Disease-free survival increased by nearly 40% with SCRT

Sequential chemoradiation (SCRT), where patients received 2 cycles of chemotherapy before and after radiation, extended disease-free survival (DFS) and distant DFS over that achieved with either concurrent chemoradiation (CCRT) or radiation therapy (RT) alone in patients with early-stage cervical cancer, according to a phase III clinical trial.

Following radical hysterectomy, DFS was 39% longer at 3 years in favor of SCRT compared with RT (hazard ratio [HR] 0.61; 95% CI, 0.42-0.89; P=0.01), senior author, Ji-Hong Liu, MD, Sun Yat–sen University Cancer Center in Guangzhou, China, and colleagues reported in JAMA Oncology.

They reported that compared to CCRT, SCRT also led to a 33% improvement in DFS (HR 0.67; 95% CI, 0.46-0.99; P=0.04).

After adjusting for lymph node status, differences in the risk for recurrence were again in favor of the SCRT arm, where the risk of recurrence was almost half that compared to RT (HR 0.52; 95% CI, 0.35-0.76) while it was 35% lower compared with CCRT (HR 0.65; 95% CI, 0.44-0.96). Distant metastases were also less likely to occur in SCRT-treated patients at 6.5% compared with 10.6% of the RT group (P=0.05) and 11% of the CCRT group (P=0.04), they added.

“In this prospective randomized clinical trial, adjuvant SCRT was associated with improved DFS in patients with early-stage cervical cancer who had pathological risk factors for recurrence resulting in 48% [and] 35% risk reductions in recurrence compared with RT or CCRT, respectively,” Liu and colleagues reported.

“[T]he DFS benefits [also did not come] at the cost of a prolonged treatment process… findings [that] together suggest… SCRT could be the most effective method among current adjuvant treatments for early-stage cervical cancer,” they concluded.

The Comparison of Different Subsequent Treatments After Radical Surgery (STARS) trial involved an intent-to-treat population of 1,048 patients who were randomized to one of the 3 treatment arms following radical hysterectomy.

Patients had stage IB1, IB2, IIA1 or IIA2 disease and at least one of the following adverse risk features for recurrence: lymph node metastasis, positive parametrium or margins, lymphatic vascular space involvement or deep stromal invasion. However, fewer patients in the RT group (18.3%) had lymph node metastasis than those in either the CCRT group (30.1%) or the SCRT group (29.7%; P=0.01).

“Patients in the RT and CCRT groups started radiation within 6 weeks after surgery,” the authors explained. Those randomized to the CCRT group received weekly cisplatin 30 to 40 mg/m2 for a maximum of 6 doses during radiation. Patients randomized to SCRT in turn began chemotherapy between 5 to 14 days after surgery, followed by radiation.

Chemotherapy in the SCRT arm consisted of 2 cycles of cisplatin, 60 to 75 mg/m2 on day 1 and 2, plus paclitaxel, 135 to 175 mg/m2 on day one in a 21-day cycle; 2 cycles of chemotherapy were given prior to radiation and 2 cycles after.

Almost all patients (98.8%) completed the assigned RT protocol, compared with 62.3% of patients in the CCRT group and 73.4% of those assigned to the SCRT protocol (P<0.001).

“The primary end point was disease-free survival (DFS) which was defined as the time from randomization to disease recurrence,” the study authors wrote.

At a median follow-up of 56 months (interquartile range [IQR], 42-80 months), a total of 16.4% experienced either disease recurrence or disease-specific death.

In the intent-to-treat population, 12.5% of patients treated with SCRT developed recurrence compared with 17.4% of those treated with CCRT and 19.4% of those treated with RT, investigators reported. Fewer patients (7.6%) in the SCRT arm were likely to have died by study endpoint compared with 9.9% of those in the CCRT arm and 11.1% of those in the RT arm.

“Sequential chemoradiation also decreased the risk of cancer-specific death compared with RT,” the authors noted, reducing that risk by 42% (HR 0.58; 95% CI, 0.35-0.95; P=0.03).

In contrast, SCRT did not significantly reduce cancer-specific death compared with CCRT (HR 0.74; 95% CI, 0.45-1.23; P=0.25).

Importantly as well, among patients with a cervical tumor in excess of 4 cm as well as in those who received neoadjuvant chemotherapy, no significant differences in DFS were observed among the 3 treatment groups.

Perhaps not surprisingly, patients treated with RT alone had the lowest percentage of grade 3 or 4 adverse events (AEs) at 12.9% compared with 28.5% of CCRT patients and 25.3% of SCRT-treated patients (P<0.001).

However, compared with the SCRT group, those treated with CCRT had higher rates of grade 3 or 4 gastrointestinal toxic effects including nausea and vomiting. In turn, more patients in the SCRT group developed lymphocele and peripheral sensory neuropathy.

“In the present study, postoperative adjuvant CCRT with single cisplatin did not meaningfully improve DFS or distant recurrence-free survival in patients with adverse factors compared with RT, whereas SCRT with [the] combination of cisplatin and [a] taxane did improve the prognosis, especially for patients with high-risk factors,” Liu and colleagues observed.

The authors noted that the much shorter interval between surgery and initiation of adjuvant treatment in the SCRT group at 8 days compared with over a month for RT and the CCRT groups was likely beneficial in terms of enhancing patient outcomes.

“[C]ompared with RT or CCRT, SCRT improved the DFS and decreased distant recurrence, as well as the risk of death, which supports [the conclusion that] SCRT should be considered a preferred adjuvant treatment after radical hysterectomy for patients with early-stage cervical cancer,” the authors concluded, adding that it represents a preferred modality for adjuvant treatment in resource-deprived countries where radiation resources are in short supply and where chemotherapy can be easily administered while patients wait for radiation.

No Small Feat

Commenting on the findings, Bradley Monk, MD, University of Arizona College of Medicine, Creighton University School of Medicine in Phoenix and colleagues congratulated the authors on the completion of this large clinical trial—no small feat in the treatment of early-stage cervical cancer, as they pointed out.

“There is clearly rationale for the addition of combination cisplatin and paclitaxel to adjuvant therapy,” Monk and his colleagues observed. However, before drawing final conclusions from the study, the editorialists noted that CCRT was poorly tolerated in this study, a fact that is inconsistent with experience in the U.S., and which underpowers the CCRT arm to make it a reliable comparison to SCRT.

“[L]ymph node metastasis, a key risk factor for disease recurrence, was biased to the CCRT and SCRT arms, and 19.1% to 22.7% of patients required neoadjuvant chemotherapy to permit surgery, making this a higher-risk population than would normally receive surgery in the U.S.,” the editorialists added.

They also noted that there were 2 prognostically distinct groups in the study, both intermediate-risk and high-risk, which were combined into a single patient cohort. As they also pointed out, the benefit of SCRT was best demonstrated in patients at high risk and less so among those at intermediate risk.

An on-going clinical trial is currently evaluating the use of CCRT in an intermediate-risk population along with SCRT for high-risk patients in early-stage cervical cancer.

In the meantime, “[t]he STARS trial results are provocative, are promising, and support the rationale for ongoing trials,” Monk and colleagues observed, adding that results from several on-going trials are eagerly awaited before oncologists should embrace SCRT as a new standard of care in adjuvant therapy following radical hysterectomy.

  1. Sequential chemoradiation offered superior disease-free survival as well as a reduced risk of recurrence and death compared with concurrent chemoradiation or radiation alone in early-stage cervical cancer patients.

  2. Postoperative adjuvant concurrent chemoradiation did not meaningfully improve disease-free survival or distant recurrence-free survival compared with radiation alone in early-stage cervical cancer patients with adverse risk features.

Pam Harrison, Contributing Writer, BreakingMED™

The study was supported by grants from the Sun Yat-sen University Clinical Research 5010 Program.

Liu reported receiving personal fees from Zai Lab and AstraZeneca.

Monk reported personal fees from Agenus, Akeso Bio, Aravive, AstraZeneca, Clovis, Easai, Elevar Therapeuics, Genmab/Seattle Genetics, Gynecologic Oncology Group Foundation, Gradalis, ImmunoGen, Karyopharm, Iovance, Merck, McKesson/US Oncology, Mersana, Novocure, Myriad, Pfizer, Puma, Roche/Genentech.

Cat ID: 120

Topic ID: 78,120,730,120,935,191,192,925,482

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