Iris malignant melanoma is the most common primary neoplasm of the iris and can be most easily seen by the physician on clinical examination. It is usually a small, discrete lesion, although it may occasionally be diffuse and infiltrative; multiple; and result in heterochromia, glaucoma, chronic uveitis, or spontaneous hyphema. Many patients are often aware of a pigmented spot on the iris that has been present for many years and only recently has begun to grow. With a slit lamp, gonioscopy, and serial slit lamp photography, the ophthalmologist can document the size and growth of the tumor without biopsy. Fluorescein angiography may be helpful in demonstrating the vascularity of the lesion, but is not diagnostic. Ultrasonography is of little value in the evaluation of iris melanoma.

Iris melanoma is relatively benign with a 5-year survival rate of approximately 95%. This is related to the fact that iris melanomas are predominantly of the spindle A-cell type and are usually smaller in size than posterior melanoma because of earlier detection. Conservative management is generally advocated whenever possible, but surgical intervention may be justified with unequivocal tumor growth and with extensive melanomas at initial examination.

Standard treatment options:

1. No treatment with careful observation including serial photography (in asymptomatic patients with stable lesions).

2. With documented growth, excisional surgery:

3. Enucleation (in some patients with diffuse involvement of the iris, with involvement of more than one-half of the iris and anterior chamber angle and documented growth, with extensive iris involvement and intractable glaucoma, with large unresectable tumors and/or extraocular extension, and with tumors in eyes with no salvageable vision).

Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary form of treatment and results in cure in approximately 50% of patients. Recurrence following surgery is a major problem and often is the ultimate cause of death. The prognosis of colon cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. These 2 characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. Many other prognostic markers have been evaluated retrospectively in the prognosis of patients with colon cancer, although most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated. Microsatellite instability, also associated with hereditary nonpolyposis colon cancer, has been shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients less than 50 years of age with colorectal cancer.Age greater than 65 years at presentation is not a contraindication to standard therapies; acceptable morbidity and mortality, as well as long-term survival, are achieved in this patient population. Racial differences in overall survival after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.

Because of the frequency of the disease, the identification of high-risk groups, the demonstrated slow growth of primary lesions, the better survival of patients with early-stage lesions, and the relative simplicity and accuracy of screening tests, screening for colon cancer should be a part of routine care for all adults starting at age 50 years, especially for those with first-degree relatives with colorectal cancer. There are groups that have a high incidence of colorectal cancer. These groups include those with hereditary conditions, such as familial polyposis, hereditary nonpolyposis colon cancer (HNPCC) or Lynch SyndromeVariants I and II, and ulcerative colitis. Together they account for 10% to 15% of colorectal cancers. Patients with HNPCC reportedly have better prognoses in stage-stratified survival analysis than patients with sporadic colorectal cancer, but the retrospective nature of the studies and possibility of selection factors make this observation difficult to interpret. More common conditions with an increased risk include: a personal history of colorectal cancer or adenomas, first degree family history of colorectal cancer or adenomas, and a personal history of ovarian, endometrial, or breast cancer. These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers.

Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease. However, the impact of such monitoring on overall mortality of patients with recurrent colon cancer is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, there have been no large-scale randomized trials documenting the efficacy of a standard, postoperative monitoring program. CEA is a serum glycoprotein frequently used in the management of patients with colon cancer. A review of the use of this tumor marker suggests: that CEA is not a valuable screening test for colorectal cancer due to the large numbers of false-positive and false-negative reports; that postoperative CEA testing be restricted to patients who would be candidates for resection of liver or lung metastases; and that routine use of CEA alone for monitoring response to treatment not be recommended. However, the optimal regimen and frequency of follow-up examinations are not well defined, since the impact on patient survival is not clear and the quality of data is poor. New surveillance methods including CEA immunoscintigraphy  and positron emission tomography are under clinical evaluation.

Treatment Options

Cellular Classification

Histologically, mesotheliomas are composed of fibrous or epithelial elements or both. The epithelial form occasionally causes confusion with peripheral anaplastic lung carcinomas or metastatic carcinomas. Attempts at diagnosis by cytology or needle biopsy of the pleura are often unsuccessful. It can be especially difficult to differentiate mesothelioma from adenocarcinoma on small tissue specimens. Thoracoscopy can be valuable in obtaining adequate tissue specimens for diagnostic purposes. Examination of the gross tumor at surgery and use of special stains or electron microscopy can often help. The special stains reported to be most useful include periodic acid-Schiff diastase, hyaluronic acid, mucicarmine, CEA, and Leu M1. Histologic appearance appears to be of prognostic value, with most clinical studies showing that epithelial mesotheliomas have a better prognosis than sarcomatous or mixed histology mesotheliomas.

Stage Information

Patients with stage I disease have a significantly better prognosis than those with more advanced stages. However, because of the relative rarity of this disease, exact survival information based upon stage is limited. A proposed staging system based upon thoracic surgery principles and clinical data is shown below. It is a modification of the older system proposed by Butchart et al. Other staging systems that have been employed, including a proposed new international TNM staging system, are summarized by the International Mesothelioma Interest Group.

Stage I: Disease confined within the capsule of the parietal pleura: ipsilateral pleura, lung, pericardium, and diaphragm

Stage II: All of stage I with positive intrathoracic (N1 or N2) lymph nodes

Stage III: Local extension of disease into the following: chest wall or mediastinum; heart or through the diaphragm, peritoneum; with or without extrathoracic or contralateral (N3) lymph node involvement

Stage IV: Distant metastatic disease

Treatment Option Overview

Standard treatment for all but localized mesothelioma is generally not curative. Although some patients will experience long-term survival with aggressive treatment approaches, it remains unclear if overall survival has been significantly altered by the different treatment modalities or by combinations of modalities. Extrapleural pneumonectomy in selected patients with early stage disease may improve recurrence-free survival, but its impact on overall survival is unknown. Pleurectomy and decortication can provide palliative relief from symptomatic effusions, discomfort caused by tumor burden, and pain caused by invasive tumor. Operative mortality from pleurectomy/decortication is less than 2%, while mortality from extrapleural pneumonectomy has ranged from 6% to 30%. The addition of radiation therapy and/or chemotherapy following surgical intervention has not demonstrated improved survival. The use of radiation therapy in pleural mesothelioma has been shown to alleviate pain in the majority of patients treated. However, the duration of symptom control is short-lived. Single agent and combination chemotherapy have been evaluated in single and combined modality studies. The most studied agent is doxorubicin, which has produced partial responses in approximately 15% to 20% of patients studied. Some combination chemotherapy regimens have been reported to have higher response rates in small phase II trials. However the toxicity reported is also higher and there is no evidence that combination regimens result in longer survival or longer control of symptoms. Recurrent pleural effusions may be treated with pleural sclerosing procedures; however, failure rates are usually secondary to the bulk of the tumor, which precludes pleural adhesion due to the inability of the lung to fully expand.

Current approaches to postremission therapy for adult acute lymphoblastic leukemia (ALL) include short-term, relatively intensive chemotherapy followed by longer-term therapy at lower doses (maintenance), high-dose marrow-ablative chemotherapy or chemoradiotherapy with allogeneic stem cell rescue (alloBMT), and high-dose therapy with autologous stem cell rescue (autoBMT). Several trials of aggressive postremission chemotherapy for adult ALL now confirm a long-term disease-free survival rate of approximately 40%. In the latter 2 series, especially good prognoses were found for patients with T-cell lineage ALL, with disease-free survival rates of 50% to 70% for patients receiving postremission therapy. These series represent a significant improvement in disease-free survival rates over previous, less intensive chemotherapeutic approaches. In contrast, poor cure rates were demonstrated in patients with Philadelphia chromosome-positive (Ph+) ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11). Administration of the newer dose-intensive schedules can be difficult and should be performed by physicians experienced in these regimens at centers equipped to deal with potential complications. Studies in which continuation or maintenance chemotherapy were eliminated had outcomes inferior to those with extended treatment durations.

AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a bone marrow transplant from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in disease-free survival in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis. The results of a retrospective study showed a similar outcome to that for intensive chemotherapy for patients receiving alloBMT in first remission in both the International Bone Marrow Transplant Registry and the German chemotherapy trial (Berlin-Frankfurt-Munster). In a prospective French trial, adults with ALL in remission and who were younger than age 40 years received alloBMT if a sibling donor was available or were randomly assigned to either ongoing chemotherapy or autoBMT. There was no advantage to alloBMT for the group of patients with standard-risk ALL.There was, however, significant survival benefit to alloBMT for patients with high-risk ALL (CD10-; B-cell lineage ALL with a white blood cell count >30,000; Ph1+ ALL). This trial confirms the experience of a single institution that suggested the utility of alloBMT for the cure of high-risk ALL. The long-term survival of patients in the French randomized study who received chemotherapy and autoBMT was identical. The use of alloBMT as primary postremission therapy is limited both by the need for an HLA-matched sibling donor and by the increased mortality from alloBMT in patients in their 5th or 6th decade. The mortality from alloBMT using an HLA-matched sibling donor ranges from 20% to 40%, depending on the study. The use of matched unrelated donors for alloBMT is currently under evaluation but, because of its current high treatment-related morbidity and mortality, is reserved for patients in second remission or beyond. The dose of total body irradiation administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.

Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin's lymphoma have shown improved outcome of prolonged disease-free status for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive). Retrospectively reviewing 3 sequential cooperative group trials from Germany, Hoelzer and colleagues found a marked improvement in survival, from zero survivors in a 1981 study that used standard pediatric therapy and lasted 2.5 years, to a 50% survival rate in 2 subsequent trials that used rapidly alternating lymphoma-like chemotherapy and were completed within 6 months. Aggressive CNS prophylaxis remains a prominent component of treatment. This report, which requires confirmation in other cooperative group settings, is encouraging for patients with L3 ALL. Patients with surface immunoglobulin but L1 or L2 morphology did not benefit from this regimen. Similarly, patients with L3 morphology and immunophenotype but unusual cytogenetic features were not cured with this approach. A white blood cell count of less than 50,000 per microliter predicted improved leukemia-free survival in univariate analysis. Because the optimal postremission therapy for patients with ALL is still unclear, participation in clinical trials should be considered.

Standard treatment options for remission induction therapy:

Most current induction regimens for adult acute lymphoblastic leukemia (ALL) include prednisone, vincristine, and an anthracycline. Some regimens also add other drugs, such as asparaginase or cyclophosphamide. Current multiagent induction regimens result in complete response rates that range from 60% to 90%.

Two subtypes of adult ALL require special consideration. B-cell ALL which expresses surface immunoglobulin and cytogenetic abnormalities such as t(8;14), t(2;8), and t(8;22)] is not usually cured with typical ALL regimens. Aggressive brief duration high-intensity regimens similar to those used in aggressive non-Hodgkin's lymphoma have shown high response rates and cure rates (75% complete remission; 40% failure-free survival). T-cell ALL, including lymphoblastic lymphoma, similarly has shown high cure rates when treated with cyclophosphamide-containing regimens. Whenever possible, such patients should be entered in clinical trials designed to improve the outcomes in these subsets. (Refer to the PDQ summary on Adult Non-Hodgkin's Lymphoma Treatment for more information on B-cell (Burkitt's) lymphoma and T-cell (lymphoblastic) lymphoma.)

Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during remission induction treatment. Facilities must be available for hematological support as well as for the treatment of infectious complications.

Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate. Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000 per cubic millimeter rather than 20,000 per cubic millimeter. The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors. Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic. Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities, including filtered air, sterile food, and gut flora sterilization are not routinely indicated but may benefit transplant patients. Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that are not responding to antibiotics. Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100 per cubic millimeter for 2 weeks), although further studies are necessary. To detect the presence or acquisition of resistant organisms, serial surveillance cultures may be helpful in such patients. The use of myeloid growth factors during remission induction therapy appears to decrease the time to hematopoietic reconstitution.

Treatment options for remission induction therapy under clinical evaluation:

Clinical trials are ongoing, and patients should be considered for these studies.

Standard treatment options for central nervous system (CNS) prophylaxis:

The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease.

1. Cranial irradiation plus intrathecal (IT) methotrexate.

2. High-dose systemic methotrexate and IT methotrexate without cranial irradiation.

3. IT chemotherapy alone.

Successful treatment of acute lymphoblastic leukemia (ALL) consists of the control of bone marrow and systemic disease as well as the treatment (or prevention) of sanctuary-site disease, particularly the central nervous system (CNS). The cornerstone of this strategy includes systemically administered combination chemotherapy with CNS preventive therapy. CNS prophylaxis is achieved with chemotherapy (intrathecal and/or high-dose systemic) and, in some cases, cranial irradiation.

Treatment is divided into 3 phases: remission induction, CNS prophylaxis, and remission continuation or maintenance. The average length of treatment of ALL varies between 1.5 and 3 years in the effort to eradicate the leukemic cell population. Younger adults with ALL may be eligible for selected clinical trials for childhood ALL.

It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is morphologically indistinguishable from the Philadelphia (Ph) chromosome. The Ph chromosome occurs in only 1% to 2% of patients with AML, but it occurs in about 20% of adults and a small percentage of children with ALL. In the majority of children and in more than one half of adults with Ph chromosome-positive (Ph+) ALL, the molecular abnormality is different from that in Ph+ chronic myelogenous leukemia (CML).

Ph+ ALL has a worse prognosis than most other types of ALL, although many children and some adults with Ph+ ALL may have complete remissions following intensive ALL treatment clinical trials. If a suitable donor is available, allogeneic bone marrow transplantation should be considered because remissions are generally short with conventional ALL chemotherapy clinical trials. Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph chromosome, have no evidence of the abnormal chromosome by cytogenetics. Because many patients have a different fusion protein from the one found in CML (p190 versus p210), the bcr-abl fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction (RT-PCR). These tests should be performed whenever possible in patients with ALL, especially those with B-cell lineage disease. Two other chromosomal abnormalities with poor prognosis are t(4;11), which is characterized by rearrangements of the MLL gene and may be rearranged despite normal cytogenetics, and t(9;22). In addition to t(9;22) and t(4;11), patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years compared to patients with a normal karyotype. In multivariate analysis, karyotype was the most important predictor of disease-free survival. L3 ALL is associated with a variety of translocations which involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus (t(2;8), t(8;12), and t(8;22)). Unlike bcr-abl-positive ALL and t(4;11) ALL, there is some evidence that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

There is no clear-cut staging system for this disease.

Untreated

For a newly diagnosed patient with no prior treatment, untreated adult acute lymphoblastic leukemia (ALL) is defined as an abnormal white blood cell count and differential, abnormal hematocrit/hemoglobin and platelet counts, abnormal bone marrow with more than 5% blasts, and signs and symptoms of the disease.

In remission

A patient who has received remission-induction treatment of ALL is in remission if the bone marrow is normocellular with less than 5% blasts, there are no signs or symptoms of the disease, no signs or symptoms of central nervous system leukemia or other extramedullary infiltration, and all of the following laboratory values are within normal limits: white blood cell count and differential, hematocrit/hemoglobin level, and platelet count.