Adjuvant therapy for endometrial cancer Sandwich therapy of

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					                                              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
Research Article

Don S Dizon1,2,3,*, Carolyn K McCourt1,3, Terissa Martin-Hanley3, Laurent
Brard1,3, AnnMarie Bradley3, Christina Bandera1,3
1
  Department of Obstetrics and Gynecology
2
  Department of Medicine, The Warren Alpert Medical School of Brown University, The Program in Women’s Oncology
3
  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: ddizon@wihri.org
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


                                                        Summary
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


                                                             395
                                       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 9.3.0.0 (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


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                                          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




                                                          397
                                       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.
                                                                                                                      2-y        DFS
                                             Cisplatin                 Volume                                         72.5%
Smith et al,
                   47    Stage IC-II         Adriamycin                directed     Sequential                        (nonpapillary
1994
                                             Cyclophosphamide          RT                                             serous
                                                                                                                      cancers)
                                                                                                                      76%
                                                                                                                      completed full
Lupe    et   al,                             Carboplatin
                   33    Stage III or IV                               EBRT         Sandwich                          regimen.
2007                                         Paclitaxel
                                                                                                                      2-y DFS and
                                                                                                                      OS: 55%
                                                                                                                      OS 78.2%.
                         Stage IC grade
Mangili et al,                                                                                                        Median time
                   23    3 or Stage IIB-     weekly paclitaxel         EBRT         Concomitant
2006                                                                                                                  to recurrence:
                         IIIC
                                                                                                                      18.6m.
                                             cisplatin    during
Greven et al,            high-risk Stage     RT                                                                       4-y DFS 85%
                   46                                                  EBRT         Sequential
2006                     IC-IIB              cisplatin/paclitaxel                                                     4-y OS 81%
                                             after RT
                                                                                                                      No significant
                                             carboplatin                                                              toxicities
Duska et al,             high-risk     any
                   20                        paclitaxel                EBRT         Sequential                        reported. No
2005                     stage
                                             doxorubicin                                                              survival data
                                                                                                                      reported.
                                                                                                                      3y DFS 68%
Fields et al,      30    I/II UPSC           Carboplatin      and                                                     OS 75%
                                                                       EBRT         Sandwich
2006               12    III/IV UPSC         paclitaxel                                                               3y DFS 53%
                                                                                                                      OS 52%
EBRT: External beam radiation therapy; RT radiotherapy; DFS disease free survival; OS overall survival; UPSC: uterine papillary
serous carcinoma.




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                                              Cancer Therapy Vol 5, page 399

They reported the regimen to be well-tolerated and at 2                   References
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