Reviews on Recent Clinical Trials - Volume 10, Issue 4, 2015

Introduction: Gestational trophoblastic disease is a spectrum of neoplastic abnormalities arising from fetal trophoblastic tissue. The range of the diseases in this group varies from relatively benign Hydatidifom mole (complete and partial mole) to highly malignant choriocarcinoma. Methods: We have reviewed the available literature and discussed the management and follow up based on the current understanding of the natural history, extent and the prognosis of the disease. Key observations: Depending on the underlying pathology the disease can subside, progress or even metastasize and lead to death, if left untreated. The treatment of the disease is relatively simple and the disease is highly curable by single or multi agent chemotherapy. Appropriate and timely treatment not only saves the women from morbidity and death but also can help preserve their fertility. Conclusions: Management of Gestational disease should ideally be done in a specialized multi-disciplinary environment and the outcome of treatment in majority of the cases is very satisfactory.

Background: Ovarian Cancer is a broad spectrum of diseases comprising several subtypes. Three major categories in younger women are germ cell tumor, sex cord stromal tumor and epithelial ovarian neoplasia. Objective: literature search was for an update on management of ovarian cancer in young women. Context: Germ cell tumor is suspected in young girls presenting with solid ovarian neoplasm as abdominal mass, discomfort, dyspnea or pain abdomen. Preoperative evaluation should include thorough clinical examination with biochemical profile tumor markers and imaging techniques. When prepubertal girls present with precocious puberty, clitoromegaly, development of secondary sexual character, one should suspect juvenile granulosa theca cell tumor. Often serum beta inhibin is elevated in these cases. Young women are not immune to other tumors. Surgery should be fertility sparing, salphingo -oopherectomy, omentectomy, peritoneal cytology, retro peritoneal lymphadenectomy whenever indicated. Except Stage I A puredysgerminoma, Stage IA grade 1 immature teratoma, Stage IA /B grade 1 epithelial ovarian carcinoma, all other histopathological types irrespective of the stage of the disease require adjuvant chemotherapy. Conclusion: Girls, young women can have ovarian cancer conservative therapy. However treatment needs to be individualized. Except stage IA disease all other patient require adjuvant chemotherapy apart from fertility sparing surgery.

As a result of increasing life expectancy, the cancer incidence in older population is on the rise. Ovarian cancer (OC) is predominantly the disease of elderly women. More than half of all OC occur in women older than 65years. The incidence of the disease increases with the advancing age, peaking during 7th decade of life and remains elevated until the age of 80 years. With the changing demographic scenario the percentage of elderly patients is increasing and gynaecologic oncologists need to focus more on these patients and their specific needs. Due to their higher risk of morbidity and mortality compared to younger patients, elderly patients with advanced ovarian cancer are challenging to treat and are often treated less radically. Their outcome is impaired despite no consistent prognostic effect of age itself. To offer optimal radical management of the elderly women with ovarian cancer and to avoid suboptimal treatment, biological age and functional status need to be considered before individualized treatment plans are defined. Pretreatment assessment can be achieved by using different assessment tools. Patients can tolerate surgery and chemotherapy, as long as they are individually assessed for their medical, psychological, and functional capabilities before therapeutic intervention is initiated. Prospective trials involving elderly women with ovarian cancer are the need of the day to offer justified evidenced based optimal treatment for those who will be benefited from the treatment.

Primary Fallopian Tube Carcinomas are rare and share many clinical and histo- pathological features with primary peritoneal and high grade serous carcinomas of ovary. The three have a considerable overlap in pathogenesis and clinical course leading to the view of them being a single entity. Due to the same reason, International Federation of Obstetrics and Gynecology (FIGO) 2014, in the latest staging have staged them collectively with the clause of designating the primary wherever possible. Presenting symptoms of fallopian tube carcinoma are vague. The diagnosis is generally made in retrospect in women operated for adnexal mass. Imaging studies have not shown to be of much help in pre-operative diagnosis. Management strategies are same for all three regardless of their ovarian, tubal, or peritoneal derivation. Due to rarity, no randomized trials are available exclusively for FTC and most treatment strategies have been extrapolated from epithelial ovarian cancers. In recent times, there has been a rapidly increasing body of evidence supporting the tubal origin for all high grade serous carcinomas of ovary. This has led to growing interest in the strategy of prophylactic salpingectomy rather than salpingooophorectomy as a preventive measure for ovarian carcinomas.

Vulvar cancer is an uncommon malignancy and accounts for around 5% of all gynecologic cancers. Incidence rates have increased for young adults and may be linked to increasing HPV prevalence. Treatment of vulvar cancer has evolved from ‘en-bloc’ surgery with high morbidity to more conservative approaches without compromising oncological safety. In recent years sentinel node evaluation has been advocated in early stage cancers to reduce complications of inguino-femoral lymphadenectomy. Minimising extent of radical excision for the vulvar growth and separate incisions for groin dissection have reduced the number of wound breakdowns, infection, lymphocoele and chronic lymphedema but complication rate is still as high as 60%. Incorporating sentinel node evaluation into clinical practice has brought down complications to less than 10% for both lymphedema and wound infection. Role of imaging is increasing in vulvar cancer, especially for locally advanced disease as a result of transition from exenterative and extensive surgery to use of neoadjuvant chemoradiation and a less moribund approach to management. Locally advanced vulvar cancer includes large primary tumors or locally advanced disease i.e. FIGO stages III and IV. Treatment decision here is still a challenge as there is no standard recommended treatment strategy. Neoadjuvant chemoradiation is an effective modality for locally advanced vulvar cancer, as it reduces tumor size and renders the lesion operable. Primary chemoradiation without post treatment surgery has been used as an alternative treatment to avoid extensive radical surgery and complex reconstructive procedures.

Context: Vaginal cancer is a rare gynecologic cancer with very little documentation. Objective: Literature search to have useful information for the management of vaginal cancer and share. Material Methods: We have searched the PUBMED database, Google search engine and other database. A total of 26 references were taken into account. Comments: Once spread from primary other cancers or vulva is ruled out, vaginal cancer is designated to be primary in origin. It was revealed that majority of vaginal cancers reported are squamous cell carcinomas. The most common risk factors implicated are Human Papiloma Virus, age. Most common presenting symptoms were abnormal vaginal bleeding,. Diagnosis requires pathological confirmation. Management depends on staging work-up. Vaginal cancer is staged by FIGO system of staging and TNM staging. There are many prognostic factors influencing the choice of treatment. Lymph node metastasis is one of the important prognostic factors, others to mention are histology, size, age. In a recent SEER analysis of over 2000 patients, the5 year disease specific survival was 84% for stage 1, 75% for stage II and 57% for advanced tumors. Early carcinomas are generally treated with either surgery or radiation therapy. Advanced cancers are treated with radiation therapy with simultaneous administration of combined chemotherapy. Preventive strategies include safe sex and HPV vaccination. Conclusion: Primary vaginal cancer is a rare entity, if there is no history of cancer cervix or vulva in past or absence of cervical squamous cell carcinoma or vulvar carcinoma within 5 years is usually considered as primary vaginal cancer. Though early stage vaginal cancers have better outcome treated with surgery or radiotherapy or surgery followed by radiotherapy, radiotherapy alone is preferred mode of treatment in vaginal cancers.

Cervical cancer has a major impact on the lives of Indian women with an estimated 122, 844 new cases of cervical cancer in the year 2012. About 80% of these cases present in a locally advanced stage leading to high morbidity and mortality. Because of lack of public awareness and infrastructure for screening and early detection in developing countries, this late presentation is likely to continue in the coming years. Radiation therapy has been the treatment of choice for patients with locally advanced cancer cervix. Many clinical trials and meta-analyses have shown a significant improvement in overall and progression-free survival with decreased local and distant recurrences with the use of concurrent chemotherapy with radiation. Most of these trials have been done in women from developed countries where the patient and disease profile are entirely different from ours. Recently, few trials from India have also shown promising results in locally advanced cancer cervix with concurrent chemoradiotherapy but toxicities remain a major concern. Further exploration is required for the use of concurrent chemo radiation prior to incorporating it into routine clinical practice.

Early cervical cancer includes a broad range of disease, from clinically undetectable micro invasive cancer to large, bulky tumours. The International Federation of Gynaecology and Obstetrics (FIGO) staging system stratifies stage I tumours into two categories, stage IA (microinvasive) and stage IB (gross tumour). There are several options for the treatment of early stage cervical cancer. Decisions about treatment depend on age, performance status and the stage of the cancer. Patients with stromal invasion of less than 3 mm (stage IA1) with no lymphovascular involvement are treated conservatively with simple hysterectomy and in selected patients who desire fertility, cone biopsy with negative surgical margins is an option. Patients with invasion of more than 3 mm or lymphovascular space involvement are at risk for pelvic lymph node metastasis and are treated with radical hysterectomy and pelvic lymphadenectomy. Stage IB1 cervical cancer is managed by either radical hysterectomy or radiotherapy with similar recurrence and survival rates. In patients with tumour less than 4 cm in diameter, the decision between radical surgery and radiotherapy depends on patient’s overall health and treatment choices. For younger women, radical surgery is preferred because ovarian function can be preserved and vaginal stenosis secondary to radiation can be avoided. Radiation therapy is preferred for women who may not tolerate radical surgery. Primary radiation therapy with or without concurrent chemotherapy is preferred for patients with tumour larger than 4 cm in diameter. Recent studies demonstrate that the addition of cisplatin-based chemotherapy given concurrently with radiation significantly improves overall survival rates.

Endometrial cancer is the most common malignancy of the female genital tract in developed countries and second to cervical cancer in India. Endometrial cancer predominately affects post menopausal women; however 15-25% of cases are diagnosed before menopause. Endometrial cancer is not amenable to screening, hence needs to be managed effectively as soon as diagnosis is made. Though quite a lot of studies have been conducted in this area, still there are controversies regarding few issues in its management. We decided to review the current literature on use of imaging techniques in diagnosing and assessing loco regional spread, mode of surgery, role of lymphadenectomy in early stage disease including sentinel lymph node status, adjuvant treatment and fertility preservation in women with endometrial cancer. Transvaginal ultrasound and MRI help in diagnosing the disease as well as locoregional spread of the tumor. Laparoscopy is replacing the conventional laparotomy without any increase in complication rate. Robotic technology being new has not been critically evaluated. Role of lymphadenectomy in early disease is still controversial. Only few studies have assessed the place of sentinel lymph node biopsy in the management of endometrial cancer. Fertility preservation in young women is the need of the hour and has been used with successful pregnancy outcome. There is need for more randomized controlled trials to clarify certain issues regarding management of endometrial cancer and on-going trials such as PORTEC3 and LACE may answer these queries.

Pancreatic cancer continues to be the most lethal malignancy with rising incidence. Traditional chemotherapy remains the standard treatment for advanced pancreatic cancer. Regimens like FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) or gemcitabine and nab-paclitaxel have been used to palliate symptoms and prolong survival. Immune therapy is changing the current treatment paradigm for malignancy, especially with the recent development of antibodies that can modulate immune checkpoint pathways. Immunotherapy to treat pancreatic cancer is a promising approach due to its low toxicity and potential for creating life- long immune response. Multiple large phase III trials using simple vaccination strategies have failed to modulate the immune response in pancreatic cancer. However novel strategies with whole cell vaccines using hyperacute rejections (Algenpantucel- L) immunotherapy demonstrated 62% and 86% 12-month disease free survival and overall survival in resected pancreatic cancer patients. Combination of whole cell vaccine GVAX and mesothelin-secreting vaccine CRS-207 demonstrated an overall survival benefit in metastatic refractory pancreatic cancer patients. In the paper, we review the recently published and ongoing clinical trials using immune based treatment for pancreatic cancer.

Poly(ADP-Ribose) Polymerase (PARP) is a family of enzymes involved in DNA repair, genome stability, cellular energy metabolism and cell division. Inhibition of PARP-1, the wellcharacterized member of this family, has been explored as a strategy for enhancing anti-cancer activity of existing drugs and for developing new drugs. Recently unique enzymatic properties and biological functions of PARP-2 and PARP-3 have been discovered, further expanding the utility of PARP as a target for cancer pharmacotherapy. We compare and contrast the structural and enzymatic properties of these three members of the PARP family. Interactions of these enzymes with proteins specific to different DNA repair pathways are summarized. Further, we evaluate progress on development of PARP inhibitors as anticancer agents. Results of Phase I and Phase II clinical trials of seven PARP inhibitors, used alone or in combination with known anticancer agents are reviewed highlighting common observations regarding the maximum tolerable dose, adverse reactions profile, PARP inhibition and anticancer effects. While further clinical studies are warranted, based on current data, Olaparib (Ola), Veliparib (Veli) and Rucaparib (Ruca) offer considerable potential. Prolonged exposure to Ola and Veli leads to resistant cancer cells, primarily through restoration of the HR pathway, overexpression of the P-glycoprotein efflux pump or modulation of PARP expression. Some resistant cancer cells continue to respond to platinum based drugs, encouraging further development of PARP inhibitors for cancer treatment. Future course of this research, specifically focusing on use of PARP inhibition as a strategy for personalized cancer therapy, is discussed.