Practice nursing care for Clients with Cancer II: Nursing Interventions Related to Side Effects of Treatment
Molecular Biology of Gynecologic Cancers
Although this most common gynecologic cancer carries the best prognosis, it is important to differentiate between the classic endometrioid tumors that tend to be estrogen dependent and well differentiated, from other less common high-risk uterine malignancies, such as uterine papillary serous carcinomas (UPSCs), clear cell carcinomas, mixed mullerian tumors (MMTs), or sarcomas, which appear to have a different biology.
The replication error (RER+) phenotype is characteristic of cancers arising in HNPCC kindreds (a familial cancer syndrome with a high incidence of colon, endometrial, gastric, and a lower incidence of ovarian and pancreatic cancers), and is also found in approximately 20% of sporadic endometrial cancers. The RER+ phenotype per se does not appear to correlate with clinicopathologic features of the tumors or clinical outcome; thus the hereditary form of endometrial cancer alone does not appear to portend a worse prognosis than the sporadic form. Mutation of the transforming growth factor (TGF) beta receptor type II gene is common in RER+ colon and gastric cancers, but uncommon in RER+ endometrial cancers even those arising in HNPCC kindreds, suggesting that the genesis of RER+ tumors even within the same familial cancer syndrome is not the same. Among sporadic endometrial cancers, when present, the microsatellite instability is confined to the malignant cells, and is not seen in the adjacent normal epithelium. Although inactivation of both alleles of either hMSH2 or MLH1 (DNA mismatch repair genes) appears to underlie microsatellite instability in tumors of HNPCC kindreds, similar to the findings in sporadic colon cancers, sporadic endometrial cancers were not associated with mutations of any of the four known human mismatch repair genes. In contrast, 25% of uterine sarcomas, an entity not recognized to be part of a familial cancer syndrome, exhibits microsatellite instability that may be related to a mutation in the hMSH2 gene. Again, clinical outcome was not correlated with RER+ status in those tumors; thus this finding does not underlie the more aggressive biology of the sarcomas.
LOSS OF HETEROZYGOSITY AND TUMOR SUPPRESSOR GENES
Unlike most other cancers studied so far, endometrial cancer is not characterized by a small number of loci that are involved by loss of heterozygosity. In endometrial cancers, most chromosomes contain regions of sustained allelic loss. Chromosome 17p is frequently involved, which contains the p53 gene known to confer a poor prognosis in endometrial cancers when mutated or deleted, and which plays an important role in the transition to carcinoma from atypical hyperplasia. Other frequently involved regions include 10q, 3p, and 18q, with no significant differences found in the chromosomal regions involved in endometrial from cervical cancers. Chromosome 18q contains the DCC gene, a putative tumor suppressor gene frequently mutated in colon cancers. While no mutations were found in the exons of the DCC gene in endometrial cancers, chromosome 18 was found to be capable of suppressing tumorigenicity of endometrial cancer cells in nude mice by the procedure of microcell fusion, with DCC expression elevated in most of the suppressed hybrids. These data strongly suggest that some gene on chromosome 18, is a tumor suppressor gene in endometrial cancers.
Kirsten (Ki)-ras activating point mutations in
codons 12 and 13 have been implicated in the development of atypical
endometrial hyperplasias and endometrioid carcinomas in Japanese women, as well
as in colon cancers. Recent studies of endometrial cancers arising in US women,
however, show the prevalence of such mutations to be significantly lower (11%
versus 31%) than in
Overexpression of HER-2/neu has been associated with advanced stage, deep myometrial invasion, and poor survival in endometrial cancers in several studies. Gene amplification did not underlie all cases of HER-2/neu overexpression, although both gene amplification and overexpression were each associated with poor outcomes. When multivariate analysis was used to determine if HER-2/neu was an independent prognostic factor in endometrial cancers taking into account other molecular features such as DNA ploidy, epidermal growth factor receptor, or p53 status, HER-2/neu status failed to achieve significance. Both c-myc gene amplification and c-fms overexpression have also been associated with advanced stage and high grade endometrial cancers.
HORMONE-RELATED MOLECULAR ABNORMALITIES
This is a logical direction for endometrial cancer research, because estrogen acts as a tumor promoter for the classic endometrioid cancers. Aromatase cytochrome p450 is part of the complex responsible for conversion of C19 steroids to estrogen; its increased expression in endometrial cancers, but not in normal endometria, suggests a role in promotion of neoplastic proliferation.
The findings of both gonadotropin-releasing hormone (GnRH) (the ligand) and its receptor, as well as the luteinizing hormone (LH) receptor in endometrial cancers may serve as a rationale for the therapeutic use of GnRH analogues in the treatment of endometrial cancer (although this approach has not been shown to be clinically relevant to date). GnRH analogues may act directly on GnRH-sensitive cancers, as well as indirectly by decreasing systemic LH levels. A clue to the signal transduction pathway of GnRH comes from data in ovarian cancers, where GnRH has an antimitogenic effect by stimulating protein tyrosine phosphatase activity.
Tamoxifen has been associated with an increased risk of development of endometrial cancers, with a possible preferential risk for the high grade nonendometrioid subtypes, such as UPSC or MMTs, although this is controversial. Molecular abnormalities associated with UPSC include overexpression of p53 and c-myc gene amplification; p53 overexpression correlated with a poor prognosis. Two functional different isoforms of progesterone receptor have been described, which may account for some of the tissue-specific differences in the effects of progestins and antiprogestins on the breast as compared with the endometrium.
MOLECULES INVOLVED IN ADHESION AND INVASION
Integrin (cell adhesion molecules) expression inversely correlates with grade in endometrial cancers, with the loss of the alpha(2)beta(1)-integrin associated with lymph node metastases. Variant forms of CD44 (a molecule important for cell adhesion and migration) were less frequently expressed in endometrial cancers than in normal endometria, and absence of CD44 was significantly associated with an increased propensity for lymph-vascular space invasion. These data suggest that CD44 may play an important role in the function of the normal endometria, where it is strongly expressed near the basement membrane, and its loss may be related to invasion and metastasis.
Most of the recent breakthroughs in understanding the molecular basis for this disease has been in the area of hereditary epithelial ovarian cancer syndromes, which affect up to 5% of ovarian cancer cases. Much work is still needed to understand the biology underlying sporadic ovarian cancers, which invariably present as advanced stage disease and have a poor long-term outcome.
CERVICAL AND VULVAR CANCER
The study of the role of viruses in the
carcinogenesis of lower genital tract malignancies (thought to be a field
effect) has focused on cervical cancer, the third most common gynecologic
cancer in the
HUMAN PAPILLOMAVIRUS. That HPV is a critical factor for cervical carcinogenesis, and that the HPV E6 and E7 genes are oncogenic are clearly established. Infection of human keratinocytes by the oncogenic HPV subtypes leads to abnormalities in differentiation and growth; however, only after long-term culture of immortalized cells does an occasional clone become tumorigenic in nude mice, suggesting that HPV infection alone is not sufficient for cervical carcinogenesis. This is supported by data from transgenic mice studies, where E6/E7 genes can give rise to hyperplastic and neoplastic lesions of epithelial cell types after a latent period, however, epidermoid cervical cancers have not been noted. Cervical cancers of mesenchymal origin were noted to arise after a long latent period in some of the female progeny of transgenic mice into whom HPV-18 LCR/E6/E7 was introduced. While the majority of invasive cancers contain integrated forms of HPV, usually at fragile sites that result in cis activation of protooncogenes such as c-myc, and the large majority of dysplasias contain episomal forms of HPV, this is not always the case. In invasive cancers, HPV-18 is always found to be integrated in the host genome, while HPV-16 can be found in an episomal location one third of the time. When DNA integration occurs, it does so by preferentially disrupting the E2 open reading frame, thus, the negative effect of the E2 protein on E6/E7 transcriptional activity; or in such a way that transcriptional initiation from host sequences gives rise to overexpression of E6/E7. High level transcription of E6/E7 is seen in CIN 3 and invasive cancers when compared to CIN 1 and 2. Such overexpression has been shown in vitro to lead to radioresistance of cervical cancer cells. Among both low grade and high grade dysplasias, the presence of oncogenic HPV subtypes has been reported to be closely associated with monoclonality.
MOLECULAR COFACTORS IMPORTANT TO CERVICAL CARCINOGENESIS
Because HPV infection is not sufficient for cervical carcinogenesis, attention has focused on molecular cofactors important to this process, such as coinfection by HSV-2, and the presence of activated Ha-ras; the latter results in rearrangements and amplifications of the HPV-16 sequence. Many positive and negative transcriptional regulators of E6/E7 transcription have been identified. The presence of the glucocorticoid response element 5' of the HPV genome probably underlies the clinical progression of HPV infection seen in pregnancy. Although retinoic acid represses HPV transcription in normal and malignant cells, its induction of retinoic acid receptor beta is restricted to normal cells. Both the retinoic acid receptor beta gene and a locus on chromosome 11q23 may have tumor suppressive properties in epidermoid cancer. Loss of heterozygosity studies demonstrate allelic loss of many chromosomes including 11q, but most frequently involving 3p, 6p, and 18q.
The immune response is likely to be key in determining malignant transformation of HPV-infected cervical epithelium. The consequences of human immunodeficiency virus infection include a dramatic increase in the risk for cervical dysplasia and invasive cancer, the degree of which correlates with the level of immunosuppression. Loss of expression of HLA class I alleles along with interference with the transporter associated with antigen presentation in cervical cancers is common; such changes may influence specific immunogenic presentation by tumors. In addition, the finding of certain HLA class II haplotypes in the cancer (when compared to cervical DNA from controls), which may influence the immune response to specific HPV-encoded epitopes, may contribute to the development of cervical neoplasia. Similar findings were seen when HLA class II haplotypes in CIN were compared to controls; the HLA DQB1 haplotype was significantly more associated with CIN.
In general, more than 90% of squamous cell cervical cancers contain HPV DNA, and rarely p53 mutations are seen. p53 mutations appear to be more common in HPV-negative cancers, although HPV-negative cancers that do not contain p53 mutations exist. The latter do not contain MDM2 gene (capable of binding to p53) amplifications either. Among HPV-negative tumors, c-myc overexpression has been associated with an increased risk of metastasis in early stage disease. Among HPV-positive cancers, nuclear c-myb expression was correlated with presence of HPV; c-myb can transactivate the HPV-16 promoter, as it can HIV-1 and c-myc. In most studies, HPV status was not a strong independent prognosticator of outcome in cervical cancer patients; however, there appears to exist a trend for HPV-negative tumors to do worse.
NON-HPV-RELATED MOLECULAR ABNORMALITIES IN CERVICAL CANCERS
Expression of other cell cycle genes such as bcl-1 and bcl-2 has been studied in cervical cancer. Bcl-1 (cyclin D1) is capable of binding to the Rb protein, and is overexpressed and amplified in the majority of cervical and vulvar cancer cell lines, and its level of expression is elevated by activated CSF-1 receptor. Bcl-2 overexpression, which protects against apoptosis and differentiation, was not found to relate to HPV status, but was more likely to be seen in CIN 3 rather than low grade dysplasias; thus, its expression may be early event important to malignant transformation. In vitro, increased bcl-2 expression is noted in cervical cancer cell lines that contain an inactive p53.
Proteinases capable of degrading extracellular
matrix may underlie the propensity of cervical cancer to invade adjacent
tissues. Both the expression (as measured by reverse transcriptase in situ PCR
and activity of metalloproteinases have been described in cervical cancers, with
more activity seen than in ovarian or endometrial cancers; the opposite finding
is seen for expression of TIMP-
CARCINOMA OF THE CERVIX
The American Cancer Society estimates that
there will be 15,800 new cases of invasive cervical cancer and 65,000 cases of
carcinoma in situ diagnosed in the
Cervical cancer continues to be the leading
cause of cancer deaths for women of many economically underdeveloped countries.
Incidence and death rates are particularly high in Latin America, Africa,
Squamous cell carcinoma of the cervix and its
intraepithelial precursor follow a pattern typical of sexually transmitted
disease. The risk of cervical cancer is increased in prostitutes and in women
who have first coitus at a young age, multiple sexual partners, sexually
transmitted diseases, or who bear children at a young age. Promiscuous sexual
behavior in male partners may also be an important risk factor. Other factors
associated with cervical cancer include cigarette smoking, immunodeficiency,
vitamin A and C deficiency, and possibly oral contraceptive use. In the
Recent studies suggest that the number of cervical adenocarcinomas affecting young women in their 20s and 30s may have increased. Although, on the basis of epidemiologic studies, some investigators have suggested an association between adenocarcinoma and prolonged oral contraceptive use, [ref: 9] others have questioned the validity of these conclusions because of the many potential confounding risk factors.
Molecular studies have demonstrated a strong relationship between human papillomavirus (HPV), cervical intraepithelial neoplasia (CIN), and invasive carcinomas of the cervix. HPV DNA has been identified in more than 60% of cervical cancers; HPV DNA transcripts and protein products also have been identified in invasive cervical carcinomas. In high-grade CIN and invasive carcinoma, the papillomavirus DNA is typically integrated into the human genome rather than remaining in an intact viral capsid. Many of the more than 70 HPV identified subtypes have been isolated, sequenced, and cloned. Types 6 and 11 usually cause benign warts (condyloma acuminata), but are occasionally associated with invasive lesions. Types 16, 18, 31, and 33 are commonly associated with high-grade CIN and invasive cervical cancer. HPV-18 has been associated with poorly differentiated carcinomas, an increased incidence of lymph node involvement, and a high rate of disease recurrence, whereas HPV-16 has been associated with large cell keratinizing tumors and a lower recurrence rate. It has been theorized that HPV-mediated carcinogenesis results from the binding of E6 and E7 proteins (produced by HPV-16 and HPV-18) to Rb and p53 tumor suppressor proteins, interfering with the normal regulation of cell proliferation.
Although most recent investigators have concluded that HPV is probably an important factor in cervical carcinogenesis, its role and that of other viral agents continues to be controversial. Some investigators have argued that other viral agents, including herpes simplex virus type II and Epstein-Barr virus, may also be important.
Human immunodeficiency virus seropositivity has been associated with a high incidence (up to 40%) of CIN and invasive cancer. This is at least partly due to an overlap in risk factors for the two diseases, although changes in cell-mediated immunity may also play a role in the development of cervical cancer. Some investigators have suggested that cervical cancer is a more aggressive disease in these immunosuppressed patients. For these reasons, frequent surveillance with Pap smears, pelvic examination, and colposcopy (when indicated) should be part of the routine care of these patients. In 1993, the Center for Disease Control added cervical cancer to the list of AIDS-defining neoplasms.
NATURAL HISTORY AND PATTERN OF SPREAD
The junction between the primarily columnar epithelium of the endocervix and squamous epithelium of the ectocervix is a site of continuous metaplastic change; this change is most active in utero, at puberty, and during first pregnancy, and declines after menopause.
Viral-induced atypical squamous metaplasia developing in this region can progress to higher-grade squamous intraepithelial lesions. The greatest risk of neoplastic transformation coincides with periods of greatest metaplastic activity, and most carcinomas arise from this zone of metaplastic transformation in the squamocolumnar junction.
The mean age of women with CIN is 15.6 years younger than that of women with invasive cancer, suggesting a slow progression of CIN to invasive carcinoma. In a 13-year observational study of women with CIN 3, Miller found that disease progressed in only 14%, whereas it persisted in 61% and disappeared in the remainder. Syrjanen and colleagues reported spontaneous regression in 38% of high-grade HPV-associated squamous intraepithelial lesions. However, in a large prospective study, Richart and Barron reported mean times to development of carcinoma in situ of 58, 38, and 12 months for patients with mild, moderate, or severe dysplasia, respectively, and predicted that 66% of all dysplasias would progress to carcinoma in situ within 10 years. Once tumor has broken through the basement membrane, it may penetrate the cervical stroma directly or via vascular channels. Invasive tumors may develop as exophytic growths protruding from the cervix into the vagina or as endocervical lesions that can cause massive expansion of the cervix despite a relatively normal appearing cervical portio. From the cervix, tumor may extend superiorly to the lower uterine segment, inferiorly to the vagina, or into the paracervical spaces via the broad or uterosacral ligaments. Tumor may become fixed to the pelvic wall by direct extension or by coalescence of central tumor with regional adenopathy. Tumor may also extend anteriorly to involve the bladder or posteriorly to the rectum, although rectal mucosal involvement is a rare finding at initial presentation. The cervix has a rich supply of lymphatics organized in three anastomosing plexuses that drain the mucosal, muscularis, and serosal layers. The lymphatics of the cervix also anastomose extensively with those of the lower uterine segment, possibly explaining the frequency of uterine extension from endocervical primary tumors. The most important lymphatic collecting trunks exit laterally from the uterine isthmus in three groups. Upper branches originating in the anterior and lateral cervix follow the uterine artery, are sometimes interrupted by a node as they cross the ureter, and terminate in the uppermost hypogastric nodes. Middle branches drain to deeper hypogastric (obturator) nodes, and the lowest branches follow a posterior course to the inferior and superior gluteal, common iliac, presacral, and subaortic nodes. Additional posterior lymphatic channels arising from the posterior cervical wall may drain to superior rectal nodes or may continue upward in the retrorectal space to the subaortic nodes overlying the sacral promontory. Anterior collecting trunks pass between the cervix and bladder with the superior vesical artery to terminate in the internal iliac nodes. Summarizes the reported incidences of pelvic and paraaortic node involvement for patients who underwent lymphadenectomy as part of primary surgical treatment or before radiation therapy for cervical carcinomas. The incidences reported for radical hysterectomy series vary widely, probably reflecting surgeons' different criteria for selecting patients for radical surgery rather than for primary radiation treatment. Many series exclude patients with extrapelvic disease. Variations in the completeness of lymphadenectomies and histologic processing may also lead to underestimates of the true incidence of regional spread from carcinomas of the cervix. Cervical cancer usually follows a relatively orderly pattern of metastatic progression initially to primary echelon nodes in the pelvis, then to paraaortic nodes and distant sites. Even patients with locoregionally advanced disease rarely have detectable hematogenous metastases at initial diagnosis of their cervical cancer. The most frequent sites of distant recurrence are lung, extrapelvic nodes, liver, and bone. Although the lumbar spine is said to be a relatively frequent site of skeletal metastases, more recent studies using abdominal imaging demonstrate that most patients with isolated lumbar spine involvement actually have direct extension of disease from paraaortic nodes.
Cervical Intraepithelial Neoplasia
Several systems have been developed to classify cervical cytology. Although criteria for the diagnosis of CIN vary somewhat between pathologists, the important characteristics of this lesion are cellular immaturity, cellular disorganization, nuclear abnormalities, and increased mitotic activity. The degree of neoplasia is determined from the extent of the mitotic activity, immature cell proliferation, and nuclear atypia. If mitoses and immature cells are present only in the lower one third of the epithelium, the lesion usually is designated CIN 1. Involvement of the middle or upper third is diagnosed as CIN 2 or CIN 3, respectively.
The term cervical intraepithelial neoplasia, as proposed by Richart, refers only to a lesion that may progress to invasive carcinoma. Although CIN 1-2 is sometimes referred to as mild to moderate dysplasia, CIN is now preferred over the term dysplasia. Because the word dysplasia means abnormal maturation, proliferating metaplasia without mitotic activity has sometimes been erroneously called dysplasia.
ADENOCARCINOMA IN SITU. The diagnosis of adenocarcinoma in situ (AIS) is made when normal endocervical gland cells are replaced by tall, irregular columnar cells with stratified, hyperchromatic nuclei and increased mitotic activity, but the normal branching pattern of the endocervical glands is maintained and there is no obvious stromal invasion. About 50% of women with cervical AIS also have squamous CIN, and AIS is often an incidental finding in patients operated on for squamous carcinoma.
Because the definition of microinvasive carcinoma is based on the maximum depth and linear extent of involvement, it can be diagnosed only from a specimen that includes the entire neoplastic lesion and cervical transformation zone. This requires a cervical cone biopsy.
The earliest invasion appears as a protrusion
of cells from the stromoepithelial junction; these cells are better
differentiated than the adjacent noninvasive cells and have abundant
pink-staining cytoplasm, hyperchromatic nuclei, and small to medium nucleoli.
As the tumor progresses, invasion occurs at multiple sites, and its depth and
linear extent become measurable. The depth of invasion should be measured with
a micrometer from the base of the epithelium to the deepest point of invasion.
Although lesions that have invaded less than
Although investigators occasionally label very small adenocarcinomas as microinvasive, the term probably should not be used for these tumors. No definable, consistent method has been found to measure the depth of an invasive adenocarcinoma because it may have originated from the mucosal surface or the periphery of underlying glands. For this reason, adenocarcinomas are generally classified as either AIS or invasive carcinoma (FIGO stage IB).
Invasive Squamous Cell Carcinoma
Between 80% and 90% of cervical carcinomas are squamous. A number of systems have been used to grade and classify squamous carcinomas, but none have been consistently demonstrated to predict prognosis. One of the most commonly used systems categorizes squamous neoplasms as either large cell keratinizing, large cell nonkeratinizing, or small cell carcinoma. The latter should not be (but often is) confused with anaplastic small cell carcinoma, which resembles oat cell carcinoma of the lung because it contains small tumor cells that have scanty cytoplasm, small round to oval nuclei, small or absent nucleoli, coarsely granular chromatin, and high mitotic activity. In contrast, small cell squamous carcinomas have small to medium nuclei, open chromatin, small or large nucleoli, and more abundant cytoplasm. About 30% to 50% of anaplastic small cell carcinomas display neuroendocrine features. Most authorities believe that patients with large cell squamous carcinoma, with or without keratinization, have a better prognosis than those with small cell neoplasms and that small cell anaplastic carcinomas behave more aggressively than poorly differentiated small cell squamous carcinomas.
Invasive adenocarcinoma may be pure or mixed with squamous cell carcinoma (adenosquamous carcinoma). A wide variety of cell types, growth patterns, and differentiation have been observed. About 80% of cervical adenocarcinomas are made up predominantly of cells whose differentiated features resemble endocervical glandular epithelium with intracytoplasmic mucin production. The remaining tumors are populated by endometrioid cells, clear cells, intestinal cells, or a mixture of more than one cell type. By histologic examination alone, some of these tumors are indistinguishable from those arising elsewhere in the endometrium or ovary. Minimal deviation adenocarcinoma (adenoma malignum) is an extremely well-differentiated adenocarcinoma in which the branching glandular pattern strongly resembles normal endocervical glands. Because of this, the tumor may not be recognized as malignant in small biopsy specimens and the correct diagnosis may be delayed. Earlier studies reported a dismal outcome for women with this tumor, but more recently, patients have been reported to have a favorable prognosis if the disease is detected early.
Young and Scully have described a villoglandular papillary subtype of adenocarcinoma that primarily affects young women, appears to metastasize infrequently, and has a favorable prognosis. Glucksmann and Cherry first described glassy cell carcinoma, a form of poorly differentiated adenosquamous carcinoma with cells that have abundant eosinophilic, granular, ground-glass cytoplasm, large round to oval nuclei, and prominent nucleoli. Other rare variants of adenosquamous carcinoma include adenoid basal carcinoma and adenoid cystic carcinoma. The former is a well-differentiated tumor that histologically resembles basal cell carcinoma of the skin and tends to have a favorable prognosis. Adenoid cystic carcinomas consist of basaloid cells in a cribriform or cylindromatous pattern and tend to have an aggressive behavior with frequent metastases, although the natural history of these tumors may be long. Whether the prognoses of these rare subtypes are different from other adenocarcinomas of similar grade is uncertain. A variety of neoplasms may infiltrate the cervix from adjacent sites, presenting differential diagnostic problems. In particular, it may be difficult or impossible to determine the origin of adenocarcinomas involving the endocervix and uterine isthmus. Although endometrioid histology suggests endometrial origin and mucinous tumors in young patients are most often of endocervical origin, both histologic types can arise in either site. Metastatic tumors from the colon, breast, or other sites may involve the cervix secondarily. Malignant mixed mullerian tumors, adenosarcomas, and leiomyosarcomas arise occasionally in the cervix, but more often involve it secondarily. Primary lymphomas and melanomas of the cervix are extremely rare.
Preinvasive disease is usually detected during routine screening from cervical cytology. Patients with early invasive disease may also be asymptomatic. The first symptom of invasive cervical cancer is usually abnormal vaginal bleeding, often following coitus or vaginal douching. This may be associated with a clear or foul-smelling vaginal discharge. Pelvic pain may result from locoregionally invasive disease or from coexistent pelvic inflammatory disease. Flank pain may be a symptom of hydronephrosis, often complicated by pyelonephritis. The triad of sciatic pain, leg edema, and hydronephrosis is almost always associated with extensive pelvic wall involvement by tumor. Patients with very advanced tumors may have hematuria or incontinence from a vesicovaginal fistula caused by direct extension of tumor to the bladder. External compression of the rectum by a massive primary tumor may cause constipation, but the rectal mucosa is rarely involved at initial diagnosis.
DIAGNOSIS, CLINICAL EVALUATION, AND STAGING
The long preinvasive stage of cervical cancer, relatively high prevalence of
the disease in unscreened populations, and the sensitivity of cytologic
screening have made cervical carcinoma an ideal target for cancer screening. In the
Clinical Evaluation of Patients With Invasive Carcinoma
All patients with invasive cervical cancer should be evaluated with a detailed history and physical examination, paying particular attention to inspection and palpation of the pelvic organs with bimanual and rectovaginal examinations. Standard laboratory studies should include complete blood count and renal function and liver function tests. All patients should have a chest radiograph to rule out lung metastases and an intravenous pyelogram to determine the kidneys' location and to rule out ureteral obstruction by tumor. Cystoscopy and proctoscopy or barium enema should be obtained in patients with bulky tumors. Many clinicians obtain computed tomography (CT) or magnetic resonance imaging (MRI) scans to evaluate regional nodes, but the accuracy of these studies is compromised by their failure to detect small metastases and because patients with bulky necrotic tumors often have enlarged reactive lymph nodes.
a large Gynecologic Oncology Group study that compared the results of radiographic
studies with subsequent histologic findings, Heller and colleagues found that
79% of the cases with paraaortic lymph node involvement were detected by
lymphangiography whereas only 34% were detected by CT. MRI can provide useful
information about the location and depth of invasion of tumors in the cervix, but
gives less accurate assessments of parametrial involvement. Clinical Staging The International Federation of Gynecology and Obstetrics
(FIGO) has defined the most widely accepted staging system for carcinomas of
the cervix. The latest (1994) update of this system is summarized in Table.
Since the earliest versions of the cervical cancer staging system, there have
been numerous changes, particularly in the definition of stage I disease. Preinvasive
disease was not placed in a separate category until 1950, and the stage IA
category for "cases with early stromal invasion" was first described
in 1962. Cases of early stromal invasion and occult invasion were redistributed
between stages IA(i), IA(ii), and IB(occult) several times until 1985, when
FIGO eliminated stage IB(occult and provided the first specific definitions of
microinvasive disease (stages IA1 and IA2). In 1994, these definitions were
changed again and, for the first time, stage IB tumors were subdivided
according to tumor diameter. Although these changes have gradually improved the
discriminatory value of the staging system, the many fluctuations in the
definitions of stage IA and IB have complicated our ability to compare the
outcomes of patients whose tumors were staged and treated during these periods.
In addition, gynecologic oncologists in the United States have for many years
stag disease using the Society of Gynecologic Oncologists' definition of a
microinvasive carcinoma, that is, tumor that "invades the stroma in one or
more places to a depth of
Although the survival and pelvic disease
control rates of cervical cancer patients are correlated with FIGO stage,
prognosis is also influenced by a number of tumor characteristics that are not
included in the staging system. Clinical tumor diameter is strongly correlated
with prognosis for patients treated with radiation or surgery. For this reason,
FIGO recently modified the stage I category to subdivide tumors according to
clinical tumor diameter (i.e.,
In a study of sera obtained before treatment from 587 patients with cervical cancers, Duk and colleagues reported a strong correlation between the concentration of squamous cell carcinoma antigen and the stage and size of the tumor as well as the presence of lymph node metastases; multivariate analysis also showed that serum squamous cell carcinoma antigen was an independent predictor of prognosis in their study.
Other clinical and biologic features that have been investigated for their predictive power with variable results include patient age, platelet count, tumor vascularity, DNA ploidy or S phase, and HPV infection. In a preliminary study of archival material from 21 patients with histologically negative lymph node dissections, Ikenberg and colleagues recently reported a higher rate of disease recurrence when a polymerase chain reaction assay of the lymph nodes was strongly positive for HPV-16 DNA.
A number of factors may influence the choice
of treatment, including tumor size, stage, and histology; evidence of lymph
node involvement; risk factors for
surgery or radiation; and patient preference.
However, as a rule, intraepithelial
lesions are treated with superficial ablative techniques, microinvasive
cervical cancers invading less than
Preinvasive Disease (Stage 0)
Patients with noninvasive squamous lesions can be treated with superficial ablative therapy (cryosurgery or laser therapy) or with loop excision if (1) the entire transformation zone has been visualized colposcopically, (2) directed biopsies are consistent with Pap smear results, (3) endocervical curettage findings are negative, and (4) there is no cytologic or colposcopic suspicion of occult invasion. If patients do not meet these criteria, a conization should be performed.
With cryotherapy, abnormal tissue is frozen
with a supercooled metal probe until an
ice ball forms that extends
Many practitioners now consider loop diathermy
excision to be the preferred treatment.
With this technique, a charged electrode is used to excise the entire transformation zone and
Microinvasive Carcinoma (Stage IA)
The standard treatment for patients with stage
IA1 disease is total (type
I) or vaginal hysterectomy. Because the risk of pelvic lymph node metastases from these minimally invasive
tumors is less than 1%, pelvic lymph
node dissection is not usually recommended. Selected patients with tumors that
meet the Society of Gynecologic
Oncologists' definition of microinvasion (FIGO stage IA1 disease without lymph-vascular space invasion) and
who wish to maintain fertility may be
adequately treated with a therapeutic cervical
conization if the margins of the cone are negative. In 1991, Burghardt and
colleagues reported one recurrence (which was fatal) in 93 women followed for more than 5 years after
therapeutic conization for minimal (less
Diagnostic or therapeutic conization for microinvasive disease is usually performed with a cold knife or carbon dioxide laser on a patient under general or spinal anesthesia. Because an accurate assessment of the maximum depth of invasion is critical, the entire specimen must be sectioned and carefully handled to maintain its original orientation for microscopic assessment. Complications occur in 2% to 12% of patients, are related to the depth of the cone, and include hemorrhage, sepsis, infertility, stenosis, and cervical incompetence. The width and depth of the cone should be tailored to produce the least amount of injury while providing clear surgical margins.
For patients with 3 to
Stages IB and IIA
Early stage IB cervical carcinomas can be treated effectively with combined external-beam irradiation and brachytherapy or with radical hysterectomy and bilateral pelvic lymphadenectomy. The goal of both treatments is to destroy malignant cells in the cervix, paracervical tissues, and regional lymph nodes.
Overall survival rates for patients with stage IB cervical cancer treated with surgery or radiation usually range between 80% and 90%, suggesting that the two treatments are equally effective. However, biases introduced by patient selection, inconsistencies in the definition of FIGO stage IB disease, and variable indications for postoperative radiotherapy or adjuvant hysterectomy confound comparisons about the efficacy of radiotherapy versus surgery.
In a 1976 review of 321 patients, Morley and Seski reported similar 5-year survival rates of 91.3% and 87.3% for patients treated with surgery or radiotherapy, respectively. Though treatment was assigned alternately for most patients in this series, the study was not truly randomized; exclusion of some patients found to have unfavorable findings at surgery and deviations from the alternating scheme could have led to biased results. In another review of their experience, Hopkins and Morley noted that a significant difference in survival favoring surgical treatment disappeared when the authors excluded from the radiation group patients who were selected for radiation treatment only after radical hysterectomy was aborted because of intraoperative findings of extrauterine disease. Because young women with small, clinically node-negative tumors tend to be favored candidates for surgery and because tumor diameter and nodal status are inconsistently described in published series, it is difficult to compare the results reported for patients treated with the two modalities.
Preliminary results of the first prospective
patients with stage IB or IIA cervical cancer to radical surgery
or radical radiotherapy were recently
reported. In the surgical arm, findings
of parametrial involvement, positive margins,
deep stromal invasion, or positive nodes led to the use of postoperative pelvic irradiation in 62 (54%)
of 114 patients with tumors
For patients with stage IB1 squamous carcinomas, the choice of treatment is based primarily on patient preference, anesthetic and surgical risks, physician preference, and an understanding of the nature and incidence of complications with the two treatment approaches (described in detail later). The overall rate of major complications is similar for patients with comparable tumors treated with surgery or radiotherapy, although urinary tract complications tend to be more frequent after surgical treatment, and bowel complications are more common after radiation therapy. Surgical treatment tends to be preferred for young women with small tumors because it permits preservation of ovarian function and may cause less vaginal shortening. Radiation therapy is often selected for older, postmenopausal women to avoid the morbidity of a major surgical procedure.
Some surgeons have also advocated the use of
radical hysterectomy as
initial treatment for patients with larger (stage IB2) tumors. However,
patients who have tumors measuring more than
RADICAL HYSTERECTOMY. The standard surgical treatment for stages IB and IIA cervical carcinomas is radical (type III) hysterectomy and bilateral pelvic lymph node dissection. This procedure involves en bloc removal of the uterus, cervix, and paracervical, parametrial, and paravaginal tissues to the pelvic sidewalls bilaterally, taking as much of the uterosacral ligaments as possible.
The uterine vessels are ligated at their origin,
and the proximal one third of the vagina
and paracolpos are resected. For women younger
than 40 to 45 years, the ovaries usually are not removed. If
intraoperative findings suggest a need for postoperative pelvic irradiation, the ovaries may be transposed
out of the pelvis. Intraoperative and
immediate postoperative complications of radical hysterectomy include blood loss
Although most patients have transient decreased bladder sensation after radical hysterectomy, with appropriate management severe long-term bladder complications are infrequent. However, chronic bladder hypotonia or atony occur in approximately 3% to 5% of patients, despite careful postoperative bladder drainage. Bladder atonia probably results from damage to the bladder's innervation and may be related to the extent of the parametrial and paravaginal dissection. Radical hysterectomy may be complicated by stress incontinence, but reported incidences vary widely. Patients may also experience constipation and, rarely, chronic obstipation after radical hysterectomy.
RADIATION THERAPY AFTER RADICAL HYSTERECTOMY.
The role of postoperative irradiation in patients with cervical carcinoma has not yet been clearly established. Most investigators have reported that postoperative irradiation decreases the risk of pelvic recurrence in patients whose tumors have high-risk features (lymph node metastasis, deep stromal invasion, insecure operative margins, or parametrial involvement). However, because the patients who received postoperative radiotherapy in these studies were selected for the high-risk features of their tumors, it is difficult to determine the impact of adjuvant irradiation on survival.
Stages IB and IIA (Continued). In 1989, Kinney and colleagues retrospectively compared the outcome of 60 patients who had postoperative irradiation with 60 unirradiated patients who were matched for stage (stage IB versus IIA), tumor size, and number and site of positive nodes. There were fewer isolated pelvic failures in the irradiated group, but there was no significant difference in survival. However, even this study did not characterize patients in terms of all the risk factors that can influence the choice of treatment. Some authors have hypothesized that the dose of radiation that can be given safely postoperatively may be inadequate to control microscopic disease in a surgically disturbed, hypovascular site. If this is true, it would be an argument for primary radiotherapeutic management of tumors with known high-risk features.
The overall risk of major complications (particularly small bowel obstructions) is probably increased in patients who receive postoperative pelvic irradiation, but inconsistencies in the methods of analysis and the relatively small number of patients in most series make studies of this subject difficult to interpret. Montz and colleagues reported a 20% risk of small bowel obstruction requiring surgery in 20 patients treated with postoperative irradiation compared with 3 (5%) of 60 patients treated with hysterectomy alone. Bandy and colleagues reported that patients who were irradiated after hysterectomy also had more long-term problems with bladder contraction and instability than those treated with surgery alone.
THERAPY. Radiation therapy also achieves excellent survival and pelvic control rates in patients
with stage IB cervical cancers.
As with radical surgery, the goal of radiation treatment is to sterilize disease in the cervix, paracervical tissues, and regional lymph nodes in the pelvis. Patients are usually treated with a combination of external-beam irradiation to the pelvis and brachytherapy. Clinicians balance external and intracavitary treatment in different ways for these patients, weighting one or the other component more heavily. However, brachytherapy is a critical element in the curative radiation treatment of all carcinomas of the cervix. Even relatively small tumors that involve multiple quadrants of the cervix are usually treated with total doses of 80 to 85 Gy to point A. This dose may be reduced by 5% to 10% for very small superficial tumors. Although patients with small tumors may be treated with somewhat smaller fields than patients with more advanced locoregional disease, care must still be taken to cover adequately the obturator, external iliac, low common iliac, and presacral nodes. Radiation technique and potential complications are discussed in more detail later.
IRRADIATION FOLLOWED BY HYSTERECTOMY.
a 1969 report from
In 1991, Mendenhall and colleagues reported
no difference in pelvic disease control
or survival rates for patients treated
before or after the University of Florida adopted a policy (in the mid-1970s) of using combined treatment for
patients with bulky (
There is, therefore, no clear evidence that adjuvant hysterectomy improves the outcome of patients with a bulky stage IB or IIA tumor, though many clinicians continue to advocate combined treatment. When combined treatment is planned, the dose of intracavitary irradiation is usually reduced by about 25%. A type I extrafascial hysterectomy is usually performed removing the cervix, adjacent tissues, and a small cuff of the upper vagina in a plane outside the pubocervical fascia. This procedure involves minimal disturbance of the bladder and ureters. Intrafascial hysterectomy is not used for cervical cancer because it does not remove all cervical tissue, and radical hysterectomy is avoided after high-dose irradiation because of an increased risk of urinary tract complications.
The Gynecologic Oncology Group recently
completed a prospective randomized trial
of irradiation with or without extrafascial
hysterectomy in patients with stage IB tumors of
CHEMOTHERAPY FOLLOWED BY RADICAL SURGERY. Since the late 1980s, a number of investigators have reported the results of treating patients with bulky stages IB and II cervical carcinomas with a combination of neoadjuvant chemotherapy followed by radical surgery. Neoadjuvant chemotherapy has usually included cisplatin and bleomycin plus one or two other drugs. The results of these uncontrolled studies cannot be easily compared with more traditional treatments because the series are small, often have short follow-up, and the criteria for patient selection are not always clear. Some or all of the patients in each of these series received postoperative pelvic irradiation, but detailed descriptions of this additional treatment are not always given. There has been one report of a prospective randomized trial comparing radical hysterectomy followed by postoperative radiotherapy with chemotherapy followed by surgery and irradiation. In this study, Sardi and colleagues observed similar outcomes with the two treatments for patients who had tumors smaller than 60 cm3 (measured ultrasonographically), but they reported a significantly better projected 4-year disease-free survival with neoadjuvant chemotherapy for patients who had larger tumors. However, most patients had been followed for less than 3 years at the time of the report. Ultimately, the cost and morbidity of this triple-modality treatment may be justified only if it proves to be more effective than treatment with radiotherapy alone. However, studies comparing this approach with radical irradiation have not yet been reported.
Stages IIB, III, and IVA
Radiation therapy is the primary treatment for most patients with locoregionally advanced cervical carcinoma. The success of treatment depends on a careful balance between external-beam radiation therapy and brachytherapy, optimizing the dose to tumor and normal tissues, and the overall duration of treatment. Five-year survival rates of 65% to 75%, 35% to 50%, and 15% to 20% are reported for patients treated with radiotherapy alone for stages IIB, IIIB, and IVA tumors, respectively. In a French Cooperative Group study of 1383 patients treated with radiotherapy according to Fletcher guidelines, Horiot and colleagues reported 5-year survival rates of 76%, 50%, and 20.5% for patients with stages IIB, IIIB, and IVA tumors, respectively. With appropriate radiotherapy, even patients with massive locoregional disease have a significant chance for cure.
External-beam irradiation is used to deliver a homogeneous dose to the primary cervical tumor and to potential sites of regional spread. An initial course of external irradiation may also improve the efficacy of subsequent intracavitary treatment by shrinking bulky endocervical tumor (bringing it within the range of the high-dose portion of the brachytherapy dose distribution) and by shrinking exophytic tumor that might prevent satisfactory placement of vaginal applicators. For this reason, patients with locally advanced disease usually begin with a course of external-beam treatment. Subsequent brachytherapy exploits the inverse square law to deliver a high dose to the cervix and paracervical tissues while minimizing the dose to adjacent normal tissues. Although many clinicians delay intracavitary treatment until pelvic irradiation has caused some initial tumor regression, breaks between external-beam and intracavitary therapy should be discouraged, and every effort should be made to complete the entire treatment in less than 7 to 8 weeks. The favorable results documented in reports from large single institutions have been based on policies that dictate relatively short overall treatment durations (less than 8 weeks), and several studies in patients with locally advanced cervical cancer have suggested that longer treatment courses are associated with decreased pelvic control and survival rates.
EXTERNAL-BEAM TECHNIQUE. High-energy photons (15 to 18 MV) are usually preferred for pelvic treatment because they spare superficial tissues that are unlikely to be involved with tumor. At these energies, the pelvis can be treated either with four fields (anterior, posterior, and lateral fields) or with anterior and posterior fields alone. When high-energy beams are not available, four fields are usually used because less penetrating 4 to 6 MV photons often deliver an unacceptably high dose to superficial tissues when only two fields are treated. However, lateral fields must be designed with great care because clinicians' estimates of the location of potential sites of disease on a lateral radiograph may be inaccurate. In particular, "standard" anterior and posterior borders that have been described in the past may shield regions at risk for microscopic regional disease in the presacral and external iliac nodes and in the presacral and cardinal ligaments; care must also be taken not to underestimate the posterior extent of central cervical disease in patients with bulky tumors. The caudad extent of disease can be determined by placing radiopaque seeds in the cervix or at the lowest extent of vaginal disease. Information gained from radiologic studies can also improve estimates of disease extent. Lymphangiograms are helpful in tailoring blocks, particularly at the anterior border of lateral fields. MRI and CT scans can also help clinicians to design lateral field borders with an improved understanding of uterine position. In fact, some investigators have argued that these studies should be obtained routinely for patients with bulky disease to avoid errors in lateral field design. However, when all these factors are considered, differences in the volume treated with a four-field or a high-energy two-field technique may be small. For this reason, some clinicians prefer to use the simpler technique for patients with bulky tumors.
Tumor response should be evaluated with periodic pelvic examinations to determine the best time to deliver brachytherapy treatment. Some practitioners prefer to maximize the brachytherapy component of treatment and begin as soon as the tumor has responded enough to permit a good placement (with very bulky tumors this may still require 40 Gy or more). Subsequent pelvic irradiation is delivered with a central block. A somewhat higher total paracentral dose can be delivered with this approach, but greater reliance is placed on the complex match between the brachytherapy dose distribution and the border of the central shield. Other clinicians prefer to give an initial dose of 40 to 45 Gy to the whole pelvis, believing that the ability to deliver a homogeneous distribution to the entire region at risk for microscopic disease and the additional tumor shrinkage achieved before brachytherapy outweigh other considerations. In fact, both approaches have been in use for several decades and, when optimally used, appear to give excellent tumor control rates with acceptable complication rates.
THE ROLE OF PARAAORTIC IRRADIATION. The role of extended-field irradiation in the treatment of cervix cancer is still being defined. Numerous small series of patients with documented paraaortic node involvement demonstrate that some enjoy long-term survival after radiation therapy. Patients with microscopic involvement have a better survival than those with gross lymphadenopathy, but even 10% to 15% of the latter appear to be curable with aggressive management. Survival is also strongly correlated with the bulk of central disease. A 1991 study by Cunningham and colleagues reported a 48% 5-year survival rate in patients who had paraaortic node involvement discovered at exploration for radical hysterectomy (which was then aborted). This experience with patients who had small, radiocontrollable primary disease demonstrates that patients with paraaortic node metastases can often be cured if their primary disease can be sterilized. This indicates that patients may have extensive regional spread without distant metastases and provides an argument for surgical staging in high-risk patients.
Two randomized prospective trials have
addressed the role of prophylactic
paraaortic irradiation in patients without known paraaortic node involvement. In a recently
updated study conducted by the Radiation
Therapy Oncology Group (RTOG), 367 patients with primary stage IIB or stages IB and IIA tumors more
Stages IIB, III, and IVA (Continued)
A second trial from the European Organization for Research and Treatment of Cancer (EORTC) involved a similar randomization between pelvic irradiation and extended fields, but had very different eligibility criteria. This study included patients with bulky stage IIB (involving distal vagina or lateral parametrium) and III disease and patients with stage I and less bulky stage IIB disease who had positive pelvic nodes on lymphangiogram or at surgery. The 4-year disease-free survival rates of 49.8% and 53.3% for patients treated with pelvic or extended fields, respectively, were not significantly different. However, the rate of paraaortic node recurrence was significantly higher in the pelvic group, and for patients in whom local control was achieved, the rate of distant metastases was 2.8 times greater if treatment was with pelvic irradiation only (P <0.01).
Both studies revealed an increased rate of enteric complications in patients treated with extended fields. In the ROTG study, most small bowel obstructions occurred in patients who had undergone pretreatment transperitoneal staging. The EORTC did not mention a relationship between surgical staging and enteric complications.
Although the morbidity of extended-field irradiation is no longer prohibitive with multiple field techniques, more modest radiation doses, and extraperitoneal staging, it is still greater than that of standard field radiotherapy. Further definition of patients most likely to benefit from prophylactic paraaortic irradiation would improve the therapeutic ratio of such treatment.
BRACHYTHERAPY TECHNIQUE. Fletcher described the following three conditions for successful cervical brachytherapy: (1) the geometry of the radioactive sources must prevent underdosed regions on and around the cervix, (2) an adequate dose must be delivered to the paracervical areas, and (3) mucosal tolerance must be respected. These factors dictate the character, intensity, and timing of brachytherapy.
Brachytherapy is usually delivered using
afterloading applicators that are placed
in the uterine cavity and vagina. A number of different intracavitary systems have been used; in the
BRACHYTHERAPY DOSE. Optimal placement of the uterine tandem and vaginal ovoids produces a pear-shaped distribution, delivering a high dose to the cervix and paracervical tissues and a reduced dose to the rectum and bladder.
Treatment dose has been specified in a number
of ways, making it very difficult to
compare experiences. Paracentral doses are most
frequently expressed at a single point, usually designated point A. This reference point has been calculated in a
number of different ways, but it is
In 1985 the International Commission on
Radiation Units and
Measurements recommended that reference points like point A not
be used because "such points are
located in a region where the dose
gradient is high and any inaccuracy in the determination of
distance results in large uncertainties
in the absorbed doses evaluated at these
points." Instead, they recommended that doses be specified in terms of the following: (1)
total reference air Kerma -- expressed
in muGy at
A detailed description of the characteristics of an ideal intracavitary system and of the considerations that influence source strength and position are beyond the scope of this chapter. However, an effort should always be made to deliver 85 Gy or more to point A for patients with bulky central disease. If the intracavitary placement has been optimized, this can usually be accomplished without exceeding a dose of 75 Gy to the bladder reference point or 70 Gy to the rectal reference point, doses that are usually associated with an acceptably low risk of major complications. The dose to the surface of the lateral wall of the apical vagina should not usually exceed 130 to 140 Gy. Suboptimal placements occasionally force compromises in the dose to tumor or normal tissues. To choose a treatment that optimizes the therapeutic ratio in these circumstances requires experience and a detailed understanding of factors that influence tumor control and normal tissue complications.
A total dose (external beam and intracavitary) of 50 to 55 Gy appears to be sufficient to sterilize microscopic disease in the pelvic nodes in most patients. It is customary to boost the dose to a total of 60 to 65 Gy in lymph nodes known to contain gross disease and in heavily involved parametria.
BRACHYTHERAPY DOSE RATE. Traditionally, cervical brachytherapy has been performed with sources that yield a dose rate (at point A) of approximately 40 to 50 cGy/hr. These low dose rates permit repair of sublethal cellular injury, normal tissues are preferentially spared, and the therapeutic ratio is optimized. To reduce the 3 to 4 days of hospitalization needed to deliver an appropriate dose of low-dose-rate irradiation, some investigators have explored the use of intermediate-dose-rate brachytherapy (80 to 100 cGy/hr). However, in a randomized trial, Haie-Meder and colleagues [ref: 275] reported a significant increase in complications when the dose rate was doubled from 40 to 80 cGy/hr, indicating that the total dose must be reduced and the therapeutic ratio of treatment may be compromised with higher dose rates.
the 1970s, computer technology has made it possible to deliver brachytherapy at very high dose rates
(more than 100 cGy/min) with a high
activity *60Co or *192Ir source and remote afterloading. High-dose-rate intracavitary therapy is now
being used for radical
treatment of cervical cancer by a number of groups, including
INTERSTITIAL BRACHYTHERAPY. Several groups have advocated the use of interstitial brachytherapy to treat patients whose anatomy or tumor distribution make it difficult to obtain an ideal intracavitary placement. Interstitial implants are usually placed transperineally, guided by a Lucite template that encourages parallel placement of hollow needles that penetrate the cervix and paracervical spaces; needles are usually loaded with *192Ir. Advocates of the procedure describe the relatively homogeneous dose distribution achieved with this method, the ease of inserting implants in patients whose uteri are difficult to probe, and the ability to place sources directly into the parametrium. Initial reports were enthusiastic, describing these theoretical advantages and high initial local control rates.
However, there have as yet been very few
reports of long-term survival rates in
patients treated with interstitial brachytherapy for primary cervical cancer. In 1986, Syed and colleagues
reported a projected
5-year survival rate of 53% for 26 patients with stage IIIB disease.
Recently several groups have been exploring the use of MRI-guided needle placement, interstitial hyperthermia, and high-dose-rate interstitial therapy to improve local control and complication rates. However, outside of an investigational setting, interstitial treatment of primary cervical cancers should probably be limited to patients who cannot accommodate intrauterine brachytherapy and to those with distal vaginal disease that requires a boost with interstitial brachytherapy.
COMPLICATIONS OF RADICAL RADIOTHERAPY. During radiotherapy of the pelvis, most patients have mild fatigue and mild to moderate diarrhea that usually is controllable with antidiarrheal medications; some patients have mild bladder irritation. When extended fields are treated, patients may have nausea, gastric irritation, and mild depression of peripheral blood counts. Acute symptoms may be increased in patients receiving concurrent chemotherapy. Unless the ovaries have been transposed, all premenopausal patients who receive pelvic radiotherapy experience ovarian failure by the completion of treatment.
Complications of intracavitary therapy include uterine perforation, fever, and the usual risks of anesthesia. Thromboembolic complications are rare. In a review of 327 patients who had gynecologic brachytherapy for a variety of indications, Dusenberry and colleagues reported four (1.2%) thromboembolic complications. In a recent unpublished review of 1784 patients treated with radiotherapy for Stage IB cervical cancer at M. D. Anderson, there were 3 (0.17%) suspected cases of pulmonary embolus, none of which were fatal. Patients with bulky disease on the pelvic wall may have a somewhat greater risk of thromboembolic events.
Estimates of the risk of late complications of
radical radiotherapy vary according to
the grading system, duration of follow-up, method of calculation, treatment method, and prevalence
of risk factors in the study population.
However, most reports quote an overall risk of major complications (requiring transfusion,
hospitalization, or surgical
intervention) of 5% to 15%. Perez and colleagues reported a crude risk of major
complications of 14.8% with a median follow-up of 12 years. In a report from the Patterns of
Care Study, Lanciano and
colleagues reported an actuarial risk of 8% at 3 years. In a study of 1784
patients with stage IB disease,
During the first 3 years after treatment,
rectal complications are most common and
include bleeding, stricture, ulceration, and fistula. In the study by
Small bowel obstruction is an infrequent complication of standard radiotherapy for patients without special risk factors. The risk is increased dramatically in patients who have undergone transperitoneal lymph node dissections. However, there appears to be little added risk if the operation is performed with a retroperitoneal approach. Other factors that can increase the risk of small bowel complications in patients treated for cervical cancer include pelvic inflammatory disease, thin body habitus, and the use of high doses or large volumes of external-beam irradiation, particularly with low-energy treatment beams and large daily fraction sizes.
Most patients treated with radical radiotherapy have some agglutination and telangiectasia of the apical vagina. More significant vaginal shortening can occur, particularly in elderly, postmenopausal women and those with extensive tumors treated with a high dose of irradiation. Vaginal function can be optimized with appropriate estrogen support and vaginal dilatation.
NEOADJUVANT CHEMOTHERAPY. Studies that have explored combinations of chemotherapy and radiation therapy for patients with locally advanced cervical cancers have generally used one of two strategies. Studies of neoadjuvant chemotherapy have attempted to exploit the high response rates of previously untreated tumors to chemotherapy by administering systemic agents before any local therapy, hopefully to reduce the volume of tumor treated with radiation. In contrast, the primary goal of studies that combine radiation therapy with concurrent chemotherapy is to use chemotherapeutic agents to sensitize tumor cells to the effects of radiotherapy.
Investigators were encouraged to explore neoadjuvant treatment because of the high response rates reported for a variety of cisplatin-containing combinations evaluated in phase II studies of previously untreated patients with cervical cancer. However, it was not possible to determine from these uncontrolled trials whether high response rates to chemotherapy would lead to improved survival rates. Five randomized trials comparing neoadjuvant chemotherapy followed by irradiation and irradiation alone have been reported. Chauvergne and colleagues randomized 151 patients with stages IIB or III disease to receive radical radiotherapy alone or preceded by chemotherapy (cisplatin, methotrexate, chlorambucil, and vincristine). Although objective responses to chemotherapy were observed in 31 (43%) of 73 patients, there was no difference in the survival or pelvic disease control rates of patients in the two treatment arms. In a randomized study of 184 patients with stages IIB to IVA squamous carcinomas, Kumar and colleagues found no significant difference in disease-free or overall survival between patients treated with bleomycin, cisplatin, and ifosfamide followed by irradiation or with irradiation alone. Tattersall and colleagues reported no difference in survival when they compared chemotherapy (cisplatin, bleomycin, and Velban) followed by pelvic irradiation with radiotherapy alone in 71 patients who had positive pelvic lymph nodes discovered at radical hysterectomy. Souhami and colleagues reported a significantly poorer survival rate (23% versus 39%; P =0.02) for patients who received neoadjuvant chemotherapy (cisplatin, bleomycin, vincristine, and mitomycin-C) in a study of 107 patients with stage IIIB cervical cancers. In another large prospective trial reported by Tattersall and colleagues, 129 patients who received neoadjuvant chemotherapy (cisplatin and epirubicin) had a significantly poorer pelvic disease control rate (P = 0.003) and survival rate (P = 0.02) than 131 patients treated with radiation therapy alone, despite a high initial response rate to chemotherapy (63%).
In summary, despite high response rates of locally advanced cervical cancers to initial chemotherapy, none of the randomized studies reported to date has demonstrated an improvement in outcome when neoadjuvant chemotherapy was added to radical radiotherapy. In many ways, this recapitulates the experience with treatment of locally advanced head and neck cancers for which it has been hypothesized that the failure to influence outcome with neoadjuvant chemotherapy may reflect cross-resistance of clonagens to drugs and radiation or accelerated repopulation of tumor clonogens induced by neoadjuvant chemotherapy.
CONCURRENT CHEMORADIATION. A number of investigators have reported high response rates and encouraging survival rates in uncontrolled phase I/II studies of patients with locally advanced cervical carcinomas treated with concurrent chemotherapy and irradiation. Drugs that are most commonly given concurrently with radiation therapy include hydroxyurea, 5-fluorouracil, mitomycin-C, and cisplatin.
Hydroxyurea, a drug that has been demonstrated
in vitro to sensitize
cells to radiation by arresting them in a sensitive portion of
the cell cycle, was identified as an
attractive subject for clinical study in
the early 1970s. After a small randomized study suggested encouraging results, the
Gynecologic Oncology Group conducted a
larger study randomizing patients with stage IIIB or IVA disease either to receive oral
hydroxyurea (80 mg/kg, up to
A third Gynecologic Oncology Group study using similar entry criteria randomized patients to receive either hydroxyurea (80 mg/kg orally twice weekly during external-beam irradiation) or cisplatin (50 mg/m*2 intravenously on days 1 and 29) and 5-fluorouracil (1000 mg/m*2 as a continuous intravenous infusion on days 2 through 5 and days 30 through 33 of radiation). This study closed to patient accrual in 1990, and the results should be analyzed and reported soon. Ongoing studies that address the value of chemosensitization in patients with locally advanced cervical cancer include (1) a Gynecology Oncology Group study randomizing patients to receive either hydroxyurea, weekly cisplatin, or a combination of hydroxyurea, 5-fluorouracil, and cisplatin during external-beam irradiation and (2) a Radiation Therapy Oncology Group study comparing cisplatin plus 5-fluorouracil (administered in three cycles during external-beam and intracavitary irradiation) with extended field irradiation plus brachytherapy.
In summary, concurrent treatment of locally advanced cervical cancers with chemotherapy and radiotherapy is an approach that holds considerable promise, although additional studies are needed to confirm the benefit of this treatment. To confirm that concurrent chemotherapy improves the therapeutic ratio achievable with radical radiotherapy, future studies also need to provide careful documentation of the late complications of treatment. The morbidity of radiotherapy with and without chemotherapy has not yet been compared in a randomized study, but one uncontrolled study suggests that late gastrointestinal toxicity may be increased with concurrent administration of some drugs.
INTRAARTERIAL CHEMOTHERAPY. Intraarterial infusion of chemotherapeutic agents delivered neoadjuvantly, concurrent with radiotherapy, or as salvage treatment for recurrent disease has generated interest for some years because of the distinct arterial supply to the central pelvis. A number of drugs have been used in small pilot studies, but 5-fluorouracil and cisplatin have been the most popular in this setting. Unfortunately, this technique is difficult and invasive, the toxicity reported in some series has been substantial, and the results have been variable in several small series of patients. However, occasional optimistic reports have maintained a low level of interest in this approach, particularly for concurrent intraarterial chemotherapy and irradiation.
Patients who present with disseminated disease are almost always incurable. Management of these patients must emphasize palliation of symptoms with appropriate pain medications, and localized radiotherapy. Tumors may respond to chemotherapy, but the duration of responses is usually short.
SINGLE-AGENT CHEMOTHERAPY. Fifty-two drugs have been studied in sufficient numbers of patients with carcinoma of the cervix to assess their activity. Nineteen of these have yielded response rates (partial and complete) of at least 15% and may be of therapeutic value.
Several of the platinum compounds have been evaluated in greater detail. Cisplatin has been studied in a variety of doses and schedules. These studies have demonstrated activity of the drug at a dose of 50 mg/m*2 given intravenously at a rate of 1 mg/min every 3 weeks. Although there appears to be a small but statistically significant increase in the response rate with a doubling of the dose to 100 mg/m*2, this has not resulted in a detectable improvement in the rates of progression-free or overall survival. More prolonged infusion of the same dose over 24 hours yields a similar response rate with less nausea and vomiting, although the recent development of more effective antiemetic agents reduces the clinical importance of this observation. The response rates of other platinum compounds (i.e., carboplatin and iproplatin) are lower than those observed with cisplatin, which remains the platinum compound of choice for patients with cervical carcinomas.
Ifosfamide has been studied as a single agent in patients with recurrent cervical cancer in at least five phase II trials. Response rates ranged between 33% and 50% in three studies that were conducted in patients who had received no previous chemotherapy. However, the response rates were much lower in two phase II trials that included patients who had received prior systemic chemotherapy, with only three partial responses (8%) in 36 patients.
COMBINATION CHEMOTHERAPY. Most reports of combination chemotherapy for carcinoma of the cervix have described uncontrolled phase II trials of drug combinations that have included at least some agents with known activity. Most studies have been small, with reported response rates ranging from 0% to 100%. In general, data from these phase II studies provide no firm evidence that any of the studied combinations are superior to single-agent therapy for patients with disseminated or recurrent cervical cancer. However, combinations based on ifosfamide and cisplatin and those based on 5-fluorouracil and cisplatin have attracted significant interest and deserve further discussion.
Several small phase II studies have evaluated treatment with combinations of ifosfamide and either cisplatin or carboplatinum in patients who had not received prior radiotherapy. Response rates for these combinations ranged between 50% and 63%. A number of investigators have combined bleomycin with ifosfamide and a platinum compound. Three studies included patients who had not had prior radiotherapy, and reported response rates were 65% to 100%. Reports of treatment with these drugs in previously irradiated patients have yielded mixed, but generally lower, response rates of between 13% and 72%.
Combinations of cisplatin and continuous infusion 5-fluorouracil also produce high response rates in previously untreated patients. Again, response rates decrease significantly if patients have had previous irradiation.
The Gynecologic Oncology Group recently completed a large prospective randomized trial comparing cisplatin alone with cisplatin plus ifosfamide and cisplatin plus dibromodulcitol in patients with advanced or recurrent cervical cancers. The addition of ifosfamide to cisplatin improved the response rate (33% versus 19%, P =0.02) and progression-free survival rate (4.6 versus 3.2 months, P < 0.05), but caused significantly greater toxicity (leukopenia, peripheral neuropathy, renal toxicity, and encephalopathy) and did not significantly improve the overall median survival. The addition of dibromodulcitol did not improve the response rate or survival duration.
PALLIATIVE RADIOTHERAPY. Localized radiotherapy can provide effective pain relief for symptomatic metastases in bone, brain, lymph nodes, or other sites. A rapid course of pelvic radiotherapy can also provide excellent relief of pain and bleeding for patients who present with incurable disseminated disease.
Side Effects of Chemotherapy
- Appetite Changes
- Bleeding Problems
- Fatigue (Feeling Weak and Very Tired)
- Hair Loss
- Memory Changes
- Mouth and Throat Changes
- Nausea and Vomiting
- Nerve Changes
- Sexual and Fertility Changes in Men
- Sexual and Fertility Changes in Women
- Skin and Nail Changes
- Swelling (Fluid Retention)
- Urination Changes
Pregnancy and contraception
Many chemotherapy drugs may cause birth defects. It is important that a woman undergoing chemotherapy avoids becoming pregnant. As most chemotherapy medications interfere with oral contraceptives it is important to use a barrier method of contraception, such as condoms, during the whole chemotherapy treatment period and for a year after treatment is completed. If you are pregnant you need to tell the medical team straight away beforehand. If you become pregnant during treatment tell the medical team straight away. What are the side effects of chemotherapy?
Most people immediately link chemotherapy with uncomfortable side effects. However, side-effect management has improved considerably over the last twenty years. Many side effects that were once inevitable can be either prevented or well controlled today.
There is no reliable way to predict how patients may react to chemotherapy. Some experience very mild side-effect, others will have none at all, while some people will report various symptoms.
Depending on the type of cancer and treatment, chemotherapy may have a bigger impact on the patient's work status than radiotherapy. Women with breast cancer who receive chemotherapy appear more likely than those treated with radiation therapy to experience a major change in work status, according to researchers at the Dana-Farber Cancer Institute.
Below is a list of the most commonly reported side effects:
Nausea and vomiting
Over half of all patients receiving chemotherapy will experience nausea and vomiting. Doctors will usually prescribe anti-emetics for this. These need to be taken even when symptoms have gone as they will prevent them from coming back. If the anti-emetics do not work the patient should contact his/her doctor who may switch to another anti-emetic.
Ginger - scientists at the
Alopecia (Hair loss)
Some chemotherapy medications cause hair loss while others don't. If hair does start to fall out this will usually happen a few weeks after treatment starts. On some occasions the hair will just become thinner and more brittle (without falling out). Hair loss can occur in any part of the body.
Although hair loss has no physical health consequences, it may cause distress and embarrassment for some people. The psychological impact tends to be greater among women than men. If you experience hair loss and find it is causing distress and embarrassment, there are several steps you can take:
Tell your doctor, who may refer you to a counselor who can provide effective help and support.
Many people find that if they purchase a wig their quality of life improves significantly.
If there is a cancer support group in your area, go to their meetings. Meeting people who share similar experiences to yourself may help give you a boost, as well as providing you with some useful tips, and possibly an opportunity to make new friends.
Cold cap - this looks a bit like a bicycle helmet and keeps the scalp cool while the chemotherapy dose is being administered. If the scalp can be kept cool less chemotherapy medication reaches the scalp, thus preventing the occurrence or reducing the severity of hair loss. Some people cannot wear a cold cap - leukemia (blood cancer) patients need the medication to reach their scalp.
The hair loss is NOT permanent - it will grow back soon after treatment if finished.
Most patients receiving chemotherapy will experience some degree of fatigue. This may be a general feeling which exists most of the day, or may only appear after certain activities. Doctors say patients need to make sure they get plenty of rest and not to perform tasks which are overtiring.
While light exercise has been shown to help, it is important to remember to keep the activities 'light'.
If the tiredness becomes severe it is important to tell the doctor, as this could be caused by a significant drop in red blood cells (anemia).
Hearing impairment (deafness, ototoxicity)
Children with cancer who suffer hearing loss
due to the toxic effects of chemotherapy might one day be able to get their
hearing back through pharmacological and gene therapy, said researchers from
St. Jude Children's
Neutropenia (low white blood cells) - Susceptibility to infections
When receiving chemotherapy the immune system will be weakened because the white blood cell count will go down. White blood cells form part of our immune system - they fight infection. Consequently, patients become more susceptible to infections.
Some patients will be prescribed antibiotics which may reduce their risk of developing infections. The following precautions will help reduce the risk of infections:
Personal hygiene - the cleaner you are, the fewer bacteria there will be around which can infect you. Regularly wash your hands with warm water and soap, have a bath/shower at least once a day, change your clothes and bathroom towels and flannels daily. Change your bed linen regularly.
Preparing food - make sure your food is free of food borne pathogens (organisms, such as bacteria that can make you ill). If you handle raw meat make sure you wash your hands before touching plates and cutlery or work surfaces. Thoroughly cook animal sourced proteins before eating them. Wash your dishes thoroughly and always use a clean plate and cutlery - keep the kitchen clean.
Infected people - stay away from people who are ill. This may include those who just have a temperature.
Skin wounds - bacteria find it hard to get in through your skin, unless there is a cut. If you graze or cut your skin, clean the area well with warm water, dry it, and cover it with a sterile dressing.
Patients receiving chemotherapy who develop an infection need immediate treatment. This may mean being hospitalized and receiving antibiotics via an intravenous drip.
Thrombocytopenia (low blood platelet count) - Blood clotting problems
Chemotherapy may lower the patient's blood platelet count. A platelet is a type of blood cell that helps the blood to clot (coagulate). Coagulation is essential, otherwise bleeding does not stop. Lower blood platelet counts linked to chemotherapy is a risk, but less so than lower red or white blood cell counts. If you are affected you will bruise more easily, you will be more likely to have nosebleeds and bleeding gums, and if you cut yourself it may be harder to stop the bleeding.
Patient's whose blood platelet counts fall too low will need a blood transfusion.
Below are some steps you may wish to take to reduce your risk of bleeding:
Shave with an electric razor (or don't shave)
Avoid hard toothbrushes
Use kitchen utensils and gardening equipment carefully
If you are gardening, wear gloves
Anemia (low red blood-cell count)
As well as lowering you white blood cell count, chemotherapy will also lower your red blood cell count. Tissues and organs inside your body get their oxygen from the red blood cells. If your red blood cell count goes down too many parts of your body will not get enough oxygen and you will develop anemia.
People with anemia feel very tired. A patient on chemotherapy who has anemia will feel extra tired - much more tired than straightforward fatigue caused by the treatment. Dyspnea (shortness of breath) is also another symptom of anemia, as are palpitations (when the heart beat is irregular).
Anemia linked to chemotherapy requires immediate treatment. A blood transfusion will bring the red blood cell count back up immediately. Erythropoietin (EPO) is a drug that makes the body produce more red blood cells.
The following foods are rich in iron, which helps red blood cells carry more oxygen. Dark green leafy vegetables, beans, meat, nuts, prunes, raisins, and apricots.
Scientists from The Medical University of Vienna, Austria found that patients with breast cancer who developed anemia during chemotherapy had nearly three times the risk of local recurrence as those who did not.
Mucositis (inflammation of the mucous membrane)
Chemotherapy attacks rapidly dividing cells, such as blood cells, bone marrow cells, and cells of the mucous membranes that line the digestive system - this includes the mouth, esophagus, stomach, intestines, and the rectum to the anus. Chemotherapy may damage and even destroy some of those mucous membrane cells.
Oral Mucositis (in the mouth) - patients more commonly experience symptoms in their mouth.
If symptoms do appear, they will usually do so about 7 to 10 days after treatment starts. The inside of the mouth may feel like sunburn; some people say it feels as if the area had been scalded. Ulcers often appear on the lining of the mouth, the tongue, and sometimes around the lips. The severity of symptoms is closely linked to the strength of the chemotherapy dose.
Some may find it painful when they eat, drink, or even talk. If the ulcers bleed there is a risk of infection.
Caphosol is often prescribed for mucositis.
A clinical trial showed that out of 100 cancer patients that were treated with DAVANAT® and chemotherapy that included 5-FU, none developed mucositis.
As better drugs are appearing, mucositis is becoming less common. Symptoms clear up a few weeks after treatment is completed.
Loss of appetite
Loss of appetite is a common side effect of chemotherapy. It is possible that the chemotherapy, or the cancer itself, affects the body's metabolism. If the loss of appetite is just due to the chemotherapy it will come back when the treatment is finished - although this may sometimes take a few weeks.
The severity of appetite and consequent weight loss depends on the type of cancer and chemotherapy treatment.
Although this is sometimes easier said than done, it is important to keep trying to eat well and take in plenty of fluids. Many patients find that smaller and more frequent meals are easier to get down than the typical three meal-a-day regime. Also, drinking liquids through a straw may result in a better fluid intake.
Patients who become seriously affected by lack of food and liquid intake may need to be hospitalized and fed through a nasogastric tube. The tube goes into the patient's nose and down to his/her stomach.
Nails and skin
Chemotherapy can sometimes cause dry and sore
skin. Nails may also become flaky and brittle. The skin may become more
sensitive to sunlight. It is important to protect yourself from too much
sunlight exposure. This includes staying out of the sun during peak times of
the day, using sun blocks, and wearing clothes that provide maximum protection.
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About one fifth of patients undergoing chemotherapy report some kind of cognitive problem, including attention, thinking and memory. This can sometimes have an impact on daily tasks. Patients who do experience these symptoms should talk to their doctor, and social worker.
Symptoms may include:
Shorter attention span; concentration, focus and attention problems
Memory problems; especially the short-term memory
Comprehension and understand problems
Judgment and reasoning problems
Organizational skills may be affected
Multitasking problems (performing/thinking about several things at the same time)
Experts are unsure how much is due to the chemotherapy, and how much is due to fatigue, stress and anxiety that comes with having cancer.
Libido (sex drive) and fertility
For a significant proportion of patients, chemotherapy may result in a lower sex drive (less interest in sex). This is temporary and usually returns after treatment is completed.
Depending on the type of medication administered, chemotherapy may also damage men's sperm. Some women may become infertile. In most cases - though not all - fertility returns after treatment is over.
Men who wish to father children and women who plan to become pregnant one day should discuss possible options with their doctors before starting treatment. It is possible to freeze sperm and embryos.
Bowel movement problems (diarrhea or constipation)
Sometimes when damaged cells in the intestinal tract are rapidly expelled from the body there is a risk of diarrhea. Constipation is also a possible risk for chemotherapy patients. You should talk to your doctor if you experience any unpleasant change in your bowel movements. Symptoms, if they do occur, will do so a few days after chemotherapy begins.
The risk of developing depression is already higher for patients with cancer. It is normal to feel distressed, anxious, sad and stressed - especially if you are concerned about what the future holds and whether treatment is going to be effective.
It is important that you talk to a member of the medical team if you feel it is all getting to be too much, or if you no longer get pleasure out of the things that you used to like. Joining a support group and talking to people who are going through the same as you and understand how you feel has helped many people with cancer. Protecting the gut from chemotherapy in cases of metastatic cancer
When cancer has spread beyond the primary tumor to other parts of the body, i.e. when it has metastasized, treatments tend to involve intensive chemoradiotherapy. These high doses of raditation therapy and chemotherapy damage good tissue and often push the patient to an early death.
Researchers from the University of Michigan School of Dentistry reported in the journal Nature that they found a way to preserve the health of the gut in laboratory mice that had been given very high doses of chemoradiotherapy.
Team leader, Jian-Guo Geng, said "All tumors from different tissues and organs can be killed by high doses of chemotherapy and radiation, but the current challenge for treating the later-staged metastasized cancer is that you actually kill the patient before you kill the tumor."
Healthy digestive tract improves survival - the scientists found that if the gut of mice with metastatic cancer stayed healthy after intensive chemoradiotherapy, their chances of survival increased exponentially.
There are stem cells in the gut of the laboratory mice that help preserve tissue after undergoing lethal doses of chemoradiotherapy. Geng and colleagues found a way of getting the gut stem cells to launch a massive healing campaign. Gene Print Predicts Who Will Survive Chemotherapy
An 8-gene "print" or "signature" can predict how long people remain cancer-free, without any relapse after undergoing chemotherapy, researchers from Academia Sinica and the National Taiwan University College of Medicine explained in the journal BMC Medicine.
Prof Ker-Chau Li and team located genes that are involved in cellular invasion - something several cancer cells do. They gathered and examined data from the National Cancer Institute's 60 human cancer cell line panel.
Prof. Li said "Our study found eight genes which were involved in invasion, and the relative activation of these genes correlated to chemotherapy outcome, including the receptor for growth factor EGF. We also found that some invasion genes had unique patterns of expression that reflect the differential cell responses to each of the chemotherapy agents - five drugs (paclitaxel, docetaxel, erlotinib, everolimus and dasatinib) had the greatest effect."
Ø Cancer support groups
Ø Cancer information workshops
Ø Low-cost medical consultation
Ø Increased government funding to seek cures
186,550 - The number of lives that could be saved each year if we ate a healthy diet and exercised regularly
186,550 - The number of lives that could be saved each year with no tobacco
American Cancer Society