Paolo Zola

Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial

Patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receive adjuvant therapy after surgery but it is not clear whether radiotherapy (RT) or chemotherapy (CT) is better. We randomly assigned 345 patients with high-risk endometrial carcinoma to adjuvant CT (cisplatin (50 mg m−2), doxorubicin (45 mg m−2), cyclophosphamide (600 mg m−2) every 28 days for five cycles, or external RT (45–50 Gy on a 5 days week−1 schedule). The primary end points were overall and progression-free survival. After a median follow-up of 95.5 months women in the CT group as compared with the RT group, had a no significant hazard ratio (HR) for death of 0.95 (95% confidence interval (CI), 0.66–1.36; P=0.77) and a nonsignificant HR for event of 0.88 (95% CI, 0.63–1.23; P=0.45). The 3, 5 and 7-year overall survivals were 78, 69 and 62% in the RT group and 76, 66 and 62% in the CT group. The 3, 5 and 7-year progression-free survivals were, respectively, 69, 63 and 56 and 68, 63 and 60%. Radiotherapy delayed local relapses and CT delayed metastases but these trends did not achieve statistical significance. Overall, both treatments were well tolerated. This trial failed to show any improvement in survival of patients treated with CT or the standard adjuvant radiation therapy. Randomised trials of pelvic RT combined with adjuvant cytotoxic therapy compared with RT alone are eagerly awaited.

Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer - results from two randomised studies

INTRODUCTION Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. METHODS Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. RESULTS In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01). CONCLUSION Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.

A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study

BACKGROUND The efficacy and tolerability of the regimen containing paclitaxel and cisplatin (TP) in the neo-adjuvant treatment of locally advanced squamous cell cervical cancer are unknown. The TIP regimen (TP plus ifosfamide) showed high efficacy but high toxicity and it is used as an internal control. PATIENTS AND METHODS In all, 154 patients were randomized to TP (paclitaxel 175 mg/m(2) + cisplatin 75 mg/m(2); n = 80) or TIP (TP + ifosfamide 5 g/m(2); n = 74), three cycles, followed by radical surgery. Pathological response to chemotherapy was classified as optimal [no residual tumor (complete response) or residual disease with < or = 3 mm stromal invasion (PR1)] or suboptimal response. RESULTS Patient characteristics (TP/TIP): stage IB2 (56%/64%), IIA (18%/14%), IIB (20%/19%), III-IVA (5%/4%) and median age (42 years/45 years). The optimal response rate in the TP group was 25%, 95% confidence interval (CI) = 16% to 37% and 43%, 95% CI = 31% to 55% in the TIP group. Grades 3-4 leukopenia (6%/53%) and neutropenia (26%/76%) were significantly more frequent on TIP. CONCLUSION TP performance was below expectation since the lower 95% confidence limit of the optimal response rate failed to reach the prespecified minimum requirement of efficacy, i.e. 22%. The TIP regimen confirmed its activity but was associated with higher haematological toxicity than TP.

An analysis of approaches to the treatment of endometrial cancer in Western Europe: A CTF study

The role of this research is to define the clinical-therapeutic approach to endometrial cancer currently being followed in some of the most important centres of reference for gynaecological cancer in Western Europe. Data was collected by means of a questionnaire, concerning specific diagnostic and therapeutic options, sent to 115 leading centres for gynaecological oncology in Western Europe, and 82 responses were received. The analysis of the management of this neoplasia in Western European countries shows significant differences regarding some particular clinical conditions. Only 24.4% of the interviewed centres stated that they perform lymphadenectomy routinely, whereas it is most commonly reserved for specific pathological conditions. The presence of lymph node spread is generally considered to be the most important prognostic element, and currently, radiotherapy of the pelvis appears to be the treatment of choice either as the sole postsurgical therapy (57%) or in combination with systemic treatment. An adjuvant treatment in stage I lymph node-negative patients is adopted in the large majority of the centres (70.5%) when poorly differentiated cancer (46%) and/or deep myometrial invasion (33.3%) are present. In this condition, radiotherapy appears to be the therapy of choice. Histotype and grading are generally recognised as important risk factors and result in treatment modification; the high percentage of primary surgical modifications is considerable (63.4%) in stage I grade 3 cancers that primarily require lymphadenectomy or recourse to radical hysterectomy. The results of our study indicate that there is no leading therapy in the advanced stages of endometrial cancers, but each therapeutic modality is adopted to more or less the same extent.

Analysis of complications of cervix carcinoma treated by radiotherapy using the Franco-Italian glossary

We analysed the complications of 215 patients with uterine cervix cancer, treated by radiotherapy (RT) alone. It was done according to the rules of the Franco-Italian glossary, presented at the 7th ESTRO meeting, held in The Hague on September 1988. They were ranked by organ sites and by degrees of gravity. The analysis was done on the total number of complications and they were scored at the highest reached grade of gravity. Seventy one complications were found in 55 patients; they were studied by patient, degree of severity, time of onset, organ system and grade, time of onset and grade, time of onset and organ sites, stage and RT doses and brachytherapy volumes. The importance of the study of complications is stressed, particularly when treatment combines external RT and brachytherapy; some guidelines are given to avoid severe complications.

Complications of uterine cervix carcinoma treatments: the problem of a uniform classification

Ninety-six articles published in English, French and Italian between 1938 and 1986 have been examined in order to analyze the classifications and reporting methods used by different researchers. Specialty and nationality of authors, classifications used, organs, systems and anatomic sites considered, weight given to the most frequently encountered complications are studied. Fifty-nine papers make no use of classification of complications of any kind, neither by onset time, nor by severity, but simply describe the observed events. The remaining 37 papers use a classification based on varying criteria. Thirty-four authors use a classification by severity according to different criteria; four authors classify complications according to the treatment required. In the remaining 30 papers a true scale is used. A total of 22 classifications emerges from these papers; in eight cases a previously published classification is used. The weight assigned by different authors to specific complications has been compared. The following main points emerge from the analysis: about two authors out of three simply describe the observed complications; 30 rely on a true scale of severity, but 22 different grading systems are used. Most classifications do not cover all possible complications, both surgical and radiotherapeutic, but concentrate on those complications which are typically generated by authors therapeutic approach. Only three take into account complications related to different treatment modalities. The observation period is not standardized: published data derive from follow-up times spanning from some months to many years. Authors mainly focus their interest on gastrointestinal and/or urinary complications; other organs and systems are rarely considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Surveillance procedures for patients with cervical carcinoma a review of the literature

Cervical cancer is still one of the most common malignancies in women. Treatment of cervical cancer is very successful, especially in the early stage. However, some patients will experience recurrence. The primary purpose of follow-up programs is early detection of recurrence disease that should be more likely to be amenable to treatment, thereby improving the clinical outcome. Although, in the literature, most studies have shown that the surveillance programs did not improve the clinical outcome of patients with diagnosis of recurrence, this clinical practice is regarded as traditional management. The use of Papanicolaou tests to detect recurrent cervical cancer is not sufficiently justified. The assessment of tumor markers such as the squamous cell carcinoma antigen could be useful. Imaging techniques are important for the detection and assessment of recurrent disease. The role of chest x-rays in detecting asymptomatic recurrence in patients treated for cervical carcinoma remains controversial. Detection of a new abnormal mass or the changes in the size of a known lesion caused by cancer growth and the determination of the extent of recurrence with computed tomography and magnetic resonance imaging may provide clinical assistance in the selection of optimal therapy. The fluoro-2-deoxy-glucose-positron emission tomography for surveillance only show 80% of specificity and accuracy with negative predictive value of 100%. Integrated fluoro-2-deoxy-glucose-positron emission tomography/computed tomography provides precise anatomic localization of suspicious areas and, therefore, a better diagnostic interpretation with a possible impact on disease-free survival as well. In conclusion, our review confirms the need for prospective studies to compare the effectiveness of different follow-up regimens measuring overall survival and quality of life parameters as outcomes.

Adjuvant treatment and survival in obese women with endometrial cancer: An international collaborative study

OBJECTIVE The purpose of this study was to determine the impact of patient weight on the frequency of surgical staging lymphadenectomy and pelvic radiation. Adverse effects, disease relapse, and survival outcomes were investigated. STUDY DESIGN Records of 766 women who underwent surgery for presumed corpus-confined endometrial cancer were reviewed. Body mass index (BMI) was calculated to categorize women as obese (BMI, > or = 30 kg/m2) or nonobese (BMI, < 30 kg/m2). Radiation-related toxicity was scored retrospectively. Median duration of follow-up period was 38 months. Chi2, logistic regression, correlation, Kaplan-Meier, and Cox multivariate proportional hazards were used for analysis. RESULTS Lymphadenectomy was completed as often in nonobese as obese women (P = .24). Adjuvant pelvic radiation treatment was administered more often in nonobese women (P = .01). Among 681 women with endometrioid histopathologic findings, 4-year cancer-related survival in obese women was 10% higher than all cause deaths, compared with 6% in nonobese women. CONCLUSION Obesity was not a barrier to lymphadenectomy, but did influence adjuvant pelvic radiation use.

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.

Pathological response on surgical samples is an independent prognostic variable for patients with Stage Ib2–IIb cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy: An Italian multicenter retrospective study (CTF Study)

OBJECTIVES The purpose of this retrospective multicenter study was to correlate patterns of recurrences and clinical outcome of cervical cancer patients who underwent neoadjuvant chemotherapy [NACT] to surgery. METHODS This study was conducted on 333 patients with FIGO stage Ib2-IIb cervical cancer who underwent NACT to surgery with pelvic lymphadenectomy. The median follow-up was 66.5 months (range, 8-212 months). Overall optimal response rate was the sum of complete and optimal partial response rates. RESULTS An overall optimal response was obtained in 64 patients (19.2%). As for the 220 sub-optimal responders (66.1%), 127 patients had negative nodes and negative parametria and/or surgical margins, 75 patients had positive nodes with positive or negative parametria and/or surgical margins, and 18 patients had positive parametria and/or surgical margins with negative nodes. At the time of the present analysis, 79 (23.7%) of the 333 patients had a recurrence after a median time of 14.9 months (range, 4.5-123 months). Recurrent disease was pelvic in 50 (63.3%), extra-pelvic in 22 (27.9%), and both in 7 (8.8%). On multivariate analysis, pathological response to NACT was an independent prognostic variable for recurrence-free and overall survival. Patients who did not achieve an overall optimal response had a 2.757-fold higher risk of recurrence and a 5.413-fold higher risk of death than those who obtained an overall optimal response. CONCLUSIONS Results appear to suggest that the chemo-surgical approach is an effective therapeutic option for patients with stage Ib2-IIb cervical cancer and that pathological response to NACT is the strongest prognostic factor for the outcome.