The Response of Second Line Chemotherapy Platinum Resistant Ovarian Cancer in Sudan: 2013-2017

Background Ovarian carcinoma is the fth leading cause of cancer death worldwide. The tumor mostly associated with variant factors such as advance age, early menstruation and gene association. We aimed to highlight the effectiveness of the second line chemotherapy in the management of ovarian cancer patients in Sudan. Methods The data were collected from the hospital patient’s records for ve years period of time, included 62 patients with ovarian cancer who is treated by the second line platinum resistant chemotherapy. Result The peak prevalence of the patients was found in Aljazeera state, and the least in Algadarif state. Age group above 55 years was the most affected group. The vast majority of patients showed partially mass disappearing, completes and continue growing tumor respectively. All patients received variant cycles of chemotherapy as fellow 3, 6, 2, 4, 5, 1 cycle respectively. 79.4% of the patients had achieved the normal value of cancer antigen 125 (CA125) levels after the treatment. 50% of patients had 1-2 months interval time before the cancer recurrence, 32.2% had 3-4 months and 17.8% had 5-6 months before the disease recurrence. The serous adenocarcinoma was found to be the most histological type in all the patients and the least two types were observed are cell carcinoma and serous papillary. Conclusion Our ndings suggested that, Aljazeera state citizens were more vulnerable to resist the rst line chemotherapy than others. The Sudanese patients with ovarian cancer may have better response to Gemzar.


Abstract
Background Ovarian carcinoma is the fth leading cause of cancer death worldwide. The tumor mostly associated with variant factors such as advance age, early menstruation and gene association. We aimed to highlight the effectiveness of the second line chemotherapy in the management of ovarian cancer patients in Sudan. Methods The data were collected from the hospital patient's records for ve years period of time, included 62 patients with ovarian cancer who is treated by the second line platinum resistant chemotherapy. Result The peak prevalence of the patients was found in Aljazeera state, and the least in Algadarif state. Age group above 55 years was the most affected group. The vast majority of patients showed partially mass disappearing, completes and continue growing tumor respectively. All patients received variant cycles of chemotherapy as fellow 3, 6, 2, 4, 5, 1 cycle respectively. 79.4% of the patients had achieved the normal value of cancer antigen 125 (CA125) levels after the treatment. 50% of patients had 1-2 months interval time before the cancer recurrence, 32.2% had 3-4 months and 17.8% had 5-6 months before the disease recurrence. The serous adenocarcinoma was found to be the most histological type in all the patients and the least two types were observed are cell carcinoma and serous papillary. Conclusion Our ndings suggested that, Aljazeera state citizens were more vulnerable to resist the rst line chemotherapy than others. The Sudanese patients with ovarian cancer may have better response to Gemzar.

Background
Ovarian cancer is one of the most widely distributed malignancies worldwide and is considered the lethal gynaecological type and the fth leading cause of cancer death (1)(2)(3)(4), because of its high recurrence rate which is resist to chemotherapy (5). Nearly, 3 out of 4 of epithelial ovarian cancer (EOC) type present with late advanced stage (6). The lifetime risk of developing ovarian cancer in general population is 1.4 per cent and the mean age of presentation is 64 years, even though his incidence are varied by regions (7).
Many factors play major role in the disease development and these includes advance age (8, 9), genetics associations (10)(11)(12), early menstruation (13), late menopausal age (14) and hormonal therapy (15). An ovarian tumor mainly originates from its own tissue but some multiple tumors such as colon (16), stomach (17), small intestine (18), pancreas (6), breast (19) and even thyroid cancer (20) can be metastasis to the ovary. The world health organization (WHO) classi ed the ovarian cancer histologically to many types based on their histological principles (21), the high grade serous ovarian carcinoma are considered the most common histological type (22). The current management for the ovarian tumours at the early stage includes surgical removal (23,24), followed by combination platinum/taxane chemotherapy (25,26), while the others two thirds of patients which presented with advance late stage respond to the conventional therapy (27). 60% of them will have disease recurrence and up to 90% will die eventually (6). The survival rate in early stage patients approaches to 90%, however most of them are diagnosed in their advance stage (28). Ovarian tumor can initiate from any site of the following potential three: fallopian tube (29), mesothelium lined peritoneal cavity (30) and ovary surfaces (31). The metastases risk of ovarian cancer depends on the stage and histological subtype of the tumor (32).
Patients with recurrent EOC are characterized by an initial platinum therapy response (33). Women with cancer of ovary have a good response to standard platinum treatment (34), although majority of patients with late stage will ultimately relapse (35), and resist the rst line treatment (35, 36). Platinum resistant ovarian cancer is de ned as disease recurrence within 6 months of completion of rst-line platinumbased chemotherapy (37), and when cancer actually demonstrate growth during treatment or no frankly evidence of cancer regression after 4-6 cycles of therapy by platinum treatment is then de ned as platinum refractory ovarian cancer (38). The platinum resistance has widely been demonstrated recently for ovarian cancer (5) and included many chemotherapy agents (39).
The decision of considering second-line chemotherapy in recurrent ovarian cancer patients is not yet fully clear, and this is related to the absent of standard chemotherapy to the recurrence ovarian cancer or the platinum-resistant (5). Until now oncologists are not capable to understand the genetic events for developing ovarian tumor and it remains unknown. This is due to lack of an experimental model system for understanding and studying human ovarian tumor in contrast to several studies conducted using the animal models for ovarian carcinogenesis (40-43).
There are no information about the chemotherapy treatment of ovarian cancer in Sudan, Therefore we are aiming to determine the effectiveness of second line chemotherapy in treatment of recurrence cancer of ovary in Sudan, determine the most effective type of second line chemotherapy and the most common histological types and metastasise site of ovarian cancer.

Methods
This is a retrospective cross sectional hospital study carried out at The Radiation and Isotopes Centre Khartoum (RICK), Khartoum, Sudan, which was conducted between the periods of 2013-2017 for a number of 62 recurrent ovarian cancer patients. The data was selected based on speci c criteria included only the patients who treated with the second line chemotherapy platinum resistance and platinum refractory. The designated questionnaire contains information con rm cancer diagnosis by clinical oncologist including clinical presenting features, patient age, occupation, geographical, ethnic distributions, histopathological reports for ovarian cancer type, computer imaging (CT), CA 125value before and after treatment receiving, the interval time between full course given treatment and the cancer recurrence, and number of chemotherapy cycle. The patients received multiple agents of second line chemotherapy such as Gemzar in dosage of 1 gram as follow: each 7 days for 3 time then repeated every 3 weeks, carboplatin in a dosage of 30 mg/m2 every 4 weeks for 3-6 cycles, Docetaxel 60-75mg/m2 intravenous (IV) administration over 1 hour followed by carboplatin AUC 5-6 IV over 1 hour day 1 repeated every 3 weeks x 6 cycle. The ethical approval and formal consent was obtained from all the patients, the federal ministry of health (FMOH) and the ethical committee of the RICK for scienti cally purpose.

Statistical analysis
Statistical software package SPSS version 17.0 has been used to analyze data of second line chemotherapy platinum resistance ovarian cancer such as percentages, frequency, valid percent and cumulative percent. P value calculations for statistical signi cant testing, evaluations data were analyzed by one-way analysis of variance (ANOVA), the level of statistical signi cance was set as P< 0.05.

Results
Gemcitabine (Gemzar) found to be the most widely used chemotherapeutic agent by 72.6 % of all the studied patients, followed by Gemzar nevalbin8.1 %,Gemzar cyclophosphamide 8.1 %, both Taxol & carboplatin 6.5 %, then Gemzar oxaliplatin 3.2 % and nally Docetaxel1.6% (Table 1). All patients received various cycles of chemotherapy, in about 40.3 % of all the patients received 3 cycles of the chemotherapy.
Patients who received 5 cycles and 1 cycle have the fewest percentage between all the patients only 6.4% of each. The other patients received different cycles of chemotherapy as follow: 21% of patients received 6 cycles, 17.7% have received 2 cycles and only 14.5% of the patients received 4 cycles ( Table 2). The most common ovarian metastatic site distinguished before initiation the second line platinum resistance chemotherapy was the pelvic by 43.5%. Abdominal ascites 24.2%, combined ascites and pelvic mass 16.1%, both pelvic and liver metastasis in same percentage 4.9%, and also liver metastasis with ascites with equal per cent 3.2%, pelvic and peritoneal metastasis 3.2%, isolated lung metastasis 3.2%, and lastly ascites with pelvic and lung metastasis together 1% (Table 3).
Regarding the chemotherapy agents effectiveness, patients who treated by Gemzar showed 42.2 % zero mass in the CT abdomen report, 46.7 % decreased masses size and 11.1% continuous increased mass size ( Table 4). The most common histopathological types isolated from the patients were serous cyst adenocarcinoma in 90.3% of all the patients, followed by mucinous adenocarcinoma 3.2%, and the remaining types in equal percent 1.6, which are transitional cell adenocarcinoma percent, endometrial adenocarcinoma percent, serous papillary adenocarcinoma and clear cell carcinoma (Table 5).
For the tumor marker CA 125, there were 24.1 % of patients were sustained values before and after treatment. About 25.8 % have returned into the normal value and 1.6 % of the patients showed increases in the level of CA125. The rest of the patients did not achieve the normal levels of CA125.Overall, 79.4 % of patients who received the second line chemotherapy were reached the normal range of CA125 value (0-34 U/mL). Regarding the age groups, there were37.1 % of the patients were above of 55 years old (Fig. 1). We also observed that both Aljazeera and Khartoum states had the highest and equal incidence among all the patients by 19 % (Fig. 2), followed Kordoufan states 16 %, white Nilestate15 %, Darfur states8 %, Kassala state 8 %, Abuhammed city 7 %, Algadarif5 % and Republic of South Sudan 3 % respectively (Fig.  2). Half the patients found to have 1-2 months interval time between full treatment course of the chemotherapy and the recurrence of the tumor, followed by 32.3 % with 3-4 months recurrence interval and 17.7 % have 5-6 months interval (Fig. 3). After receiving the second line chemotherapy, 30.6 % of the patients showed complete mass disappearing with 54.8 % of regression in the mass size and 14.5% failed treatment response with continuous of tumor size increases (Fig. 4).

Discussion
Many factors can contribute in causing the ovarian tumor, and this may include genetic mutation such as Breast Cancer (BRCA) mutation (44)(45)(46)(47), postmenopausal stage (48), talcum powder (49) and hormonal change in advance age (50). Generally this type of cancer is considered to be one of the most devastating tumors, due to the lack of speci c clinical symptoms related to it, until to be spread beyond level of the primary site and become less curable (50). The current study demonstrated platinum resistance ovarian cancer patients for four years period of time. The study showed that an age group above 55 years was presented more than the one third of the patients. Our results are similar with earlier reported that malignant ovarian neoplasms age prevalence estimated above 55 years of age (5,(51)(52)(53). Other reports revealed the age group above the 65 years, constitutes 30-40 % of all ovarian cancer patients (22,54). This higher prevalence of age linked ovarian malignancy may related menopausal period (14) and advance age (50).
Here we reported for the rst time that both Aljazeera and Khartoum states had the same incidence 19 %. But taken in account the population density between two states, the prevalence were higher in Aljazeera state compared to Khartoum state 2:1 respectively (51). The second line platinum resistance chemotherapy include many type such as liposomal pegylated doxorubicin (55), topotecan (56), paclitaxel (57), oral etoposide (58) and gemcitabine (51). All of these chemotherapy agents have similar response treatment rate which is about 10 % (5). Our ndings showed that the Gemzar agent treatment patients had better response among the others types of drugs by 42.2% of the studied patients treated. In addition, Gemzar treatment showed complete response by 46.7% with partially shrinkage tumor size and the remaining 11.1% of the patients resisted the treatment. Our ndings mismatch with previous study that reported less affectivity of Gemzar to ovarian cancer patients, as only 18.5% of cases showed complete response, 29.6% with partially response and 51.9% with disease progression (22). This could be due to the antitumor activity and higher tolerability against toxicity (54,59).
The serous cyst adenocarcinomas are the most isolated histological type, and had been identi ed in 90.3 % of our studied patients. Our results are in agreement with those reported from others studies which show the same isolated histological type (22,50,(60)(61)(62). This may related to higher signi cant frequency number of abnormality genetics copy in adenocarcinoma type (63, 64), and absence of BRCA function (65).The pelvic mass was the most common metastatic site of ovarian cancer in our patients. And this is related to the unique nature of the ovarian tumor itself, where it tends to spread more easily by passive mechanism of the physiological movement to the peritoneum and omentum through the peritoneal uids (30). Therefore, its disseminates by the pelvic and para-aortaic lymph nodes but rarely through the vasculature (66). Unlikely, other types of cancer cells such as colon and breast where they metastasis can be established with other organs, and hence the pelvic will be the most affected site of ovarian carcinoma (67, 68). Generally, the study estimated the incidence of the patients not the prevalence; it's also included some resident patients from south Sudan country. Most of our studied patients received three cycle of treatment but no complication had been observed as side effects despite of other studies who recorded many, for instance ascites and edema especially after the fth cycle (69). Yet, no certain explanation had been identi ed.
The interval time duration between full treatment and relapse of the tumor had been used to determine the condition response of the second line treatment (70). The tumor relapse within three months is considered platinum refractory, six months resistant and beyond that as sensitive (70). According to this classi cation, our studied categorized patients into two groups, platinum refractory and platinum resistant in equal percent. Please mentioned agreement or disagreements of previous studies with their citations and justify why agree or disagree in this paragraph.
The tumor marker Cancer antigen (CA) 125 is consider a gold standard in cancer of ovary (71). Elevated levels of CA125 are used for monitoring treatment response (72), relapse (73), and progression of the disease (74). In our study, we detected 25.8% of the patients returned their normal value of the CA125 (0-34 U/ml) after receiving the rst line platinum treatment in contrary to 79.4% who achieved the same value after receiving second line. Our results are in line with other study that revealed better CA125 response in second line platinum treatment than initial chemotherapy (75). The alterations in CA 125 values depend on different factors, such as agents interference with metabolism of the CA125 (76), tumor clone mix (76) and agent a nity for tumor tissues expression of CA125 (76). Considering the above factors diagnostic criteria for CA125, it needs to be established to evaluate the treatment effectiveness.
The limitation of our study is no BRCA testing was available to the patients.

Conclusions
Age group above 55 years was the commonest affected age group. Al Jazeera state is as the most geographical region treated by the second line platinum resistance. Serous adenocarcinoma is the most histological nding and pelvic are the most vulnerable organ to metastasise. Gemzar was found to be the most abundant chemotherapy agent been used and showed more than one third curable rate. The value of CA125 has reduced markedly after treatment. These ndings could enhance establishing a new guideline for treatment of ovarian cancer by second line chemotherapy.

Declarations Con ict of interest
All authors declare that they have no any con ict of interest.

Ethical approval
Obtained from federal ministry of health (FMOH), Khartoum, Sudan.     Figure 1 demonstrates the age distribution of the patients.  show the time interval in all the between the complete course of the second line platinum resistance chemotherapy and the disease recurrence.