Ординатура / Офтальмология / Английские материалы / Orbital Tumors Diagnosis and Treatment_Karcioglu_2005

Maarten Egeler et al.104 reported 18 patients with either recurrent multifocal or extensive/systemic LCH that required treatment. They treated their patients with cytosine arabinoside, prednisolone, and vincristine. Of the 18 patients, two died of their disease despite aggressive therapy; both patients who died had systemic involvement with organ involvement.

Ceci et al. reported the results of a large, multicenter cooperative trial for the treatment of children with LCH.105 This trial utilized a sequential approach: good-prognosis patients were successively treated with immunotherapy (“thymic extract”) followed by vinblastine, doxorubicin, then etoposide. Each new agent was begun only if the patient did not respond to the previous agent. Poor-prognosis patients were treated with combination chemotherapy (prednisone, vincristine, cyclophosphamide, and doxorubicin) up front. Of the good-prognosis patients, only 10% of those treated with immunotherapy had a complete response, whereas 63% of those treated with vinblastine and 88% of those treated with etoposide had a complete response. Results with doxorubicin were intermediate. Only 18% of patients with poor prognosis responded to the multiagent regimen. This group concluded that etoposide resulted in the best response rate, but that the best therapy for LCH was not known.

More recently, the Histiocyte Society directly compared etoposide with vinblastine for the treatment of LCH.106 One hundred forty-three children were treated with high-dose methylprednisolone, along with either etoposide (150 mg/m2 for 3 days every 3 weeks) or vinblastine (6 mg/m2 weekly). Both groups were treated for 24 weeks. Overall, 62% of the children had a response to therapy with no significant differences between the groups. This outcome was felt to be remarkably good, considering that many of these children had multisystem disease with organ dysfunction and were believed likely to have a poor prognosis without multiagent therapy. Also of note, patients with a rapid early response had a better outcome than did those with poor early response. The followup study, LCH-II, is comparing initial treatment with two versus three agents.

In summary, the manifestations of Langerhans cell histiocytosis remain protean, with orbital involvement seen in a significant percentage of patients. The correct therapy remains elusive, and a number of agents have been used with some success. Progress has been made; however, real improvement will come only with time and a concerted effort to enter children with this rare disease in cooperative trials.

CONCLUSIONS

Orbital tumors are rare events in children. The treatments for many, if not all of these tumors are

works in progress, and conclusions that are true today may not hold up, even in the near future. The standard of care for children with cancer is to be treated as part of a clinical study whenever possible. Therefore, when a child presents to the ophthalmologist with a potential malignancy, it is crucial that the pediatric oncologist be notified as soon as possible. Coordination of sample collection, pathologic evaluation, staging, and treatment is a team effort. This team approach has produced fantastic progress in both ocular outcome and overall survival in merely the past 40 years. As we continue to work together, the outlook for children with orbital tumors can only improve.

References

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The orbit contains a variety of tissues, including bone, striated and smooth muscles, peripheral and cranial nerves, fibrovascular adipose tissue and cartilage. The walls of the orbit are composed of seven bones, which lie adjacent to the paranasal sinuses and cranial cavity. Given its unique composition and location, the orbit may manifest a wide spectrum of disease that may be of primary origin, secondarily invasive, or a part of a more extensive systemic and inflammatory disorder. Comprehensive reviews of orbital diseases have been published.1–6 Primary neoplasms and systemic and inflammatory disorders each account for roughly 30% of all orbital diseases, while secondary neoplasms and metastases account for roughly 10 and 4%, respectively.1 This vast range of possible tumors lends itself to multimodality therapy. Radiation and surgery, where possible, are the mainstays of treatment; however, some diseases, such as those that are systemic and inflammatory, are best managed with chemotherapy. This chapter reviews the chemotherapeutic agents and their indications for usage in the treatment of orbital tumors as well as other diseases. The side effects and toxicities of each agent are reviewed at the end of the chapter. Because the literature contains numerous isolated case reports citing individual patients’ responses to novel regimens, the focus is on representative established

chemotherapeutic protocols.

INFLAMMATORY AND LYMPHOPROLIFERATIVE DISORDERS

Thyroid Eye Disease (Graves Disease)

Graves disease (GD) is an autoimmune disorder most commonly associated with hyperthyroidism but has been associated with both euthyroid and hypothyroid states. Lymphocytes infiltrate the orbit leading to deposition of mucopolysaccharides, glycosaminoglycans, and collagen. The resultant signs and symptoms of lid lag, exophthalmos, strabismus, and visual loss are well recognized. Management may include systemic immunosuppression, external beam radiation, and/or surgical decompression of the orbit. Strabismus and

eyelid surgery may follow once the disease has become quiescent.7

Indications for immunosuppression vary, and it should be noted that owing to differences between the acute and the chronic phases of inflammation, not all patients with GD show a significant response. Patients with an acute lymphocytic infiltrate will respond to immunosuppression, whereas those with chronic fibrotic changes will not.7 Thus, an accurate assessment of disease activity is needed.

Systemic corticosteroids are the most common immunosuppressants used in the treatment of GD. The exact mechanism by which these drugs decrease the orbital inflammation remains unclear; however, it most likely involves inhibiting the activity of T- and B-cell lymphocytes through a reduction in the recruitment of neutrophils, monocytes, and macrophages and subsequent reduction in the release of inflammatory mediators such as cytokines. This sequence ultimately would decrease the deposition of glycoaminoglycans by orbital fibroblasts.8,9

Patients who present with severe orbital inflammation and congestion with or without compressive optic neuropathy should be considered for corticosteroids. Oral prednisone (1.0–1.5 mg/kg) should be started for 7 to 10 days and subsequently tapered. In cases of severe visual loss, intravenous pulse methylprednisolone can be administered. Rapid improvement of signs and symptoms should occur; however, complete resolution is uncommon. Rebound of symptoms should be expected as the steroids are tapered and the dosage adjusted accordingly. Definitive therapy may ultimately be needed with orbital radiation and/or surgical decompression.10,11

Numerous side effects have been associated with prolonged use of corticosteroids. Most notably these include avascular necrosis of the hip, cataracts, cushingoid features, diabetes, glaucoma, hypertension, increased appetite, mood disturbances, osteoporosis, and gastric ulcers. Corticosteroid use should be limited to a few months. Agents that protect against osteoporosis and gastric irritation should be considered.

In addition to corticosteroids, cyclosporine, cyclophosphamide, and azathioprine have been used in patients who are resistant to or intolerant of steroids.8 Of these, cyclosporine has been the most extensively

studied. Cyclosporine inhibits both the activation of cytotoxic T cells and the antigen presentation by monocytes and macrophages and activates T-suppres- sor cells.12 Cyclosporine has been studied as a single agent and in combination with prednisone. As a single agent, cyclosporine is less effective than steroids; however, the combination of cyclosporine and prednisone proved more effective than single agent ther- apy.12–16 Side effects of cyclosporine are significant and include nephrotoxicity, hypertension, gastric irritation, hepatic toxicity, and paresthesias. The dosage should not exceed 7.5 mg/kg/day.15,16

Cyclophosphamide is a polyfunctional alkylating agent that selectively depletes activated B cells and inhibits lymphocyte proliferation. No clinical trials comparing its efficacy to corticosteroids have been published. Cyclophosphamide has been administered as 700 mg intravenously monthly or 85 to 100 mg/day orally to decrease orbital congestion. Careful consideration should be given to its use, since side effects include sterility, leukopenia, alopecia, and hematuria.17

Azathioprine has had limited use in the treatment of thyroid eye disease. Control studies using 2 mg/ kg/day failed to demonstrate efficacy as either an alternative or adjunct to corticosteroids.17,18

Idiopathic Orbital Inflammation

Idiopathic orbital inflammation, or orbital pseudotumor, represents a spectrum of disease, most often presenting as acute inflammatory proptosis. The swelling associated with inflammation, occurring in the absence of either underlying stimulus or an associated systemic disease, mimics an underlying orbital neoplasm, hence the description as pseudotumor. Inflammation may be generalized throughout the orbit or limited to an individual structure and as such is better classified as a myositis or dacryoadenitis. One or both orbits may be involved, with swelling and erythema of the eyelids; visual acuity and extraocular motility may be impaired, and the conjunctiva and underlying tendons may be edematous. Computed tomography (CT) and/or magnetic resonance (MR) imaging is useful in diagnosis and may differentiate pseudotumor from thyroid eye disease by revealing inflammation spreading along the tendinous insertions of the rectus muscles. Biopsy samples are characterized by a mixed inflammatory infiltrate composed of lymphocytes, plasma cells, degranulated eosinophils, and polymorphonuclear leukocytes. As the disease progresses, fibrosis may become more prominent.

The acute phase of the disease is very responsive to corticosteroids. Either oral prednisone (1–1.5 mg/ kg/day) or intravenous methylprednisilone (125 mg every 6 hours) should provide rapid relief of symptoms. An extended taper of the corticosteroids is advised to prevent rebound inflammation. Recurrence of disease

is not uncommon and should also respond to cortico- steroids.19–22

Protracted disease may necessitate additional therapeutic measures. Both external beam radiotherapy and immunosuppressive agents have been reported to be effective.23–24 Paris and colleagues reported on their success in treating 5 patients with refractory orbital pseudotumor using prednisone (100 mg/day) and either cyclophosphamide (100 mg/day) or chlorambucil (10 mg/day) in 5-day pulses.25 All patients responded clinically without serious side effects. Additional reports in the literature have substantiated these findings.26,27 Low-dose cyclosporine (2–5 mg/kg/day) and methotrexate (12.5 mg/week) have also been used to treat patients with steroid-resistant orbital pseudotumor with few serious side effects.28–30 Both drugs required 6 to 24 months of usage to suppress all inflammation. Recent work with the tumor necrosis factor inhibitor infliximab has shown promise in the treatment of ocular inflammatory syndromes; however, reports specific to the treatment of orbital pseudotumor are not yet available.31,32

Lymphoma

Lymphoproliferative diseases are the most common space-occupying lesions in the orbit and incorporate a spectrum of benign, borderline, and malignant processes: benign reactive lymphoid hyperplasia, atypical lymphoid hyperplasia, and malignant lymphoma (see Chapter 13).33,34 Most malignancies are non-Hodgkin’s lymphomas, expressing B-cell phenotype; either diffuse intermediate cell lymphomas (mucosa-associated lymphoid tissue lymphomas, mantle cell lymphomas) or diffuse, low-grade, small-cell lymphocytic or lymphoplasmacytic lymphomas.33,34 High-grade lymphomas have been reported in patients with acquired immunodeficiency syndrome (AIDS).33,34 Patients present with slow, gradually increasing proptosis, usually lasting several weeks to months. Inflammatory signs are minimal.

Radiotherapy is the mainstay of treatment for localized, low-grade B-cell lymphomas of the orbit in adults. For high-grade lymphomas, systemic chemotherapy may be added to the treatment regimen.35–37 This is particularly true in patients with AIDS who have large-cell immunoblastic lymphomas. Protocols using cyclophosphamide, etoposide, Adriamycin, vincristine, prednisone, bleomycin, and cisplatin have been tried in combination with radiation.38,39 Leff et al. described a case of ocular and adnexal lymphoma treated successfully with systemic cyclophosphamide, actinomycin, vincristine, and prednisolone.40

Recently rituximab, an anti-CD20 monoclonal antibody, has been shown to be effective in the treatment of orbital lymphomas. Esmaeli et al. administered 375 mg/week intravenously for 4 weeks to achieve control of the disease in 4 patients.41 Cohen

et al. used similar doses to treat a high-grade Burkitt’s lymphoma in an elderly patient.42

Rosai–Dorfman Disease

Nonneoplastic sinus histiocytosis with massive lymphadenopathy, or Rosai–Dorfman disease (RDD), is a rare disorder. RDD typically presents with painless massive cervical lymphadenopathy, caused when the lymph node sinuses are distended by an accumulation of lymphocytes and histiocytes. RDD can be distinguished by the preserved architecture of the lymph node and by the individual histiocytes containing intact lymphocytes or in some cases, other cells in the cytoplasm, a phenomenon known as emperipolesis.43 Although people of any age can be affected, this disease occurs most often in young adults and adolescents.43 Although RDD is usually indolent, the alternating episodes of worsening and resolving of symptoms make the disease unpredictable.43 The only treatment is surgery in select patients when nodal or extranodal lesions compromise vital organs. Anecdotal responses to chemotherapy have been documented, including the combination of alkylating agents with vincristine and steroids,44 and the combination of methotrexate and vinblastine.44,45 Radiation therapy with doses greater than 20 to 30 Gy appears to induce responses according to anecdotal reports.46 Unfortunately, meaningful conclusions cannot be drawn from these anecdotal responses. In fact most patients have persistent stable disease even though between 70 to 80% of the patients have spontaneous responses and resolution of the symptoms.43,44

Nodal disease is present in most but not all cases of RDD: more than 40% of patients experience extranodal involvement, and almost any system can be affected.43 RDD has a predilection for the tissues of the head and neck, including involvement of the upper aerodigestive tract, including the nasal and oral cavities, and the paranasal sinuses in about 20% of the cases.43,47 Involvement of the orbits or the central nervous system occurs in only 5 to 10% of cases.

PRIMARY ORBITAL MALIGNANCY

Carcinomas

The lacrimal gland is the only orbital structure with epithelium and thus is the site of origin of all primary orbital carcinomas, which account for approximately 3% of all orbital tumors. The most common carcinomas of the lacrimal gland are adenoid cystic carcinoma, malignant mixed tumors, and adenocarci- noma.1–6 Excision and external beam radiotherapy are recommended.

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma of the lacrimal gland has a mean age of presentation of 40 years. Patients are usually symptomatic for less than 1 year prior to diagnosis. Presenting symptoms may include ptosis, numbness, pain, and diplopia. Computed tomography shows a rounded, nonencapuslated lesion with adjacent destructive bony changes.47 Although exenteration with removal of involved bone has yielded a survival of only 20 to 60% at 10 years, adjunctive radiotherapy has been thought to improve survival.48–50 Conservative therapy for lesions confined to the lacrimal gland, namely, en bloc excision of the lacrimal gland followed by proton beam radiotherapy, has been promoted recently.51

Adenoid cystic carcinoma is a highly malignant tumor with a predisposition for the head and neck. Reports regarding the use of chemotherapy for treatment of adenoid cystic carcinoma of the orbit are limited and build on data from the otolaryngology literature. Meldrum and colleagues treated two patients with extensive adenoid cystic carcinoma of the orbit with intracarotid cisplatin and intravenous doxorubicin prior to orbital exenteration.52 Postoperatively, the patients received 55 to 60 Gy of orbital irradiation, augmented by additional intravenous cisplatin and doxorubicin. Limited morbidity was experienced, and both patients achieved long-term survival.

Adenoid cystic carcinomas of the head and neck have been treated effectively with cisplatin-based chemotherapy.53,54 Cisplatin alone or in combination with doxorubicin and bleomycin provided a median progression-free survival of 36 months. Additional investigators report the use of mitomycin C, 5-flu- orouracil, cyclophosphamide, vincristine, and Adriamycin in varying combination in attempted salvage therapy.55–57

Adenocarcinomas and malignant mixed tumors are so rare that no meaningful recommendations can be drawn from the medical literature regarding the use of chemotherapy. Surgery and radiotherapy remain the recommended treatment.

Sarcomas

The most common sarcomas of the orbit in adults are malignant fibrous histiocytoma, hemangiopericytoma, fibrosarcoma, malignant peripheral nerve sheath, chondrosarcoma, and liposarcoma, each accounting for less than 1% of all orbital tumors.1–6,58 Although excision and radiotherapy are the standard treatment, the relatively infrequent occurrence of these tumors plus their diverse histology and presentation have made it difficult for any one institution to have enough patients to directly compare, in a randomized prospective fashion, one treatment with an-

other for purposes of determining the optimal primary therapy. Combination chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dacarbazine has been proven effective in treating soft tissue sarcomas located both inside and outside the orbit.59,60 Regimens using doxorubicin and ifosfamide and cisplatin, etoposide, and ifosfamide have also proven effective in treating sarcoma.61 Discretion in the use of chemotherapy to treat these rare orbital tumors should be left to the ophthalmologist and the medical oncologist.

Osteosarcoma

Osteosarcoma is the most common malignant bone tumor in the pediatric age group,62 ranking tenth among all newly reported pediatric cancer patients in the United States. Accounting for 2.6% of all neoplasms in children, osteosarcoma is a malignant neoplasm derived from primitive mesenchymal cells and characterized by the presence of osteoid-producing spindle cell stroma.63 Most osteosarcomas occur in males more often than females, during the first two decades of life when rapid skeletal growth occurs. Preexisting pathologic osseous conditions such as Paget’s disease, fibrous dysplasia, or previously irradiated areas account for more than 25% of osteosarcomas in adults.62 Less than 5% of the osteosarcoma cases occur in the head and neck area; of those, the disease is more common in the maxilla or mandible, but a small number of tumors develop in the orbit.64 A study of 91 patients with second malignant bone sarcomas confirmed that secondary osteosarcoma frequently occurs from irradiation. Of the 72 cases that were osteosarcoma, 52 (72%) occurred within previously irradiated fields.65 The median time for the development of the secondary tumor was 9.6 years. Accounting for up to 44% of cases, osteosarcoma is the most common second neoplasm seen in children with retinoblastoma; in fact, the estimated 50-year cumulative incidence for secondary neoplasms in these children is 51% in hereditary cases and 5% in nonhereditary cases.66 Further, osteosarcoma of the irradiated orbital bones may not develop until the patient has reached adolescence or early adulthood. Another risk factor for the development of secondary nonocular tumors is hereditary retinoblastoma, regardless of whether the patient has previously undergone irradiation to the primary site.66,67

Death from metastatic disease occurred in more than 80% of patients diagnosed with osteosarcoma prior to the use of adjuvant chemotherapy.68 In the 1960s and early 1970s, the use of chemotherapy in the treatment of osteosarcoma was established by nonrandomized clinical trials Twenty to 40% of patients with metastatic disease responded to high-dose methotrexate or doxorubicin.68,69 Today, 50 to 75% of patients with nonmetastatic disease are cured through

the use of standard chemotherapy regimens incorporating various combinations of platinum compounds, doxorubicin, and high-dose methotrexate.70,71

SECONDARY ORBITAL MALIGNANCY

Secondary orbital malignancies are those that invade the orbit from adjacent structures: eyelids, conjunctiva, eye, and paranasal sinuses. Squamous cell and basal cell carcinomas are by far the most common cancers to invade the adult orbit. Other less common orbital tumors include sebaceous cell carcinoma and uveal melanoma.

Basal Cell Carcinoma

Basal cell carcinoma is the most common malignant tumor of the eyelid. Methods of treatment include surgical excision, cryotherapy, and radiation. Large and deeply invasive lesions are often unresectable and pose difficult management problems. Systemic chemotherapy with cisplatin alone or in combination with doxorubicin has been used to reduce tumor volume, allowing for less extensive surgical resection.72–74 Local administration of cisplatin delivered via iontophoresis has also produced modest results.75 Intralesional injections of human interferon alfa have been reported to produce complete regression of basal cell carcinomas of the eyelid.76

Squamous Cell Carcinoma

Squamous cell carcinomas that secondarily invade the orbit may arise from the eyelid, paranasal sinuses, or the conjunctiva. In the past, these tumors of the eyelid have been treated similarly to basal cell carcino- mas.72–75 Advances in the treatment of head and neck squamous cell carcinomas lend themselves to the treatment of aggressive squamous cell carcinoma arising in any of the periorbital structures. As with the treatment of basal carcinoma, most chemotherapy regimens have been cisplatin-based.77 Intra-arterial delivery of cisplatin, in conjunction with external beam radiotherapy, represents one of the multiple uses of this chemotherapy agent.78–80 Other protocols that have proven to be effective include docetaxel, cisplatin and 5-fluorouracil, paclitaxel, cisplatin, and 5-fluor- ouracil, cisplatin, and tegafur. Most patients required radiation treatment as well.81–86 Recent attention has been paid to cetuximab, an antiepidermal growth factor receptor antibody. Cetuximab enhances the antitumor effects of chemotherapy by inhibiting cell proliferation, angiogenesis, and metastasis and by promoting apoptosis.87–89

Squamous cell carcinoma of the conjunctiva and/or cornea is best treated primarily with excision and

cryotherapy. For recurrent disease and for tumors that encompass a significant proportion ( 50% of the limbus) of the ocular surface, topical mitomycin C has been shown to be an effective treatment. Concentrations varying from 0.01% to 0.04% have been prescribed, each demonstrating minimal toxicity when applied to an intact epithelium.90,92 Topical 5-fluor- ouracil has also proven successful in the treatment of these lesions, once again displaying minimal toxicity.93,94 Human interferon alfa has also been used to treat squamous carcinoma of the conjunctiva and/or cornea with reports of complete regression with limited toxicity. Other topical agents that have been investigated include urea, thiotepa, and dinitrochlorobenzene.95,96 Although each was shown to be effective, none is currently accepted as standard treatment.

Malignant Melanoma

Melanomas may invade the orbit from eyelids, conjunctiva, or eyes. Best treated with wide local excision, melanomas of the eyelids may arise de novo, from preexisting nevi, or from lentigo maligna.96 Concurrently, a sentinel node biopsy may be performed to evaluate for possible micrometastatic disease and the need for systemic chemotherapy.98,99 At present, no good treatment for metastatic melanoma has been developed. Most recent studies have investigated biochemotherapy; using interleukin 2 and interferon alfa in conjunction with a nitrosurea such as carmustine (BCNU).100–103 Based on the depth of invasion by the melanoma into the subcutaneous tissues, adjuvant therapy may be warranted to bolster the immune system, even if there is no detectable metastatic disease. Interferon alfa and granulocyte–macrophage colonystimulating factor have been investigated as immune boosters, and shown to prolong disease-free sur- vival.104–106 Immunotherapy with vaccines is also an area of current research that shows some success.105–107

Conjunctival melanomas more closely mimic cutaneous melanomas in their behavior, with prognosis relating to the thickness of the lesion at the time of excision. Melanomas of the conjunctiva may arise de novo, from preexisting nevi, or from primary acquired melanosis with atypia. Complete excision with cryotherapy is the recommended treatment.108 Melanomas of the conjunctiva will metastasize to the preauricular or submandibular lymph nodes. As with melanomas of the eyelid, a sentinel node biopsy may be performed at the time of excision to detect micrometastic disease.98,99 Finger and colleagues showed that topical mitomycin C can reduce tumors, minimizing the amount of surgery needed.109 Premalignant lesions such as primary acquired melanosis with atypia respond to topical mitomycin C, decreasing the likelihood of a subsequent malignancy.109,110 The

treatment of metastases is the same as for cutaneous lesions described earlier.100–107

Uveal melanomas may invade the orbit along an emissary canal. Small foci of disease may be included in the field of radiation if the patient elects to be treated with 125I episcleral plaque brachytherapy.111 In cases of enucleation, a partial tenonectomy may be performed with or without subsequent radiation. Massive orbital involvement requires an exenteration. Metastatic disease is now most often treated with biochemotherapy.100–103 For isolated liver metastases, isolated hepatic perfusion with melphalan has been performed and found to prolong relapse-free survival.112–114

METASTASES

In adults, breast, prostate, lung, and gastrointestinal carcinomas are the most frequent to metastasize to the orbit. In the absence of known metastatic disease, a biopsy should be performed to confirm the diagnosis. For newly diagnosed metastatic disease, the patient should be restaged by the oncologist. Isolated orbital metastases may be treated with radiation alone; however, in the setting of systemic metastases, it is necessary to decide whether to proceed with radiation or wait to determine the efficacy of chemotherapy. Vision-threatening metastases require urgent treatment, and radiation should be initiated as soon as possible. The prescribed chemotherapy will be based on the primary tumor, prior treatment, and extent of disease.

SIDE EFFECTS OF CHEMOTHERAPY

Chemotherapeutic agents are able to preserve life and spare vision but should be used judiciously owing to the potential serious side effects. The drugs are best administered under the direction of a medical oncologist. The incidence and location of side effects relate to the route of administration, the dose, and tissues exposed to treatment. Table 35.1 summarizes the chemotherapeutic agents discussed in this chapter and their systemic toxicities. For a more complete discussion, consult Hardman and Limbard’s text, The Pharmacological Basis of Therapeutics (9th edition).115

In summary, the akylating agents include nitrogen mustards, ethylenimines, nitrosureas, and the triazenes. The primary clinical toxicity of each of these agents is myelosuppression. Nausea and vomiting are also common side effects of alkylating agents. More specifically, ifosfamide has caused central nervous system and renal toxicity in some patients. BCNU can cause both nephrotoxicity as well as pulmonary toxicity. The antimetabolites include methotrexate, 5-