Cancer Therapy Vol 5, page 395
Cancer Therapy Vol 5, 395-400, 2007
Adjuvant therapy for endometrial cancer:
“Sandwich therapy” of carboplatin and paclitaxel
with radiation therapy. The Women and Infants’
Hospital experience and review of the literature
Don S Dizon1,2,3,*, Carolyn K McCourt1,3, Terissa Martin-Hanley3, Laurent
Brard1,3, AnnMarie Bradley3, Christina Bandera1,3
Department of Obstetrics and Gynecology
Department of Medicine, The Warren Alpert Medical School of Brown University, The Program in Women’s Oncology
Women and Infants’ Hospital Providence, RI
*Correspondence: Don S Dizon, Program in Women’s Oncology, Women & Infants’ Hospital, 101 Dudley Street, Providence, RI
02905, USA; Tel: 401-453-7520. Fax: 401-453-7529. E-mail: email@example.com
Key words: Patient demographics, Adjuvant therapy, chemotherapy, radiation therapy, endometrial cancer, carboplatin, paclitaxel
Abbreviations: external beam radiotherapy, (EBRT); Gynecologic Oncology Group, (GOG)
Received: 7 May 2007; Revised: 14 May 2007
Accepted: 17 May 2007; electronically published: November 2007
Ideal adjuvant regimens for advanced stage or high-risk endometrial cancer remain unclear. The purpose of this
study was to review our experience with combined modality therapy, or sandwich treatment, where radiotherapy is
given in the middle of chemotherapy. Our objectives were to report the feasibility, side effect profile, recurrence
rates, and survival noted in women treated with sandwich therapy for this disease. Patients were identified from our
Institutional Cancer Registry. Demographics, surgical staging information, details of therapy, and follow-up data
were obtained by chart review. Survival estimates were calculated by Kaplan-Meier method. We identified 25
women who underwent surgical staging for endometrial cancer between 2000 and 2005, followed by chemotherapy
for three cycles, comprehensive pelvic radiation, and then further chemotherapy (“sandwich” therapy). Twenty-
four (96%) had a complete surgical staging procedure including nodal evaluation. Chemotherapy consisted of
Carboplatin AUC 5-6 and paclitaxel 135-175 mg/m2. The median age was 66 (range, 41-79). Four women (16%) had
Stage IIB disease, 5 (20%) had IIIA, 15 (60%) had IIIc, and 1 (4%) had Stage IV disease. The predominant
histologies were endometrioid (48%), mixed carcinoma (24%), clear cell (12%), and serous (8%). Twenty-one
patients (84%) completed the prescribed therapy. A total of 138 cycles of chemotherapy was administered and
seven cycles were delayed, most of which occurred after radiation. At a median follow-up of 32 months, 7 (28%)
have experienced recurrent disease. Median disease-free and overall survival has not been reached. Radiation
therapy sandwiched between cycles of carboplatin and paclitaxel represents a feasible option for women requiring
adjuvant therapy for endometrial cancer. Alongside other data reported elsewhere, we feel there is sufficient
rationale to proceed with a randomized trial of sandwich therapy vs chemotherapy to definitively determine the
efficacy of combined treatment in advanced or high-risk uterine cancer.
cancers are diagnosed at an early stage and effectively
I. Introduction treated with surgical resection alone. However, clear cell
The American Cancer Society estimates that 39,080
and papillary serous carcinomas of the uterus are
women will be diagnosed with uterine cancer in 2007 and
associated with more aggressive behaviors than the more
7,400 women will die of disease (Cancer Facts and
common endometrioid carcinomas, and even at an early
Figures. 2007). Fortunately the majority of endometrial
Dizon et al: Adjuvant therapy for endometrial cancer
stage are associated with five year survival between 60- were used for continuous variables. Fisher’s Exact test was used
66% (Huh et al, 2003). Other factors considered for categorical variables. Survival endpointes were measured
worrisome for recurrence include nodal involvement, high from the end of adjuvant therapy. Median progression-free and
grade tumors, and deep myometrial invasion, and the overall survival at 3-years were estimated by Kaplan-Meier
method. Statistical analyses were performed using MedCalc for
presence of disease outside of the uterus. Patients
Windows, version 220.127.116.11 (MedCalc Software, Mariakerke,
exhibiting any of these features are often characterized as Belgium).
having high-risk endometrial cancer, for which adjuvant
therapy is often recommended.
Optimal adjuvant therapy for women with high-risk III. Results
disease, however, has yet to be defined. Prior clinical trials A. Patient demographics
using post-operative radiotherapy has been shown to We identified 25 women who met eligibility criteria
reduce the risk of local relapses but have not improved (Table 1). The median age of patients was 66 (range, 41-
overall survival, due to the development of distant 79). Four patients (16%) had Stage IIB disease, 20 had
metastases (Grevan et al, 1989). Trials of chemotherapy Stage III disease (80%) and one (4%) had Stage IV
have demonstrated that combination of adriamycin and disease. The majority had endometrioid carcinoma (48%);
cisplatin, is more active than single agent therapy 12% had clear cell carcinoma and 8% had serous cancers.
(Fleming et al 2004; Randall et al 2006). A recently Twenty percent had mixed tumor histologies and 3
reported randomized trial of this combination against patients (12%) had other types including a mucinous
whole abdominal radiation therapy in women with adenocarcinoma in one and mixed Mullerian tumor
advanced endometrial cancer with minimal residual (carcinosarcoma) in two. For all patients, chemotherapy
disease following surgical resection showed improvement consisted of carboplatin and paclitaxel; the dose of
in both 5-year progression free survival (50% vs 38%, carboplatin was at an AUC 5-6 and for paclitaxel was 135-
respectively) and overall survival (55% vs 42%, 175 mg/m2.
respectively) (Fleming et al, 2004). Of the 25 patients treated, 21 (84%) completed
Given the risks of both local and distant relapse, prescribed therapy. One person refused further treatment
interest in giving combined chemotherapy and radiation after her first dose of chemotherapy and two refused
either concomitantly or sequentially has continued to be an further chemotherapy after completing radiation therapy.
attractive option. One such option is the use of One person experienced disease progression shortly after
chemotherapy prior to and then following pelvic radiation,
also referred to as sandwich therapy. It has been an
appealing regimen because it attempts to incorporate both Table 1. Patient Demographics (n=25)
treatments in a timely and efficient manner while
potentially minimizing the toxicity associated with each. Median age (range) 66 41-79
Fields, et al, evaluated the combination of carboplatin and Median weight (pds, range) 162 94-276
paclitaxel combined with volume-directed radiotherapy. Characteristic N (%)
Of 12 patients treated with Stage III or IV uterine papillary Endometrioid 12 48
serous carcinoma, three-year disease-free and overall Serous 2 8
survival were 53% and 53%, respectively (Fields et al, ClearCell 3 12
2006). However, the small proportion of patients treated in Mixedadenocarcinoma 5 20
this study and lack of randomization makes any Other 3 12
conclusions impossible. More recently, the Duke group Tumor Grade
reported their findings of a large retrospective study of 1 3 12
chemotherapy vs. radiation vs. concomitant 2 10 40
chemoradiation in women with Stage III or IV uterine 3 12 48
cancer (Alvarez et al, 2007). Their analysis suggested that >50% myometrial
22 (12) 88 (54.5)
chemoradiation improved progression free and overall invasion
survival, particularly in patients who were optimally Lymphovascular invasion 21 84
resected. However, information regarding regimen and present
sequence of therapy could not be readily discerned in their Lower Uterine Segment 17 68
analysis. Given the limited data in support of this regimen, involved
we were interested in evaluating our experience with Cervical stroma involved 11 44
sandwich therapy in women with endometrial cancer. Nodes evaluated 24 96
Pelvic nodes positive 16 67
II. Methods Para-aortic nodes 4 17
This retrospective study was reviewed and approved by the positive
Institutional Review Board of Women & Infants’ Hospital. We Extrauterine disease* 9 36
identified women treated for endometrial cancer between 1990 FIGO Stage
and 2006, who received adjuvant chemotherapy with sandwich II 4 16
radiation therapy. Demographic and treatment data were III 20 80
collected by chart review, as was dates of progression, death, and IV 1 4
last follow-up. Toxicities and dates of hospitalization were *excludes nodal disease.
retrospectively recorded but not graded. Descriptive statistics
Cancer Therapy Vol 5, page 397
completing pelvic radiation. A total of 138 cycles of IV. Discussion
chemotherapy were delivered and of these, only seven Adjuvant treatment for high-risk endometrial cancer
(5%) were delayed. Of these delays, five occurred after continues to evolve. While there is an established place for
pelvic radiation. Only one of these delays was due to chemotherapy, efforts to improve treatment by the use of
neutropenia. There were no hospitalizations recorded better tolerated agents, incorporation of biologic agents,
during treatment. and the addition of radiotherapy all continue to be
At a median follow-up of 32 months twenty patients evaluated. Concomitant or sequential chemotherapy with
are (80%) are alive without evidence of disease and 3 radiotherapy offers the potential to confer both local and
women (12%) have died of their disease. In this cohort, systemic control to prevent recurrence, in hopes of curing
the 3-year estimated progression free survival is 70% more women with advanced or high risk-disease.
(Figure 1); for overall survival it is 83% (Figure 2).
Figure 1. Progression free survival.
Figure 2. Overall survival
Dizon et al: Adjuvant therapy for endometrial cancer
Unfortunately, clinical trials proving this hypothesis have received chemotherapy, the overall response rate was
been relatively sparse. 47%. Currently, the Gynecologic Oncology Group (GOG)
We report on our center experience using sandwich is conducting a randomized trial comparing carboplatin
therapy employing three cycles of carboplatin and and paclitaxel to cisplatin, adriamycin, and paclitaxel in
paclitaxel before and after radiation therapy in women women with high-risk, advanced, or metastatic
with endometrial cancer. Our retrospective analysis endometrial cancer, which should conclusively of
suggests that the regimen is feasible with no reports of caroplatin and paclitaxel against the standard three-drug
hospitalization during therapy and the majority of cycles regimen containing adriamycin.
delivered without delay. Three-year estimates of both In addition to Fields and colleagues noted earlier in
progression-free and overall surival suggest this is an 2006, others have reported their results using combined
active regimen as well. Although cisplatin and chemotherapy and radiation (Table 2). Morrow et al,
adriamycin-based therapy is considered standard of care in conducted a randomized prospective trial in 92 women
endometrial cancer, carboplatin and paclitaxel is an often with high-risk Stage I or II endometrial cancer who were
used regimen. Despite the absence of randomized trials randomized to doxorubicin or no further therapy following
evaluating superiority or equivalence with other standard surgery and comprehensive volume-directed radiotherapy,
regimens, the improvement in tolerability and activity of with fields dependent on the extent of disease identified on
carboplatin and paclitaxel in other tumor types, notably final pathologic analysis (Morrow et al, 1990). No
ovarian cancer, has made it an acceptable regimen in high- differences in survival was noted with the use of this
risk or advanced endometrial cancer. Most recently, the regimen of chemotherapy following radiation treatment.
Memorial Sloan-Kettering group recently published their Smith et al, evaluated the outcomes in 47 women with
experience in women with advanced or recurrent disease Stage IC-II endometrial cancer treated with cisplatin,
(Sovak et al, 2007). In their cohort of previously treated doxorubin, and cyclophosphamide, also followed by
patients, the response rate was 43%, including complete volume-directed radiation (Smith et al, 1994).
responses in 5%. However, for patients who had never
Table 2. Adjuvant trials in Endometrial cancer evaluating chemotherapy and radiation therapy
Reference N Population Chemotherapy RT Schedule Results
Morrow et al, doxorubicin vs no Sequential (RT then +/- No difference
92 Stage I-II EBRT
1990 doxorubicin chemotherapy) in survival.
Cisplatin Volume 72.5%
Smith et al,
47 Stage IC-II Adriamycin directed Sequential (nonpapillary
Cyclophosphamide RT serous
Lupe et al, Carboplatin
33 Stage III or IV EBRT Sandwich regimen.
2-y DFS and
Stage IC grade
Mangili et al, Median time
23 3 or Stage IIB- weekly paclitaxel EBRT Concomitant
2006 to recurrence:
Greven et al, high-risk Stage RT 4-y DFS 85%
46 EBRT Sequential
2006 IC-IIB cisplatin/paclitaxel 4-y OS 81%
Duska et al, high-risk any
20 paclitaxel EBRT Sequential reported. No
doxorubicin survival data
3y DFS 68%
Fields et al, 30 I/II UPSC Carboplatin and OS 75%
2006 12 III/IV UPSC paclitaxel 3y DFS 53%
EBRT: External beam radiation therapy; RT radiotherapy; DFS disease free survival; OS overall survival; UPSC: uterine papillary
Cancer Therapy Vol 5, page 399
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