Malignant Melanoma

INTRODUCTION

Background: Malignant melanoma is a neoplasm of melanocytes or of the cells that develop from melanocytes. Once considered an uncommon disease, the annual incidence of melanoma has increased dramatically over the last few decades.

Prognosis is related to the depth of invasion and to nodal status at diagnosis. Early-stage melanoma is curable; but, once the melanoma has metastasized, prognosis is grim, with a median survival of only 6-9 months. For this reason, physicians must be aware of the clinical characteristics of melanoma to make an early diagnosis. Prognosis is also related to the type of melanoma.

Pathophysiology: Melanomas originate from melanocytes, which arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis.

Melanomas may develop in or near a previously existing precursor lesion or in healthy-appearing skin. A malignant melanoma developing in healthy skin is said to arise de novo, without evidence of a precursor lesion. Many of these melanomas are induced by solar irradiation. The greatest risk of sun exposure-induced melanoma is associated with acute, intense, and intermittent blistering sunburns. This risk is in opposition to squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

Melanoma also may occur in unexposed areas of the skin, including the palms, soles, and perineum. Certain lesions are considered to be precursor lesions of melanoma, which include the common acquired nevus, dysplastic nevus, congenital nevus, and cellular blue nevus.

Melanomas have 2 growth phases, radial and vertical. During the radial growth phase, malignant cells grow in a radial fashion in the epidermis. With time, most melanomas progress to the vertical growth phase, when the malignant cells invade the dermis and develop the ability to metastasize.

Many genes are implicated in the development of melanoma, including CDKN2A (p16), CDK4, RB1, CDKN2A (p19), PTEN/MMAC1, and ras. CDKN2A (p16) appears to be especially important in both sporadic and hereditary melanomas. This tumor suppressor gene is located on band 9p21, and its mutation plays a role in various cancers.

Five different forms or histologic types of melanoma exist, which are as follows:

Superficial spreading melanomas

Approximately 70% of cutaneous malignant melanomas are the superficial spreading melanoma (SSM) type and often arise from a pigmented dysplastic nevus. SSMs typically develop after a long-standing stable nevus changes, such as ulceration, enlargement, or color changes. A SSM may be found on any body surface, especially the head, neck, and trunk of males and the lower extremities of females.

Nodular melanomas

Nodular melanomas (NMs) represent approximately 10-15% of melanomas and also are found commonly on all body surfaces, especially the trunk of males. These lesions are the most symmetrical and uniform of the melanomas and are dark brown or black in color. The radial growth phase may not be evident in NMs; however, if this phase is evident, it is short lived because the tumor advances rapidly to the vertical growth phase, thus making the NM a high-risk lesion. Amelanotic melanomas represent approximately 5% of all NMs.

Lentigo maligna melanomas

Lentigo maligna melanomas (LMMs) also account for 10-15% of melanomas. They typically are found on sun-exposed areas (eg, hand, neck). LMMs may have areas of hypopigmentation and often are quite large. LMMs arise from a lentigo maligna precursor lesion.

Acral lentiginous melanomas

Acral lentiginous melanomas (ALMs) are the only melanomas that have an equal frequency among blacks and whites and occur on the palms, soles, and subungual areas. Subungual melanomas often are mistaken for subungual hematomas (splinter hemorrhages). Like the NM, ALM is extremely aggressive, with rapid progression from the radial to vertical growth phase.

Mucosal lentiginous melanomas

Mucosal lentiginous melanomas (MLMs) develop from the mucosal epithelium that lines the respiratory, gastrointestinal, and genitourinary systems. These lesions account for approximately 3% of the melanomas diagnosed annually and may occur on any mucosal surface, including the conjunctiva, oral cavity, esophagus, vagina, female urethra, penis, and anus. Noncutaneous melanomas commonly are diagnosed in advanced-aged patients. When compared to cutaneous melanomas, MLMs appear to have a more aggressive course, although this may be because they commonly are diagnosed at a later stage of disease than the more readily apparent cutaneous melanomas.

Frequency:
　

• In the US: Although melanoma only accounts for approximately 5% of skin cancers, it is responsible for 3 times as many deaths each year as nonmelanoma skin cancers. The incidence of melanoma increases by 5-7% yearly, an annual increase second only to lung cancer in women. While the lifetime risk of developing melanoma in 1935 was only 1:1500, the lifetime risk in 2000 is estimated at 1:75.

• Internationally: Queensland, Australia has the highest incidence of melanoma in the world, approximately 57 cases per 100,000 people per year. Israel also has one of the highest incidences at approximately 40 cases per 100,000 people annually.

Mortality/Morbidity: If detected early, melanoma can be cured with surgical excision.

• Stage I: Lesions less than 1.5 mm thick with no evidence of metastases are associated with a 5-year survival rate of greater than 90%.

• Stage II: Melanomas greater than 1.5 mm but less than 4 mm with no evidence of metastases have an overall 5-year survival rate of 70-80%.

• Stage III: Patients with melanomas larger than 4.0 mm or with lymph node invasion have a survival that decreases to approximately 35-48%.
  
  　
• Stage IV: Patients with distant metastases have a grim prognosis, with a 5-year survival rate of less than 2%.

Race: Melanoma is more common in whites than in blacks and Asians. The rate of melanoma in blacks is estimated to be up to one twentieth that of whites. White people with dark skin also have a much lower risk of developing melanoma than those with light skin. The typical patient with melanoma has fair skin and a tendency to sunburn rather than tan. White people with blond or red hair and excessive freckling appear to be most prone to melanomas. In Hawaii and the southwestern US, whites have the highest incidence, approximately 20-30 cases per 100,000 people per year.

Sex: Melanoma is slightly more common in men than women (1.2:1). Melanoma is the sixth most common malignancy in women and the seventh most common malignancy in men.

Age: Melanoma may occur at any age, although children younger than 10 years rarely develop a de novo melanoma.

• The average age at diagnosis is 57 years, and as much as 75% of cases are patients younger than 70 years.

• Melanoma is the most common malignancy in women aged 25-29 years and accounts for more than 7,000 deaths annually.

CLINICAL

Section 3 of 11

History:

• Family history: Carefully obtain the family history of melanoma or skin cancer. Also, a family history of irregular, prominent moles is important. Approximately 10-20% of all patients with melanoma have a family history of melanoma. These patients typically are diagnosed at an earlier age and tend to have multiple dysplastic nevi. These patients also more likely have multiple primaries.

• Patient history: Previous history of melanoma must be elicited from patients, because these patients are at an increased risk for developing a second melanoma. Patients have reported as many as 8 or more primary melanomas. Multiple primaries especially are prevalent in patients with multiple dysplastic nevi. The term familial atypical mole or melanoma (FAMM) syndrome is used to describe this hereditary tendency to develop multiple dysplastic nevi and melanomas.

• Sun exposure: Extensively question the patient about previous sun exposure, including severe sunburns in childhood. The capacity to tan also is important because individuals who tan easily are less likely to develop a melanoma than those who burn easily.

• Moles: Question the patient about any changes noted in moles. Any history of change in size, color, or symmetry, as well as knowledge of bleeding or ulceration of the lesion must be obtained. Also elicit history or family history of multiple nevus syndrome.

Physical:

• Total body examination

• A total body skin examination is crucial when evaluating a patient with an atypical nevus or a melanoma. The skin exam should be performed both on initial evaluation of the patient and at all subsequent visits.

• Crucial to a good skin examination is a well-lit examining room and a completely disrobed patient.

• Serial photography and new techniques, such as epiluminescence microscopy and computerized image analysis, are useful adjuncts. Epiluminescence microscopy uses a magnifying lens to examine a lesion that has had oil applied. Computerized image analysis stores images of the lesions and makes them available for comparison over time.

• Skin exam: During a skin exam, assess the total number of nevi present on the patient's skin. Attempt to differentiate between typical and atypical lesions. The ABCDs for differentiating early melanomas from benign nevi include the following:

• A - Asymmetry (melanoma lesion more likely to be asymmetric)

• B - Border irregularity (melanoma more likely to have irregular borders)

• C - Color (melanoma more likely to be very dark black or blue and have variation in color than a benign mole, which more often is uniform in color and light tan or brown)

• D - Diameter (mole <6 mm in diameter usually benign)

• Lymph node examination: If a patient is diagnosed with a melanoma, examine all lymph node groups. Melanoma may disseminate both through the lymphatics, leading to involvement of regional lymph nodes, and hematogenously, leading to involvement of any node basin in the body.

Causes:

• Exposure to ultraviolet radiation (UVR) is a critical factor in the development of most melanomas.

• Both ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-320 nm, potentially are carcinogenic and actually may work in concert to induce a melanoma.

  　

• UVR appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA.

• Interestingly, melanoma does not have a direct relationship with the amount of sun exposure because it is more common in white-collar workers than in those who work outdoors.

  　

• The greatest risk for melanoma is associated with acute, intermittent, blistering sunburns, especially on areas that occasionally receive sun exposure. LMM is an exception to this rule, because it frequently appears on the head and neck of older individuals who have a history of long-term sun exposure.

  　

• Importantly, other factors exist that may predispose an individual to melanoma; chemicals and viruses are 2 etiologic agents that also have been implicated in the development of melanoma.

• Greatly elevated risk factors for cutaneous melanoma

• Changing mole

• Dysplastic nevi in familial melanoma

• Greater than 50 nevi, 2 mm or greater in diameter

• Moderately elevated risk factors for cutaneous melanoma

• One family member with melanoma

  　

• Previous history of melanoma

  　

• Sporadic dysplastic nevi

  　

• Congenital nevus

• Slightly elevated risk factors for cutaneous melanoma

• Immunosuppression

• Sun sensitivity

• History of acute, severe, blistering sunburns

• Freckling

WORKUP

Lab Studies:
　

• Complete blood count

• Chemistry panel (complete)

• The chemistry panel may give a clue to possible metastatic disease. For example, an elevated alkaline phosphatase may signal metastatic disease to the bone or liver, while elevation of liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) may represent metastatic disease to the liver.

• Total protein and albumin provides information concerning the overall health and nutritional status of the patient and may afford prognostic information.

• Many chemotherapy regimens may be toxic to the kidneys; therefore, a creatinine level is necessary prior to initiation of any treatment.

• Lactate dehydrogenase

• Lactate dehydrogenase (LDH) is elevated with many conditions, including many malignancies. Although the LDH is not specific for melanoma, it may be useful at diagnosis and also in the follow-up care of patients with melanoma. A markedly elevated LDH at diagnosis or at follow-up visit may indicate distant metastases, especially in the lung and liver.

• Although the specificity and sensitivity of this test are low, multiple studies show an elevated LDH to be an independent predictive factor for poor prognosis and now is considered part of the staging system for melanoma.

Imaging Studies:
　

• Chest x-ray

• For patients with stage I or II disease, a chest x-ray is obtained, although it likely will be negative. To date, no studies support obtaining an x-ray in these patients, but a normal chest x-ray at diagnosis provides a baseline for future comparison.

• Patients with stage III disease, intransit disease, or local recurrence should have a chest x-ray or CT scan of the chest because the lungs often are the first site of metastatic disease.

• CT scan or MRI of the brain

• A CT scan or MRI of the brain should be obtained during the workup of a patient with known distant metastases to detect additional asymptomatic metastatic disease.

• A CT scan or MRI of the brain in patients without known metastatic disease should be reserved for those patients who are symptomatic.

• Chest CT scan

• A chest CT scan should be included in the staging workup of a patient with stage IV disease (ie, the patient with known distant metastases) to detect asymptomatic metastatic lesions.

• In patients with stage I, II, or III disease, a chest CT scan should be performed only if clinically indicated.

• CT scan of the abdomen: A CT of the abdomen often is obtained when evaluating a patient with stage III, locally recurrent, or intransit disease. Although the yield is low, a negative CT scan provides a baseline study for future comparison.

• CT scan of the pelvis: This study is only indicated if a patient has local regional recurrence below the waist, is symptomatic, or has known metastatic disease with a history of primary tumors below the waist.

Procedures:
　

• Biopsy of a suspicious lesion

• A complete excisional biopsy is preferred and should include a 1-2 mm margin of healthy skin, to include all layers of skin and some subcutaneous fat.

  　

• If the suspicious lesion is large or situated in a cosmetically sensitive area, an incisional or punch biopsy may be appropriate. The incisional biopsy should be taken from the most abnormal area of the lesion.

  　

• Because all layers of the skin are included in the biopsy, a shave biopsy is contraindicated.

• Surgical excision or reexcision after biopsy

• Because the failure to perform a reexcision after biopsy of a melanoma is associated with as much as 40% local recurrence, a reexcision must be performed.

• Current recommendations for margins of excision are as follows:
  • Lesions less than 1 mm in thickness to 1 cm margin
  • Lesions 1-4 mm in thickness to 2 cm margin
  • Lesions greater than 4 mm to at least 2 cm margin

• Elective lymph node dissection

• Patients with clinically enlarged lymph nodes and no evidence of distant disease should undergo a complete regional lymph node dissection (LND).

• For years, patients without clinically enlarged nodes underwent LND. Recent studies show that patients with melanomas that are 1-4 mm thick may not have a significant difference in survival whether or not they undergo a LND.

• The only patients who seem to benefit from the LND are those with lesions 1.1-2 mm and who are younger than 60 years.

  　

• Patients with lesions greater than 4 mm in thickness are widely considered not to benefit from removal of clinically negative nodes.

• Sentinel lymph node dissection

• Lymphatics from any given region on the skin drain to a single lymph node. This node is called the sentinel lymph node and almost always is the first site of nodal involvement when melanoma spreads to regional nodes.

• To determine which node is the sentinel node, the following 2 techniques, often in combination, are used. The combination of the 2 techniques allows the detection of the sentinel node in as many as 98% of cases.

  　

  • The first technique involves injecting a blue dye at the site of the primary and, through a small incision over the nodal basin, determining the location of the sentinel node. The node is then removed for pathological evaluation.

    　

  • The second technique involves a radiolabeled solution injected into the site of the primary and the use of a hand-held gamma detector to determine the location of the sentinel node.

  It is now clear that sentinel node biopsy offers important prognostic, diagnostic, and therapeutic information.

Histologic Findings: Although no single histologic feature is pathognomonic for melanoma, many characteristic features exist. Cytologic atypia virtually always is noted, with enlarged cells containing large pleomorphic hyperchromic nuclei with prominent nucleoli. Numerous mitotic figures often are noted. A pagetoid growth pattern with upward growth of the melanocytes, so they are no longer confined to the basal layer, is considered pathognomonic for melanoma by some pathologists.

Although immunohistochemical stains usually are not necessary for diagnosis, they are generally performed for a complete diagnosis. Both S-100 and homatropine methylbromide (HMB45) stains are positive in melanoma. The S-100 is highly sensitive, although not specific for melanoma, while the HMB45 is highly specific and moderately sensitive for melanoma. The 2 stains, in concert, can be useful in diagnosing poorly differentiated melanomas.

Staging: The staging system for cutaneous melanoma is being revised. The current staging system is outlined below, followed by the proposed staging system, which is being used by some oncologists at this time and likely will be adopted by the American Joint Committee on Cancer (AJCC) in early 2001.

• Clark staging
• Level I - All tumor cells above basement membrane (in situ)
• Level II - Tumor extends into papillary dermis
• Level III - Tumor extends to interface between papillary and reticular dermis
• Level IV - Tumor extends between bundles of collagen of reticular dermis (extends into reticular dermis)
• Level V - Tumor invasion of subcutaneous tissue

• Breslow classification (thickness)
• Less than or equal to 0.75 mm
• 0.76-1.50 mm
• 1.51-4.0 mm
• Greater than or equal to 4.0 mm

• AJCC staging system (TNM)

• Primary tumor (pT)
  • pTX - Primary tumor cannot be assessed
  • pT0 - No evidence of primary tumor
  • pTis - Melanoma in situ (atypical melanocytic hyperplasia, severe melanocytic dysplasia), not an invasive lesion (Clark level I)
  • pT1 - Tumor 0.75 mm or less in thickness and invades the papillary dermis (Clark level II)
  • pT2 - Tumor more than 0.75 mm but not more than 1.5 mm in thickness and/or invades to papillary-reticular dermal interface (Clark level III)
  • pT3 - Tumor more than 1.5 mm but not more than 4 mm in thickness and/or invades the reticular dermis (Clark level IV)
  • pT3a - Tumor more than 1.5 mm but not more than 3 mm in thickness
  • pT3b - Tumor more than 3 mm but not more than 4 mm in thickness
  • pT4 - Tumor more than 4 mm in thickness and/or invades the subcutaneous tissue (Clark level V) and/or satellite(s) within 2 cm of the primary tumor
  • pT4a - Tumor more than 4 mm in thickness and/or invades the subcutaneous tissue
  • pT4b - Satellite(s) within 2 cm of the primary tumor

  Regional lymph nodes (N)

  • NX - Regional lymph nodes cannot be assessed
  • N0 - No regional lymph node metastasis
  • N1 - Metastasis 3 cm or less in greatest dimension in any regional lymph node(s)
  • N2 - Metastasis more than 3 cm in greatest dimension in any regional lymph node(s) and/or intransit metastasis
  • N2a - Metastasis more than 3 cm in greatest dimension in any regional lymph node(s)
  • N2b - Intransit metastasis
  • N2c - Both (N2a and N2b)
  • Note: Intransit metastasis involves skin or subcutaneous tissue more than 2 cm from the primary tumor but not beyond the regional lymph nodes.

• Distant metastasis (M)
  • MX - Distant metastasis cannot be assessed
  • M0 - No distant metastasis
  • M1 - Distant metastasis
  • M1a - Metastasis in skin or subcutaneous tissue or lymph node(s) beyond the regional lymph nodes
  • M1b - Visceral metastasis
• AJCC groupings based on TNM classification
  • Stage 0 - pTis, N0, M0
  • Stage I - pT1, N0, M0; pT2, N0, M0
  • Stage II - pT3, N0, M0
  • Stage III - pT4, N0, M0
    • Any pT, N1, M0
    • Any pT, N2, M0
  • Stage IV - Any pT, any N, M1

• The proposed staging system is as follows:
  • T classification (thickness)
    • T1a - 1.0 mm without ulceration and level II or III
    • T1b - 1.0 mm with ulceration or level IV or V
    • T2a - 1.01-2.0 mm without ulceration
    • T2b - 1.01-2.0 mm with ulceration
    • T3a - 2.01-4.0 mm without ulceration
    • T3b - 2.01-4.0 mm with ulceration
    • T4a - Greater than 4.0 mm without ulceration
    • T4b - Greater than 4.0 mm with ulceration
  • N classification
    • N1a - 1 node positive for micrometastasis
    • N1b - 1 node positive for macrometastasis
    • N2a - 2-3 nodes positive for micrometastasis
    • N2b - 2-3 nodes positive for macrometastasis
    • N2c - Intransit met(s) or satellite(s) without metastatic nodes
    • N3 - 4 or more metastatic nodes or matted nodes or intransit met(s) or satellite(s) and metastatic node(s). Micrometastases are diagnosed after elective or sentinel lymphadenectomy. Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.
  • M classification
    • M1a - Distant skin, subcutaneous, or nodal metastases, normal LDH
    • M1b - Lung metastases, normal LDH
    • M1c - All other visceral metastases or any distant metastases with an elevated LDH

TREATMENT

Medical Care:

• Adjuvant therapy

• Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy and treatment of patients with advanced melanoma.

• Because fewer than one half of the patients with deep primaries (>4 mm) or regional lymph node involvement have long-term disease-free survival, these patients are considered high risk and should be considered for adjuvant therapy.

• Although controversy surrounds the use of adjuvant therapy in these patients, a recent, large, multicentered study showed improvement in both long-term survival and disease-free survival using high-dose interferon-alpha-2b (IFN). Based on this study, the Food and Drug Administration (FDA) approved IFN as adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence.

• Advanced-stage melanoma (stage IV)

• Treatment of patients with advanced-stage melanoma (stage IV) has not improved significantly in recent years. At this time, no combination chemotherapy regimen has proven to be significantly better than single-agent dacarbazine (DTIC), which has only a 10-15% response rate.

  　

• Two combination regimens commonly are used in the treatment of patients with advanced-stage melanoma. The first regimen is the cisplatin, vinblastine, and DTIC (CVD) regimen. The second commonly used regimen is the Dartmouth regimen, which is a combination of cisplatin, DTIC, carmustine, and tamoxifen.

  　

• Biological therapies now are being used alone and with chemotherapy regimens in the treatment of patients with advanced-stage melanoma. To date, studies do not show that IFN added to DTIC is better than DTIC alone.

  　

• Immunotherapy with high-dose interleukin-2 (IL-2) shows promise because it can cure approximately 10% of patients with advanced-stage disease.

  　

• Melanoma vaccines and gene therapy are 2 additional treatment options, which hopefully will become available. Because numerous protocols for patients with advanced-stage melanoma exist, eligible patients should be referred to an oncology center participating in these studies.

Surgical Care: Surgery is the definitive treatment for early-stage melanoma. A wide local excision with sentinel lymph node biopsy and/or elective LND is considered the mainstay of treatment for patients with primary melanoma.

Consultations:

• A patient with a suspicious lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy.

• If diagnosis of melanoma is made, the patient should then be referred to an oncologist after definitive surgery is performed.

MEDICATION

Factors predicting the likelihood of response to treatment include the following:

• Good performance status
• Soft-tissue disease or only a few visceral metastases
• Age younger than 65 years
• No prior chemotherapy
• Normal hepatic and renal function
• Normal CBC
• Absence of CNS metastases

Drug Category: Antineoplastics -- Chemotherapeutic agents used to treat melanoma, including dacarbazine, cisplatin, vinblastine, carmustine, and tamoxifen.

Drug Category: Recombinant cytokines -- Immunotherapy (biotherapy) currently used to treat these patients includes IFN and IL-2. An oncologist should administer these treatments.

FOLLOW-UP

Further Outpatient Care:
　

• Follow-up care of a patient with melanoma is based on the stage of the primary. The follow-up exam should be performed with the knowledge that the patient has an increased risk for a second primary and that, of all solitary sites of visceral recurrence, the lungs are the most frequent.

• Although no absolute guidelines exist, the patient with a primary less than 1 mm in thickness should be examined every 6 months for the first 2 years and every year after that for the next 8 years. Blood chemistries should be obtained at every other visit, and chest x-rays should be obtained yearly for 5 years and then every 2 years for the next 5 years.

• Suggested follow-up care for patients with primaries 1-4 mm in thickness consists of a physical examination every 3-4 months for the first 3 years, every 6 months for the 2 years after that, and yearly for the next 5 years. Blood chemistries should be obtained at every other visit, and chest x-rays should be obtained yearly for the first 5 years and every other year for the 5 years after that.

• Patients with a primary greater than 4 mm and negative nodes should have a physical exam every 3-4 months for the first 3 years, every 6 months for the 2 years after that, and yearly for years 5-10. Blood chemistries should be obtained at every other visit for the first 5 years and yearly after that.

• Patients with any thickness primary and positive nodes should be examined every 3 months for the first 3 years, every 6 months for the 2 years after that, and yearly for years 5-10. Blood chemistries and chest x-rays should be obtained at every other visit for the first 5 years and yearly after that.

Deterrence/Prevention:
　

• First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations.

Prognosis:
　

• Prognosis depends on the stage at diagnosis.

• Patents with stage I disease have a greater than 90% 5-year survival rate.

• Patients with stage II disease have a 70% 5-year survival rate.

• Those patients with stage III disease have only a 35-45% 5-year survival rate.

• Patients with metastatic disease have a grim prognosis, with a less than 2% 5-year survival rate.

Patient Education:
　

Medical/Legal Pitfalls:
　

• Failure to correctly biopsy a suspicious lesion (shave biopsies are contraindicated). Need for wide excision.

• Failure to correctly diagnose a melanoma

• Failure to prescribe a treatment regimen that is considered the standard of care