Katz et al provided information on the incidence of illnesses in a subgroup
of 1,115 men from the San Francisco City Clinic Cohort study who were diagnosed
with AIDS prior to 1991 and died prior to 1993. The mean age at diagnosis
was 37.6 years. Kaposi's sarcoma (KS) was the initial AIDS-defining illness
in 32.2% of these patients and was seen at some point in the disease course
An autopsy study of 565 patients who died of AIDS from 1982 to 1993
in Los Angeles found a mean time from diagnosis of AIDS to death of 11.8
months. At autopsy, 24% of these patients were found to have KS. Among
those with KS, it was the cause of death in only 18%. Overall, only 4%
of autopsied patients died from KS.
Thus, it seems safe to assume that KS will be seen in as many as 60%
of homosexual patients with AIDS prior to death, although for an unknown
percentage, this malignancy will be clinically insignificant.
Clinically, KS presents in a vast array of forms, including macular,
nodular, or plaque-like lesions; lymphadenopathic involvement; and visceral
spread. The earliest presentation is a small, flat, painless, purplish
lesion, arising anywhere on the skin or mucosal surfaces; the lesion varies
in size from several millimeters to several centimeters. Kaposi's sarcoma
may present as either a single lesion or multiple lesions scattered on
the skin surface.
Preferred skin sites include the nose and face, pinnae and retroauricular
regions, trunk, groin, penis, buttocks, extremities, and toes and soles
of the feet; usually, the palms are spared. One particularly common feature
is a symmetrical distribution of lesions (such as the arches of both soles
or similar locations on each extremity). Other frequently involved surfaces
that are easily examined include the conjunctivae, palate, tonsils, alveolar
ridge, posterior pharynx, and low rectum. Superinfection with fungi or
bacteria may be present, changing the characteristic appearance of lesions.
Biopsy confirmation of KS is strongly recommended prior to initiation
of any aggressive therapy, as the diagnosis carries with it a tremendous
psychological burden for the patient. Although KS may present at any time
in the course of HIV disease, fewer than one-sixth of cases occur when
the CD4 count is above 500 cells/mm³. In the 1990s, the majority
of patients present after their CD4 count has fallen below 100 cells/mm³.
Isolated lesions may remain stable for months to years, with an occasional
new lesion discovered on a weekly or monthly basis as long as the person
is in reasonably good health. The psychological burden of the disease is
immense from the time of diagnosis. As HIV disease progresses, the immune
system declines and new infectious complications occur. With the resolution
or progression of each of these insults, KS tends to seize the opportunity
and advance, as evidenced by a shower of new lesions, decreasing interval
between new lesions, growth of existing lesions with associated ecchymosis,
and coalescence of lesions into a larger plaque form. Lesions may take
on a nodular appearance, are often painful, and become more extensive subcutaneously.
Involvement of the regional lymph nodes and lymphatic spaces occurs,
leading to progressive edema, most commonly in the legs, groin, genitalia,
or facial region. Massive edema may develop due to complete obstruction
of the lymphatic channels, interfering with the patient's ability to walk,
urinate, or see. Edema in the lower extremities may eventually result in
breakdown of the skin with severe pain and superinfection.
Internal involvement with KS (present at autopsy in up to 75% of patients
with cutaneous disease) is usually quiet in the early stages of disease,
but may become life-threatening in 10% to 20% of patients. Gastrointestinal
(GI) tract involvement occurs in up to 50% of patients, and lung involvement
in 41% eventually. Patients with GI involvement may develop substantial
bleeding, particularly with stomach and rectal lesions, requiring intervention.
Pulmonary involvement may progress rapidly to florid respiratory compromise
and death, with a median life expectancy of only 3 to 4 months.
Patients can initially be divided into three categories based on the
amount of KS present: (1) those with only a few lesions that are relatively
stable or associated with minor symptoms; (2) those with advanced disease,
including lesions too numerous to count, lymphadenopathic or visceral involvement,
and large plaque-like areas of involvement; and (3) those with an intermediate
burden who have many lesions, which are mostly asymptomatic and not associated
with appreciable edema. The first group can be further subdivided into
three subgroups based on immune status and history of opportunistic infections:
(1) CD4 count more than 200 cells/mm³ with no major prior opportunistic
infections; CD4 count more than 200 cells/mm³ with a limited history
of opportunistic infections; and (3) CD4 count close to 0 cells/mm³
with multiple opportunistic infections. Viral burden, as measured by one
of a number of available technologies[18,24] and rapidity of the downward
trend in the CD4 count are better indicators of the stability of the overall
immune system than is the absolute CD4 number alone.[18,25,26]
When managing the newly diagnosed patient, antiretroviral therapy must
be maximized. The introduction of protease inhibitors in patients with
KS often results in a cessation of growth of existing lesions, a prolonged
period during which no new lesions emerge, and actual regression of existing
lesions. These effects may be due to stabilization and reversal of the
immune decline or interference with cytokine-mediated stimulation, or to
some as yet unidentified direct effect on the KS itself. Although the duration
of this positive effect is unpredictable, the use of antiretroviral agents
may be sufficient to manage KS without the need for more aggressive intervention.
For patients with minimal disease and a relatively intact immune system
whose problems persist despite the use of antiretroviral therapy, local
interventions, such as cryotherapy, intralesional vinblastine injections,
laser removal, topical agents such as retinoids, or radiation therapy are
helpful. With any local modality, visible evidence of the disease process
generally remains, in the form of a scar or residual pigmentation. The
aim of local modalities is to limit progression at the local site.
Watchful waiting is an acceptable approach in patients with minimal
disease and minimal immune impairment, to allow determination of the rapidity
of disease progression. These patients have long life expectancies (in
the range of years), and care should be taken to avoid treating them in
such a way as to hasten the progression of the HIV disease. Since many
of these patients continue to work and carry on full active lives, however,
cosmetic concerns must be addressed.
Patients with minimal stable disease but a collapsed immune system (as
evidenced by a low CD4 count, high viral burden, or recent aggressive opportunistic
infections) should also be treated symptomatically with local therapies.
This group, as well as those with minimal but noticeably progressive disease,
should be considered for entry into trials of novel nonchemotherapeutic
biologic response modifiers, such as the interleukins, gonadotropins, or
Patients who present with advanced disease, including those with significant
areas of painful and growing KS, lymphatic spread, and sludging with resultant
edema, and visceral involvement, should be considered for systemic therapy,
for example, with liposomal doxorubicin (Doxil).
Radiosensitivity in the Setting of KS and HIV
Clinical observations suggest that radiation repair mechanisms may be
impaired in patients with HIV-related KS. Fibroblast cell cultures from
patients with AIDS and KS, as well as cell lines from non-HIV/non-KS patients
were irradiated to define the D0 (dose of radiation necessary to reduce
survival by a factor of 0.37). The mean D0 for cell lines from patients
with KS was 78 cGy (range, 65 to 91 cGy), which was substantially lower
than the mean of 112 cGy (range, 82 to 143 cGy) for cell lines from patients
The mechanism for the increased radiosensitivity of cell lines infected
with both HIV and the KS herpesvirus (KSHV or HHV-8)[33,34] has not been
elucidated, but these findings are consistent with the clinical findings
of increased sensitivity to radiation seen in patients with KS and HIV.[35-37]
However, HIV patients without KS who have received radiation therapy to
much higher doses for such diseases as prostate, anal, head and neck,
and lung cancer have not consistently shown increased radiosensitivity.
In our experience, patients with CD4 counts higher than 200 cells/mm³
have tolerated full-course radiation for these non-HIV related malignancies
without requiring excessive breaks in treatment or dose reductions. Nor
have there been reports of excessive radiation intolerance in patients
with classic KS, suggesting that the radiosensitivity of HIV-related KS
may be due to an interaction of the two viral strains (HIV and KSHV) rather
than to either strain alone. With the development of antibody testing for
KSHV-related nuclear antigens that can identify patients prior to the development
of clinical KS, it may become possible to identify patients who are
at particular risk for excessive radiation toxicity.
Radiation Approach to KS
Radiation is effective therapy both as a local modality in the patient
with minimal disease and for relief of local symptoms that are unresponsive
to systemic therapy.[35,36,39-44] Radiation is recommended in the treatment
of mucocutaneous KS to relieve pain in any location, reduce edema due to
lymphatic obstruction (especially in the periorbital or pelvic regions),
improve function, and provide cosmetic eradication of visible lesions on
the face, neck, and extremities.
Commonly involved sites that respond well to radiation treatment include
those on the face (ears, eyelids,[36,43] conjunctiva, nose), genitalia,[35,46]
and feet.[35,40] The usual response is a reduction in the size and thickness
of the lesion and a change in color from a violaceous hue to brown, which
may last from months to years. Pain relief usually occurs within days of
Skin Lesions--Small superficial lesions are best treated with
low-energy electrons, which have the advantage of penetrating a short distance
into tissue, thereby sparing deeper structures from unnecessary irradiation.
Alternatively, an orthovoltage unit, which deposits dose heavily in the
superficial layers and rapidly drops off at depth, may be used.
Larger plaque-like areas of disease with diffuse nodularity, multiple
satellite lesions, or considerable edema may require coverage with megavoltage
photons. If large-field irradiation is employed, it must be used cautiously,
especially in the lower extremities, such as when treating an edematous
leg or groin region. Patients with larger plaque-like lesions may go on
to receive multiple courses of medications, such as doxorubicin (either
the standard formulation or as a liposomally encapsulated preparation),
bleomycin (Blenoxane), or vinblastine. The development of radiation recall
(a reemergence of acute dermatitis within the previously irradiated field
long after the completion of irradiation, temporally associated with the
use of certain chemotherapeutic agents) is occasionally seen in such patients.[47,48]
Oropharyngeal KS--The hard palate commonly has small, focal or
diffuse, flat areas of disease that are asymptomatic,[36,37,40,49] but
bulkier lesions are sometimes associated with the teeth and may extend
onto the anterior gingival surfaces, surrounding the base of the teeth,
causing loosening and loss of teeth. Bleeding, pain, and interference with
chewing occurs in advanced disease. Flat, asymptomatic, palatal lesions
are generally not treated with radiation, since they may remain quiescent
for months to years.
Since radiation, at any dosing schedule, is associated with the development
of significant painful mucositis,[36,37,49] our preference is to wait until
symptoms develop before initiating such therapy. In order to minimize morbidity,
prior to irradiation patients are aggressively treated for any thrush or
herpetic lesions with difluconazole (200 mg/d), and acyclovir (200 mg five
times daily) for 2 days prior to therapy, during treatment, and for 7 to
10 days afterward. Radiation fields are kept as small as possible, covering
only the areas of visible involvement.
Typically, pain associated with patchy mucositis occurs about 7 to 10
days after the initiation of radiation therapy, whether a single or fractionated
approach is used. This requires short-term narcotic therapy for relief.
Bulky disease may arise in the base of the tongue, larynx, and supraglottic
region, causing pain, choking, or difficulty swallowing. Rarely, disease
may interfere with breathing due to laryngeal edema or epiglottic involvement.
In the presence of such symptoms, direct laryngoscopy may be necessary
to define the true extent of disease prior to treatment.
Edema--Progressive lymphatic and subdermal infiltration by KS
frequently results in severe edema in regions as diverse as the face, periorbital
area, lower extremities, groin, and genitalia, interfering with vision,
ambulation, and urination and leading to the development of skin breakdown
and stasis ulcers with superinfection. Initially in the AIDS epidemic,
wide-field irradiation was routinely administered for this condition. Although
an initial reduction in edema was commonly seen, the disease continued
to progress, with recurrence of the edema, as well as brawny induration
and thickened KS in the previously irradiated field, which complicated
Reirradiation was occasionally undertaken for short-term benefit, but
a significant price was paid by those who survived more than a few months;
this took the form of progressive radiodermatitis, skin breakdown, ulceration,
and infection distal to and within the irradiated field. These complications
were due to progressive disease, radiation insult, and the direct effects
of chemotherapeutic agents.[47,48]
Systemic chemotherapy should be considered early in these cases before
obstruction is complete and chronic. Radiation is often effective in temporarily
relieving the obstruction, however, and should still be considered in the
person who cannot tolerate systemic therapy.[40,42]
Visceral Involvement--Autopsy studies reveal that internal involvement
by KS is seen in up to 50% of patients with cutaneous involvement.
Symptoms are uncommon but, when present, may be quite severe and include
bleeding, pain, and obstruction.
Although systemic therapy is preferred, radiation therapy is effective
in rapidly reducing symptoms and should be considered in the patient who
does not respond to or cannot tolerate systemic therapy. Specific areas
of concern are the rectum and stomach, where ulcers may be particularly
troublesome. Care should be taken to keep the radiation field as small
as possible while still encompassing endoscopically visualized disease.
Pulmonary involvement occurs late in the course of KS and has a very
poor prognosis.[20,23,40,51] In the autopsy study of Klatt et al, 41% of
patients had pulmonary involvement.
Palliative radiation has been attempted with some success in patients
with pulmonary involvement who do not respond to chemotherapy. Meyer treated
25 patients with doses of 1,050 to 1,500 cGy in 150-cGy fractions, with
subjective improvement seen in 89% of patients and radiographic improvement
in 78%. Overall, however, life expectancy was very short, with only
9 of the 25 patients surviving beyond 12 weeks after therapy.
The optimal radiation dosage is debatable. Reports of single doses of
800 cGy and fractionated schemes with total doses ranging from 1,500 cGy
to more than 4,000 cGy have been declared effective.[35,36,40-42,44]
In a prospective trial involving 14 patients with 71 lesions, three
regimens were compared: 800 cGy in a single fraction, 20 Gy in 10 fractions,
or 40 Gy in 20 fractions, using 6-MeV electrons. Lesions treated to
20 to 40 Gy had a 79% to 83% complete response rate (defined as complete
resolution of palpable disease regardless of residual pigmentation); the
complete response rate after single doses was only 50%. No residual pigmentation
was observed in 8% of patients in both the 20- and 8-Gy groups, as compared
with 43% of the 40-Gy group. The 40- week actuarial failure rate was 48%
with 40 Gy, 62% with 20 Gy, and 84% with 8 Gy.
No differences in the acute toxicity of the three regimens were noted.
Late toxicity was reported only in the high-dose arm, however. Given the
prolonged life expectancy of some of these patients, the eventual use of
other chemotherapeutic agents at the time of treatment failure, and the
reported increased sensitivity of these patients to radiation,[36,37,50,52,53]
great caution must be used when increasing doses in these particular patients.
A retrospective review of 375 lesion sites in 187 patients at the University
of California, San Francisco (UCSF) showed no difference in duration of
response between patients treated with a single 8-Gy fraction and those
treated with higher, fractionated doses; however, the incidence of acute
toxicity was lower with the single fraction. After receiving 8 Gy,
93% of patients had a response, defined as a reduction to 50% of the pretreatment
size, regardless of residual pigmentation. At 6 months, the actuarial control
rate was 69%.
In another study of 8 Gy as a single dose, subjective cosmetic improvement
was reported in 90% of patients, pain relief in 100%, and improved lymphatic
drainage in 75%. Duration of control was short in this study, with
two-thirds of patients showing disease progression at 4 months.
Suggested radiation regimens for different groups of patients
with KS are summarized in Table 1. Patients who have consistently high
viral burdens despite aggressive antiretroviral therapy, a long history
of severe opportunistic diseases, and short life expectancies are best
treated with a single dose of 8 Gy to symptomatic areas of involvement,
including oral cavity lesions, bleeding rectal lesions, and painful cutaneous
lesions. Such treatment is easy on the patient, eliminates the need for
multiple trips to the radiation department, and is likely to provide significant
palliation for the duration of life. Although large areas may be treated
with short fractionated courses to improve tolerance if bowel or oropharyngeal
exposure is a concern, in our experience 800 cGy is well tolerated at any
Patients whose KS continues to progress despite an excellent reduction
in viral load and who have rising CD4 levels pose a particular challenge.
These patients may have a prolonged life expectancy, and their disease
course is more like that of patients with HIV-unrelated classic KS. These
patients should be treated with a protracted course of radiation if needed,
in an attempt to prolong the duration of response for as long as possible
and to reduce the risk of late toxicity. One should bear in mind, however,
that these patients may later be exposed to agents with recall potential,
such as doxorubicin.
The recommended approach is to use 200-cGy fractions to 2,400 cGy, with
frequent assessment of level of reaction. This dose is lower than the highest
dose regimen in the randomized study, but was chosen to reduce the
risk of late toxicity. This group of patients should be entered into trials
of therapies with less potential toxicity than chemotherapy or radiation,
since the impact of oncogenic therapies on HIV replication is currently
Of 1,115 men in the San Francisco City Clinic Cohort Study who died
of AIDS prior to 1992, 4.2% had NHL as their initial AIDS-defining illness,
and 12.6% developed the disease prior to death. Nationally, the CDC
reported that 3.4% of patients with HIV had NHL as their AIDS-defining
illness. In an autopsy study of Los Angeles men who died of AIDS between
1982 and 1993, NHL was listed as the cause of death in 8%, and 16% were
found to have NHL.
A 1991 National Cancer Institute report projected that, of the 36,000
expected new cases of NHL in the United States in 1992, between 8% and
27% would be AIDS-related. These numbers will continue to rise as the
epidemic spreads and patients survive longer.
Systemic NHL presents as widespread disease with extranodal involvement
in up to 95% of cases.[56,57] Common extranodal sites of involvement include
the GI tract (27%) and CNS (25%),[57,58] although any site may be involved
and frequently there is no evidence of nodal involvement.
In a review of cases from San Francisco General Hospital, two-thirds
of patients presented with stage IV disease. Non-Hodgkin's lymphoma
may develop at any point in the course of the immunosuppression, with a
mean CD4 count of 189 cells/mm³ reported in a study of 49 patients
with non-CNS lymphoma. Of these patients, 37% had a prior diagnosis
Approximately two-thirds of NHL cases in the setting of HIV are large-cell
immunoblastic or diffuse large-cell varieties (with variable findings of
c-myc gene rearrangement), and one-third are small noncleaved, Burkitt's
lymphomas (with a high incidence of c-myc rearrangement). Large-cell
lymphomas display both monoclonal and polyclonal lineages and often have
a significant T-cell component, whereas Burkitt's lymphomas are predominantly
Chemotherapy is the mainstay of therapy for patients with systemic
lymphoma. A number of different treatment regimens have been used, with
complete response rates varying from 33% to 83%.[9,57,60] These regimens
include CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone),
MACOP-B (methotrexate, Adriamycin, cyclophosphamide, Oncovin, prednisone,
and bleomycin), m-BACOD (methotrexate, bleomycin, Adriamycin, cyclophosphamide,
Oncovin, and dexamethasone), high-dose cytarabine plus high-dose methotrexate,
and Pro-MACE-MOPP (cyclophosphamide, etoposide, Adriamycin, cytarabine,
bleomycin, Oncovin, methotrexate, and prednisone).
Standard-dose m-BACOD and low-dose m-BACOD were compared in a prospective,
randomized AIDS Clinical Trial Group trial that accrued 198 patients.
Complete responses rates were the same with the two doses (50% vs 46%),
as were time to progression (34 vs 31 weeks) and death from AIDS (12 vs
20 patients). Grade 3/4 hematologic toxicity occurred more frequently in
patients receiving the standard dose, suggesting that low-dose m-BACOD
is a safer and equally effective approach for the majority of patients
until better therapy is found. Opportunistic infections are the most common
cause of death in patients with systemic NHL, with uncontrolled disease
a close second.
Prognostic Factors--Factors that are usually quite important
in determining prognosis in NHL in the HIV-negative patient (stage, number
of extranodal sites, meningeal involvement, lactic dehydrogenase level)
have no prognostic value in patients with HIV. Kaplan et al have defined
a group with an improved life expectancy after the diagnosis of HIV-related
lymphoma, however, who should be considered for aggressive therapy. Patients
with CD4 counts more than 100 cells/mm³, no prior AIDS-defining illnesses,
Karnofsky performance status more than 70, and no extranodal disease had
a median survival after therapy of 24 months, as opposed to a median survival
of only 5.5 months for all others.
In a recent report assessing the molecular characteristics of patients
with AIDS-related lymphoma, Epstein-Barr virus (EBV) DNA sequences, the
presence of the c-myc gene, heavy- and light-chain rearrangements,
and polyclonality vs monoclonality were evaluated as prognosticators.
An improved complete response rate (78% to 83% vs 28% to 31%) and a significantly
longer median survival (median survival not reached at a minimum follow-up
of 26 months vs 3.5 to 5.5 months) were seen in those patients who had
CD4 counts more than 200 cells/mm³ and showed evidence of polyclonality
compared to those patients with CD4 200 or less cells/mm³ and/or monoclonality.
Radiation Therapy--Little has been reported on the routine use
of radiation in the setting of HIV-related lymphomas, with the exception
of CNS disease. Among patients with a good prognosis who have clinically
localized non-CNS disease, focal involved-field radiation (to doses of
36 to 40 Gy) may be considered as a consolidative boost in those with areas
of bulky disease who demonstrate a partial or slow response to initial
chemotherapy (Table 1). Radiation is
also an excellent palliative measure in patients with recurrent or unresponsive
disease and in patients who cannot tolerate systemic chemotherapy.
Primary CNS Lymphoma
Primary CNS disease develops in only 2% of patients with non HIV-related
lymphoma but appears in 25% of patients with AIDS-related lymphoma.[59,64]
The majority of AIDS-related CNS lymphomas are large-cell immunoblastic
types, show little evidence of c-myc rearrangement, and are monoclonal.
Epstein-Barr virus DNA is found almost universally in association with
CNS lymphoma in AIDS, suggesting that infection with this virus may play
a major role in B-cell proliferation and the development of primary CNS
lymphoma in the late stages of AIDS.[58,65]
Primary CNS lymphoma presents much later in the course of immune decline
than does systemic NHL, with mean CD4 counts of less than 50 cells/mm³.[59,64]
The average Karnofsky performance status prior to initiation of therapy
was 50 in the UCSF series. Radiographically, lymphoma may present as
either focal (35%) or multifocal (65%) disease, findings that are generally
indistinguishable from those of toxoplasmosis. Serum toxoplasmosis titers
are routinely obtained in patients with findings suggestive of either NHL
or toxoplasmosis, and antitoxoplasmosis therapy is instituted immediately.
In the setting of a negative serum titer or progressive neurologic decline
despite antitoxoplasmosis measures, the clinician should perform a stereotactic
biopsy of lesions, if possible, to establish or eliminate the diagnosis
Radiation Therapy--Ling et al reported on 41 patients with HIV-related
primary cerebral NHL treated with radiation therapy over a 10-year period.
Doses of radiation varied from 38 to 62 Gy, and were delivered with initial
opposed lateral whole-brain fields. Of 38 evaluable patients, 71% had minor
to excellent symptomatic response to irradiation, with no significant morbidity
noted. The mean length of survival from initiation of therapy was only
3.2 months. A prior report from the same institution stated that deaths
were due to opportunistic infections and not to uncontrolled CNS disease.
Studies evaluating the addition of chemotherapy to radiation therapy
do not reveal an increase in survival over radiation alone.
The current recommendation for the treatment of primary CNS lymphoma
in the setting of AIDS is whole-brain radiation for palliation of symptoms.
At UCSF, the current dose used is 300 cGy/d to a total dose of 3,000 cGy
(Table 1). Boosts are not routinely delivered
but are considered in patients with good Karnofsky performance status prior
to treatment, unifocal disease on CT scan, and no major opportunistic infections.
Such patients are also eligible for an intergroup trial (AIDS Clinical
Trial Group, Cancer and Leukemia Group B, Radiation Therapy Oncology Group,
Eastern Cooperative Oncology Group) trial of CHOD (cyclophosphamide, doxorubicin
HCl, Oncovin, dexamethasone, and granulocyte colony-stimulating factor)
and radiation (2.5 Gy/d of whole-brain radiation to 3,000 cGy, followed
by an additional 1,000-cGy boost to the CT-defined tumor plus 2-cm margins).
In 1993, the CDC revised the AIDS case definition to include patients
with cervical carcinoma in the setting of HIV infection, despite the
fact that there has not been a reported increase in the incidence of frankly
invasive cervical carcinoma in HIV-infected women.[54,68-70] Patients infected
with HIV are at increased risk of having cervical or anal intraepithelial
lesions in conjunction with detectable human papillomavirus (HPV) infections,
as compared with their HIV-negative counterparts from similar risk groups.[70-73]
Cervical cancer is a preventable disease and is highly curative if detected
at an early, preinvasive stage. Its inclusion in the CDC criteria was meant
to emphasize the importance of close gynecologic care and surveillance
in the HIV-infected woman.
Cervical carcinoma has a more aggressive course in the immunocompromised
patient than in the immunocompetent host. In a population of 84 women with
cervical cancer and known HIV status, 16 were HIV-positive, 14 of whom
did not have evidence of other opportunistic diseases. Fifty percent
of the HIV-positive women presented with stage III/IV cervical cancer,
with a mean CD4 count of 616 cells/mm³ (range, 129 to 616 cells/mm³);
in contrast, only 19% of the HIV-negative women had stage III or IV disease.
Of the 16 HIV-positive women with cervical cancer, 11 died at a mean interval
of 9.2 months from diagnosis; nine of the deaths were due to cervical cancer.
The most appropriate treatment regimen for patients with HIV-related
cervical cancer varies, depending on the degree of immune system impairment
and stage of disease (Table 1).
Patients With Intact Immune System--Patients with a relatively
intact immune system (CD4 count more than 200 cells/mm³, no major
opportunistic disease) who have a reasonable chance of surviving several
years with appropriate medical care and prophylaxis should be aggressively
treated, using standard surgical and radiotherapeutic techniques. The use
of prophylactic para-aortic irradiation or the addition of chemotherapy
should be avoided in these patients, however, as each would unduly stress
the marrow and small intestine. Enlarged lymph nodes may be related to
the underlying HIV disease rather than evidence of metastatic cervical
carcinoma, and extraperitoneal node sampling may be helpful in establishing
proof of involvement.
In the patient with early-stage disease (nonbulky stage I/IIA) amenable
to a radical hysterectomy, surgery would be preferred over radiation, as
it would have a lesser immunosuppressive effect. Although radiation may
be well tolerated by such a patient, it is not clear that this would be
a prudent approach.
Patients with stage IB/IIA (bulky), IIB, III/IVA should be treated aggressively
with standard radiotherapeutic approaches, since death due to progressive
cervical disease is a more immediate risk than progression of AIDS. The
use of antiretrovirals and continuation of appropriate prophylaxis against
opportunistic infections is recommended during this period of potentially
Patients With Moderate Immune Impairment--For patients with CD4
counts from 50 to 200 cells/mm³ who are in reasonably good condition
but show a downward trend (as evidenced by a decreasing CD4 count and a
rising viral burden), aggressive local therapy is still warranted. Zeal
must be tempered by an awareness of the risks of increased intolerance
to radiation, as well as the profound risk of developing concomitant opportunistic
infections. Once again, use of antiretroviral agents and prophylactic measures
should be maintained.
Radiation fields should be kept as tight as possible to reduce irritation
of bowels that may already be plagued by such offenders as cryptosporidiosis,
M avium-intracellulare, or cytomegalovirus (CMV). The decision to
treat clinically uninvolved nodes must therefore be individualized. Surgical
approaches are preferred for early-stage disease, and chemotherapy is recommended
for advanced disease, used very judiciously and with the support of colony-stimulating
factors to reduce the degree of iatrogenic immunosuppression.
Patients With Severe Immune Impairment--A palliative approach
is reasonable for those with significant impairment of the immune system
(CD4 count less than 50 cells/mm³; one or more life-threatening opportunistic
diseases, such as progressive multifocal leukoencephalopathy, M avium-intracellulare
infection, CNS toxoplasmosis, and CMV esophagitis; and a poor performance
status) whose life expectancy is measured in months. Reduction of pain
and cessation of bleeding for the last remaining months are very important
in allowing patients to be managed at home with dignity.
A short course of radiation, such as that used in the Radiation Therapy
Oncology Group (RTOG) study for advanced pelvic malignancies (370 cGy bid
for 2 days, followed by a 2- to 3-week break, with the whole sequence repeated
for two more courses), has been well-tolerated. Some of these patients
will die of other diseases prior to completion of all three courses, but
significant improvement in symptoms is seen usually after the first course.
Great care is taken not to irradiate bowel unnecessarily.
Several reports suggest that there has been a slight increase in the
incidence of squamous cell carcinoma of the anus associated with the HIV
epidemic.[3,6,71] Anal cancer was on the rise among homosexual males prior
to the AIDS epidemic due to increased transmission of HPV via anal intercourse.
In 1992, a linkage was established between the AIDS registries and cancer
registries of nine regions of the United States, including information
on 859,398 reports of cancer and 50,050 cases of AIDS. Epidermoid anal
cancer was found in 39 cases, with a relative risk of 63.4 after a diagnosis
of AIDS compared to the general population. The risk was highest in the
period immediately before the diagnosis of AIDS or in the pursuant years.
As patients continue to live longer due to improved antiretroviral and
prophylactic antibiotic therapy, a rise in invasive anal carcinoma is expected,
arguing for heightened surveillance to detect early changes in this population,
as is recommended for cervical dysplasia.
Anal intraepithelial neoplasia (AIN) associated with infection by HPV
(subtypes 16, 18, 31, 33, 35) is recognized as an increasingly difficult
problem in the AIDS population, requiring screening of at-risk patients
and close observation of affected individuals. Carcinoma in situ may be
quite extensive, and is generally treated with conservative measures, such
as topical podophyllin, fluorouracil preparations, electrocautery, and
laser excision. Once invasion occurs, however, the risk of spread to nodes
rapidly increases, and limited local procedures are insufficient.
Of 62 patients with anal carcinoma treated at UCSF between 1980 and
1993, 7 patients were HIV-positive, 4 of whom had clinical criteria for
the diagnosis of AIDS. All seven patients received chemoradiation,
three with fluorouracil, two with fluorouracil plus mitomycin (Mutamycin),
and two with platinum. Patients with HIV required longer breaks from therapy
for skin reactions, and all seven required dose reductions due to neutropenia.
The four patients with a diagnosis of AIDS died a mean of 8 months following
therapy. Three of the four suffered local failures. The three HIV-positive
patients with no diagnosis of AIDS were alive and free of disease at a
mean follow-up of 16 months.
Patients with anal carcinoma and HIV disease but no diagnostic criteria
of AIDS receive fluorouracil plus radiation. The report of the RTOG trial
showing a colostomy-free survival benefit from the addition of mitomycin
to fluorouracil and radiation in non-HIV-related anal carcinoma must
be weighed against the potential risk of significant myelotoxicity secondary
to mitomycin in the AIDS patient. In most cases, radiation fields are designed
to cover the main lesion, inguinal nodes, and low pelvic nodes. Decisions
to avoid prophylactic inguinal and pelvic nodal irradiation must be made
on an individualized basis. Once again, antiretroviral therapy and prophylaxis
against opportunistic infections are highly recommended.
In patients with frank AIDS who prove unresponsive to antiretroviral
therapy, the decision to treat is tempered by the short life expectancy
and the fact that combination therapy is associated with significant toxicity
in this group. Preferred approaches include the prudent use of debulking
surgery with limited-field postoperative radiation, or radiation alone
to areas of known disease.
The dose delivered and fractionation scheme used depend on the overall
condition of the patient. For patients in reasonable condition with very
low CD4 counts but no active opportunistic disease, definitive doses used
for non-HIV anal carcinoma may be attempted, with careful observation during
treatment. Since the failure rate is significant in this group (three of
four cases at UCSF with anal cancer and frank AIDS died with locally uncontrolled
disease), high doses are necessary to control disease for as long as
possible. For the patient with advanced disease, the palliative approach
outlined above for cervical carcinoma is also appropriate.
Prior to 1996, epidemiologic reviews failed to show a significant rise
in the incidence of other malignancies in the setting of HIV disease or
AIDS,[4,80] although some reports suggested that Hodgkin's disease might
be increasing in this population.[81,82] Hodgkin's disease is more likely
to present in advanced stages (75% to 89% of HIV-positive patients present
with stage III or IV disease, as opposed to less than 33% of HIV-negative
patients), have a higher percentage of mixed cellularity or lymphocyte-depleted
disease (53% to 63%), a greater incidence of B symptoms (83%), and a variable
complete response rate to therapy (44% to 79%).[7,81]
With the viral load reductions seen in patients treated with protease
inhibitors and multiple-drug therapy,[16,17,83] there is hope that life
expectancies will lengthen. Cancers commonly seen in the population as
a whole, such as lung, prostate, and colon cancer, will continue to occur
in the HIV-infected population as that population ages, posing a therapeutic
dilemma for the radiation and medical oncologist. As with each of the previously
mentioned diseases, therapeutic decisions should be based on an understanding
of the patient's current location on the timeline of their HIV disease.
In the experience at UCSF, HIV-positive patients with CD4 counts more
than 200 cells/mm³ acutely tolerate radiation therapy as well as do
HIV-negative patients. Patients with intact immune systems have been treated
for cancers of the lung, head and neck, and prostate without an increase
in the number or duration of breaks in therapy, and have been managed with
full radiation doses. The effect of such treatment on viral loads has not
been routinely assessed, however.
Strong consideration should be given to the use of combination antiretroviral
therapy during the course of radiation for any of these diseases, since
the treatment itself represents a major stress that may afford a window
of opportunity for increased viral replication and progression of the HIV
disease.[9,75] Likewise, the use of extensive radiation fields for prophylaxis
of nodal spread or combined chemoradiation in an unproven setting should
be analyzed in terms of its expected risk-benefit ratio. The patient has
not been helped if overly aggressive treatment results in rapid progression
to full-blown AIDS.
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