Neglected Respiratory Toxicity Caused by Cancer Therapy

3.1. Respiratory Muscle Impairment

Procarbazine, cytarabine, chlorambucil and above all vincristine may cause neuropathies which can affect respiratory muscle function [8]. The primary manifestations are usually sensory, but drug-induced motor or sensorimotor neuropathies also occur, most commonly caused by vincris-tine. Most of these case are mild or even subclinical symmetric distal neuropathies. It is not clear whether the respiratory muscles are ever involved, though some of the many cases of idiopathic phrenic nerve palsies are likely to be drug-induced [9]. The pathogenic mechanism seems to be neurotubular damage. This adverse event may be particularly serious when anesthesia is administered to these patients [10].

3.2. Acute Encephalopathy and Respiratory Depression (Ifosfamide and Methotrexate)

This side-effect merits special attention, given the high prevalence of chronic obstructive lung disease and sleep apnea-hypopnea syndrome. Both entities can cause chronic hypercapnia which may deteriorate with the addition of an extra offending agent that favors respiratory depression [8].

Direct pulmonary toxicity due to ifosfamide is very rare but possible [11]. The risk of CNS depression following ifos-famide therapy (about 12%) [12–13] should be considered in patients with advanced chronic obstructive lung disease, a common association in lung cancer, since somnolence may worsen hypercapnia and enhance encephalopathy. Caution is also needed in the case of underlying central or obstructive sleep apnea syndrome, since its prevalence in the general population is relatively high.

Methotrexate (MTX) is a cell cycle-specific agent that inhibits the enzyme dihydrofolate reductase, preventing the conversion of folic acid to tetrahydrofolic acid and inhibiting cell replication. MTX crosses the blood-brain barrier and can be administered intravenously and via an intrathecal route to eradicate leukemic cells from the CNS and prevent CNS recurrence. This is why chemotherapeutic regimens include methotrexate for acute lymphocytic leukemia treatment. Both high-dose intravenous MTX and intrathecal MTX are associated with demyelination, white matter necrosis, loss of oligodendroglia, axonal swelling, microcystic encephalo-malacia, and atrophy relatively selective for the deep cerebral white matter. A diminished choline-to-creatine ratio has been reported in children with MTX-related neurotoxicity; this may be related to disturbances of myelin metabolism or inhibition of glucose metabolism induced by MTX [14].

Acute MTX neurotoxicity usually results in stroke-like symptoms, such as aphasia, weakness, sensory deficits, ataxia, and seizures. Several cases of MTX-induced acute encephalopathy have been reported [15–19], presenting with confusion and even coma with high-dose methotrexate therapy. As with ifosfamide, clinicians should bear in mind the possibility of respiratory compromise in severe COPD.

3.3. Non-Cardiogenic Pulmonary Edema

Non-cardiogenic pulmonary edema may be caused by several drugs and multiple mechanisms In some cases, CNS toxicity due to intrathecal methotrexate may be the cause [20–21]. Less frequently, this methotrexate administration route has been associated with interstitial pneumonitis [22]. Non-cardiogenic pulmonary edema may also be the result of increased permeability. This has been reported with IL-2 infusions as well as with docetaxel [23]. Sirolimus (previously called rapamycin) is a macrolide antibiotic isolated from the fungus Streptomyces hygroscopicus. It has potent anticandida activity, but subsequent studies have revealed impressive antitumor and immunosuppressive activities as well [24]. The drug is used to prevent rejection of organs and bone marrow transplants and is also under investigation as a treatment for cancer. Among its side-effects, pulmonary edema or distress syndrome have occasionally been described [25].

3.4. Pleural Effusion

Docetaxel may cause pleural effusion by increasing permeability. However, although large effusions may cause severe respiratory compromise, some authors do not consider this to be a classic pulmonary toxicity. Occasionally, methotrexate has also been found to cause pleurisy [26].

4.1. Granulocyte Colony-Stimulating Factor (G-CSF)

These drugs are frequently prescribed to hasten recovery from cancer chemotherapy-induced neutropenia. Some have been reported to induce pulmonary edema. Pegfilgrastim is a long-acting G-CSF, recently approved by the Food and Drug Administration [28], and lenograstim is the glycosylated recombinant form of human granulocyte colony stimulating factor [29].

4.2. Monoclonal Antibodies

Monoclonal antibodies are a new class of non-cytotoxic agents targeted at specific receptors on cancer cells. In addition to their direct cellular effects, antibodies can carry substances such as radioactive isotopes, toxins, and antineoplastic agents to the targeted cells. Five monoclonal antibodies-rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan -- are available for clinical use. Monoclonal antibodies currently under study include edrecolomab and tositumomab [30–31].

Trastuzumab is a humanized anti-HER2 mAB which achieves response rates of 15-40% when used as a single agent in patients with metastatic HER2-overexpressing breast cancer, and prolongs survival when added to chemotherapy in first line therapy in these patients [32]. The major side-effects include pulmonary [33] and cardiac toxicity. Fleming et al. [32]. treated 45 patients with trastuzumab and IL2, a regimen that is no longer given today; grade 3 pulmonary toxicity or higher was found in five patients and attributed to intermediate-dose IL2 in three. Of the seven grade 2 pulmonary toxicities, six occurred in 21 patients known to have lung metastasis Several trastuzumab first-dose infusion-related reactions with pulmonary components were also found. Byrd et al. [34] observed that the five patients they treated with trastuzumab developed severe pulmonary infusion-related toxicity. Occasionally, organizing pneumonia has also been attributed to trastuzumab [35].

Rituximab is also known to cause pulmonary dysfunction, though probably less frequently than trastuzumab. Alveolar hemorrhage [36], acute pneumonitis and pulmonary fibrosis have been observed [37–40]. Very occasionally, a desquamative alveolitis is also found [41].

Recently, Biehn et al. [42] reported the first case of bronchiolitis obliterans organizing pneumonia caused by rituxi-mab. However, lung toxicity seems to be quite rare. In a recent study, Kanelli et al. [43] observed only one case of toxicity in a cohort of 27 patients.

Gemtuzumab ozogamicin was approved in 2000 by the FDA. Its major side-effect is hepatotoxicity (31% of patients show abnormal liver enzymes) but adult respiratory distress syndrome (ARDS) has also been reported [44]. Alentuzumab causes immunosuppression, increasing the risk of infections [31] and possibly ARDS [45]. Novel monoclonal antibodies such as tositumomab, edrecolomab and cetuximab appear promising but are still under evaluation [46–49].

4.3. All-Trans Retinoic Acid

Retinoids are natural or synthetic derivatives of vitamin A. All-trans retinoic acid has clinical applications in acute promyelocytic leukemia. More than half the patients treated with this drug experience retinoic acid syndrome, a disorder characterized by fluid retention, weight gain, respiratory distress, radiographic pulmonary infiltrates, hectic fever and pleural or pericardial effusion [50].

4.4. New Iatrogenic Risk Factors for Deep Venous Thrombosis and/or Pulmonary Embolism

It has long been recognized that patients with malignancies have an increased risk of thromboembolism [51], sometimes preceding cancer diagnosis or, more commonly, as complications. In addition to the well-known risk factors such as chemotherapy, hormonal therapy and tumor type and stage, other therapeutic strategies have been added to the list of risk factors for developing deep venous thrombosis and/or pulmonary embolism.

4.5. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (Gefitinib and Erlotinib)

Recent advances in cancer biology have led to the identification of several potential molecular targets that play a key role in cancer development and progression. Selective targeting of cancer cells on the basis of their molecular phenotype can provide effective anticancer activity, avoiding the side effects commonly induced by cytotoxic chemotherapy. Among these targets, the epidermal growth factor receptor (EGFR) has been widely investigated in different human malignancies due to its critical role in cancer proliferation and survival. The epidermal growth factor receptor (EGFR) is involved in cancer progression and development and, being overexpressed in a variety of human malignancies, is an attractive target for selective anticancer therapy. EGFR tyro-sine kinase inhibitors (TKIs) produce dramatic and durable responses in a fraction of non-small cell lung cancer patients [68–69].

Lung toxicity related to this tyrosine kinase activity inhibitor is very uncommon and usually mild [70]. Worldwide, the incidence of interstitial lung disease is <1% [2]. However, severe pulmonary reactions have also been reported [71].

5.1. Bronchial Artery Infusion of Cytostatic Drugs

Though not a new therapy, the effectiveness of the infusion of cytotoxic drugs into the bronchial artery has been reconsidered during the past decade for treatment of central advanced and early staged lung cancer [72] as well as for lung metastasis, although the instances reported in the latter case are fewer [73]. Though the technique allows the infusion of high-density chemotherapeutics into objective limited lesions [72] side-effects are not eliminated. In their study, Osaki et al. [72] treated seven patients, three of whom subsequently presented severe bronchial ulcers and one of whom died of pulmonary hemorrhage. Suzuki et al. [73] recently reported a massive hemoptysis from a bronchial pulmonary arterial fistula in a patient with lung metastasis. Lung hemorrhages usually occur between one and three months after bronchial artery infusion. Other side-effects include esophageal ulceration, spinal cord damage, and bronchial esophageal fistulas.

5.2. Intrathoracic Extravasation of Cytostatics

Most extravasation accidents involve the limbs However few data are available regarding intrathoracic extravasation of cytostatic agents administered in central venous lines. To date, only seven cases have been reported [74], in one child and six adults. In three cases the perforations were acute and were entirely procedure-related. Pain and fever were the prominent symptoms and leukocytosis was present in three patients. Computed tomography chest scan was the diagnostic method used. Late perforations may be related to an increased concentration of cytostatics due to elevated venous pressure which may favor the erosion of the vessel wall. Although there is no commonly accepted treatment at present, the standard administration of dalteparin/warfarin can allow the central line to remain in situ with little risk of line failure or recurrence/extension of the DVT [75]. Recent guidelines do not recommend antithrombotic prophylaxis (AP) to prevent catheter-related thrombosis in cancer patients with a central line. In their study, Fagnani et al. observed no difference in catheter-related thrombosis in patients given AP or not (2.8% vs 2.2% respectively). Systemic venous throm-boembolism (including deep and superficial thromboses and pulmonary embolism) was less frequent with AP (4% versus 8.2%), mortality was also lower (25% versus 44%, but only advanced cancer, not AP, was found to be significantly associated with mortality. No major bleeding was recorded with AP. So current AP schedules do not appear to prevent catheter-related thrombosis. Systemic venous thromboembolism and patients’ mortality, however, appeared lower after pro-phylaxis [76].

5.3. Venous Thromboembolism Associated to Central Venous Catheters

The first long-term central venous catheter (CVC) was introduced in 1973 by Boviac for parenteral nutrition. In the early 1980s, totally implantable port systems were introduced in clinical practice. Among early pulmonary complications are pneumothorax, hemothorax and air embolism (estimated rate ranging between 0.3% and 12%) [77]. CVC-related deep venous thrombosis are among late complications. The reported incidence of symptomatic catheter-related deep venous thrombosis in adults varies from 0.3% to 28% while the incidence of venographically demonstrated thrombosis ranges between 27 and 66%. The incidence with subcutaneous ports seems to be lower, around 1% (2 out of 175 patients [78–79].