Adjuvant chemotherapy in stage I–II uterine leiomyosarcoma: A multicentric retrospective study of 140 patients

Objective

About 50–60% of patients with stage I–II uterine leiomyosarcoma (ULMS), primarily treated with surgery, relapse and die from progressive disease. In this retrospective study we describe the impact of adjuvant chemotherapy in this subset of patients.

Methods

140 women treated from 1976 to 2011 were included in the study. Univariate and multivariate analysis were used to test the association of clinical features and adjuvant treatments with overall survival (OS) and disease-free survival (DFS).

Results

62 women did not receive any further treatment after hysterectomy, 14 had radiotherapy (RT), 52 chemotherapy and 12 chemo-radiotherapy. Chemotherapy based on doxorubicin and ifosfamide combination was used in 54 cases. After a median follow-up of 63 months, 87 women (62%) have relapsed, and 62 (44%) have died. The vast majority of patients who relapsed had distant recurrences (72%).The 5 year median DFS and OS were 43% and 64% respectively. After 5 years of follow up 68.7% of women treated with chemotherapy (± RT) vs 65.6% of patients only observed were alive (p = 0.521). In the univariate analysis no factors had a statistical impact on DFS, while number of mitosis (> 20 × 10HPF), age (> 60 years) and adjuvant radiotherapy were found as negative prognostic factors for OS. In the multivariate analysis only mitosis and age remained significant for OS.

Conclusion

Adjuvant chemotherapy was not associated with a significant survival benefit and should not be considered as standard of care for patients with stage I–II ULMS until randomized clinical studies will give further information.     

Pathologic prognostic factors in stage I–III uterine carcinosarcoma treated with postoperative radiotherapy

Purpose

To analyse the impact of prognostic factors on specific overall survival (SOS) after postoperative radiotherapy (P-RT) in carcinosarcomas.

Methods

We retrospectively analysed 81 patients who received P-RT from 1977 to 2010 after the diagnosis of carcinosarcomas. 2009 FIGO stage: 25-IA, 20-IB, 6-II, 9-IIIA, 11-IIIC. Age, stage, vascular and lymphatic space invasion (VLSI), myometrial invasion, grade, mitotic index, sarcomatous/epithelial components, tumour size and necrosis were considered for the analysis. Statistics: we used the Kaplan–Meier method for survival analysis and the Cox model for risk factor evaluation.

Results

The mean follow-up of the series was 78.86 months (range 7–381). The median age was 72 years (range 51–89). 30 out 81 (37 %) patients relapsed and died (22.2 % pelvic and abdominal, 13.5 % exclusive distant metastasis). On univariate and multivariate analysis only stage had a significant impact on SOS. At 5 years, stage I–II had a SOS of 66 % in comparison with stage III with 30 %.

Conclusions

Two groups of patients showing different outcome were found after P-RT in uterine carcinosarcomas: stage I–II patients had a life expectancy 2.5-fold longer compared to stage III patients. New therapeutic strategies are warranted in carcinosarcomas considering the high incidence of distant metastasis.     

The treatment of uterine papillary serous carcinoma (UPSC): are we doing the right thing?

Abstract. Tay EH, Ward BG. The treatment of uterine papillary serous carcinoma (UPSC): are we doing the right thing?
In an earlier study ⁽¹⁾ of 21 patients with uterine papillary serous carcinoma (UPSC), Ward et al . found a poor 3-year survival, even for patients with surgically documented localized disease, and a high rate of recurrence outside the field of treatment. Eight years later, we performed a retrospective study on 67 patients who were treated initially by surgery, which included the 21 patients previously reported, to evaluate any changes in the management approach since 1990 and its impact on the survival of such patients. The clinical characteristics of patients treated before and after 1990 were similar. However, after 1990, more patients had omentectomy and complete surgical staging (42% vs. 17%); chemotherapy was more widely used (63% vs. 33%); all chemotherapies were platinum-based regimens and less radiotherapy was administered (47% vs. 83%). The overall 3-year survival was 43% and 5-year survival was 35%, with a median survival period of 31 months. There was no significant difference in the survival outcome between patients managed before and after 1990, after adjusting for stage and spread of disease. Based on the results of this retrospective study, it appears that the current treatment strategy has not resulted in an improvement in the survival of patients with UPSC.     

Prognostic impact of the expression of Hedgehog proteins in cervical carcinoma FIGO stages I–IV treated with radiotherapy or chemoradiotherapy

Objective

Hedgehog signaling proteins were assessed in patients with cervical carcinoma receiving chemoradiation. Associations between five Hedgehog proteins and prognosis were studied.

Methods

In all, 131 cases of cervical carcinomas (FIGO stages I–IV) were immunohistochemically (IHC) analyzed for Patched (PTCH), Smoothened (SMO), and GLI1, GLI2 and GLI3 protein expression. Associations between Hedgehog protein expressions, clinicopathological factors, and clinical outcome data were examined.

Results

Positive IHC staining for the five Hedgehog proteins was recorded in 8% to 37% of the tumor cells. The highest frequency was noted for SMO and the lowest for GLI1. There was a significant association between low SMO- and GLI2-expression and KRAS-mutation. Tumors with overexpressed SMO had a higher frequency of residual tumor or local recurrences than tumors with low SMO expression. Patients with tumors expressing PTCH in more than 75% of the cells had significantly (P = 0.023) better recurrence-free survival than patients with tumors with low expression. The opposite situation was true for SMO. For GLI2, there was a statistically significant difference with regard to overall (P = 0.004) and distant (P = 0.015) relapse rate for groups with expression of GLI2 in the range of 5–25% compared to higher rates.

Conclusions

A predictive and prognostic value was found for PTCH, SMO, and GLI2 with regard to residual carcinoma, local recurrences, and for GLI2 distant relapses. The Hedgehog signaling pathway also seems to play an important role in cervical carcinogenesis together with HPV16-infection and KRAS-mutation.     

Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma – A multi-institutional cohort

Objectives

To determine if 6 versus 3 cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC).

Sonographic assessment of the lower uterine segment during active labor in women with or without a uterine scar – a prospective study

Objectives: No study thus far has evaluated the LUS thickness in active labor. In this study, we endeavored to assess the LUS during active labor.

Methods: Using transabdominal sonography in the mid-sagittal position with a full urinary bladder, the thickness of the LUS was measured during active labor phase in women with or without a history of a previous cesarean section.

Results: A total of 28 women with a previous cesarean delivery were compared to 29 women without a history of uterine surgery. The median LUS was significantly thinner in women with a uterine scar both during (4 versus 5?mm, p?=?.001) and between contractions (5 versus 7?mm, p?=?.011). Paired comparison of LUS thickness between and during contractions within each group showed that thinning of LUS during contraction was significant for both the previous CS group (p?p?Conclusions: In this study, we characterized for the first time the LUS during active labor. We found that LUS was significantly thinner in women after a previous CS and that the LUS was significantly thinner during contraction.     

Outcome of patients with bulky IB (≥ 6 cm) cervical squamous cell carcinoma with and without cisplatin-based neoadjuvant chemotherapy

ObjectiveTo study the surgical morbidity and outcomes of patients with markedly bulky cervical squamous cell carcinoma (≥ 6 cm Cx-SCC) who underwent radical hysterectomy (RH) with and without neoadjuvant chemotherapy (NACT).Materials and methodsThis retrospective study enrolled patients with International Federation of Gynecology and Obstetrics (FIGO) IB markedly bulky Cx-SCC who were treated with either three courses of weekly single agent cisplatin NACT (50 mg/m2) and subsequent radical hysterectomy (NACT-RH) or direct radical hysterectomy (RH) between 1996 and 2001. A total of 60 patients fulfilled the criteria, including 35 and 25 patients with NsACT-RH and RH, respectively.ResultsThere was no statistically significant difference in basic characteristics between the two groups, except the smaller pathological tumor size, less blood loss, and lower immediate complication rate in the NACT-RH group. Median survival was 143.8 months in the NACT-RH group and 129.8 months in the RH group, respectively, without a statistically significant difference. Multivariate analysis showed that large pathological tumor size [hazard ratio (HR) 10.66, 95% confidence interval (CI) 2.93–38.80], the presence of para-aortic lymph node metastases and an immediate complication (HR 8.33 and 4.55, 95% CI 1.66–41.75 and 1.35–15.27, respectively) contributed to a worse outcome.ConclusionWeekly single agent cisplatin NACT indeed reduced the pathological tumor size and immediate complication rate during the RH, supporting the feasibility of subsequent RH in the management of patients with bulky Cx-SCC.     

Comparison of “sandwich chemo-radiotherapy” and six cycles of chemotherapy followed by adjuvant radiotherapy in patients with stage IIIC endometrial cancer: a single center experience

Objective

To compare “sandwich chemo-radiotherapy” with six cycles of chemotherapy followed by adjuvant radiotherapy with respect to tolerability and acute toxicity.

Materials and methods

Twenty-five women with surgically staged IIIC endometrial cancer were included. Treatment consisted of either three cycles of paclitaxel (175 mg/m²) and carboplatin (AUC 6) on a q21-day schedule followed by irradiation (45–50.4 Gy) or six cycles of the same chemotherapy followed by radiotherapy. Acute toxicity related to either chemotherapy or radiotherapy was evaluated.

Results

Median age was 61.5 years (range 36–83 years). Eleven patients had sandwich chemo-radiotherapy, and the other 14 patients had 6 cycles of chemotherapy followed by radiotherapy. Three out of the five patients who could not complete all the cycles in the sandwich chemo-radiotherapy group had pelvic and para-aortic radiotherapy. Acute radiotherapy related grade 1–2 gastrointestinal system (GIS) and genitourinary system (GUS) toxicities were observed in 72.8 and 63.6 % of patients, respectively, for sandwich group. Undesired treatment breaks in the course of radiotherapy were observed in six patients for sandwich chemo-radiotherapy and in one patient receiving six cycles of chemotherapy followed by radiotherapy. All the patients who had undesired treatment breaks in the sandwich chemo-radiotherapy group had pelvic and para-aortic radiotherapy.

Conclusion

Sandwich chemo-radiotherapy seems to be more toxic particularly for patients who had pelvic and para-aortic irradiation. Therefore, it might be more convenient to delay radiotherapy after six cycles of chemotherapy for patients with the indication of pelvic para-aortic radiotherapy.     

Polymerase ε (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro

Objective

Up to 12% of all endometrial-carcinomas (EC) harbor DNA-polymerase-ε-(POLE) mutations. It is currently unknown whether the favorable prognosis of POLE-mutated EC is derived from their low metastatic capability, extraordinary number of somatic mutations thus imparting immunogenicity, or a high sensitivity to chemotherapy.

A phase II trial of cisplatin,ifosfamide, and mesna in patients with advanced or recurrent uterine malignant mixed müllerian tumors with evaluation of potential molecular targets

OBJECTIVE: The aim of this study was to determine the efficacy of cisplatin, ifosfamide, and mesna in uterine malignant mixed müllerian tumor (MMMT) and to evaluate the expression of clinically relevant molecular markers. METHODS: Women with advanced or recurrent MMMT were treated every 28 days with cisplatin (75 mg/m(2)), ifosfamide (1.2 gm/m(2)), and mesna (240 mg/m(2)). Treatment continued until disease progression or for six courses in the case of nonmeasurable disease. Immunohistochemical analysis for estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, C-kit, Abl, and PDGFR-beta expression were performed. RESULTS: Sixteen patients received 1-10 cycles; 2 died of disease progression after 1 cycle; 3 stopped after 1 cycle because of toxicity. Of 6 with measurable disease, 2 had a partial response, 1 had stable disease (SD), and 3 had progression (RR 33%). Partial response durations were 6 and 9 months; SD duration was 6 months. Of 5 patients without measurable disease, 4 received 6 cycles; 1 received 4 cycles. Four died of recurrent disease and 1 was without disease 6.5 years after treatment. Thirty-six percent experienced at least one neutropenic G3 or G4 event. All experienced G1 gastrointestinal toxicity. Four required dose reductions. At 7.5 months, only 1 with measurable disease was still living. Immunohistochemical analyses revealed that 24% expressed ER or PR, 19% expressed HER-2/neu, and none expressed C-kit. However, 45% expressed Abl and 100% expressed PDGFR-beta. CONCLUSION: Although the combination of cisplatin, ifosfamide, and mesna in patients with MMMT had moderate activity, the high toxicity and short response duration in this uncommon, aggressive malignancy suggest that this regiment continues to be a disappointing treatment choice for uterine MMMT. HER-2/Neu, Abl, or PDGFR-beta expression may be of value in order to investigate novel multimodality treatment strategies.     

Is there a role for postoperative treatment in patients with stage Ib2–IIb cervical cancer treated with neo-adjuvant chemotherapy and radical surgery? An Italian multicenter retrospective study

Purpose

Neoadjuvant chemotherapy [NACT] followed by radical hysterectomy is an alternative therapeutic option to concurrent chemotherapy–radiotherapy for locally advanced cervical cancer. However there are very few data about the effectiveness of any post-operative treatment in this clinical setting. The purpose of this study was to correlate the patterns of recurrence and the clinical outcomes of cervical cancer patients who received NACT, with postoperative adjuvant treatment.

Patients and methods

This retrospective multicenter study included 333 patients with FIGO stage Ib₂–IIb cervical cancer who underwent platinum-based NACT followed by radical surgery. Pathological responses were retrospectively assessed as complete; optimal partial; and suboptimal response. Overall optimal response rate was the sum of complete and optimal partial response rates.

Results

On the whole series, recurrence-free survival was significantly longer in patients who achieved an overall optimal response than in those who did not (p < 0.0001), and in patients who received adjuvant chemotherapy compared to those who did not (p = 0.0001). On multivariate analysis, consolidation therapy (p = 0.0012) was the only independent prognostic variable for recurrence-free survival; whereas FIGO stage (p = 0.0169) and consolidation therapy (p = 0.0016) were independent prognostic variables for overall survival.

Conclusion

Optimal responders after chemo-surgical treatment for FIGO stage Ib₂–IIb cervical cancer do not need any further treatment. Additional cycles of chemotherapy could be of benefit for patients with suboptimal response and intra-cervical residual disease. Both adjuvant chemotherapy and adjuvant radiation treatments do not seem to improve the clinical outcome of patients with extra-cervical residual disease compared to no further treatment.     

Prenatal diagnosis of short-rib polydactyly syndrome type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) associated with compound heterozygous mutations in DYNC2H1 in a fetus

Objective

We present the perinatal imaging findings and molecular genetic analysis in a fetus with short-rib polydactyly syndrome (SRPS) type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3).

Docetaxel and carboplatin as first-line chemotherapy in patients with advanced gynecological tumors. A phase I/II trial of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO-OVAR) Ovarian Cancer Study Group

OBJECTIVES: We performed a phase I-II study in patients with ovarian and other gynecological cancers to determine the dose-limiting toxicities, maximum tolerated dose (MTD) and efficacy of docetaxel/carboplatin. METHODS: Thirty patients were treated in three cohorts with carboplatin (AUC 5) and escalating docetaxel (60, 75 and 90 mg/m2), administered intravenously on day 1, repeated every 3 weeks. Premedication consisted of 16 mg dexamethasone per os on day -1, and +1 and 4 mg intravenously before docetaxel. RESULTS: A total of 6, 11 and 12 patients were eligible and treated on dose levels 1, 2 and 3, respectively. At docetaxel 90 mg/m2, febrile and prolonged neutropenia were dose-limiting, and 75 mg/m2 with carboplatin AUC 5 was considered the MTD. Prolonged neutropenia occurred in two, four and nine patients of dose levels 1-3, respectively, and febrile neutropenia in 2, 1, and 2 patients of dose level 1-3. Thrombocytopenia grade 4 was observed in one patient of dose level 1. Non-hematological toxicity including neuropathy was usually mild across all dose levels. Overall response rate was 73%. Median time to progression was 18.0 months, and median overall survival will exceed 24.4 months. CONCLUSIONS: Docetaxel/carboplatin can be safely administered to patients with gynecological cancer despite substantial myelotoxicity and appears to be active in the treatment of ovarian cancer. Low neurotoxicity offers an option for comparison with paclitaxel-containing regimens.     

Detection and typing of human papillomavirus DNA in uterine cervices with coexistent grade I and grade III intraepithelial neoplasia: biologic progression or independent lesions?

OBJECTIVE: To examine the HPV type infection of cervical cone specimens with coexistent CIN1 and CIN3 lesions, in order to define if coexistence of low- and high-grade lesions in the same cervix represent different stages of evolution in a continuing process that is caused by a single viral type or independent lesions induced by different HPV types. STUDY DESIGN: The examined material included 43 cases with coexistent CIN1 and CIN3 in the cone biopsy specimen. Detection and typing of HPV was made by RFLP-PCR. RESULTS: All CIN1 lesions were HPV positive, while three CIN3 lesions were HPV-negative. The proportion of agreement of the HPV type in the two lesions, excluding negative cases (n = 40), was 60% (95% confidence interval: 43.3-75.1). HPV 16 was the most common type in both CIN3 (56.8%) and CIN1 (46.5%). CONCLUSIONS: The so-called morphologic progression of CIN is not always synonymous with biologic progression, since many coexistent CIN lesions are caused by different HPV types, and so represent different cell clones. Clonality of coexistent CIN lesions may be implicated in the evolution of CIN as other recent studies have shown.     

Recombinant follicle-stimulating hormone (follitropin alfa) for ovulation induction in Japanese patients with anti-estrogen-ineffective oligo- or anovulatory infertility: results of a phase II dose–response study

Purpose  

To determine the optimal regimen of recombinant human follicle-stimulating hormone (r-hFSH) for ovulation induction (OI) in Japanese women with amenorrhea I or anovulatory infertility.     

Association of estrogen receptor alpha (ERα) gene polymorphisms with endometrial thickness and lipid profile in women with breast cancer treated with aromatase inhibitors

Aromatase inhibitors (AIs) provide an alternative to tamoxifen as an adjuvant therapy for post-menopausal, hormone-receptor positive breast cancer patients. The aim of the present study was to evaluate the effect of PvuII and XbaI polymorphisms of the ERα gene at ΑΙs treatment’s adverse effects in post-menopausal women with breast cancer. The study included 87 post-menopausal women with ER-positive breast cancer treated with AIs and 80 healthy controls. The overall presence of ERα polymorphisms in all women with breast cancer was not different from the healthy controls. Endometrial thickness under AIs treatment was reduced from (mean value ± SD) 6,404 ± 2,901 mm to 3,666 ± 1,4656 mm. Moreover, the AA XbaI genotype was associated with greater reduction in endometrial thickness during therapy with AIs (p = 0.005). The presence of the CC PvuII and the AA XbaI genotypes were associated with elevated LDL levels and elevated triglycerides. In conclusion, the results of the present study showed that the genotype of women with breast cancer under AIs treatment might influence treatment’s adverse effects, as, the presence of the CC PvuII and the AA XbaI genotypes of the ERα were associated with elevated LDL and triglycerides serum levels, while the AA XbaI genotype was associated with a greater reduction in endometrial thickness.