- Email: [email protected]
Neoadjuvant Chemotherapy Using Low-Dose Consecutive Intraarterial Infusions of Cisplatin Combined with 5-Fluorouracil for Locally Advanced Cervical Adenocarcinoma
Gynecologic Oncology 81, 496 – 499 (2001) doi:10.1006/gyno.2001.6195, available online at http://www.idealibrary.com on
Neoadjuvant Chemotherapy Using Low-Dose Consecutive Intraarterial Infusions of Cisplatin Combined with 5-Fluorouracil for Locally Advanced Cervical Adenocarcinoma Yoichi Aoki, M.D., 1 Takaaki Sato, M.D., Minoru Watanabe, M.D., Masaru Sasaki, M.D., Ikunosuke Tsuneki, M.D., and Kenichi Tanaka, M.D. Department of Obstetrics and Gynecology, Faculty of Medicine, Niigata University, 1-757 Asahimachi dori Niigata 951-8510, Japan Received December 13, 2000
Objective. The goal of this work was to evaluate response rate, toxicity, and survival in treatment with intraarterial 5-fluorouracil (5-FU) and cisplatin in a neoadjuvant setting; this combination was administered to patients with locally advanced cervical adenocarcinoma. Methods. Eleven patients were treated with preoperative neoadjuvant chemotherapy. Those eligible included patients with previously untreated stage IB, II, or III adenocarcinoma with good performance status. Treatment consisted of bilateral internal iliac artery infusion of cisplatin (a total of 10 mg/day) for 30 min, followed by 5-FU (a total of 250 mg/day) given by 24-hour continuous infusion for 10 days. Treatment was repeated every 3 weeks for a total of two or three cycles. All except one patient with progressive disease underwent radical hysterectomy following neoadjuvant chemotherapy. Postoperative radiotherapy was given to the whole pelvis to 6 patients; 3 of the 6 patients with involved common iliac nodes received radiotherapy to a paraaortic field in addition to the whole pelvis. Results. Among 11 eligible patients, 7 had a partial response (64%). Stable disease was observed in 3 cases (27%) and progressive disease in 1 (9%). Histopathological changes related to chemotherapy, however, revealed only mild effects. Of the 24 treatment cycles administered, no Grade 3 or 4 toxicity was observed and there were no therapy-related deaths. The median follow-up period was 30 months (range, 1– 65 months). The mean survival period was 34.7 months and the 5-year survival rate was 21.2%. Conclusions. Intraarterial neoadjuvant chemotherapy effectively reduced tumor size in patients with locally advanced cervical adenocarcinoma; however, a survival advantage was not clear. © 2001 Academic Press Key Words: cervical adenocarcinoma; neoadjuvant chemotherapy; low-dose intraarterial infusion; cisplatin and 5-fluorouracil.
INTRODUCTION Cancer of the cervix is the second most common malignancy in women worldwide [1]. Of its histological subtypes, squa1
To whom correspondence should be addressed. Fax: 81-25-227-0789. E-mail: [email protected]. 0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
mous cell carcinoma is the most common, while adenocarcinoma represents a minority of cervical cancers, accounting for approximately 5 to 15% of all cases, but increases its number. Adenocarcinoma of the cervix carries a worse prognosis than its squamous counterpart, in particular when cancer cells spread beyond the uterine cervix [2, 3]. In particular, tumors with lymph node metastasis have miserably poor prognosis [4, 5]. This is derived from the observation that adenocarcinoma is less sensitive to radiation therapy and has a tendency to spread into lymphatic drainage even at an early stage [6, 7]. Recently, neoadjuvant chemotherapy for bulky or locally advanced cervical cancer has received increasing attention and some authors have reported a promising response rate [8, 9]. The use of neoadjuvant chemotherapy as part of a multimodal treatment offers some theoretical advantages in advanced diseases. Chemotherapy may shrink bulky tumors and may also reduce the incidence of lymph node metastases. Accordingly, radical surgery can remove residual main tumor after neoadjuvant chemotherapy. Due to the rarity of adenocarcinoma of the cervix, the majority of such reports have focused on squamous cell carcinoma, and so far only a few data are available for patients with cervical adenocarcinoma. In this study we report our experience with a neoadjuvant intraarterial chemotherapy including low-dose cisplatin combined with 5-fluorouracil (5-FU) for bulky or locally advanced cervical adenocarcinoma. PATIENTS AND METHODS Between January 1993 and December 1998, 11 patients with primary cervical adenocarcinoma who presented to Niigata University Hospital were entered into this study. All the patients gave written informed consent to receive the proposed treatment. The eligibility criteria were as follows: histologically proven cervical adenocarcinoma; no prior treatment; age younger than 70; International Federation of Gynecology and Obstetrics (FIGO) stage IB with deep cervical stromal invasion (outer one-third) by magnetic resonance imaging (MRI) or
496
497
INTRAARTERIAL NEOADJUVANT CHEMOTHERAPY FOR CERVICAL ADENOCARCINOMA
TABLE 1 Criteria for Evaluation of the Histopathological Effects of Solid Cancer Chemotherapy Grade 0
No effect Few degenerative or necrotic changes after chemotherapy Mild effect Very mild effect Degeneration or necrosis occurred in less than one-third of the cancer cells Mild effect Degeneration, necrosis, or cytolysis occurred in more than one-third but less than two-thirds of the cancer cells Moderate effect Remarkable degeneration, necrosis, cytolysis, or disappearance of cancer cells in more than two-thirds of the cancer cells Marked effect All cancer cells become necrotic, cytolysis occurred, or granulomatous tissue or fibrosis was present
Grade 1 Grade 1a
Grade 1b
Grade 2
Grade 3
stage II or III; no distant metastases; adequate renal, pulmonary, hepatic, bone marrow, and cardiac function. Tumor size was measured by MRI before and after neoadjuvant chemotherapy, and radical hysterectomy was carried out in all 10 patients after neoadjuvant chemotherapy, except in one patient with progressive peritoneal carcinomatosis during neoadjuvant chemotherapy. Neoadjuvant chemotherapy consisted of bilateral internal iliac artery infusion of low-dose cisplatin (a total of 10 mg/day) for 30 min, followed by 5-FU (a total of 250 mg/day) given for 24 hours on Days 1 to 10 consecutively using a subcutaneously implanted drug delivery system. Treatment was repeated every 3 weeks for a total of two or three cycles. Whether patients would receive two or three courses of chemotherapy depended on tumor response to the chemotherapy and operability diagnosed by pelvic physical examination.
Chemotherapy response was defined as follows: complete response (CR) was disappearance of all measurable disease; partial response (PR) was a 50% or greater reduction in the product of the transverse diameters of the cervical lesions; progressive disease (PD) was a 50% or greater increase in the product of the transverse diameters of the cervical lesions; and stable disease (SD) was any condition not meeting the preceding criteria. All except one patient with PD underwent radical hysterectomy following the neoadjuvant chemotherapy. Histopathological changes related to chemotherapy were examined in extirpated or biopsied tissues obtained after the completion of chemotherapy in comparison with biopsied specimens obtained before treatment in 10 patients. The specimens were evaluated by grading according to the criteria of the Japan Society for Cancer Therapy (Table 1). Postoperative radiotherapy (Table 2) was given to the whole pelvis to 6 patients; 3 of the 6 patients with involved common iliac nodes received radiotherapy to a paraaortic field up to the level of T-12 in addition to the whole pelvis. External irradiation using a parallel opposing portal technique with 60Co was performed for postoperative radiotherapy. The external irradiation consisted of 44 –50 Gy whole-pelvis and the fractionation was 1.8 –2.0 Gy daily, five fractions per week. For paraaortic field irradiation in addition to the whole pelvis, the dose was 44 –50 Gy and the fractionation was 1.8 –2.0 Gy daily, five fractions per week. For one patient with vaginal invasion close to a surgical margin, brachytherapy by remote control after loading was added; the dose was 15 Gy at 5-mm depth of the vaginal mucosa. Three patients (patients 6, 9, and 10 in Table 2) refused to receive postoperative radiation therapy, although they were found to have positive lymph node metastasis. Survival was calculated using the product-limit estimate by the Kaplan–Meier method.
TABLE 2 Main Characteristics of the Patients and Outcome a Tumor size by MRI (cm)
Case
Age
FIGO stage
Histology type
NAC courses
1 2 3 4 5 6 7
42 67 69 51 30 45 34
IIB IB1 IIB IIIB IIB IIB IB1
4.3 ⫻ 4.1 2.5 ⫻ 1.7 2.7 ⫻ 2.0 6.0 ⫻ 4.4 5.1 ⫻ 4.6 3.7 ⫻ 3.1 3.1 ⫻ 1.8
EC, G2 EC, G1 EC, G1 EM, G2 EC, G2 Ad.Sq. EM, G1
3 2 3 2 3 2 2
8 9 10 11
34 55 61 62
IB2 IB2 IIB IIB
4.4 ⫻ 3.1 5.0 ⫻ 3.8 3.3 ⫻ 2.7 4.6 ⫻ 3.3
EC, G1 Serous, G1 EC, G2 EC, G3
2 2 2 1
Surgical margin
Postop therapy
Clinical response
Histological response
Parametrial infiltration
LN metastasis
RH RH RH RH RH RH RH
⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
WP None WP ⫹ PAN WP ⫹ PAN WP None WP ⫹ BT
PR PR PR PR SD PR SD
1A 1B 1B 1B 1B 1A 0
⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺
⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫹
RH RH RH Not done
⫺ ⫺ ⫺ ⫺
WP ⫹ PAN None None None
PR PR SD PD
1A 1A 0 NA
⫹ ⫹ ⫹ NA
⫺ ⫹ ⫹ NA
Surgery
Site of recurrence Lung
Nodes Vagina Vagina Lung Liver, nodes Lung Pelvis Peritoneum
Status 56 65 63 14 43 20 24
months months months months months months months
DOD NED NED DOD DOD DOD NED
30 months DOD 28 months DOD 10 months DOD 1 month DOD
a EC, endocervical type; EM, endometrioid type; Ad.Sq., adenosquamous; Serous, serous adenocarcinoma; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; RH, radical hysterectomy; WP, whole-pelvis radiation; PAN, paraaortic node radiation; BT, brachytherapy; NA, not assessed; DOD, died of disease; NED, no evidence of disease.
498
AOKI ET AL.
RESULTS The present study included 4 patients with stage IB (2 IB1 and 2 IB2) carcinoma, 6 with stage IIB, and 1 with stage IIIB. The mean age of these patients was 50 (range, 30 – 69). Seven patients had endocervical-type adenocarcinoma, 2 had endometrioid-type adenocarcinoma, 1 had serous adenocarcinoma, and 1 had adenosquamous carcinoma (Table 2). Ten subjects (91%) completed the planned course of treatment. One patient (patient 11) required discontinuation of the treatment after the one administration because of the progression of peritoneal carcinomatosis. Seven patients received two courses of treatment and the remaining 3 patients had three courses of treatment. This regimen was well tolerated by the patients, as confirmed by no need for a delay in the treatment schedule and by the number of subjects requiring discontinuation. There was no significant nausea or vomiting, which was attributable to the cisplatin. Myelotoxicity was very mild, and no nephrotoxicity or neurotoxicity was observed in this series. There were no therapy-related deaths. We observed 7 (64%) PRs and 3 (27%) SD in 11 evaluable patients. Histopathological changes related to chemotherapy were evaluated by grading according to the criteria of the Japan Society for Cancer Therapy (Table 1). Mild changes (Grade 1A or 1B) were detected in 7 PR patients and Grade 0 was observed in 3 SD patients. No Grade 2 or 3 change was recognized and cancer cells still remained in all specimens. Lymph node metastasis was confirmed histopathologically in 7 patients (70%) and ovarian metastasis in 3 (30%). Parametrial infiltration was detected histologically in 5 patients (50%). With respect to surgical margin, however, no patients had positive parametrial and vaginal margins. Six patients in this series received postoperative radiation therapy. Four patients had Grade 2 diarrhea due to radiation colitis, and 3 patients had mild radiation dermatitis during radiation, which were improved conservatively. Also, one patient had proctosigmoiditis 18 months after radiation therapy. The median follow-up period was 30 months (range, 1– 65 months). Eight patients died of recurrent or persistent disease, and 2 patients are alive without evidence of recurrence. The remaining one patient had a pulmonary recurrence and underwent right partial lobectomy 13 months after an initial treatment. She is alive without evidence of disease (patient 7 in Table 2). The mean survival period was 34.7 months, and the 5-year survival rate was 21.2% (Fig. 1). The recurrences were located in the vagina in 3 cases and in a distant region in 5 cases (3 in the lung, 1 in the liver and paraaortic lymph nodes, and 1 in the paraaortic lymph nodes). The remaining one case had progressive peritoneal carcinomatosis during neoadjuvant chemotherapy. DISCUSSION In recent years, systemic trials of neoadjuvant chemotherapy for adenocarcinooma of the cervix have been reported. Zanetta
FIG. 1.
Kaplan–Meier survival curve of the study population.
et al. examined the effects of neoadjuvant chemotherapy with a combination of cisplatin and epirubicin in 21 patients with locally advanced adenocarcinoma of the cervix and the vagina [10]. They observed 4 clinically CRs and 10 PRs (total response rate ⫽ 67%). Fujiwaki et al. found that patients with endometrial carcinoma have a favorable clinical response rate (87.5%) to intraarterial neoadjuvant chemotherapy with cisplatin and doxorubicin, but those with cervical adenocarcinoma have disapointing results (response rate ⫽ 58.3%). No CR was observed in the group with cervical adenocarcinoma [11]. Iwasaka et al. has reported that neoadjuvant chemotherapy consisting of cisplatin, mitomycin, and etoposide for adenocarcinoma of the cervix resulted in 3 CRs and 5 PRs (response rate ⫽ 50%), and the mean survival period of responders was 47.5 months whereas that of nonresponders was 28.3 months [4]. In our study, we used cisplatin combined with 5-FU in low-dose consecutive intraarterial infusions for patients with cervical adenocarcinoma in a neoadjuvant setting. Low-dose consecutive infusions have been reported to achieve higher areas under the time– concentration curve (AUCs), although lower maximum concentrations (C max) of cisplatin, as compared with bolus infusion [12, 13], which leads to a better clinical response with milder adverse effects. The antitumor effect of cisplatin depends on the AUC of filterable platinum obtained following administration of the agent, but not on the C max of the agent [12]. We achieved a 64% response rate (no CRs, 7 PRs), which was almost equal to or higher than those reported previously by others [4, 10, 11, 14, 15]. Also, even in 3 SD patients, tumor volume showed a 25% or greater, (but ⬍50%) reduction, but no CR was observed. Previous reports addressed that chemoresponsiveness is the most potent predictor of cure in patients with locally advanced cervical adenocarcinoma treated with neoadjuvant chemotherapy [4, 15]. Histological examination, however, revealed only mild effects even in the PR patients in our study. Despite the relatively high
INTRAARTERIAL NEOADJUVANT CHEMOTHERAPY FOR CERVICAL ADENOCARCINOMA
response rate, no CR was observed, which indicates that the chemotherapy regimen we used may not effectively lead to a cure of adenocarcinoma of the cervix. Accordingly, 2 patients with negative lymph nodes survive without evidence of recurrence (63 and 65 months), 1 is alive without disease after resection of pulmonary recurrence for 24 months, and the remaining 7 patients have died of disease. Of 9 recurrences, 3 were local and 5 were distant. The remaining one was progressive peritoneal carcinomatosis during neoadjuvant chemotherapy. A relatively high rate of distant recurrence implies that low-dose intraarterial cisplatin combined with 5-FU infusion may not be appropriate strategy for bulky or locally advanced adenocarcinomas of the cervix. However, since the regimen we used reduced the size of the bulky tumor to allow radical surgery with a final pathological diagnosis of negative parametrial and vaginal margins, this treatment might be of benefit to such patients. Although the relatively small number of patients in this study limits the power of the assessment, a survival advantage was not clear. The increased frequency and poor prognosis of cervical adenocarcinoma call for new therapeutic strategies, especially for locally advanced disease. REFERENCES 1. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993;54:594 – 606. 2. Kjorstad KE, Bond B. Stage Ib adenocarcinoma of the cervix: metastatic potential and patterns of dissemination. Am J Obstet Gynecol 1984;150: 297–9. 3. Aoki Y, Sasaki M, Watanabe M, Sato T, Tsuneki I, Aida H, Tanaka K. High-risk group in node-positive patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation. Gynecol Oncol 2000;77:305–9. 4. Iwasaka T, Fukuda K, Hara K, Yokoyama M, Nakao Y, Uchiyama M, Sugimori H. Neoadjuvant chemotherapy with mitomycin C, etoposide, and cisplatin for adenocarcinoma of the cervix. Gynecol Oncol 1998;70: 236 – 40.
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5. Weiss RJ, Lucas WE. Adenocarcinoma of the uterine cervix. Cancer 1986;57:1996 –2001. 6. Chen RJ, Chang DY, Yen ML, Lee EF, Huang SC, Chow SN, Hsieh CY. Prognostic factors of primary adenocarcinoma of the uterine cervix. Gynecol Oncol 1998;69:157– 64. 7. Natsume N, Aoki Y, Kase H, Kashima K, Sugaya S, Tanaka K. Ovarian metastasis in stage IB and II cervical adenocarcinoma. Gynecol Oncol 1999;74:255– 8. 8. Sardi JE, Giaroli A, Sananes C, Ferreira M, Soderini A, Bermudez A, Snaidas L, Vighi S, Gomez Rueda N, di Paola G. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results. Gynecol Oncol 1997;67:61–9. 9. Chang TC, Lai CH, Hong JH, Hsueh S, Huang KG, Chou HH, Tseng CJ, Tsai CS, Chang JT, Lin CT, Chang HH, Chao PJ, Ng KK, Tang SG, Soong YK. Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. J Clin Oncol 2000;18: 1740 –7. 10. Zanetta G, Lissoni A, Gabriele A, Landoni F, Colombo A, Perego P, Mangioni C. Intense neoadjuvant chemotherapy with cisplatin and epirubicin for advanced or bulky cervical and vaginal adenocarcinoma. Gynecol Oncol 1997;64:431–5. 11. Fujiwaki R, Takahashi K, Kitao M. Decrease in tumor volume and histologic response to intraarterial neoadjuvant chemotherapy in patients with cervical and endometrial adenocarcinoma. Gynecol Oncol 1997;65: 258 – 64. 12. Shimizu Y, Akiyama F, Umezawa S, Ishiya T, Utsugi K, Hasumi K. Combination of consecutive low-dose cisplatin with bleomycin, vincristine, and mitomycin for recurrent cervical carcinoma. J Clin Oncol 1998; 16:1869 –78. 13. Sato H, Fujiwara K, Azuma T, Akiya K. Multidisciplinary, intra-arterial chemotherapy (IAC) with CDDP and 5-FU against cervical cancer. Gan To Kagaku Ryoho 1988;15:2443–7. 14. Kavanagh JJ, Gershenson D, Copeland L, Robert WAS. Combination chemotherapy for metastatic or recurrent adenocarcinoma of the cervix. J Clin Oncol 1987;5:1621– 4. 15. Benedetti-Panici P, Greggi S, Scambia G, Salerno MG, Amoroso M, Maneschi F, Cutillo G, Caruso A, Capelli A, Mancuso S. Locally advanced cervical adenocarcinoma: is there a place for chemo-surgical treatment? Gynecol Oncol 1996;61:44 –9.
Neoadjuvant Chemotherapy Using Low-Dose Consecutive Intraarterial Infusions of Cisplatin Combined with 5-Fluorouracil for Locally Advanced Cervical Adenocarcinoma Yoichi Aoki, M.D., 1 Takaaki Sato, M.D., Minoru Watanabe, M.D., Masaru Sasaki, M.D., Ikunosuke Tsuneki, M.D., and Kenichi Tanaka, M.D. Department of Obstetrics and Gynecology, Faculty of Medicine, Niigata University, 1-757 Asahimachi dori Niigata 951-8510, Japan Received December 13, 2000
Objective. The goal of this work was to evaluate response rate, toxicity, and survival in treatment with intraarterial 5-fluorouracil (5-FU) and cisplatin in a neoadjuvant setting; this combination was administered to patients with locally advanced cervical adenocarcinoma. Methods. Eleven patients were treated with preoperative neoadjuvant chemotherapy. Those eligible included patients with previously untreated stage IB, II, or III adenocarcinoma with good performance status. Treatment consisted of bilateral internal iliac artery infusion of cisplatin (a total of 10 mg/day) for 30 min, followed by 5-FU (a total of 250 mg/day) given by 24-hour continuous infusion for 10 days. Treatment was repeated every 3 weeks for a total of two or three cycles. All except one patient with progressive disease underwent radical hysterectomy following neoadjuvant chemotherapy. Postoperative radiotherapy was given to the whole pelvis to 6 patients; 3 of the 6 patients with involved common iliac nodes received radiotherapy to a paraaortic field in addition to the whole pelvis. Results. Among 11 eligible patients, 7 had a partial response (64%). Stable disease was observed in 3 cases (27%) and progressive disease in 1 (9%). Histopathological changes related to chemotherapy, however, revealed only mild effects. Of the 24 treatment cycles administered, no Grade 3 or 4 toxicity was observed and there were no therapy-related deaths. The median follow-up period was 30 months (range, 1– 65 months). The mean survival period was 34.7 months and the 5-year survival rate was 21.2%. Conclusions. Intraarterial neoadjuvant chemotherapy effectively reduced tumor size in patients with locally advanced cervical adenocarcinoma; however, a survival advantage was not clear. © 2001 Academic Press Key Words: cervical adenocarcinoma; neoadjuvant chemotherapy; low-dose intraarterial infusion; cisplatin and 5-fluorouracil.
INTRODUCTION Cancer of the cervix is the second most common malignancy in women worldwide [1]. Of its histological subtypes, squa1
To whom correspondence should be addressed. Fax: 81-25-227-0789. E-mail: [email protected]. 0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
mous cell carcinoma is the most common, while adenocarcinoma represents a minority of cervical cancers, accounting for approximately 5 to 15% of all cases, but increases its number. Adenocarcinoma of the cervix carries a worse prognosis than its squamous counterpart, in particular when cancer cells spread beyond the uterine cervix [2, 3]. In particular, tumors with lymph node metastasis have miserably poor prognosis [4, 5]. This is derived from the observation that adenocarcinoma is less sensitive to radiation therapy and has a tendency to spread into lymphatic drainage even at an early stage [6, 7]. Recently, neoadjuvant chemotherapy for bulky or locally advanced cervical cancer has received increasing attention and some authors have reported a promising response rate [8, 9]. The use of neoadjuvant chemotherapy as part of a multimodal treatment offers some theoretical advantages in advanced diseases. Chemotherapy may shrink bulky tumors and may also reduce the incidence of lymph node metastases. Accordingly, radical surgery can remove residual main tumor after neoadjuvant chemotherapy. Due to the rarity of adenocarcinoma of the cervix, the majority of such reports have focused on squamous cell carcinoma, and so far only a few data are available for patients with cervical adenocarcinoma. In this study we report our experience with a neoadjuvant intraarterial chemotherapy including low-dose cisplatin combined with 5-fluorouracil (5-FU) for bulky or locally advanced cervical adenocarcinoma. PATIENTS AND METHODS Between January 1993 and December 1998, 11 patients with primary cervical adenocarcinoma who presented to Niigata University Hospital were entered into this study. All the patients gave written informed consent to receive the proposed treatment. The eligibility criteria were as follows: histologically proven cervical adenocarcinoma; no prior treatment; age younger than 70; International Federation of Gynecology and Obstetrics (FIGO) stage IB with deep cervical stromal invasion (outer one-third) by magnetic resonance imaging (MRI) or
496
497
INTRAARTERIAL NEOADJUVANT CHEMOTHERAPY FOR CERVICAL ADENOCARCINOMA
TABLE 1 Criteria for Evaluation of the Histopathological Effects of Solid Cancer Chemotherapy Grade 0
No effect Few degenerative or necrotic changes after chemotherapy Mild effect Very mild effect Degeneration or necrosis occurred in less than one-third of the cancer cells Mild effect Degeneration, necrosis, or cytolysis occurred in more than one-third but less than two-thirds of the cancer cells Moderate effect Remarkable degeneration, necrosis, cytolysis, or disappearance of cancer cells in more than two-thirds of the cancer cells Marked effect All cancer cells become necrotic, cytolysis occurred, or granulomatous tissue or fibrosis was present
Grade 1 Grade 1a
Grade 1b
Grade 2
Grade 3
stage II or III; no distant metastases; adequate renal, pulmonary, hepatic, bone marrow, and cardiac function. Tumor size was measured by MRI before and after neoadjuvant chemotherapy, and radical hysterectomy was carried out in all 10 patients after neoadjuvant chemotherapy, except in one patient with progressive peritoneal carcinomatosis during neoadjuvant chemotherapy. Neoadjuvant chemotherapy consisted of bilateral internal iliac artery infusion of low-dose cisplatin (a total of 10 mg/day) for 30 min, followed by 5-FU (a total of 250 mg/day) given for 24 hours on Days 1 to 10 consecutively using a subcutaneously implanted drug delivery system. Treatment was repeated every 3 weeks for a total of two or three cycles. Whether patients would receive two or three courses of chemotherapy depended on tumor response to the chemotherapy and operability diagnosed by pelvic physical examination.
Chemotherapy response was defined as follows: complete response (CR) was disappearance of all measurable disease; partial response (PR) was a 50% or greater reduction in the product of the transverse diameters of the cervical lesions; progressive disease (PD) was a 50% or greater increase in the product of the transverse diameters of the cervical lesions; and stable disease (SD) was any condition not meeting the preceding criteria. All except one patient with PD underwent radical hysterectomy following the neoadjuvant chemotherapy. Histopathological changes related to chemotherapy were examined in extirpated or biopsied tissues obtained after the completion of chemotherapy in comparison with biopsied specimens obtained before treatment in 10 patients. The specimens were evaluated by grading according to the criteria of the Japan Society for Cancer Therapy (Table 1). Postoperative radiotherapy (Table 2) was given to the whole pelvis to 6 patients; 3 of the 6 patients with involved common iliac nodes received radiotherapy to a paraaortic field up to the level of T-12 in addition to the whole pelvis. External irradiation using a parallel opposing portal technique with 60Co was performed for postoperative radiotherapy. The external irradiation consisted of 44 –50 Gy whole-pelvis and the fractionation was 1.8 –2.0 Gy daily, five fractions per week. For paraaortic field irradiation in addition to the whole pelvis, the dose was 44 –50 Gy and the fractionation was 1.8 –2.0 Gy daily, five fractions per week. For one patient with vaginal invasion close to a surgical margin, brachytherapy by remote control after loading was added; the dose was 15 Gy at 5-mm depth of the vaginal mucosa. Three patients (patients 6, 9, and 10 in Table 2) refused to receive postoperative radiation therapy, although they were found to have positive lymph node metastasis. Survival was calculated using the product-limit estimate by the Kaplan–Meier method.
TABLE 2 Main Characteristics of the Patients and Outcome a Tumor size by MRI (cm)
Case
Age
FIGO stage
Histology type
NAC courses
1 2 3 4 5 6 7
42 67 69 51 30 45 34
IIB IB1 IIB IIIB IIB IIB IB1
4.3 ⫻ 4.1 2.5 ⫻ 1.7 2.7 ⫻ 2.0 6.0 ⫻ 4.4 5.1 ⫻ 4.6 3.7 ⫻ 3.1 3.1 ⫻ 1.8
EC, G2 EC, G1 EC, G1 EM, G2 EC, G2 Ad.Sq. EM, G1
3 2 3 2 3 2 2
8 9 10 11
34 55 61 62
IB2 IB2 IIB IIB
4.4 ⫻ 3.1 5.0 ⫻ 3.8 3.3 ⫻ 2.7 4.6 ⫻ 3.3
EC, G1 Serous, G1 EC, G2 EC, G3
2 2 2 1
Surgical margin
Postop therapy
Clinical response
Histological response
Parametrial infiltration
LN metastasis
RH RH RH RH RH RH RH
⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
WP None WP ⫹ PAN WP ⫹ PAN WP None WP ⫹ BT
PR PR PR PR SD PR SD
1A 1B 1B 1B 1B 1A 0
⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺
⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫹
RH RH RH Not done
⫺ ⫺ ⫺ ⫺
WP ⫹ PAN None None None
PR PR SD PD
1A 1A 0 NA
⫹ ⫹ ⫹ NA
⫺ ⫹ ⫹ NA
Surgery
Site of recurrence Lung
Nodes Vagina Vagina Lung Liver, nodes Lung Pelvis Peritoneum
Status 56 65 63 14 43 20 24
months months months months months months months
DOD NED NED DOD DOD DOD NED
30 months DOD 28 months DOD 10 months DOD 1 month DOD
a EC, endocervical type; EM, endometrioid type; Ad.Sq., adenosquamous; Serous, serous adenocarcinoma; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; RH, radical hysterectomy; WP, whole-pelvis radiation; PAN, paraaortic node radiation; BT, brachytherapy; NA, not assessed; DOD, died of disease; NED, no evidence of disease.
498
AOKI ET AL.
RESULTS The present study included 4 patients with stage IB (2 IB1 and 2 IB2) carcinoma, 6 with stage IIB, and 1 with stage IIIB. The mean age of these patients was 50 (range, 30 – 69). Seven patients had endocervical-type adenocarcinoma, 2 had endometrioid-type adenocarcinoma, 1 had serous adenocarcinoma, and 1 had adenosquamous carcinoma (Table 2). Ten subjects (91%) completed the planned course of treatment. One patient (patient 11) required discontinuation of the treatment after the one administration because of the progression of peritoneal carcinomatosis. Seven patients received two courses of treatment and the remaining 3 patients had three courses of treatment. This regimen was well tolerated by the patients, as confirmed by no need for a delay in the treatment schedule and by the number of subjects requiring discontinuation. There was no significant nausea or vomiting, which was attributable to the cisplatin. Myelotoxicity was very mild, and no nephrotoxicity or neurotoxicity was observed in this series. There were no therapy-related deaths. We observed 7 (64%) PRs and 3 (27%) SD in 11 evaluable patients. Histopathological changes related to chemotherapy were evaluated by grading according to the criteria of the Japan Society for Cancer Therapy (Table 1). Mild changes (Grade 1A or 1B) were detected in 7 PR patients and Grade 0 was observed in 3 SD patients. No Grade 2 or 3 change was recognized and cancer cells still remained in all specimens. Lymph node metastasis was confirmed histopathologically in 7 patients (70%) and ovarian metastasis in 3 (30%). Parametrial infiltration was detected histologically in 5 patients (50%). With respect to surgical margin, however, no patients had positive parametrial and vaginal margins. Six patients in this series received postoperative radiation therapy. Four patients had Grade 2 diarrhea due to radiation colitis, and 3 patients had mild radiation dermatitis during radiation, which were improved conservatively. Also, one patient had proctosigmoiditis 18 months after radiation therapy. The median follow-up period was 30 months (range, 1– 65 months). Eight patients died of recurrent or persistent disease, and 2 patients are alive without evidence of recurrence. The remaining one patient had a pulmonary recurrence and underwent right partial lobectomy 13 months after an initial treatment. She is alive without evidence of disease (patient 7 in Table 2). The mean survival period was 34.7 months, and the 5-year survival rate was 21.2% (Fig. 1). The recurrences were located in the vagina in 3 cases and in a distant region in 5 cases (3 in the lung, 1 in the liver and paraaortic lymph nodes, and 1 in the paraaortic lymph nodes). The remaining one case had progressive peritoneal carcinomatosis during neoadjuvant chemotherapy. DISCUSSION In recent years, systemic trials of neoadjuvant chemotherapy for adenocarcinooma of the cervix have been reported. Zanetta
FIG. 1.
Kaplan–Meier survival curve of the study population.
et al. examined the effects of neoadjuvant chemotherapy with a combination of cisplatin and epirubicin in 21 patients with locally advanced adenocarcinoma of the cervix and the vagina [10]. They observed 4 clinically CRs and 10 PRs (total response rate ⫽ 67%). Fujiwaki et al. found that patients with endometrial carcinoma have a favorable clinical response rate (87.5%) to intraarterial neoadjuvant chemotherapy with cisplatin and doxorubicin, but those with cervical adenocarcinoma have disapointing results (response rate ⫽ 58.3%). No CR was observed in the group with cervical adenocarcinoma [11]. Iwasaka et al. has reported that neoadjuvant chemotherapy consisting of cisplatin, mitomycin, and etoposide for adenocarcinoma of the cervix resulted in 3 CRs and 5 PRs (response rate ⫽ 50%), and the mean survival period of responders was 47.5 months whereas that of nonresponders was 28.3 months [4]. In our study, we used cisplatin combined with 5-FU in low-dose consecutive intraarterial infusions for patients with cervical adenocarcinoma in a neoadjuvant setting. Low-dose consecutive infusions have been reported to achieve higher areas under the time– concentration curve (AUCs), although lower maximum concentrations (C max) of cisplatin, as compared with bolus infusion [12, 13], which leads to a better clinical response with milder adverse effects. The antitumor effect of cisplatin depends on the AUC of filterable platinum obtained following administration of the agent, but not on the C max of the agent [12]. We achieved a 64% response rate (no CRs, 7 PRs), which was almost equal to or higher than those reported previously by others [4, 10, 11, 14, 15]. Also, even in 3 SD patients, tumor volume showed a 25% or greater, (but ⬍50%) reduction, but no CR was observed. Previous reports addressed that chemoresponsiveness is the most potent predictor of cure in patients with locally advanced cervical adenocarcinoma treated with neoadjuvant chemotherapy [4, 15]. Histological examination, however, revealed only mild effects even in the PR patients in our study. Despite the relatively high
INTRAARTERIAL NEOADJUVANT CHEMOTHERAPY FOR CERVICAL ADENOCARCINOMA
response rate, no CR was observed, which indicates that the chemotherapy regimen we used may not effectively lead to a cure of adenocarcinoma of the cervix. Accordingly, 2 patients with negative lymph nodes survive without evidence of recurrence (63 and 65 months), 1 is alive without disease after resection of pulmonary recurrence for 24 months, and the remaining 7 patients have died of disease. Of 9 recurrences, 3 were local and 5 were distant. The remaining one was progressive peritoneal carcinomatosis during neoadjuvant chemotherapy. A relatively high rate of distant recurrence implies that low-dose intraarterial cisplatin combined with 5-FU infusion may not be appropriate strategy for bulky or locally advanced adenocarcinomas of the cervix. However, since the regimen we used reduced the size of the bulky tumor to allow radical surgery with a final pathological diagnosis of negative parametrial and vaginal margins, this treatment might be of benefit to such patients. Although the relatively small number of patients in this study limits the power of the assessment, a survival advantage was not clear. The increased frequency and poor prognosis of cervical adenocarcinoma call for new therapeutic strategies, especially for locally advanced disease. REFERENCES 1. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993;54:594 – 606. 2. Kjorstad KE, Bond B. Stage Ib adenocarcinoma of the cervix: metastatic potential and patterns of dissemination. Am J Obstet Gynecol 1984;150: 297–9. 3. Aoki Y, Sasaki M, Watanabe M, Sato T, Tsuneki I, Aida H, Tanaka K. High-risk group in node-positive patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation. Gynecol Oncol 2000;77:305–9. 4. Iwasaka T, Fukuda K, Hara K, Yokoyama M, Nakao Y, Uchiyama M, Sugimori H. Neoadjuvant chemotherapy with mitomycin C, etoposide, and cisplatin for adenocarcinoma of the cervix. Gynecol Oncol 1998;70: 236 – 40.
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