Nicholas Pavlidis

Coexistence of Pregnancy and Malignancy

Cancer complicating pregnancy is a rare coexistence. The incidence is approximately 1 in 1,000 pregnancies. The most common cancers are those more frequently seen during the reproductive age of a woman. Breast cancer, cervical cancer, Hodgkins disease, malignant melanoma, and leukemias are the most frequently diagnosed malignancies during gestation. The diagnostic and therapeutic management of the pregnant patient with cancer is especially difficult because it involves two persons, the mother and the fetus. In this paper we review: A) the therapeutic and diagnostic management of these patients; B) the safety of diagnostic and therapeutic procedures; C) the metastatic pattern of the maternal tumors to the placenta and fetus, and D) the potential recommendations for therapeutic abortion.

Carboplatin Plus Paclitaxel in Unknown Primary Carcinoma: A Phase II Hellenic Cooperative Oncology Group Study

PURPOSE To evaluate the efficacy of the carboplatin/paclitaxel combination in patients with carcinoma of unknown primary site (CUP). PATIENTS AND METHODS Seventy-seven consecutive CUP patients (45 women and 32 men; median age, 60 years) were treated with carboplatin at target area under the curve 6 mg/mL/min followed by paclitaxel 200 mg/m(2) as a 3-hour infusion and granulocyte colony-stimulating factor from days 5 to 12. Treatment courses were repeated every 3 weeks to a maximum of eight cycles. Forty-seven patients had adenocarcinomas, 27 had undifferentiated carcinomas, and three had squamous cell carcinomas. Thirty-three patients presented with liver, bone, or multiple organ metastases, 23 with predominantly nodal/pleural disease, and 19 (16 women) with peritoneal carcinomatosis. RESULTS The overall response rate by intent-to-treat analysis was 38.7% (95% confidence interval, 27.5% to 49.9%). There were no differences in response between adenocarcinomas and undifferentiated carcinomas, but efficacy varied among clinical subsets. The response rates and median survival times in the three clinically defined subsets were 47.8% and 13 months, respectively, for patients with predominantly nodal/pleural disease, 68.4% and 15 months, respectively, in women with peritoneal carcinomatosis, and 15.1% and 10 months, respectively, in patients with visceral or disseminated metastases. Chemotherapy was well-tolerated. CONCLUSION Carboplatin plus paclitaxel combination chemotherapy is effective in patients with predominantly nodal/pleural metastases of unknown primary carcinoma and in women with peritoneal carcinomatosis. However, in patients with liver, bone, or multiple organ involvement, the combination offers limited benefit. The investigation of novel treatment approaches is highly warranted for this group of patients.

Clear evidence that long-term, low-dose tamoxifen treatment can induce ocular toxicity. A prospective study of 63 patients.

The current study has prospectively investigated the incidence and course of ocular toxicity after low‐dose tamoxifen treatment. Sixty‐three patients with cancer who could be examined were analyzed. Tamoxifen was administered on a 20‐mg daily dose. Median duration of treatment was 25 months. Median total tamoxifen dose was 14.4 gr. Four patients had retinopathy and/or kera‐topathy 10, 27, 31, and 35 months, respectively, after tamoxifen initiation (an incidence of 6.3%). Ophthalmo‐logic findings consisted of decreased visual acuity, bilateral macular edema, yellow‐white dots in the para‐macular and fovea areas in all patients as well as corneal opacities in one patient. After tamoxifen withdrawal almost all ocular abnormalities were found to be reversible, except for the retinal opacities. This is the first prospective study in the literature indicating that even conventional low‐dose tamoxifen treatment can induce ocular toxicity. In addition, the authors review and discuss the literature of the last decades.

Carcinoma of unknown primary (CUP)

Carcinoma of unknown primary (CUP) is one of the 10 most frequent cancers worldwide. It constitutes 3-5% of all human malignancies. Patients with CUP present with metastases without an established primary site. CUP manifests as an heterogeneous group of mainly epithelial cancers recognised by distinct clinicopathological entities. The diagnostic work-up includes extensive histopathology investigations and modern imaging technology. Nevertheless, the primary tumour remains undetected most of the time. Molecular diagnosis with DNA microarrays demonstrates high sensitivity, but its prognostic contribution is still uncertain. Certain clinicopathological CUP entities are considered as favourable sub-sets responding to systemic platinum-based chemotherapy or managed by locoregional treatment. These sub-sets are: the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, peritoneal papillary serous adenocarcinomatosis in females, poorly differentiated neuroendocrine carcinomas, isolated axillary node adenocarcinomas in females or cervical nodal involvement by a squamous cell carcinoma. Patients who belong to the non-favourable sub-sets have a worse prognosis.

Safety of pregnancy following breast cancer diagnosis: A meta-analysis of 14 studies

BACKGROUND Due to the rising trend of delaying pregnancy to later in life, more women are diagnosed with breast cancer before completing their families. Therefore, enquiry into the feasibility and safety of pregnancy following breast cancer diagnosis is on the rise. Available evidence suggests that women with a history of breast cancer are frequently advised against future conception for fear that pregnancy could adversely affect their breast cancer outcome. Hence, we conducted a meta-analysis to understand the effect of pregnancy on overall survival of women with a history of breast cancer. METHODS Two of the authors independently performed a literature search up to September 2009 with no language restrictions. Eligible studies were published retrospective control-matched, population-based and hospital-based studies that have addressed the impact of pregnancy on the overall survival of women with history of breast cancer. Pooling of data was done using the random effect model. Unpublished statistics from three studies were obtained to perform further subgroup and sensitivity analyses. This included examining the effect of pregnancy according to age at diagnosis, healthy mother effect, type of study, nodal status and other parameters. RESULTS Fourteen studies were included in this meta-analysis (1244 cases and 18,145 controls). Women who got pregnant following breast cancer diagnosis had a 41% reduced risk of death compared to women who did not get pregnant [PRR: 0.59 (90% confidence interval (CI): 0.50-0.70)]. This difference was seen irrespective of the type of the study and particularly in women with history of node-negative disease. In a subgroup analysis, we compared the outcome of women with history of breast cancer who became pregnant to breast cancer patients who did not get pregnant and were known to be free of relapse. In this analysis, we did not find significant differences in survival between either group [PRR: 0.85; 95% CI: 0.53-1.35]. CONCLUSIONS This study confirms that pregnancy in women with history of breast cancer is safe and does not compromise their overall survival. Hence, breast cancer survivors should not be denied the opportunity of future conception.

Multiple-Treatments Meta-analysis of Chemotherapy and Targeted Therapies in Advanced Breast Cancer

BACKGROUND Many systemic nonhormonal regimens have been evaluated across several hundreds of randomized trials in advanced breast cancer. We aimed to quantify the relative merits of these regimens in prolonging survival. METHODS We performed a systematic review of all trials that compared different regimens involving chemotherapy and/or targeted therapy in advanced breast cancer (1973-2007). Regimens were categorized a priori into different treatment types. We performed multiple-treatments meta-analysis and calculated hazard ratios for each treatment category relative to monotherapy with old agents (ie, regimens not including anthracyclines, anthracenediones, vinorelbine, gemcitabine, capecitabine, taxanes, marimastat, thalidomide, trastuzumab, lapatinib, or bevacizumab). RESULTS We identified 370 eligible randomized trials (54,189 patients), of which 172 (31,552 patients) compared different types of treatment. Survival data from 148 comparisons pertaining to 128 of the 172 trials (26,031 patients, 22 different types of treatment) were available for inclusion in the multiple-treatments meta-analysis. Compared with single-agent chemotherapy with old nonanthracycline drugs, anthracycline regimens achieved 22%-33% relative risk reductions in mortality (ie, hazard ratio [HR] for standard-dose anthracycline-based combination: 0.67, 95% credibility interval [CrI] 0.57-0.78). Several newer regimens achieved further benefits (eg, HR [95% CrI] 0.67 [0.55-0.81] for single-drug taxane, 0.64 [0.53-0.78] for combination of anthracyclines with taxane, 0.49 [0.37-0.67] for taxane-based combination with capecitabine or gemcitabine), and similar benefits were seen with several regimens including molecular targeted treatments. Most regimens had very similar efficacy profiles (<5% difference in HR) as first- and subsequent-line therapies. CONCLUSIONS Stepwise improvements in efficacy of chemotherapy and targeted treatments cumulatively have achieved major improvements in the survival of patients with advanced breast cancer. Many options that can be used in first and subsequent lines of therapy have comparable efficacy profiles.

Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: Solid tumors.

The association of cancer and pregnancy is increasingly encountered nowadays in clinical practice. Due to the relative rarity of the situation, it lacks a systematized approach. Different systemic therapies are used in managing cancer with uncertainty regarding the potential hazards they could pose on the pregnancy and/or the fetus. We have performed a systematic review of literature to identify all reports addressing cancer patients who were exposed to any of the known systemic therapies during the course of the pregnancy. The results were discussed in two parts; part I addresses pregnant patients with solid tumors while part I for those with hematological malignancies. In part I, we identified different solid tumors diagnosed and treated during the course of pregnancy. Breast cancer was the most commonly treated followed by ovarian cancer. Other tumors were treated as well including lung cancer, cervical cancer, sarcoma and melanomas. It is important to acknowledge the intent of therapy (palliative vs. curative) and the patients has to be properly counseled to reach an informed decision. We aim to provide a more robust consensus on how to approach these cases and provide a higher degree of evidence to support the safety of applying certain management strategies over the other.

Endobronchial metastases secondary to solid tumors: report of eight cases and review of the literature

Endobronchial metastases (EBM) secondaries to extrapulmonary solid malignant tumors are rare. Breast, colon and renal adenocarcinomas are the most frequent tumors associated with EBM. Since 1990 we have treated eight patients with EBM secondary to renal adenocarcinoma (three cases), colon adenocarcinoma (two cases), gastric adenocarcinoma (one case), bladder carcinoma (one case) and basal cell carcinoma (one case). Endobronchial lesions were detected by bronchoscopy and their metastatic nature was confirmed histopathologically in all eight cases. We also conducted a review of EBM reporting studies published in English language. The median interval from the diagnosis of the primary tumour was 41 months. Symptoms and radiological findings were indistinguishable from those of primary lung cancer. Five patients were treated with external radiotherapy with symptomatic improvement while two patients had chemotherapy and one patient underwent surgical resection of the metastasis. Systemic treatment was used in six cases with no significant effect on EBM. Median survival after EBM diagnosis was 9 months with one patient surviving 3.5 years and two patients still alive at 1 year. In conclusion, EBM usually represent a late manifestation requiring differential diagnosis from a primary lung cancer. Local treatment may result in symptomatic improvement but prognosis is generally poor averaging 1-2 years in most series.

Prevention of chemotherapy-induced alopecia using an effective scalp cooling system.

Alopecia is a distressing side-effect of cancer treatment. Taxanes (TX), anthracyclines (ANR) and etoposide (ET) have been consistently associated with significant alopecia. We studied an effective scalp cooling system, the Penguin Cold Cap system, for the prevention of chemotherapy-induced alopecia in 70 patients receiving chemotherapy, including one of the following major alopecia-causing agents: Group A, TX-based regimes (without ANR); Group B, TX+ANR; Group C, ANR-based regimes (without TX); Group D, ET-based regimes. Protection from hair loss was achieved by maintaining scalp temperatures below 15 degrees C before, during and after chemotherapy by frequent changing of the caps. Assessment was carried out using a grading system from 0 to 4. Grades 0-2 were considered as satisfactory hair protection, whilst Grades 3-4 were considered failures. 57 patients were evaluable for assessment. An overall 81% protection was achieved. In groups C and D 11 of 12 patients (92%) had no alopecia, whilst 30 of 34 patients (88%) treated with taxanes had adequate hair protection. In Group B, 4 of 11 patients (36%) had adequate hair protection. The system was well tolerated and is a very effective method for protection from hair loss caused by TX, ANR and ET. Our results are comparable with and, in most cases, better than those reported in other studies using various alopecia preventive methods.

Prognosis of pregnancy-associated breast cancer: A meta-analysis of 30 studies

BACKGROUND Pregnancy-associated breast cancer (PABC) is relatively rare with considerable controversy regarding its prognosis. PATIENTS & METHODS Two of the authors independently performed a literature search with no date or language restrictions. Eligible studies were control-matched, population-based and hospital-based studies that addressed the outcome of patients diagnosed during pregnancy or 1-year afterwards. The primary and secondary end-points were overall and disease-free survival respectively. Pooling of data was done using the random effect model. RESULTS 30 studies were included in this meta-analysis (3,628 cases and 37,100 controls). PABC patients had a significantly higher risk of death compared to those with non-pregnancy-related breast cancer (pooled hazard ratio (pHR): 1.44; 95% CI [1.27-1.63]). The same results were encountered on restricting the analysis to HRs of multivariate analyses (pHR: 1.40 [1.17-1.67]). A clearer trend of poorer outcome was seen in those diagnosed postpartum (pHR: 1.84; 95% CI [1.28-2.65]) than those diagnosed during pregnancy (pHR: 1.29; 95% CI [0.74-2.24]). DFS analysis showed a significantly higher risk of relapse associated with PABC as well (pHR: 1.60 [1.19-2.16]). CONCLUSION Our results show that PABC is independently associated with poor survival particularly those diagnosed shortly post-partum. This underscores a possible impact of the pregnant breast microenvironment on the biology and consequently the prognosis of these tumors.