Drs. Kim and Alvarez have written an excellent, in-depth review and
update on the use of chemotherapy as an adjunct to radiation therapy
in locally advanced cervical cancer, elegantly summarizing recent
study results. New evidence of the benefits of adjuvant
chemotherapy[1-5] has been, by far, the most significant breakthrough
of the past several decades in the treatment of women with this disease.
In their article, the authors convincingly show that chemotherapy
must be given concurrently with, not before, radiation therapy in
order to be effective. They summarize the disappointing outcomes of
neoadjuvant chemotherapy studies and provide radiobiological
rationales for the observed clinical resultslimited tumor
response rate to chemotherapy alone, accelerated repopulation, and
therapy delayexplanations that, in retrospect, seem logical.
Concurrent Radiosensitizing Chemotherapy
The concurrent use of cytotoxic and radiosensitizing drugs
with radiation therapy improves survival in advanced cervical cancer
by 15% (P = .004), over radiotherapy alone, a gain that had
not been achieved by altered fractionation, hyperbaric oxygen or
previous radiosensitizers (eg, hydroxyurea). These recent studies
have now reproduced the favorable results of concurrent cisplatin
(Platinol)-based radiosensitizing chemotherapy in epithelial head and
neck, esophageal, and anal cancer and demonstrated that the use of
radiosensitizing cytotoxic agents can produce clinically relevant
modulation of radiotherapy outcome in yet another epithelial tumor:
The authors suggest, however, that the promising results of these
studies leave us with more questions than answers: Which concurrent
chemotherapy regimen is optimal? Which regimens are appropriate for
Which Combination to Choose?
Choosing the optimal concurrent chemotherapy combination in patients
treated with radiation therapy for advanced cervical cancer remains a
challenge. Only one study has randomized patients with nonresected
disease to a control arm of radiation therapy alone vs
cisplatin-based chemoradiotherapy. In this trial, the two-drug
combination of cisplatin and fluorouracil (5-FU) improved pelvic
tumor control and survival. Based on these data, should
cisplatin/5-FU become the standard adjunct for patients treated with
radiation therapy for advanced disease? The answer is clearly controversial.
Gynecologic Oncology Group (GOG) study 120 randomized the
triple-drug combination cisplatin/5-FU/hydroxyurea vs cisplatin alone
in slightly different patient populations (surgically staged,
node-negative patients). Comparison of one vs three radiosensitizers
showed no advantage over the single-agent cisplatin regimen. However,
the confounding factor of hydroxyurea, which has since been shown to
be ineffective and to increase toxicity, makes these results
difficult to interpret.[6,7]
Would two effective radiosensitizers be better than one? A randomized
comparison of one vs two well-established cytotoxic
radiosensitizersie, cisplatin vs cisplatin/5-FUhas yet to
be conducted, and there are presently no plans for such a comparison
in cooperative groups. However, the ongoing GOG study 165 is
comparing cisplatin and 5-FU as single-agent adjuncts to radiation therapy.
Meanwhile, new cytotoxic and radiosensitizing agents are being
developed and entering clinical trials. Paclitaxel (Taxol), which has
radiosensitizing properties, is being studied in phase I trials as
an adjunct to radiation therapy. The topoisomerase inhibitor
topotecan (Hycamtin), may be another candidate for concurrent use
with radiation therapy.[10,11]
With the impending availability of several chemotherapy agents for
concurrent use with radiation therapy, the next question will be how
to optimally select, combine, and time these agents with radiation
therapy in order to maximize responseparticularly in patients
who remain at high risk for treatment failure, despite presently used
concurrent chemoradiation therapy regimens.[1,2]
Better Staging and Outcome Predictors
How can we determine the appropriate degree of (local and/or
systemic) therapy intensity for the individual patient, in order to
provide the best chance of tumor control and least chance of
morbidity for her particular tumor, and at what risk? Do we have
sufficient outcome predictors to categorize tumor aggressiveness and
help determine therapy selection?
The classic staging evaluations and the International Federation of
Gynecology and Obstetrics (FIGO) staging system, upon which entry
into the recent randomized studies[1-5] was largely based, have been
widely criticized as suboptimal in determining the true extent of the
primary tumor, regional extension, and biological aggressiveness of
cervical cancer. We need to develop a refined prognostic algorithm of
tumor aggressiveness beyond clinically/radiographically based staging
to determine the intensity of required therapy.
Tumor-cell hypoxia and tumor blood supply remain among the most
important biological parameters of radiation response; they may also
relate to chemotherapy response and metastatic potential.[12-14]
However, assays available to the clinic to assess these factors have
been difficult to implement in the patient care setting, requiring,
for example, insertion of needle oximetry electrodes for hypoxia
measurements or other invasive procedures.
The recent advances, increasing availability, and decreasing cost of
tumor-imaging modalities provide new opportunities to refine staging
and therapy outcome prediction. Functional tumor imaging, such as
magnetic resonance perfusion imaging, have made the assessment of
microvascular function and tumor microcirculation (which is closely
related to tumor hypoxia) easier to accomplish in day-to-day clinical
practice and widely available for patient management.
Beyond these imaging-based parameters, new molecular predictors of
therapeutic response are also emerging. Molecular predictors,
including the mitotic index of proliferating cells, Ki-67, HER2, bcl-2,
and BAX, have been shown to predict response to radiation therapy
and may be useful prognostic markers.[16-19] These novel outcome
predictors hold promise in providing us with parameters of tumor
aggressiveness that can be feasibly employed in daily clinical
practice. They may provide guidance for the selection of therapy
intensity, particularly with respect to multimodality therapy and
Increased Morbidity vs Survival Benefits
It is likely that the addition of chemotherapy to radiation therapy
will increase treatment-related morbidity. Although short-term
hematologic and gastrointestinal toxicities are relatively easy to
overcome, long-term therapy-related complications in the bowel and
other pelvic organs as well as second malignancies are of greater
concern. It will take at least another decade of follow-up data from
the randomized studies to quantify the risk of late morbidity. In the
interim, radiation oncologists must make a maximal effort to reduce
Recent advances in radiation therapy techniques, including
three-dimensional, imaging-based radiotherapy planning, provide an
opportunity to further reduce the volume of normal tissues,
particularly the bowel, in the treatment field for external-beam
radiation. By implementing imaging-based, and where applicable,
conformal radiation therapy, and perhaps by using a more conformal
imaging-based approach for brachytherapy, we may be able to further
reduce the probability of complications in normal tissues.
Cytoprotective agents, such as amifostine (Ethyol), may also
supplement these efforts to reduce toxicity and should be fully explored.
We have never had more options at hand in the therapy of women with
advanced cervical cancerconcurrent chemotherapy, emerging
functional/biological outcome predictors, high-precision
imaging-based radiation therapy, and cytoprotective agents. The
challenge of the next decade will be to employ these tools wisely so
that not only the tumor response, but also the lives of women with
advanced cervical cancer, can be improved.
1. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent
chemotherapy with pelvic and para-aortic radiation for high-risk
cervical cancer. N Engl J Med 340:1137-1143, 1999.
2. Whitney CW, Sause W, Bundy BN, et al: Randomized comparison of
fluorouracil plus cisplatin vs hydroxyurea as an adjunct to radiation
therapy in stage IIB-IVA carcinoma of the cervix with negative
para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest
Oncology Group study. J Clin Oncol 17:1339-1348, 1999.
3. Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based
radiotherapy and chemotherapy for locally advanced cervical cancer. N
Engl J Med 340:1144-1153, 1999.
4. Peters WA III, Liu PY, Barrett R, et al: Cisplatin, 5-fluorouracil
plus radiation therapy are superior to radiation therapy as
adjunctive in high-risk, early-stage carcinoma of the cervix after
radical hysterectomy and pelvic lymphadenectomy (abstract). Gynecol
Oncol 72:443, 1999.
5. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and
adjuvant hysterectomy compared with radiation and adjuvant
hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med
6. Stehman FB, Bundy BN, Keys H, et al: A randomized trial of
hydroxyurea vs misonidazole adjunct to radiation therapy in carcinoma
of the cervix: A preliminary report of a Gynecologic Oncology Group
study. Am J Obstet Gynecol 159:87-94, 1988.
7. Leibel S, Bauer M, Wasserman T, et al: Radiotherapy with or
without misonidazole for patients with stage IIIB or IVA squamous
cell carcinoma of the uterine cervix: Preliminary report of a
Radiation Therapy Oncology Group randomized trial. Int J Radiat Oncol
Biol Phys 13:541-549, 1987.
8. Liebmann J, Cook JA, Fisher J, et al: In vitro studies of Taxol as
a radiation sensitizer in human tumor cells. J Natl Cancer Inst
9. Chen MD, Paley PJ, Potish RA, et al: Phase I trial of Taxol as a
radiation sensitizer with cisplatin in advanced cervical cancer.
Gynecol Oncol 67:131-136, 1997.
10. Lamond JP, Wang M, Kinsella TJ, et al: Concentration and timing
dependence of lethality enhancement between topotecan, a
topoisomerase I inhibitor, and ionizing radiation. Int J Radiat Oncol
Biol Phys 36:361-368, 1996.
11. Rich TA, Kirichenko AV: Camptothecin radiation sensitization:
Mechanisms, schedules, and timing. Oncology 12(suppl 6):114-120, 1998.
12. Brizel DM, Scully SP, Harrelson JM, et al: Tumor oxygenation
predicts for likelihood of distant metastases in human soft tissue
sarcoma. Cancer Res 46:941-943, 1996.
13. Höckel M, Schlenger K, Aral B, et al: Association between
tumor hypoxia and malignant progression in advanced cancer of the
uterine cervix. Cancer Res 56:4509-4515, 1996.
14. Hawighorst H, Knapstein P, Weikel W, et al: Angiogenesis of
uterine cervical carcinoma: Characterization by pharmacokinetic
magnetic resonance imaging-based parameters and a histomorphological
approach in correlation with disease outcome. Clin Cancer Res
15. Mayr NA, Hawighorst H, Yuh WTC, et al: MR microcirculation in
cervical cancer: Correlations with histomorphological tumor markers
and clinical outcome. J Magn Reson Imaging 10:267-276, 1999.
16. Pillai MR, Jayaprakash PG, Nair MK: Bcl-2 immunoreactivity but
not p53 accumulation associated with tumour response to radiotherapy
in cervical carcinoma. J Cancer Res Clin Oncol 125(1):55-60, 1999.
17. Harima Y, Harima K, Shikata N, et al: Bax and Bcl-2 expressions
predict response to radiotherapy in human cervical cancer. J Cancer
Res Clin Oncol 124(9):503-510, 1998.
18. Nakano T, Oka K: Differential values of Ki-67 index and mitotic
index of proliferating cell population: An assessment of cell cycle
and prognosis in radiation therapy for cervical cancer. Cancer
19. Nakano T, Oka K, Ishikawa A, et al: Immunohistochemical
prediction of radiation response and local control in radiation
therapy for cervical cancer. Cancer Detect Prev 22(2):120-128, 1998.
20. Mayr NA, Yuh WTC, Magnotta VA, et al: Tumor perfusion studies
using fast magnetic resonance imaging technique in advanced cervical
cancer: A new noninvasive predictive assay. Int J Radiat Oncol Biol
Phys 36:623-633, 1996.
21. Travis LB, Holowaty EJ, Bergfeldt K, et al: Risk of leukemia
after platinum-based chemotherapy for ovarian cancer. N Engl J Med
22. Altmann S, Hoffmanns H: Cytoprotection with amifostine in
radiotherapy or radio-chemotherapy of head and neck tumors [German].
Strahlenther Onkol 175(suppl 4):30-33, 1999.