respect, one study demonstrated that the risk of fibrosis formation in the lung after irradiation is correlated with the levels of transforming growth factor (TGF)-b in serum [60]. The risk of symptomatic radiation-induced pulmonary toxicity has been related using physical (V30) and biologic parameters (TGF-b), stratifying patients of low, medium, and high risk of developing this toxicity [61]. The probable predictive effect of TGF-b has also been reported for the selection of patients with a lower risk of pulmonary toxicity in whom greater doses of radiation may be administered within dose-escalation programs [62]. Table 3 Incidence of pulmonary toxicity

Toxicity grade Acute toxicity Grade 3 Grade 4 Grade 5 Late toxicity Grade 3

Jeremic et al [5]

Turrisi et al [6]

Takada et al [7]

No. of patients (%)

No. of patients (%)

No. of patients (%)

52

206

112

1 (2) — —

9 (4) 2 (1) 3 (1)

— — —

1 (2)

—

—

474

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In conclusion, it may be said that the lung is a limiting or critical organ of great importance in the chemoradiotherapy of lung cancer. Immediate cellular damage is produced following irradiation that is determined by multicellular interactions of cytokines with induction and progression of inflammatory reactions and fibrosis of the tissues. Pentoxifylline appears to reduce the production of proinflammatory cytokines, particularly tumor necrosis factor– alpha (TNF-a), in response to harmful stimuli and may, in contrast, protect against the cellular damage mediated by cytokines and produced by irradiation. In an experimental study, Ru¨be et al [63] demonstrated a significant increase in TNF-a levels at a pulmonary level in the phase of pneumonitis and also observed an important reduction in TNF-a in the study group that received pentoxifylline and radiation therapy compared with the group that received radiation therapy alone. Other studies are required to confirm the efficacy of this drug and its prophlylactic use to avoid pneumonitis. In combination with vitamin E, pentoxifylline has been found to be effective in the treatment of radiation-induced fibrosis of other localizations [64]. At present, only corticoids are available for the symptomatic treatment of pneumonitis; however, prophylactic administration does not prevent the appearance of toxicity. The administration of 1 m/kg prednisone is recommended immediately after diagnosis and during several weeks with a posterior downscaling schedule.

Other toxicities As a critical organ at a thoracic level, cardiac toxicity may be considered among the other toxicities that may be found with concurrent irradiation in SCLC. The heart may receive an appreciable dose of radiation because SCLC tends to have large, even contralateral adenopathies. An increase in cardiac toxicity has not been reported, however, as a result of the use of new schedules based on cisplatin and etoposide together with radiotherapy. Light pericardic effusion postirradiation has been described in the irradiation of intrathoracic tumors related to the dose, the volume of the heart irradiated, and the dose per fraction administered, which is not usually of clinical importance [65]. On rare occasions, late pericarditis may appear, requiring pericardiocentesis. Nonetheless, with the technologic advances of three-dimensional planning, this last secondary effect has become exceptional. In any case, evidence of the presence of ischemic coronary disease secondary to irradiation should be collected. The exact measurement of the toxicity that may be produced with concurrent chemoradiotherapy in lung cancer can probably be determined by monitoring cardiac troponin levels, an early marker of myocardial damage. This marker has been shown to be useful in demonstrating this subclinical toxicity after high-dose chemotherapy [66]. Because some groups (mainly European) continue to use adriFig. 2. Preventive or support treatment for toxicity by chemoradiotherapy in SCLC. CSF, colonystimulating factors; NTCP, the probability of complications in normal tissue.

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amycin in alternating treatments with cisplatin and etoposide—the latter coinciding with thoracic irradiatio—the appearance of cardiac toxicity could be evaluated with the methods mentioned or with others. A frequent (although not life-threatening) toxicity that appears to alter the quality of life of the patient is the neuropathy associated with cisplatin. Different treatments such as tricyclic antidepressants and vitamin E have been suggested. Although a randomized study did not show nortriptyline to have any beneficial effect [67], vitamin E (300 mg/day) as prevention therapy administered during chemotherapy with cisplatin and subsequently for 3 more months has been found to reduce the incidence and severity of peripheral neuropathy [68]. The toxicity of the treatment may alter the nutritional level of the patients and, secondarily, the functional status. Possible actions may include alimentary or pharmacologic dietetic support with appetite stimulants. A certain percentage of patients require psychologic support after diagnosis, which on many occasions, their physicians cannot or do not know how to approach adequately, thereby requiring help from professionals of this expertise.

Summary At present, early, concurrent chemoradiotherapy (probably based on hyperfractionation plus prophylactic cranial irradiation) after complete response is the treatment of choice in LD SCLC. Polychemotherapy continues to be the standard treatment in ED, although in a recent randomized study [69], the possible role of thoracic irradiation has been suggested in patients with complete response. Despite a high initial response to treatment, only a small percentage of SCLC patients survive for more than 3 years. The low survival rate and rapid metastasis in these patients justifies intensive treatment from the beginning, which is not without toxicity, mainly located in the bone marrow, esophagus, and normal lung tissue. The acute manifestations of treatment-derived toxicity in these critical organs may compromise not only the administration of adequate or more effective treatment but also the life of the patient. Insufficient active treatment and the toxicity itself converge to lower the probability of survival. The acute effects of treatment may be modified or prevented during the administration of treatment. Thus, the concept of preventive or support treatment for toxicity has emerged with the aim of increasing tolerance, quality of life of the patients during concomitant therapy, treatment compliance, and survival (Fig. 2). At a hematologic level, leukopenia and anemia should be carefully monitored. Nonetheless, in leukopenia, the prophylactic use of colony-stimulating factors has not yet shown sufficient effectiveness with respect to greater survival, frequency of infection, or neutropenic fever. Moreover, treatment toxicity may increase if administered concomitantly with mediastinic irradiation. The prophylactic administration of antibiotics (ciprofloxacin plus roxitromycin), however, has been found to be useful in the reduction of mortality of infectious origin. In relation to anemia, different aspects coexist, making it a toxicity of importance. First, it is

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related to the quality of life of the patient because its main symptom, fatigue, noticeably affects the functional state of the patient. Second but no less important, anemia has been shown to be a negative prognostic factor for survival and treatment efficacy, especially in the case of radiotherapy, for radiobiologic reasons. Thus, different studies, from meta-analyses to prospective studies, and the recom mendations of scientific societies such as ASCO advise the correction of anemia and the maintenance of values close to 12 g/dL, especially in intensive treatments in elderly patients or in cases with important chronic diseases. In these patients, r-HuEPO, especially of the alpha type (Eprex), has shown both its efficacy and its possible impact on the functional state and survival of patients with SCLC. At an esophageal level, the combined toxicity of radiotherapy and chemotherapy should be considered from the point of view of investigation with optimization of three-dimensional planning with intensity-modulated radiotherapy and the use of radio- and chemoprotectors such as amiphostine, which has shown promising although occasional contradictory results. Prospective studies are required to determine the relationship between esophagitis and intense leukopenia. Esophagitis, with the pain it provokes, limits and compromises the alimentary tract and, thus, the nutrition of the patient. Esophagitis should be prevented or treated with anesthetics, anti-inflammatory drugs, antacids, antifungal drugs, or even morphine, especially, according to the authors’ results, with transdermic fentanyl if necessary. At a pulmonary level, pneumonitis of healthy lung tissue should be prevented or taken into account with the advance in the knowledge of prognostic factors for its appearance. Dose-volume histograms and particularly V20 or other mathematic models for predicting the probability of toxicity in healthy tissue have shown to be especially useful. Biologic factors such as TGF-b may be useful to evaluate the appearance of toxicity during treatment and thus, to undertake preventive measures. Recent experimental studies have demonstrated the protector effect of pentoxifylline on pulmonary toxicity, although further randomized prospective studies are required for confirmation.

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