Cervical cancer

doi:10.1016/S0140-6736(03)13778-6

The Lancet

Volume 361, Issue 9376, 28 June 2003, Pages 2217-2225

https://doi.org/10.1016/S0140-6736(03)13778-6 Get rights and content

Summary

Cervical cancer is a serious health problem, with nearly 500 000 women developing the disease each year worldwide. Most cases occur in less developed countries where no effective screening systems are available. Risk factors include exposure to human papillomavirus, smoking, and immune-system dysfunction. Most women with early-stage tumours can be cured, although long-term morbidity from treatment is common. Results of randomised clinical trials have shown that for women with locally advanced cancers, chemoradiotherapy should be regarded as the standard of care; however, the applicability of this treatment to women in less developed countries remains largely untested. Many women with localised (stage IB) tumours even now receive various combinations of surgery and radiotherapy, despite unresolved concern about the morbidity of this approach compared with definitive radiotherapy or radical surgery. Treatment of recurrent cervical cancer remains largely ineffective. Quality of life should be taken into account in treatment of women with primary and recurrent cervical cancer.

Section snippets

Epidemiology and risk factors

Worldwide, cervical cancer is the second most common malignant disease among women, with nearly 80% of cases arising in less developed countries (table 1).¹ The American Cancer Society estimates that during 2002, 13 000 cases of cervical cancer were diagnosed in women living in the USA, and that 4100 women will die as a result of this disease.² In North America, the median age at diagnosis is 47 years, and nearly half of cases are diagnosed before the age of 35. However, women older than 55

Diagnosis and pathology

Cervical cancer may be suspected on analysis of a Pap smear or visualisation of a lesion on the cervix. A biopsy sample must be taken from any suspicious lesion, because many Pap smears are non-diagnostic or falsely negative in the presence of invasive cancer. If a biopsy sample shows cells suggesting microinvasion, and if the patient does not have a grossly apparent invasive cancer, a cone biopsy should be done. For accurate staging of clinically occult lesions, sufficient underlying stroma

Staging and prognosis

Once a tissue diagnosis of invasive carcinoma has been established, the patient is staged (table 2). Stage is determined at the time of primary diagnosis and should never be changed, even after recurrence or on discovery of more extensive disease during surgery. Stage is determined clinically, on the basis mainly of the size of the tumour in the cervix or its extension into the pelvis. Modifications to the FIGO staging system were made in 1994 to clarify the description of microinvasive

Stage IA

In many more developed countries with established Pap-smear screening systems, microinvasive or stage IA cervical cancers are commonly detected in women who are symptom free with cervices that seem normal on gross examination. The diagnosis is usually made after a cervical conisation, although many cases of superficially invasive cervical cancer are incidentally discovered after hysterectomy. If the focus of invasion extends no deeper than 3 mm below the basement membrane (stage IA1), the risk

Chemotherapy

Chemotherapy for advanced or recurrent disease has been and continues to be considered palliative. Many agents have been investigated, as single or combined regimens.⁸⁶ Response rates in multicentre phase-2 trials average 10–40%, with complete responses seen only rarely and for short duration. Cisplatin is at present deemed the most active single agent in recurrent disease. When it was combined with paclitaxel in a phase-2 study, an overall response rate of 46·3% was recorded (12·2% with

Conclusion

Over the past decade, women with cervical cancer of all stages have benefited from tremendous improvements in the treatment of this disease. These advances, unfortunately, have not been extended to the vast majority of women affected by the disease, who live in impoverished countries with limited resources and no screening programmes. Gynaecological and radiation oncologists practising in more affluent countries are aware of the substantial discrepancy in treatment options available for women

Search strategy and selection criteria

I searched Medline (1990–2001) using the terms “cervical cancer” and “cervical neoplasia”. Initial search results were selected from papers published in English on human beings, then limited by use of the terms “epidemiology”, “natural history”, “treatment”, “radiation therapy”, “chemotherapy”, “chemoradiation therapy”, and “surgery”. Reference lists of articles identified by this strategy were searched, and additional relevant publications were selected. Preference for inclusion was

References (92)

M Scheffner et al.
The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53
Cell
(1990)
M Scheffner et al.
The HPV-16 and E6–AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53
Cell
(1993)
SF Daly et al.
Can the number of cigarettes smoked predict high-grade cervical intraepithelial neoplasia among women with mildly abnormal cervical smears?
Am J Obstet Gynecol
(1998)
AA Melikian et al.
Identification of benzo[a]pyrene metabolites in cervical mucus and DNA adducts in cervical tissues in humans by gas chromatography-mass spectrometry
Cancer Lett
(1999)
SP Wilczynski et al.
Human papillomaviruses and cervical cancer: analysis of histopathologic features associated with different viral types
Hum Pathol
(1988)
HC Wagenaar et al.
Tumor diameter and volume assessed by magnetic resonance imaging in the prediction of outcome for invasive cervical cancer
Gynecol Oncol
(2001)
PY Kim et al.
Cervical cancer with paraaortic metastases: significance of residual paraaortic disease after surgical staging
Gynecol Oncol
(1998)
CS Tsai et al.
The prognostic factors for patients with earyly cervical cancer treated by radical hysterectomy and postoperative radiotherapy
Gynecol Oncol
(1999)
G Delgado et al.
Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study
Gynecol Oncol
(1990)
G Thomas
The effect of hemoglobin level on radiotherapy outcomes: the Canadian experience
Semin Oncol
(2001)

CJ Tseng et al.

Conservative conization for microinvasive carcinoma of the cervix

Am J Obstet Gynecol

(1997)

WT Creasman

Stage IA cancer of the cervix: finally some resolution of definition and treatment?

Gynecol Oncol

(1999)

WT Creasman et al.

Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis: a Gynecologic Oncology Group study

Am J Obstet Gynecol

(1998)

WB Jones et al.

Early invasive carcinoma of the cervix

Gynecol Oncol

(1993)

LD Roman et al.

Influence of quantity of lymph-vascular space invasion on the risk of nodal metastases in women with early-stage squamous cancer of the cervix

Gynecol Oncol

(1998)

A Covens et al.

Prognostic factors for relapse and pelvic node metastasis in early stage I adenocarcinoma of the cervix

Gynecol Oncol

(1999)

JO Schorge et al.

Prospective management of stage IA1 cervical adenocarcinoma by conization alone to preserve fertility: a preliminary report

Gynecol Oncol

(2000)

ME Potter et al.

Early invasive cervical cancer with pelvic lymph node involvement: to complete or not to complete radical hysterectomy?

Gynecol Oncol

(1990)

F Landoni et al.

Class II versus class III radical hysterectomy in stage IB-IIA cervical cancer: a prospective randomized study

Gynecol Oncol

(2001)

A Sedlis et al.

A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a Gynecologic Oncology Group Study

Gynecol Oncol

(1999)

WK Kinney et al.

Value of adjuvant whole-pelvis irradiation after Wertheim hysterectomy for early-stage squamous carcinoma of the cervix with pelvic nodal metastasis: a matched case-control study

Gynecol Oncol

(1989)

DG Petereit et al.

High-dose-rate versus low-dose-rate brachytherapy in the treatment of cervical cancer: analysis of tumor recurrence-the University of Wisconsin experience

Int J Radiat Oncol Biol Phys

(1999)

CA Perez et al.

Carcinoma of the uterine cervix. I. Impact of prolongation of treatment time and timing of brachytherapy on outcome of radiation therapy

Int J Radiat Oncol Biol Phys

(1995)

BJ Monk et al.

Extent of disease as an indication for pelvic radiation following radical hysterectomy and bilateral pelvic lymph node dissection in the treatment of stage IB and IIA cervical carcinoma

Gynecol Oncol

(1994)

F Landoni et al.

Randomised study of radical surgery versus radiotherapy for stage IB-IIA cervical cancer

Lancet

(1997)

F Landoni et al.

Class II versus class III radical hysterectomy in stage IB-IIA cervical cancer: a prospective randomized study

Gynecol Oncol

(2001)

A O'Quinn et al.

Guidelines for conservative hysterectomy after irradiation

Gynecol Oncol

(1980)

W Mendenhall et al.

Stage IB-IIA-B carcinoma of the intact uterine cervix greater than or equal to 6 cm in diameter: is adjuvant extrafascial hysterectomy beneficial?

Int J Radiat Oncol Biol Phys

(1991)

CA Perez et al.

Radiation therapy alone or combined with surgery in treatment of barrel-shaped carcinoma of the uterine cervix (stage IB, IIA, IIB)

Int J Radiat Oncol Biol Phys

(1985)

JD Bloss et al.

A phase II trial of neoadjuvant chemotherapy prior to radical hysterectomy and/or radiation therapy in the management of advanced carcinoma of the uterine cervix

Gynecol Oncol

(1995)

JA Green et al.

Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis

Lancet

(2001)

C Haie et al.

Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiotherapy group

Radiother Oncol

(1988)

AJ Mundt et al.

Initial clinical experience with intensity-modulated whole pelvis radiation therapy in women with gynecologic malignancies

Gynecol Oncol

(2001)

L Portelance et al.

Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation

Int J Radiat Oncol Biol Phys

(2001)

T Ijaz et al.

Radiation therapy of pelvic recurrence after radical hysterectomy for cervical carcinoma

Gynecol Oncol

(1998)

RL Coleman et al.

Radical hysterectomy for recurrent carcinoma of the uterine cervix after radiotherapy

Gynecol Oncol

(1994)

MA Penalver et al.

Continent urinary diversion in gynecologic oncology

Gynecol Oncol

(1989)

LR Schover

Quality counts: the value of women's perceived quality of life after cervical cancer

Gynecol Oncol

(2000)

E Greimel et al.

Prospective assessment of quality of life of female cancer patients

Gynecol Oncol

(2002)

ParkinDM et al.

Cancer incidence in five continents, vol VII

International Agency for Research on Cancer, Scientific Publications number 143

(1997)

A Jemal et al.

Cancer statistics, 2002

CA Cancer J Clin

(2002)

H Sung et al.

Papanicolaou smear history and diagnosis of invasive cervical carcinoma among members of a large prepaid health plan

Cancer

(2000)

FX Bosch et al.

Prevalence of human papillomavirus in cervical cancer: a worldwide perspective

J Natl Cancer Inst

(1995)

S Chichareon et al.

Risk factors for cervical cancer in Thailand: a case-control study

J Natl Cancer Inst

(1998)

C Ngelangel et al.

Causes of cervical cancer in the Philippines: a case-control study

J Natl Cancer Inst

(1998)

LA Koutsky et al.

A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection

N Engl J Med

(1992)

Cited by (866)

Incidence, prognostic factors, and a nomogram of cervical cancer with lung metastasis: A SEER-based study
2024, Journal of Gynecology Obstetrics and Human Reproduction
The purpose of this study was to investigate the incidence, survival and prognostic factors of cervical cancer with lung metastasis at the initial diagnosis and to develop a visual nomogram to predict the prognosis of these patients.
We used the Surveillance, Epidemiology and End Results (SEER) database to screen patients diagnosed with cervical cancer from 2010 to 2015. After strict inclusion and exclusion, the chi-square test was used to evaluate the differences in the clinical characteristics of patients with cervical cancer, and then we used Kaplan–Meier method to perform survival analysis among cervical cancer patients with lung metastasis. Next, univariate and multivariate Cox proportional hazard regression models were used to estimate prognostic factors of these patients and we developed a visualized and novel nomogram to judge the prognosis.
476 patients with lung metastasis and 12,016 patients without lung metastasis were included in this study. The incidence of lung metastasis was higher in unmarried white cervical cancer patients between the ages of 40 and 60, and grade III cervical squamous cell carcinoma patients were more likely to have lung metastasis. In addition, grade, surgery, radiotherapy, sequence of surgery and radiotherapy and chemotherapy were significantly related to the outcomes of cervical cancer patients with lung metastasis. Furthermore, our nomogram could predict the 3-year and 5-year overall survival (OS) of these patients. Finally, the AUC of 3-year OS and 5-year OS were confirmed to be 0.969 and 0.939 respectively by ROC curves, with good consistency.
Age at diagnosis, race, marital status, and characteristics of the tumor can influence the incidence of lung metastasis in cervical cancer patients. Besides, grade, surgery, radiotherapy, sequence of surgery and radiotherapy and chemotherapy may deeply affect the prognosis of cervical cancer patients with lung metastasis. The nomogram built in this study may help clinicians to formulate individualized treatment strategies and encourage the development of more and more comprehensive and accurate predictive models.
Diagnostic assessments and treatment results of well-differentiated gastric-type adenocarcinoma of the uterine cervix (Adenoma malignum): A multicenter retrospective analysis of KROG 22-03 study
2024, Gynecologic Oncology
Among cervical adenocarcinomas, well-differentiated gastric adenocarcinoma of the uterine cervix (WD-GAS), previously termed adenoma malignum (minimal deviation adenocarcinoma) is not well understood. Because of its rarity and difficulty in diagnosis, there is no standard care for WD-GAS. Thus, we conducted the first multicenter retrospective study on WD-GAS to clarify prognostic factors for long-term survival and recurrence.
Patients diagnosed with WD-GAS at eight hospitals participated in this multi-center study. Overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. Additionally, OS between the early and advanced FIGO stage groups were compared with the log-rank test. Cox regression analysis was conducted to identify significant factors associated with recurrence-free survival (RFS).
A total of 73 patients from eight hospitals in South Korea were included in the analysis. The median follow-up period was 44.8 months, and all patients underwent curative surgical intervention as the primary treatment. Recurrence was observed in 17 patients (23.3%). Ten patients had locoregional recurrence, four patients had distant metastasis, and three patients presented with both locoregional recurrence and distant metastasis. The Cox regression analysis identified several statistically significant factors associated with RFS, including vaginal invasion (VI), parametrial invasion (PMI), resection margin (RM), and nodal and lymphovascular invasion (LVI). When considering these five factors together, patients without any of the factors exhibited recurrence-free survival (RFS) of 97.0% at three years and those with more than one of these factors had a 3-year RFS of 65.4% (P < 0.001).
WD-GAS showed relatively high locoregional recurrence rate. Positive PMI, VI, RM, nodal involvement, and LVI were associated with a significant increase in recurrence or distant metastasis rates.
Radiosensitization by Hyperthermia Critically Depends on the Time Interval
2024, International Journal of Radiation Oncology Biology Physics
Hyperthermia is a potent sensitizer of radiation therapy that improves both tumor control and survival in women with locally advanced cervical cancer (LACC). The optimal sequence and interval between hyperthermia and radiation therapy are still under debate.
We investigated the interval and sequence in vitro in cervical cancer cell lines, patient-derived organoids, and SiHa cervical cancer hind leg xenografts in athymic nude mice and compared the results with retrospective results from 58 women with LACC treated with thermoradiotherapy.
All 3 approaches confirmed that shortening the interval between hyperthermia and radiation therapy enhanced hyperthermic radiosensitization by 2 to 8 times more DNA double-strand breaks and apoptosis and 10 to 100 times lower cell survival, delayed tumor growth in mice, and increased the 5-year survival rate of women with LACC from 22% (interval ≥80 minutes) to 54% (interval <80 minutes). In vitro and in vivo results showed that the sequence of hyperthermia and radiation therapy did not affect the outcome.
Shortening the interval between hyperthermia and radiation therapy significantly improves treatment outcomes. The sequence of hyperthermia and radiation therapy (before or after) does not seem to matter.
Pterostilbene upregulates MICA/B via the PI3K/AKT signaling pathway to enhance the capability of natural killer cells to kill cervical cancer cells
2024, Experimental Cell Research
Natural killer (NK) cells are triggered by the innate immune response in the tumor microenvironment. The extensive set of stimulating and inhibiting receptors mediates the target recognition of NK cells, and controls the strength of the effector reaction countering specific targeted cells. Yet, lacking major MHC (histocompatibility complex) MICA/B class I chain-related proteins on the membrane of tumor cells results in the failure of NK cell recognition and ability to resist NK cell destruction. Searching databases and molecular docking suggested that in cervical cancer, pterostilbene (3,5-dimethoxy-40-hydroxystilbene; PTS) in Vaccinium corymbosum extract could constrain PI3K/AKT signaling and improving the MICA/B expression. In flow cytometry, MTT assay, viability/cytotoxicity assay, and colony development assays, PTS reduced the development of cervical cancer cells and increased apoptosis. The quantitative real-time PCR (qRT-PCR) and a Western blot indicate that PTS controlled the cytolytic action of NK cells in tumor cells via increasing the MICA/B expression, thus modifying the anti-tumor immune response in cervical cancer.
Activity of African medicinal plants against cervical cancer cells
2024, Advances in Botanical Research
Globally, the highest incidence of cervical cancer is seen in Sub-Saharan Africa. Plants have long been recognized as a fascinating source of anti-tumor medications. The present chapter aimed at compiling information on African medicinal plants and the phytochemicals they produce that have been reported for their anticancer properties and modes of action against cervical malignancies. Based on the established cutoff points for the classification of anticancer activity of natural products, 55 anti-cervical cancer plants were identified from eleven African countries. The most active African botanicals against cervical cancer are Rosmarinus officinalis, Sarcocephalus pobeguinii, Acokanthera schimperi, Kalanchoe petitiana, and Euphorbia schimperiana. Among the identified compounds from African medicinal plants, the most active against cervical cancer lines are diterpenoids ent-trachyloban-3β-ol (1) and ent-trachyloban-3-one (3). The potent cytotoxic botanicals and phytochemicals identified are potential sources of anti-tumor drugs against cancer and should be further explored to develop herbal medicine and pharmaceuticals to tackle cervical cancer.
Copper pyrazole complexes as potential anticancer agents: Evaluation of cytotoxic response against cancer cells and their mechanistic action at the molecular level
2024, Coordination Chemistry Reviews
This review-based study presents the anticancer potential of pyrazole-based copper complexes, aiming to evaluate their mechanistic action at the molecular level and find correlations between the biological activity and chemical structures of these complexes. Additionally, an attempt is made to provide evidence for the prospective anticancer applications of these compounds. The surveyed pyrazole-based copper complexes, with a variety of structural geometries and coordination numbers, exhibit a high potential for utilization as effective anticancer agents and alternatives to approved drugs with lower side effects. In vitro investigations reveal that the majority of the reported complexes display high antiproliferative activity, with some cases showing better cytotoxicity than approved standard drugs. However, various laboratory conditions, such as different incubation times for cytotoxicity determination, variations in the type and number of applied cell lines, and other influencing factors, can affect their inhibitory effects. Generally, the cell death mechanism of pyrazole-based copper complexes is synergistic and influenced by several parameters, including the oxidation state of the copper ion, various substitutions on the pyrazole derivative, the variety of donor chelating atoms, structural geometry, coordination number around the copper center, and dipole moment of the complexes. Possible cell death mechanisms include topo I, II (DNA topoisomerase I, II) inhibition, DNA cleavage, mitochondrial damage, arresting S and G2/M phases in the cell cycle, elevating intracellular oxidative stress, altering nuclear morphology, inducing endoplasmic reticulum stress, caspase-dependent and caspase-independent pathways, production of ROS (Reactive oxygen species) or peroxide-based pathways, and inducing apoptosis and paraptosis cell death mechanisms.

View all citing articles on Scopus

View full text

SeminarCervical cancer

Summary

Section snippets

Epidemiology and risk factors

Diagnosis and pathology

Staging and prognosis

Stage IA

Chemotherapy

Conclusion

Search strategy and selection criteria

Cell

Cell

Am J Obstet Gynecol

Cancer Lett

Hum Pathol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Semin Oncol

Am J Obstet Gynecol

Gynecol Oncol

Am J Obstet Gynecol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Lancet

Gynecol Oncol

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Lancet

Radiother Oncol

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Cancer incidence in five continents, vol VII

International Agency for Research on Cancer, Scientific Publications number 143

Cancer statistics, 2002

CA Cancer J Clin

Papanicolaou smear history and diagnosis of invasive cervical carcinoma among members of a large prepaid health plan

Cancer

Prevalence of human papillomavirus in cervical cancer: a worldwide perspective

J Natl Cancer Inst

Risk factors for cervical cancer in Thailand: a case-control study

J Natl Cancer Inst

Causes of cervical cancer in the Philippines: a case-control study

J Natl Cancer Inst

A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection

N Engl J Med

Seminar
Cervical cancer