Radiation Oncology: A Question-Based Review

Ovarian Cancer

Richard Tuli and Lilie Lin

image Background

In the U.S., where does ovarian cancer rank as a cause of cancer death in women?

In the U.S., epithelial ovarian cancer (EOC) is the 5th leading cause of cancer mortality in women. It is the 2nd most common gyn malignancy and the leading cause of death in this group.

What is the annual incidence and mortality of ovarian cancer in the U.S.?

Annually, there are ~22,000 new Dx and ~14,600 deaths from ovarian cancer in the U.S. (ACS, Facts and figures 2009).

What is the median age at Dx of ovarian cancer?

The median age at Dx of ovarian cancer is 63 yrs. The incidence increases with age and is most prevalent during the 8th decade of life.

Is routine screening for ovarian cancer recommended?

No. Routine screening is not recommended for ovarian cancer. A prospective randomized trial failed to show that screening with transvaginal US and CA 125 led to the detection of more early-stage cancers. (Partridge E et al., Obstet Gynecol 2009). However, preliminary data from the ongoing UKCTOCS trial, which compares US and CA 125 vs. US vs. no screening, suggests that more early-stage cancers are being detected with multimodal screening (Menon U et al., Lancet Oncol 2009).

What are the histopathologic subtypes of ovarian cancer in order of decreasing frequency?

Ovarian cancer subtypes: EOC (80%) > ovarian stromal tumors > germ cell neoplasms > carcinosarcomas/malignant mixed mullerian tumors (MMMTs)

What risk factors are associated with the development of ovarian cancer?

Risk factors associated with the development of ovarian cancer:

1.     Nulliparity

2.     Advanced age at time of 1st birth (>35 yrs)

3.     HRT

4.     High fat/lactose diet

5.     Hx of ≥2 1st-degree relatives with ovarian cancer

6.     Family Hx of BRCA1/2 or HNPCC

7.     Older age

(Finch A et al., JAMA 2006)

What is the role of prophylactic oophorectomy in BRCA1/2-positive women?

Prophylactic oophorectomy has been shown to reduce the risk of ovarian and fallopian tube malignancies in BRCA1/2 women; however, the risk of primary peritoneal cancer persists. (Finch A et al., JAMA 2006; Rebbeck TR et al., J Natl Cancer Inst 2009)

What factors portend a decreased risk for the development of ovarian cancer?

Factors associated with decreased lifetime risk of ovarian cancer:

1.     Younger maternal age at 1st birth (≤25 yrs)

2.     Use of oral contraception

3.     Breast-feeding

What are the regional LN drainage routes from the ovaries?

Regional LNs of the ovaries include internal iliac, obturator, sacral, external iliac, common iliac, para-aortic, and inguinal LNs.

What are the most common sites of DMs for ovarian cancer?

Common sites of DMs from ovarian cancer include the liver parenchyma, lung, bone, and axillary and supraclavicular LNs. Whereas intra-abdominal spread to the peritoneum and diaphragmatic and liver surfaces is common, these are formally FIGO III Dz.

What are the common presenting signs and Sx of ovarian cancer?

The NCCN has released the following consensus guidelines for ovarian cancer Sx: bloating, abdominal/pelvic pain, difficulty eating, early satiety, new urinary Sx (frequency/urgency >12 days/mo), palpable abdominal/pelvic mass, and ascites. Identification of such Sx should prompt a workup for ovarian cancer.

image Workup/Staging

What is CA 125, and what is its utility in ovarian cancer?

CA 125 is a mucinous protein encoded by the MUC16 gene and is used to assess response to Tx and predict prognosis after Tx for ovarian cancer. Due to its low sensitivity and specificity as a diagnostic test, it is not used as a screening tool.

What is OvaSure, and can it be used as a diagnostic test for ovarian cancer?

OvaSure is a serum-based test for leptin, prolactin, osteopontin, IGF II, macrophage inhibitory factor, and CA 125 being investigated as a screening tool for ovarian cancer. The Society of Gynecologic Oncologists has not yet endorsed its routine use due to lack of adequate clinical validation. (Visintin I et al., Clin Cancer Res 2008)

What are the initial steps in the workup of pts with an undiagnosed pelvic mass?

Pts with signs/Sx suspicious for ovarian cancer should undergo a full H&P, including a thorough family Hx and pelvic examination, CBC, CMP, CA 125, US, CT abdomen/pelvis, and CXR. Final staging is determined through surgical/pathologic evaluation of the abdomen and pelvis. (NCCN 2010)

What is the FIGO staging system for ovarian cancer?

1.     Stage IA: limited to 1 ovary with capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings

2.     Stage IB: limited to both ovaries with capsules intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings

3.     Stage IC: limited to 1 or both ovaries with any of the following: ruptured capsule, tumor on ovarian surface, malignant cells in ascites, or peritoneal washings

4.     Stage IIA: extension and/or implants on uterus and/or tube(s); no malignant cells in ascites or peritoneal washings

5.     Stage IIB: extension to and/or implants on other pelvic tissues; no malignant cells in ascites or peritoneal washings

6.     Stage IIC: pelvic extension and/or implants (T2a or T2b) with malignant cells in ascites or peritoneal washings

7.     Stage IIIA: microscopic peritoneal mets beyond pelvis (no macroscopic tumor)

8.     Stage IIIB: macroscopic peritoneal mets beyond pelvis ≤2 cm in greatest dimension

9.     Stage IIIC: peritoneal mets beyond pelvis >2 cm in greatest dimension and/or regional LN mets

10. Stage IV: DM (excludes peritoneal mets)

If a pt with ovarian cancer is found to have a liver met, what stage is she?

In ovarian cancer, the stage implications of a liver met depend on whether the met was on the liver capsule or in the parenchyma. Liver capsule mets are T3/stage III, and liver parenchymal mets are M1/stage IV.

What is the difference between the FIGO and AJCC TNM staging for ovarian cancer?

As of 2010, the FIGO and AJCC staging systems do not differ for ovarian cancer.

What % of pts with newly diagnosed ovarian cancer present with advanced-stage Dz?

~70% of all newly diagnosed ovarian cancer pts present with advanced-stage Dz (stage I, 20%; stage II, 12%; stage III, 45%; stage IV, 23%). Dx at earlier stages is difficult due to the location of the ovaries.

image Treatment/Prognosis

What is the general Tx paradigm for ovarian cancer?

Ovarian cancer Tx paradigm: Pts with suspected ovarian cancer should undergo a comprehensive diagnostic and therapeutic laparotomy for surgical staging and cytoreduction, respectively. This should include peritoneal lavage; total abdominal hysterectomy with bilat salpingo-oophorectomy; and resection of suspicious LNs, including bilat pelvic/periaortic nodes in stage IIIB pts with a goal to cytoreduce to <1 cm of gross residual Dz.

Are there situations where unilat salpingo-oophorectomy may be considered in pts with ovarian cancer?

For a young woman with early-stage Dz or a low malignant potential tumor wishing to preserve fertility, a unilat salpingo-oophorectomy may be considered.

How should early-stage ovarian cancer be treated?

The gold standard for Tx of all stages of ovarian cancer is surgery. For stage IA-B, grade 1, non–clear cell tumors treated with cytoreductive staging laparotomy, 5-yr OS rates approach 95% and no adj therapy is indicated. All other stages of Dz should rcv adj chemo. (Young RC et al., NEJM 1990; Trimbos JB et al., J Natl Cancer Inst 2003)

What trials support the use of chemo in the postsurgical setting for pts with ovarian cancer?

The ICON1/ACTION trials randomized mostly stage I–II ovarian cancer pts (some advanced-stage pts in ICON1) to postsurgical platinum-based chemo (4–6 cycles) vs. chemo. Adj chemo significantly increased 5-yr OS (82% vs. 74%) and RFS (76% vs. 65%). (Trimbos JB et al., J Natl Cancer Inst 2003)

What is the ideal duration of adj chemo for early-stage ovarian cancer?

GOG 157 randomized 427 stage IA-B (grade 2–3), IC, and II ovarian cancer pts to 3 vs. 6 cycles of adj carboplatin and paclitaxel. The estimated 5-yr probability of recurrence (25.4% vs. 20.1%) and OS were not significantly different. Neurotoxicity, anemia, and granulocytopenia were significantly higher in the longer-therapy arm. Thorough surgical staging was incomplete or inadequately documented in 29% of included pts (Bell J et al., Gynecol Oncol 2006). GOG 175 is exploring the role of consolidative paclitaxel after 3 cycles of adj carboplatin/paclitaxel.

How should advanced-stage ovarian cancer be treated?

GOG 158 randomized 792 advanced-stage ovarian cancer pts with residual Dz ≤1 cm to adj paclitaxel/cisplatin vs. paclitaxel/carboplatin. There was no significant difference in outcome, yet there were more GI, renal, and hematologic toxicities with cisplatin (Ozols R et al., JCO 2003). GOG 47 and GOG 111 had previously established the benefits of platinum- and taxane-based chemos in the postop setting, respectively (Omura G et al., Cancer 1986; McGuire WP et al., NEJM 1996).

What is the role of neoadj chemo in the Tx of ovarian cancer?

Generally, neoadj chemo may be considered for pts with inoperable, bulky, advanced-stage, Bx-proven ovarian cancer (Hou JY et al., Gynecol Oncol 2007Steed H et al., Int J Gynecol Cancer 2006). The EORTC Gynaecological Cancer Group/NCIC Clinical Trials Group reported preliminary results of a randomized trial comparing primary debulking surgery +/− neoadj chemo in stage IIIC and IV ovarian, fallopian tube, and peritoneal cancer in 2008. After a median follow-up of 4.8 yrs, median OS was 30 mos vs. 29 mos, respectively, and median PFS was 11 mos in both groups; complications were lower in the 2nd arm, leading the authors to conclude that neoadj chemo should be considered the preferred Tx. This study has been criticized due to the low OS/PFS rates in the control arm relative to other studies (Vergote I et al., 12th mtg Int Gynecol Cancer Soc IGCS 2008)

What is the ~5-yr stage-adjusted survival of pts with ovarian cancer treated with standard of care therapy?

Survival by stage for treated ovarian cancer pts:

1.     Stage I: 80%

2.     Stage II: 60%

3.     Stage III: 30%

4.     Stage IV: 10%

What is the role of RT in the Tx of ovarian cancer?

In the postsurgical setting, whole abdomen irradiation (WAI) has resulted in similar outcomes when compared to chemo (with melphalan) in the Tx of ovarian cancer pts, yet it has led to more toxicity (Smith JP et al., Natl Cancer Inst Monogr 1975; Chiara S et al. Am J Clin Oncol 1994). As a result, the use of RT in the adj setting has fallen out of favor. We are unaware of any recent phase 3 randomized trials comparing WAI to current standard of care chemo in the adj setting.

Is there a role for consolidative RT after cytoreductive surgery and adj chemo for ovarian cancer?

Yes. A prospective randomized trial compared consolidative RT vs. chemo vs. observation in 172 pts with stage III EOC initially treated with cytoreductive surgery and adj chemo. In the subgroup with complete surgical and pathologic remission, pts receiving RT had significantly improved 5-yr PFS (56% vs. 36% vs. 35%). However, Tx-related side effects were also more frequent in pts receiving RT, including severe, late GI toxicity in 10% (Sorbe B et al., Int J Gynecol Cancer 2003). Small institutional studies have also reported on the feasibility and apparent benefit of WAI as a consolidative Tx after standard of care therapy (laparotomy and platinum/taxane chemo) in advanced- stage ovarian cancer (Rochet N et al., BMC Cancer 2007).

Has the utility of IMRT been investigated for WAI?

Yes. The feasibility of applying IMRT to WAI has been reported both in concept and practice and is shown to allow excellent PTV coverage with better sparing of organs at risk. (Hong L et al., IJROBP 2002; Rochet N et al., Strahlenther Onkol 2008)

Is there a role for WAI in persistent, chemo-refractory ovarian cancer?

This is uncertain. There is no prospective, randomized data available. Cmelak et al. retrospectively analyzed 41 women with persistent or recurrent ovarian carcinoma after initial Tx with surgical debulking and chemo who were treated with WAI (median dose: abdomen, 28 Gy; pelvis, 48 Gy). 5-yr DSS for pts with residual Dz <1.5 cm before WAI was 53% vs. 0% if >1.5 cm. 29% failed to complete WAI secondary to acute toxicity. Late toxicity requiring surgery occurred in 3 pts. The authors recommend WAI in pts who have failed initial chemo with small-sized residual tumor burden. (Gynecol Oncol 1997)

Can RT be used to effectively palliate recurrent, cisplatin-refractory, focal ovarian cancer lesions?

This is uncertain. There is no prospective, randomized data available. Corn et al. retrospectively analyzed the efficacy of RT in palliating focally recurrent, symptomatic ovarian cancer lesions. Complete palliative response was 51%, overall palliative response was 79%, and median duration of palliation was 4 mos. The likelihood of obtaining a complete symptomatic response was related to a Karnofsky performance status ≥70% and a biologic effective dose 10 >44 Gy. (Cancer 1994)

Describe the WAI fields used to treat ovarian cancer pts.

Pts being planned to rcv WAI should undergo CT simulation. An AP/PA open-field technique is historically used with borders as follows:

1.     Superior: top of diaphragm

2.     Inferior: obturator foramen

3.     Lateral: peritoneal reflection

What dose is prescribed when treating ovarian cancer pts with WAI?

Pts being treated with WAI should rcv 30 Gy in 1.5 Gy/fx with a para-aortic boost to 45 Gy and pelvic boost to 50 Gy. Kidney and liver blocks should be applied at 15 Gy and 25 Gy, respectively.

What are the NCCN follow-up recommendations after Tx for ovarian cancer?

After surgery +/− chemo for Tx of ovarian cancer, pts should rcv full interval H&P (including pelvic exam) every 2–4 mos for the 1st 2 yrs, every 3–6 mos for 3 yrs, and annually thereafter. CA 125 should be checked at every visit if it was elevated at the time of Dx. Routine labs should be checked if there is an indication. Imaging should be ordered if clinically necessary.

How should pts with a rising CA 125 be managed following CR to initial therapy in the absence of clinical or radiographic evidence of Dz recurrence?

Pts who are chemo naive should be treated the same as newly diagnosed pts (complete surgical staging + / − chemo, if appropriate). Tx options for pts who have previously rcv chemo include observation until clinical relapse, hormonal therapy (e.g., tamoxifen), systemic therapy, or clinical trial enrollment.

What is the median time to clinically or radiographically detectable Dz after an isolated CA 125 relapse?

The median time to clinical relapse in the setting of a rising CA 125 is 3–6 mos.

Are most relapses of ovarian cancer local or distant?

~80% of relapsed ovarian cancers are local.

How should ovarian cancer relapses be managed?

Pts with platinum-sensitive relapsed ovarian cancer (relapse ≥6 mos after initial chemo) should be treated with platinum-based combination chemo (Fung Kee Fung M et al., Curr Oncol 2007). In cases of platinum-resistant Dz, single agents such as docetaxel, gemcitabine, etoposide, pemetrexed, and others can be used (Mutch DG et al., JCO 2007). Response rates in the latter range from 20%–30%.

image Toxicity

What is the most common severe toxicity experienced by ovarian cancer pts treated with WAI?

Grade 3–4 diarrhea occurs in ~30% of ovarian cancer pts treated with WAI. (Chiara S et al., Am J Clin Oncol 1994)