Scheduling

Dose-dense therapy

Dose-dense chemotherapy, where the interval between chemotherapy cycles is reduced, has been considered to improve the activity of drugs used to treat ovarian cancer.⁷³ Dose-dense chemotherapy reduces the time for tumour re-growth between cycles.⁷⁴  The cumulative drug dose remains constant but the same amount of drug is administered over a shorter period of time.⁷⁴

In an RCT conducted in Japan (JGOG 3016) 637 patients with FIGO stage II-IV disease were randomly assigned to receive paclitaxel (80 mg/m²) once weekly and carboplatin every three weeks (dose-dense therapy) or carboplatin (AUC6)and paclitaxel 180 mg/m² given every three weeks (standard therapy).⁴⁸

Overall survival

Dose-dense paclitaxel improved overall and progression-free survival compared to the standard treatment.  Overall survival at two and three years was significantly better in the dose-dense paclitaxel arm compared to the standard dose arm (2 yrs: 83.6% vs. 77.7%, p=0.049; 3 yrs: 72.1% vs. 65.1%, p= 0.03).  At five years, OS was higher in the dose-dense group 58.6% vs. 51.0%, HR 0.79, 95% CI 0.63-0.99, p=0.0448).  At 6.4 years of median follow up, median survival had not been reached in the dose-dense group.⁴⁷

Progression-free survival

JGOG 3016 also reported improved progression-free survival.  Median progression-free survival was 28 months in the dose-dense paclitaxel arm, compared with 17.2 months in the standard arm, adjusted HR 0.65, (95% CI 0.53 to 0.80), p = 0.0001.  PFS was longer in the dose-dense arm across all sub-groups, except amongst women with clear-cell or mucinous tumours. 

Adverse events

Sixty-two percent (62%) of patients in the dose-dense arm received six or more cycles compared to 73% in the standard arm. The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.001). The frequencies of other toxic effects were similar between groups.

Quality of life

A 2014 publication of the JGOG 3016 trial by Harano et al, reported QoL outcomes. QoL was assessed at baseline, 6 months and 12 months using FACT-general scale, FACT-taxane subscale and FACT-ovary subscale. The authors reported no significant difference in QoL between the two treatment groups up to 12 months after randomisation (p=0.46). However, QoL was significant lower in the dose-dense group according to the FACT-taxane subscale, compared with the conventional chemotherapy group (p=0.02).⁴⁹

Dose-dense chemotherapy has been adopted in some centres. However, given that JGOG 3016 involved patients recruited only in Japan (mostly stage III) and that patients who had treatment delays or neutropenic complications received granulocyte-colony stimulating factor (G-CSF), a number of international trials  (including the Italian trial MITO7, ICON8 AND GOG 262) are in progress to further assess the applicability of dose-dense regimens for other populations.⁷³

Complex high-dose chemotherapy regimens

In two trials that investigated complex high-dose chemotherapy regimens including peripheral blood stem cell support, no overall or progression-free survival differences were reported between the intervention and standard treatment arms.^{56, 57}

Intraperitoneal (IP) chemotherapy

A Cochrane systematic review published in 2011, included RCTs published up to May 2011 on IP chemotherapy.⁴⁵  Only one of the nine trials (Kirmani 1994) directly compared intravenous (IV) to IP (without additional IV) chemotherapy; the remaining trials compared administered a certain component of chemotherapy via IV or IP, along with IV chemotherapy in both arms. The chemotherapy component administered IP always included a platinum agent, usually cisplatin, with or without additional agents. The IV chemotherapy given to both arms usually included paclitaxel or cyclophosphamide.⁴⁵

Overall survival

The Cochrane review reported significantly improved overall survival for women who received an IP component of chemotherapy.⁴⁵ From meta-analysis of data from eight studies (2026 women) for overall survival, the hazard ratio was 0.81 (95% CI 0.72 to 0.90), p=0.0002 for women who received an IP component of chemotherapy compared to only IV chemotherapy. Results were similar when only data from the six high quality trials was used: HR 0.80 (95% CI 0.72 to 0.90), p=0.0001 and when the analysis was restricted to trials that used the same chemotherapy regimens in each arm (data from 3 studies: HR 0.79 (95% CI 0.67 to 0.92)).⁴⁵   

Progression-free survival

The Cochrane review reported significantly improved progression-free survival for women who received an IP component of chemotherapy.⁴⁵ From meta-analysis of five studies (1311 women) the hazard ratio was 0.78 (95% CI 0.70 to 0.86), p<0.00001. The data were reported to be homogenous.

Adverse events

The Cochrane review reported that women in the IP chemotherapy groups were significantly more likely to experience severe adverse effects (grade 3/4): fever (RR 1.64), fatigue (RR 2.32), gastrointestinal adverse events (RR 1.70), infection (RR 3.34), metabolic adverse events (RR 4.45) and pain (RR 7.47).⁴⁵  Hearing loss was more common in the IV chemotherapy groups (RR 0.67).  There were no significant differences between interventions for haematological adverse events (such as anaemia, thrombocytopenia and leukopenia), renal, neurological and pulmonary adverse events.⁴⁵ However, substantial heterogeneity was noted in these meta-analyses.

Insufficient data were available for meta-analysis of catheter-related complications of IP drug administration, including infection, blockage and discontinuation of therapy.

Treatment compliance

An additional paper was identified in the Cancer Australia literature review which investigated factors affecting the completion of IP chemotherapy in women with ovarian cancer.⁷⁵  The study included 140 patients from one US centre who received IP chemotherapy as initial treatment; some of these  were part of the GOG 172 trial as well as other IP chemotherapy trials.

Of these 140 patients, 95 (68%) completed all six planned cycles of treatment.

The reasons for non-completion of the planned regimen included:

• Occlusion of the port (28 patients, 20%)
• Progression of disease (7 patients, 5%)
• Refusal by the patient to accept further IP treatment (6 patients, 4%)
• Infection of the port/port site (3 patients, 2%)
• Rupture of the port tubing (1 patient, <1%).⁷⁵

Quality of life

Only GOG 172 assessed quality of life (QoL) as an outcome measure. Women who received higher dose IP therapy experienced more QoL disruption compared to those who received IV therapy. Those in the IP arm reported worse QoL and pain prior to the fourth chemotherapy cycle and worse QoL three to six weeks post-treatment. However, there were no significant QoL or PAIN score differences between arms at one year post-treatment.

Neoadjuvant chemotherapy

One randomised controlled trial (EORTC 55971) was identified that compared neoadjuvant chemotherapy with primary surgery followed by adjuvant chemotherapy.⁴⁴  The trial included 670 women from 59 institutions with stage IIIC or IV invasive epithelial ovarian cancer, primary peritoneal or fallopian tube cancer, with extensive disease (61% metastases >10 cm at primary debulking).^{44, 76} Most (76%) of the included patients had stage IIIC ovarian cancer. The median age range was 62-63 (range 25-86) and the majority of patients had serous histology (62%).

The trial randomised women to either:

1. Three courses of neoadjuvant platinum-based chemotherapy followed by debulking surgery in all patients with a response or stable disease, followed in turn by at least three courses of platinum-based chemotherapy (n=334)

or

2. primary debulking surgery followed by at least six courses of platinum-based chemotherapy (n=336).⁴⁴

Optimal resection with no macroscopic residual tumour was achieved in 19% of cases after primary debulking and in 51% after interval debulking. However, debulking rates differed from country to country in this international trial.⁷⁶

The most common chemotherapy regimen was paclitaxel (175mg/m2) plus carboplatin (AUC6). Eighty-six per cent of patients in the neoadjuvant chemotherapy group received at least six cycles of chemotherapy compared with 82% in the primary surgery group. Around 7% of patients in the primary surgery group received no chemotherapy, mainly due to post-surgery complications or the diagnosis of another primary tumour, while 88% of patients in the neoadjuvant group underwent interval debulking surgery.⁴⁴

Overall survival

The trial found no difference in the median overall survival between the two groups (median 30 months in the neoadjuvant chemotherapy group compared with 29 months in the primary surgery group, HR 0.98 (90% CI 0.84 to 1.13)).⁴⁴  Subgroup analyses by age, FIGO stage, WHO performance status, histologic type, and presence or absence of pleural fluid showed no survival differences between the treatment groups.  The only difference reported was that neoadjuvant chemotherapy appeared to improve survival among patients with metastatic tumours that were less than 5 cm in diameter at randomisation (HR 0.64 (95% CI 0.45-0.93)).⁴⁴

Progression-free survival

The trial reported no difference in the median progression-free survival between the two groups (median 12 months in neoadjuvant chemotherapy group compared with 12 months in primary surgery group, HR 1.01 (90% CI 0.89 to 1.15)).⁴⁴

Adverse events

There was a higher percentage of post-operative deaths (<28 days after surgery) in the primary surgery group (2.5%) compared with neoadjuvant chemotherapy (0.7%) (statistical significance not reported).⁴⁴  Grade 3 or 4 haemorrhage, infections and venous complications were worse in the primary surgery group compared with the neoadjuvant chemotherapy group (statistical significance not reported).⁴⁴ Direct statistical comparison was not possible as post-operative morbidity and mortality in the primary chemotherapy group could only be analysed in the 92% of patients who underwent interval debulking; the remaining 8% either died or had disease progression and may have selected out poor-risk patients who were included in the post-operative analysis after primary cytoreduction.⁷⁶

Quality of life

Quality of life was assessed using the EORTC QLQ-C30. The trial reported no significant differences between groups in the QLQ-C30 global health scores at any of the assessment times. The overall test for a treatment effect on global health was also not significant.⁴⁴

Additional studies of interest

The CHORUS trial (CRUK 07/009), a randomised controlled trial investigating neoadjuvant chemotherapy, has reported outcomes in a conference abstract.⁷⁷ Patients with clinical FIGO stage III-IV ovarian cancer were randomised to standard treatment (n= 276; primary surgery followed by six cycles of platinum-based chemotherapy) or neoadjuvant chemotherapy (n= 274; three cycles platinum-based chemotherapy either side of surgery). The median age was 65 years, median tumour size was 80mm and 25% of patients were FIGO stage IV.

At median follow-up of  three years, intention to treat analysis showed a median overall survival of 22.8 months for primary surgery vs 24.5 months for neoadjuvant chemotherapy (hazard ratio (HR) 0.87 in favor of neoadjuvant chemotherapy, 80% CI 0.76 – 0.98) and median progression free survival of 10.2 vs 11.7 months (HR 0.91, 0.81 – 1.02). The 12-month survival rates were 70% for primary surgery and 76% for neoadjuvant chemotherapy. For patients treated with primary surgery, 15% were debulked to 0cm residual disease, compared to 35% for neoadjuvant chemotherapy.⁷⁷

A small, phase II trial of 83 women (PRIMOVAR) reported no differences in outcomes between women receiving three cycles of neoadjuvant chemotherapy versus two cycles prior to surgery.⁷⁸