Treatment results for Stage Ib cervical cancer after stage subdivision by MRI evaluation.

PURPOSE OF INVESTIGATION: The authors analyzed treatment results for cervical cancer after subdividing Stage Ib into Stages Ib1 and Ib2 according to magnetic resonance imaging (MRI) information. MATERIALS AND METHODS: The subjects comprised 40 cases of Stage Ib cervical cancer treated by definitive radiotherapy in Kitasato University hospital and Tokyo University hospital from January 2000 to December 2008. The patients' ages ranged from 28 to 85 years (median: 68 years). The maximum tumor diameter measured with MRI ranged from undetectable to 60 mm (median: 25 mm). The authors classified tumors with the greatest dimension less than 40 mm as Stage Ib1 (29 cases) and those with the greatest dimension more than 40 mm as Ib2 (11 cases). All cases were treated with a combination of external beam irradiation and high-dose-rate intra-cavitary brachytherapy. Chemotherapy was combined with radiotherapy in 11 cases. RESULTS: The follow-up time was from four to 109 months (median: 53 months). At the time of last observation, 37 cases survived, local recurrence was seen in none, and two cases showed distant metastasis. The two- and five-year overall survival rates of all cases were 97.5% and 89.5%, respectively. When a stage was subdivided and examined, the five-year overall survival rate of Stage Ib1 was 100% and that of Stage Ib2 was 50.5% (p = 0.001). CONCLUSION: The authors suggest that the subdivision of stages using image information reflects the prognosis of Stage Ib cervical cancer.

Concomitant expression of HER2 and HIF-1alpha is a predictor of poor prognosis in uterine cervical carcinoma treated with concurrent chemoradiotherapy: prospective analysis (KGROG0501).

BACKGROUND: In previously reported retrospective analyses of uterine cervical carcinoma cases, HER2 was correlated with poor radiation sensitivity and poor treatment outcomes and HIF-1alpha was found to be an indicator of poor prognosis. To date, no prospective studies have been performed to evaluate the radiation sensitivity and treatment outcomes of patients with uterine cervical carcinoma relative to HER2 and HIF-1alpha expressions. We conducted a prospective evaluation of HER2 and HIF-1alpha in cases of locally advanced uterine cervical carcinoma treated with concurrent chemoradiotherapy. METHODS: Between June 2005 and April 2008, 25 patients with locally advanced uterine cervical carcinoma were registered in this study, KGROG0501. Their clinical stages were Ib2/IIb/IIIb/IVa in 1/2/22/1 cases, respectively. Nineteen cases had squamous cell carcinoma and six had adenocarcinoma. HER2 expression and HIF-1alpha expression were analyzed using an immunohistochemical kit on pretreatment biopsied specimens. HIF-1alpha expression was studied using another commercial immunohistochemical kit on pretreatment biopsied specimens. The survival rates were compared between patients with and without positive HER2 and HIF-1alpha expressions. RESULTS: The 20-month survival of HER2(-) and HIF-1alpha(-) cases (n = 6) was 100% and that of HER2(+) and HIF-1alpha(+) cases (n = 4) was 37.5% (p = 0.0032). CONCLUSIONS: In this first prospective analysis of patients with uterine cervical carcinoma treated with concurrent chemoradiotherapy, concomitant expression of HER2 and HIF-1alpha was suggested to be a strong indicator of poor prognosis. A novel therapy including molecular targeted therapy such as anti-HER2 and anti-HIF-1alpha may be worth considering in patients with concomitant expression of HER2 and HIF-1alpha.

Initial analysis of relationship between plasma platinum concentration and hematological adverse reaction associated with weekly chemotherapy using nedaplatin in combination with radiotherapy for cervical carcinoma.

PURPOSE: Established therapeutic guidelines for cervical carcinoma recommend concurrent chemo- and radiotherapy as standard treatment for locally advanced cervical carcinoma. Nedaplatin (CDGP) is a platinum agent developed in Japan that is less nephrotoxic than cisplatin (CDDP), but with equivalent antitumor potency. In the standard dosage regimen for cervical carcinoma, CDGP is administered once every four weeks (monthly regimen). We investigated the efficacy and safety of a new dosage regimen, in which CDGP was administered once weekly for five weeks (weekly regimen). METHODS: We measured plasma platinum concentration of patients after administration of CDGP, and analyzed the relationship between plasma platinum concentration and hematological adverse reactions such as thrombocytopenia and leucopenia. RESULTS: The relative rates of change in platelet and white blood cell counts tended to increase as the plasma concentration of platinum increased. Furthermore, the rate of change in platelet counts in relation to the area under the curve was greater for the monthly regimen as compared to weekly. On the other hand, the relative rates of change in WBC were nearly the same between the regimens. CONCLUSIONS: These findings indicate that when using chemotherapy with CDGP for a patient with a cervical carcinoma, a weekly regimen might reduce the severity of thrombocytopenia, while still exhibiting the same therapeutic efficacy as the monthly regimen.

Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma (LAUCC): Kitasato Gynecologic Radiation Oncology Group (KGROG 0501)--initial analysis.

OBJECTIVE: Locally advanced uterine cervical carcinoma (LAUCC) treated with chemoradiotherapy is considered to be the standard treatment regimen. However, no evidence of its efficacy and safety has been obtained from the Japanese population. Furthermore, the total dose of Japanese radiation therapy protocol is less than that of the USA which indicated that chemoradiotherapy for LAUCC is better than radiation therapy alone by phase III clinical trials. Thus, the current phase II study was designed to evaluate chemoradiotherapy with a lower radiation dose for LAUCC using weekly nedaplatin effectively and safely in the Japanese population. Nedaplatin is a platinum drug and no hydration is required to infuse patients because it is less toxic on renal function. If this phase II trial is successful, chemoradiotherapy for LAUCC in out-patient clinics could be possible. PATIENTS AND METHODS: Patients registered in the current study were found to have LAUCC based on the following criteria i) pathologically proven squamous cell carcinoma or adenocarcinoma, ii) FIGO clinical Stage Ib, IIa, IIb with bulky tumor (diameter > 40 mm assessed by pelvic magnetic resonance imaging) or pelvic lymph node swelling (diameter > 10 mm assessed by pelvic computed tomography); iii) FIGO clinical Stage IIIa, IIIb and IVa with no paraaortic lymph node swelling (diameter > 10 mm) observed by abdominal computed tomography; iv) age: 20-75 years; v) performance status: 0-2. The treatment protocol was as follows: Radiation therapy in a combination of external beam radiation therapy (total dose: 50 Gy-52 Gy/25-27 fractions with central shielding after 30-32 Gy) with high-dose rate intracavitary irradiation (24-30 Gy/4-6 fractions to point A). Chemotherapy applied in the current study was weekly nedaplatin infused intravenously (30 mg/mm2/time, once a week, total 150 mg/mm2/5 weeks). Sample size in the current study was 45 LAUCC patients recruited for three years at a single institution. This protocol was permitted by the ethics committee of Kitasato University Hospital. RESULTS: Ten patients were registered in this study between June 2005 and March 2006. The median age was 57.5 years (range 36-73). PS0 was five and PS1 was five. As for clinical stage, nine were IIIb and only one was IIb. Nine patients were proven to have squamous cell carcinoma and one adenocarcinoma. The median maximum tumor diameter was 62.5 mm (range 30-100 mm). As for initial response, eight had CR and two had PR (100% response rate). As for hematological acute morbidity, three were grade 2, six were grade 3, and one was grade 4. CONCLUSIONS: This initial analysis of the phase II study confirmed that concurrent chemoradiotherapy using nedaplatin is safe and efficacious, thus we decided to undergo further studies.

Optimal dose for stage IIIB adenocarcinoma of the uterine cervix on the basis of biological effective dose.

PURPOSE: Prognosis of uterine cervical adenocarcinoma in locally advanced stage treated with radiation therapy has been considered to be much worse than that of squamous cell carcinoma because the optimal dose for the former one has not been determined. Thus, the current study was performed to investigate the optimal dose for Stage IIIB, locally advanced stage, adenocarcinoma of the uterine cervix on the basis of the biological effective dose (BED). METHODS: One-hundred and seventy-nine patients with Stage IIIB carcinoma of the uterine cervix were treated with curative intended therapy at Kitasato University Hospital between 1976 and 2000. Out of them, 13 patients had an adenocarcinoma component in pathological findings. Nine patients were diagnosed with adenocarcinoma and four patients were diagnosed with adenosquamous cell carcinoma. All patients were treated with external radiation therapy combined with intracavitary radiation therapy. The total BED10 (T-BED10) was caluculated from the BED of the external beam radiation therapy (E-BED10) plus the BED of the intra-cavitary radiation therapy (A-BED). RESULTS: Overall survival rate was 51%. Stratified by T-BED10 overall survival rate of the T-BED10 > or = 100 Gy group was 57% and that of the T-BED10 < 100 Gy group was 30%. There was a trend toward a better survival rate of the T-BED10 > or = 100 Gy group than the T-BED10 < 100 Gy group. CONCLUSION: The current study suggested that the optimal dose for Stage IIIB adenocarcinoma of the uterine cervix might be T-BED10 > or = 100 Gy.

Relationship between p21/WAF-1/CIP-1 and apoptosis in cervical cancer during radiation therapy.

PURPOSE: P21/WAF-1/CIP-1 was not considered to be involved in the regulation of apoptosis, an important indicator of radiosensitivity. However, it has been reported recently that apoptosis was suppressed when p21 expressed. The purpose of this study was to clarify the relationship between p21 and apoptosis and to evaluate the role of p21 in cervical cancer during radiation therapy (RT). METHODS AND MATERIALS: Twenty-one patients with cervical cancer were treated by RT. Tissue samples were obtained from cervical tumors of all patients before RT, and 6 hours after the fifth dose of 1.8 Gy (5th Dose). Samples were subjected to nick end labeling for apoptosis and immunohistochemical staining for p21 and p53 antigen expression. RESULTS: The mean apoptotic index, p21 labeling index and p53 labeling index were 0.27%, 9.24% and 6.60%, respectively, before RT and increased significantly to 1.20%, 17.5% and 13.9%, respectively, after 5th Dose. The apoptotic index at 5th Dose was inversely correlated with the p21 labeling index (r = -0.50, p = 0.025). Furthermore, a positive correlation was observed between the p21 and p53 labeling indices both before RT and at 5th Dose (r = 0.52, p = 0. 02; r = 0.63, p < 0.01, respectively). CONCLUSION: Our results demonstrate that apoptosis and expression of p21 and p53 were induced in cervical cancer during RT. p21 expression was dependent on p53 expression and moreover, it is suggested-that p21 might be a potential suppressor of radiation-induced apoptosis in cervical cancer during RT.

Oxygenated and reoxygenated tumors show better local control in radiation therapy for cervical cancer.

The presence of hypoxic cells is one of the major factors affecting resistance against radiation therapy. In the clinical setting, little information exists as to the relationship between intratumoral oxygen partial pressure (pO(2)) and outcome. This study involved 30 consecutive patients with cervical cancer, who were treated with a combination of external and high-dose rate intracavitary irradiation. The pO(2) was measured before radiation therapy and at 9 Gy, using a needle-type polarographic oxygen electrode. The mean intratumoral pO(2) before radiation therapy was 17.3 +/- 10.8 mm Hg. The 3-year local control rates of patients with pO(2)< or = 20 mm Hg and pO(2) > 20 mm Hg before radiation therapy were 52% and 100%, respectively, representing a significant difference (P= 0.035). At 9 Gy, mean intratumoral pO(2) was 23.6 +/- 9.1 mm Hg, a significant increase compared to the value before radiation therapy (P= 0.006). The 3-year local control rates of tumors with pO(2)< or = 20 mm Hg and pO(2) > 20 mm Hg at 9 Gy were 35% and 93%, respectively, representing a significant difference (P= 0.001). The significantly better local control for oxygenated tumors at 9 Gy as well as before radiation therapy indicated that the oxygen effect and reoxygenation by radiation played an important role in local control in radiation therapy for cervical cancer.

Long-term progression-free survival of invasive uterine cervical carcinoma infected with human immunodeficiency virus: a case report.

We report the case of a patient with invasive uterine cervical carcinoma, who is also infected with human immunodeficiency virus. This patient has had the longest progression-free survival of any with acquired immunodeficiency syndrome uterine cervical carcinoma. She was found to be human immunodeficiency virus positive in February 1996 and found to have uterine cervical carcinoma stage IB in July 1996. Shortly thereafter, she underwent radiation therapy. She died of renal and liver failure in January 1999. However, no residual tumor existed at that time. The longest progression-free survival in this case may be attributable to maintenance of the CD4 cell count from the onset of uterine cervical carcinoma to death, which meant the patient's immune system to the cancer cells worked.

Prognostic significance of c-erbB-2/HER2 expression in advanced uterine cervical carcinoma with para-aortic lymph node metastasis treated with radiation therapy.

This paper looks at whether c-erbB-2/HER2 expression in uterine cervical carcinoma before treatment is a predictive parameter of prognosis in patients with para-aortic lymph node metastasis (PALN) in advanced disease after treatment with radiation therapy (RT). Twenty-one patients with PALN at the first visit and/or during follow-up and treated with RT for PALN lesions were studied. Their clinical stages were IIIB or greater and they were referred to the National Institute of Radiological Sciences Hospital for RT between 1987 and 1995. They consisted of 12 patients with PALN detected at the first visit and nine with PALN detected during the follow-up period. All patients had no distant metastasis except PALN. They were treated with a combination of external whole pelvis and intracavitary irradiation to the primary pelvic lesions. The PALN was treated with external irradiation alone with anterior-posterior parallel opposed fields and anterior oblique fields or anterior-posterior parallel opposed oblique fields. The average total dose to PALN was 53.3 Gy (40-61Gy). Tissue samples were obtained from cervical tumors (primary lesions) before RT. Immunohistochemical staining was performed using anti-c-erbB-2/HER2 monoclonal antibody for conventional paraffin sections. c-erbB-2/HER2 positive staining was observed in cancer membrane and cytoplasm. Nine specimens were positive for c-erb-B2/HER2 and the total positive rate was 43%. The 5-year survival rate was 38% for all patients. The 5-year survival rate of the c-erbB-2/HER2 positive patients was 28%, representing a trend toward poorer prognosis than the 52% of negative patients (P = 0.10). Multivariate analysis using Cox proportional hazards model showed that c-erbB-2/HER2 was an independent prognostic factor (P = 0.024). The present study suggests that c-erbB-2/HER2 expression of cervical tumors might be a predictive parameter of prognosis after radiation therapy for PALN of very advanced uterine cervical carcinoma patients.

Bax protein expression correlates with radiation-induced apoptosis in radiation therapy for cervical carcinoma.

BACKGROUND: Bax protein serves as a positive regulator of apoptosis by forming heterodimers with bcl-2 protein, thereby promoting cell survival. It is unclear whether the regulation of apoptosis reported in many studies is applicable to the apoptotic phenomenon observed in conventional fractionated radiation therapy for cervical carcinoma. METHODS: The authors assessed the relation between apoptosis and the expression of Bax and bcl-2 protein in fractionated radiation therapy for cervical carcinoma by using in situ nick end labeling (ISEL) and immunohistochemical methods. RESULTS: Specimens were excised from the cervical tumors of 20 patients before and after administration of a total irradiation dose of 9 gray (Gy). The apoptotic cell index (AI) in tumor cells was 0.22% before irradiation and 1.20% after the administration of the 9 Gy, which represented a significant increase (P=0.0004). The positive rate of Bax protein increased from 15% (in 3 of 20 patients) before irradiation to 60% (in 12 of 20 patients) after the 9 Gy was administered, a statistically significant change (P=0.0126). In addition, there was a significant correlation between Bax protein expression and apoptosis positivity after the 9 Gy was administered (P=0.018). CONCLUSIONS: These results suggest that Bax protein is associated with apoptosis induced by fractionated radiation therapy.

Mucinous adenocarcinoma of Bartholin gland treated with radiation therapy: a case report.

Adenocarcinoma of Bartholin gland is a very rare disease and its molecular pathological features are poorly delineated. A 92-year-old woman with mucinous adenocarcinoma of Bartholin gland with metastasis to the right inguinal lymph node was treated with radiation therapy alone. Despite intensive radiation therapy, the tumor was locally recurrent and the patient died 10 months after radiation therapy. We searched for the presence of human papillomavirus 16 and 18 DNA and the expression of p53 protein, CA19-9, CEA and MIB-1 antigen. Immunohistochemical study showed that mucinous adenocarcinoma of Bartholin gland produced CA19-9 and CEA.