Background The advent of effective chemotherapeutic agents for ovarian carcinoma has made radical abdominopelvic radiation redundant. Nevertheless, palliative pelvic Aimsradiotherapy still has a role in palliating local symptoms. However, its effect on progression-free survival (PFS) may be debated.
Aims To study the outcome of fractionated palliative pelvic radiotherapy in relapsed ovarian cancers in terms of symptom control and PFS.
Methods Twenty-three patients of ovarian cancers, heavily pretreated with chemotherapy and with recurrent or residual pelvic masses, were planned for palliative pelvic radiotherapy to the dose of 46–50 Gy in 23–25 fractions in 4.5–5 weeks. Symptom control and outcomes have been analyzed.
Results Post-radiotherapy, abdominal pain was controlled in 15 out of 17 patients (88.2 %), bleeding per vaginum in all 5 patients and vaginal discharge stopped in 4 out of 5 patients (80 %). On follow-up, of 23 patients, 17 (74 %) had progressive disease post-radiation, and median time to disease progression was 10 months (range 1–49). On univariate analysis, increased PFS was observed in patients who received radiation late in their course of disease, those with serous histology, and with lesser disease bulk in pelvis (<=2 cm) prior to radiation initiation.
Conclusion Fractionated palliative pelvic radiotherapy is an efficient method for symptom palliation in relapsed ovarian cancers. Patients who are heavily pretreated with chemotherapy and have a small-volume pelvic disease may show a prolonged PFS with addition of pelvic radiotherapy. Indications of radiotherapy, however, need to be defined.
Keywords : Ovarian cancer, Recurrent, Radiotherapy, Palliation, Progression-free survival
Ovarian cancer is the leading cause of death from gynecological malignancies worldwide. The ideal management is aggressive surgical removal of tumor (debulking) and platinum-based chemotherapy [1]. At present, role of radiotherapy in ovarian cancers is confined to symptom palliation alone. However, these cancers are known for relapse, and the relapses are often associated with low response rates to further chemotherapy and subsequent poor prognosis [2]. In recent years, there has been resurgence of interest in the use of radiotherapy in ovarian cancers especially with localized pelvic recurrences.
The present study is the retrospective analysis of ovarian cancer patients treated with surgery and chemotherapy, and who have recurred frequently. They were treated with radiotherapy especially when the recurrences were confined to pelvis, and the outcomes were analyzed.
Patients
Between January 2008 and December 2013, patients of ovarian carcinoma who at any time during their course of treatment received pelvic radiotherapy were analyzed. Twenty-three such patients were identified. All these were managed on the lines of standard treatment of ovarian cancer, i.e., early-stage patients had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH and BSO) followed by paclitaxel and platinum- based chemotherapy. Locally advanced patients underwent maximum debulking surgery followed by adjuvant chemotherapy, or neoadjuvant chemotherapy followed by maximum debulking surgery and adjuvant chemotherapy. For second-line chemotherapy, patients with platinum-sensitive disease were treated with Injection Carboplatin and Liposomal Doxorubicin, and those with platinum resistance or refractory disease received singleagent liposomal doxorubicin. In selected patients, in whom multiple recurrences were managed by two or three lines of chemotherapy, and post-chemotherapy, recurrence was localized to pelvis (confirmed by contrast enhanced computed tomography (CECT) chest abdomen pelvis, or Positron emission tomography (PET), or further chemotherapy could not be tolerated, radiation was used with palliative intent.
Radiation Technique and Dose
Patients were simulated on Simulator CT and treated with 6- or 15-MV photons, by parallel opposed anterior-posterior portals, or conformal radiation. Dose delivered to pelvic region was 46–50 Gy in 23–25 fractions in 4.5–5 weeks.
Follow-Up
Patients were monitored weekly during radiotherapy for acute radiation toxicity [gastrointestinal (GI) and genitourinary (GU) toxicities] using RTOG (Radiation Therapy Oncology Group) toxicity scoring for acute reactions. Weekly hemogram was done during the course of radiotherapy for assessing hematological toxicity. First followup after radiation was scheduled at 4 weeks with repeat CT scan and CA-125, and thereafter patients were followed every 3 months with clinical examination and CA-125 levels. RECIST criteria 1.0 (Response evaluation criteria in solid tumors) was used for response evaluation following radiotherapy. Partial response was documented by at least 30 % decrease in tumor size and progressive disease by more than 20 % increase in tumor size [3].
Statistical Analysis
Frequency tables were used to describe treatment characteristics of the patients. Symptom control was defined in terms of response rates. Progression-free survival (PFS) was calculated by Kaplan–Meier method. Univariate analysis was done using log-rank test.
Patient Profile
Table 1 defines the characteristics of the patients, who later in their course of disease received pelvic radiotherapy.
Relapse Pattern
Median follow-up period was 50 months. At the time of first relapse, 20 patients (87 %) had relapsed loco-regionally in the pelvis and 3 (13 %) had distant metastasis.
Treatment After Relapse
All patients were planned with chemotherapy at the time of their first relapse. In 4 patients (17.4 %), radiotherapy was delivered after second line of chemotherapy, in 12 patients (52.2 %) after third line of chemotherapy, in 4 patients (17.4 %) after fourth line of chemotherapy and in 3 patients (13 %) after fifth line of chemotherapy.
Fifteen patients (65.2 %) out of these had received six cycles of three weekly chemotherapy immediately before radiotherapy, and 8 (34.8 %) were planned with radiotherapy without upfront chemotherapy.
Reasons for Treating with Pelvic Radiotherapy
All these patients were planned with pelvic radiotherapy with palliative intent, with the aim to treat local pelvic symptoms, like lower abdominal pain in 10 patients, bleeding per vaginum in 2 patients, discharge per vaginum in 3 patients, both abdominal pain and bleeding in 3 patients, abdominal pain and discharge in 2 patients. Also,
all these patients at the time of radiotherapy were not suitable in terms of their general condition for any further systemic chemotherapy.
On evaluation by CT scans, at the time of radiotherapy, 11 patients (47.8 %) had local pelvic tumor size of B2 cm; rest had tumor size ranging from 3 to 8 cm in the largest dimension. CA125 levels ranged from 2 to 326 U/ml.
Acute Toxicity
During radiotherapy, hematological toxicity was seen in 3 patients (13 %). Two out of three patients had neutropenia which required gap in the radiotherapy for 2 and 3 days, respectively, and 1 developed anemia, which required blood transfusion. Acute grade 1 and 2 GU toxicity was seen in 3 (13 %) and 1 patient (4.3 %), respectively. All these 4 patients had received chemotherapy prior to radiation. Acute grade 1 and 2 GI toxicity was seen in 5 (21.73 %) and 2 (8.7 %) patients, respectively, but these were easily manageable. None experienced grade 3 or 4 toxicities.
Late Toxicity
None of the patients experienced late GI toxicity in the form of bowel obstruction, or perforation.
Response to Radiotherapy
Response to treatment was assessed clinically by analyzing symptom control and radiologically by CT scans done 4–6 weeks after radiotherapy completion.
Pain control was seen in 15 out of 17 patients (88.2 %).Bleeding per vaginum was controlled in all 5 patients(100 %). Vaginal discharge stopped after radiotherapy in 4out of 5 patients (80 %). None of the patients hadobstructive symptoms before they were started onradiotherapy.
At week 6, radiological complete response to radiation(disappearance of pelvic mass) was seen in 9 patients(39.1 %), partial response in 5 patients (21.7 %), andprogressive disease was seen in 9 patients (39.1 %). Nonehad stable disease.
Disease Progression and Survival Post-RadiationAt the time of last follow-up, out of 23 patients, 17 (74 %)had progressive disease. The median time to disease pro-gression post-radiotherapy was 10 months (range 1–49).Out of these 17, 5 had local pelvic residual disease, 10progressed distally, and 2 patients had rising CA 125 alone.
Disease Progression and Survival
Post-RadiationAt the time of last follow-up, out of 23 patients, 17 (74 %)had progressive disease. The median time to disease pro-gression post-radiotherapy was 10 months (range 1–49).Out of these 17, 5 had local pelvic residual disease, 10progressed distally, and 2 patients had rising CA 125 alone.
PFS and Univariate Analysis (Table2)
Univariate analysis was done to find a correlation between thePFS post-radiotherapy and timing of radiation (early or lateradiotherapy), histology (serous or non-serous), and initialtumor bulk on CT scans prior to radiotherapy (less than ormore than 2 cm). Here early radiotherapy refers to the timingof start of radiation immediately after first line ofchemotherapy, and late radiotherapy means timing of radio-therapy at least after two or more lines of chemotherapy.
As seen in Fig.1, increased PFS was seen in patientswho received radiation late in their course of disease [10-month PFS=54.2 vs. 33.3 %, respectively (p=0.9; HR1.05, 95 % CI 0.23–4.68)]. In addition, patients who hadnon-serous histology had lower PFS compared to patientswith serous histology [10-month PFS=32.2 vs. 85.7 %,respectively (p=0.01; HR 4.5, 95 % CI 1.18–16.68)](Fig.2). And finally, the patients who had bulky diseaseprior to radiotherapy had lower PFS compared to thosepatients who had less volume of disease in pelvis [10-month PFS=40.4 % vs. 61.4 %, respectively (p=0.13;HR 2.2, 95 % CI 0.77–6.3)] (Fig.3). However, correlationbetween histology and PFS only could reach statisticalsignificance.
Post-radical surgery, local pelvic radiotherapy was longbefore tried in curative management of ovarian malignan-cies. However, ovarian cancer disseminates dominantlythroughout the peritoneal cavity. In fact, at first relapse,regardless of therapy, tumor is confined to the abdominalcavity in approximately 85 % of patients [4]. Thus, forradiation to be of curative benefit, techniques that encom-pass the whole peritoneal cavity, rather than just the pelvis,are likely to be most beneficial. In the past, whole abdomenradiation (WAR) has been used in ovarian cancers as partof a combined modality approach; in early-stage cancers asadjuvant therapy and in advanced stages as consolidativetherapy. [5,6]. However, its use has long been declinednow in view of the radiation toxicities and emergence ofnewer and effective role of chemotherapeutic drugs [7,8].
At present, radiotherapy in ovarian cancers is largelylimited to palliation/consolidation alone, either for localpelvic symptoms or for metastatic disease in bone or brain.For palliation, hypofractionated schedules like 30 Gy in tenfractions, 20 Gy in five fractions, or single fractions of5–10 Gy are used in clinical practice [9].
The standard management for ovarian cancers is plat-inum-based chemotherapy. Even on relapse, further several lines of chemotherapy are tried and have been found usefulin increasing survival of the patients. However, these drugshave their own limitations. Once platinum-insensitive, theresponse rates to chemotherapy fall to 10–15 % [10]. Inaddition, at some point of time, patient fails to toleratethese drugs.
Radiotherapy as palliative modality in ovarian cancer isoften neglected but may be useful if the dominant symp-tomatic problem for patient is localized to the site, that canbe safely encompassed in a radiation field.
In our study, we have tried to find out when and howlocal pelvic radiotherapy can be best and judiciously uti-lized for ovarian cancer patients during relapse. Patients inthis study were treated with fractionated radiotherapy, andsymptoms in terms of local pain, bleeding or discharge pervaginum, were effectively controlled without producingsignificant side effects.
Reports on symptomatic response to fractionated pelvicradiotherapy treatment in ovarian cancer are lacking in theliterature. Most of the results are with hypofractionated regimens. Corn et al. [11] treated 33 patients in the pelviswith response rate of 90 % for vaginal bleeding. Theyreported that patients who received biologically effectivedose of at least 44 Gy10, equal to 35 Gy in 14 fractions,had higher chance of achieving complete response. Choanet al. [10] reported their experience with 53 patients treatedwith pelvic radiotherapy, 25 were complaining of vaginalbleeding and their response rate to treatment was 100 and88 % achieved a complete response; however, hypofrac-tionated regimens of 30 Gy/10# and 20 Gy/5# were mostcommonly utilized regimens.
In present study also, effective palliation was achieved.Additionally, this study demonstrated another aspect oftreating relapsed patients with local pelvic radiotherapy. Inour study, median time to disease progression post-radio-therapy was 10 months, which is significant especially inpatients in whom multiple lines of chemotherapy havealready been utilized, and further chemotherapy is notpossible. Also, our study indicates that early introductionof radiotherapy in ovarian cancers has no benefit inincreasing PFS.
On analyzing these four patients who received pelvicradiotherapy early in their course, i.e., immediately afterfirst-line chemotherapy, it was found that all these wereplatinum-refractory patients (who relapsed within three to4 months of completion of chemotherapy). This could be apossible reason why early radiotherapy was introduced inthese patients, with the concern that further chemotherapymay not be of additional benefit. Also, 3 out of these 4patients had mucinous histology and 1 had clear cell his-tology. This also explains the lower PFS in these patients,as non-serous histologies like mucinous and clear cellhistologies are usually considered to show poor response tochemotherapy. In addition, all these patients had bulkypelvic disease prior to radiotherapy.
Our study also demonstrated higher PFS rates in patientswith low-volume pelvic disease prior to radiotherapy (tu-mor size on CT scanB2 cm). Survival data on the use oflocal pelvic radiotherapy in relapsed/recurrent ovariancancers are limited. Most of the studies in past have usedWAR and that too in adjuvant setting or in initiallyadvanced ovarian cancers showing minimal residual dis-ease after second-look laparotomy [6].
Dembo analyzed patients who had surgery followed byWAR in five published trials [5]. The studies revealed thatapproximately 40–50 % of the patients who had minimalresidual (\2 cm) disease were cured after radiotherapy.The proportion of survivors was directly related to theamount of residual disease post-surgery.
Sorbe assigned 98 ovarian cancer patients (who hadinitial cytoreductive surgery followed by chemotherapy), toreceive either chemotherapy, WAR, or no further treatment [12]. The patients who had WAR had significantly betterPFS rate (56 %) compared to chemotherapy (36 %) and nofurther treatment (33 %).
Pickel et al. [13] used WAR for consolidation in stageIII ovarian cancer patients and showed survival advantagein those patients who had clinical remission afterchemotherapy.
Though these studies have used WAR, but these dodemonstrate that bulk of the disease prior to radiotherapyhas an impact on PFS, and low-volume pelvic disease atthe time of relapse/recurrence can be judiciously taken upfor local pelvic radiotherapy.
Our study also demonstrated decreased PFS post-ra-diotherapy in non-serous histologies like mucinous, clearcell and endometrioid type; however, the results are notconsistent with those in the literature. Studies by Nagaiet al. [14] and Hoskin et al. [15] have shown better DFSand OS in patients with clear cell and mucinous histolo-gies, treated with WAR post-surgery and chemotherapy,but in these patients, radiotherapy was given as consol-idative treatment. As these histologies are poor respondersto chemotherapy compared to serous histology, therefore DFS and OS are better when radiotherapy is addedimmediately after chemotherapy [16]. The possible reasonfor this variable outcome with respect to histology in ourstudy could be because of small number of patients andalso because all these were relapsed/recurrent cases ofovarian cancer, where the disease prognosis is alreadydismal.
Regarding toxicities, these were initially of concernwhen patients were planned with WAR. However, in thepresent study, local pelvic radiation was well tolerateddespite the fact that most patients had receivedchemotherapy immediately prior to radiation. This can beexplained by the use of conformal techniques by whichdesired dosimetric parameters can be achieved with max-imal sparing of organs at risk [17]. Thus, radiotherapy mayhave a greater role in future.
Though clinical outcomes of WAR cannot be directlyextrapolated to local pelvic radiotherapy, the results of ourstudy demonstrate that limited relapsed disease/small-vol-ume persistent disease in pelvis can be well taken care byusing fractionated pelvic radiotherapy as a salvage treat-ment, especially in patients in whom further chemotherapyis not feasible.The retrospective nature of this study and small numberof patients do make it difficult to provide significant impactof certain important factors (like timing of radiotherapyand tumor bulk) on PFS, yet this study provides the scopefor further possible research with larger number of patients,utilizing palliative radiotherapy, in refractory ovariancancer, in an attempt to achieve higher PFS rates.
Conflict of interest All authors declare that they have no conflict ofinterest.
Ethical standard All procedures followed were in accordance withthe ethical standards of the responsible committee on human exper-imentation (institutional and national) and with the Helsinki Decla-ration of 1975, as revised in 2008 (5).
Informed Consent Since this is retrospective study, formal consentwas not required.
Animals RightsThere are no ethical issues with animal subjects.This article does not contain any studies with animals performed byany of the authors.
