Patients with an early stage non-bulky cervical cancer (IA2, IB1 and IIA) are often treated with radical hysterectomy and pelvic lymphadenectomy. However, some patients remain at high risk of recurrence and have worse survival outcomes. Patients with positive pelvic nodes, positive margins or parametrial involvement have the highest risk. The Southwestern Oncology group enrolled 243 patients with early stage disease (IA2, IB1 or IIA) who underwent radical hysterectomy with pelvic lymphadenectomy and were found to have one of the following high risk factors: positive pelvic lymph nodes (~85 %), parametrial extension (~34 %) and positive margins (~5 %). Patients were randomized to either external pelvic radiation therapy (49.3 Gy) alone or combined with concurrent chemotherapy with four cycles of cisplatin 70 mg/m² and 5-fluouracil 1 g/m²/day as 96-h infusion on week 1, 4, 7 and 11 (Table 36.1). Patients with positive high common iliac lymph nodes received radiation to para-aortic field (45 Gy) [16]. No brachytherapy was allowed in this study. After median follow up of 42 months, the projected progression free survival and overall survival was significantly higher for patients received concurrent chemoradiation therapy compared to patients received radiation alone (4-year PFS 80 % vs. 63 %, 4-year survivals 81 % vs. 71 % respectively). The rate of pelvic and extra-pelvic recurrence was less frequent in patients received concurrent chemotherapy. However there was no significant difference in the pattern of recurrence between the two treatment arms (Table 36.2). This study established chemoradiation therapy as the standard adjuvant therapy in patients with high risk factors early stage disease after radical surgery. An updated follow-up was released showing that after a median follow-up of 5.2 years, the estimated 5-year survival was 80 % vs. 66 % favoring the chemoradiation group [21]. Because chemotherapy was given both during radiation and for two additional cycles, this study raised an important question as whether the chemotherapy was effective as a radiosensitizer only or as adjuvant chemotherapy or both. Currently, there is an ongoing intergroup study (RTOG/GOG 0724) evaluating the impact of adding four cycles of adjuvant chemotherapy with carboplatin and paclitaxel after completing chemoradiation therapy with concurrent cisplatin (Table 36.1). Interestingly this trial also showed that patients with adenocarcinoma or adenosquamous carcinoma who received radiation alone had worse prognosis compared to squamous cell carcinoma case. In contrast, this difference disappeared in patients who received chemoradiation therapy with improved survival in both groups. These data raise the question whether patients with adenocarcinoma or adenosquamous carcinoma will benefit more from concurrent chemoradiation therapy and even adjuvant chemotherapy compared to patients with squamous cell carcinoma. Further studies are needed to answer this question.

A second question is raised is whether there is a role for chemoradiation therapy as an adjuvant therapy for patients with early stage disease who were found to have intermediate risk factors after radical hysterectomy (large clinical tumor size, deep >1/3 stromal invasion and lymphovascular space invasion). The Gynecologic Oncology study by Sedlis et al. evaluated the impact of adjuvant radiation therapy versus postoperative observation in 277 patients with stage IB with at least two of the three intermediate risk factors. Patients received adjuvant radiation therapy had significant reduction in recurrence rate and disease progression but not a significant difference in overall survival [22, 23]. This study established radiation therapy as the standard treatment after radical hysterectomy in patients with early stage disease who were found to have intermediate risk factors. Currently, there is an ongoing intergroup trial (GOG263/KGOG) evaluating the role of chemoradiation therapy with concurrent cisplatin in patients with stage I–IIA disease with two or more intermediate risk factors after radical hysterectomy and pelvic lymphadenectomy (Table 36.1).

Large tumor >4 cm in size is well established as a poor prognostic factor in patients with stage IB disease with higher recurrence rate compared with smaller tumor. This led to the FIGO definition of IB1 (≤4 cm) and 1B2 (>4 cm). A variety of treatment schemas including surgery, radiation, and chemotherapy have been used to treat stage IB2 cervical cancer. A Gynecologic Oncology Group study performed prior to the chemoradiation era (GOG 71) demonstrated that adjuvant extrafascial hysterectomy did reduce the rate of pelvic recurrences [24]. Therefore to evaluate the impact of chemoradiation, the Gynecologic Oncology Group enrolled 369 patients with stage IB2 cervical cancer into a trial comparing radiation therapy to radiation therapy combined with concurrent weekly cisplatin followed in all patients by adjuvant hysterectomy (GOG#123) (Table 36.1). Patients who received concurrent weekly cisplatin had more frequent pathologic clearance in the hysterectomy specimen (52 % vs. 41 %), and decreased recurrence rate (21 % vs. 37 %) compared to patients received radiation therapy alone (Table 36.2). Significant improvement in both progression free survival (relative risk 0.51) and overall survival (relative risk 0.54) was noted favoring chemoradiation therapy group. With a median follow up of 36 months, the estimated 3-year survival was 83 % for chemoradiation therapy group compared with 74 % in the radiation only group. On the other hand, more grade 3 or 4 toxicities mainly hematologic and gastrointestinal toxicities were noted in the chemoradiation therapy group but these were transient with no serious consequences [17, 25] (Table 36.2). At 72 months of follow-up, the difference in progression-free survival and overall survival remained significant favoring the chemoradiation group compared to the radiation only group (PFS 71 % vs. 60 % and 78 % vs. 63 % respectively) [25]. With mature follow up on GOG 71 it was found that adjuvant hysterectomy did not improve survival. The authors of the study concluded that chemoradiation alone would be adequate therapy. A retrospective study of 49 patients treated for stage I B2 cervical cancer with chemoradiation alone found similar survivals to chemoradiation and adjuvant hysterectomy [26].

Three randomized clinical trials were conducted in patients with locally advanced cervical cancer (stage IIB-IVA) comparing chemoradiation therapy with radiation alone. In GOG#85, 368 patients with locally advanced cervical cancer (stage IIB-IV) were randomly assigned to receive either chemoradiation therapy with concurrent cisplatin (50 mg/m²) and 5-fluorouracil (1 g/m²/day for 4 days) on day 1 and 29 versus hydroxyurea orally 80 mg/kg twice weekly (Table 36.1). Patients in the cisplatin and 5-fluorouracil containing arm had significant improvement in progression free survival and overall survival compared to hydroxyurea arm. After a median follow-up of 8.7 years, 43 % vs. 57 % had disease progression and 45 % vs. 57 % had died in 5-fluouracil/cisplatin and hydroxyurea containing arms respectively. Grade 3 and 4 toxicities mainly hematologic and gastrointestinal were more prominent in patient received hydoxyurea compared to those who received cisplatin and 5-fluorouracil (26 % vs. 4 %, Table 36.2) [18].

In a subsequent randomized clinical trial, the Radiation Oncology Group (RTOG) enrolled 388 patients with stage IB/IIA (≥5 cm clinical tumor size or positive pelvic lymph nodes, 34 % in each arm)-IVA cervical cancer comparing chemoradiation therapy with concurrent cisplatin (75 mg/m²) and 5- fluorouracil (1 g/m²/day as a 96-h infusion) for three cycles versus extended field radiation therapy (Table 36.1). Para-aortic lymph nodes were assessed by either lymphangiography or surgical staging. Chemoradiation therapy with cisplatin and 5-FU showed superior outcome in term of recurrence rate, progression free survival and overall survival. The estimated 5-year progression free survival and overall survival were 67 % vs. 40 % and 73 % vs. 58 % respectively for chemoradiation arm and extended field radiation arm [19]. The rate of locoregional and distant metastasis were significantly lower in the cisplatin/5-FU containing arm compared to extended field radiation arm (14 % vs. 33 % and 19 % vs. 35 % respectively) (Table 36.2). Patients received combined chemoradiation therapy had more frequent grade 3 and 4 toxicities compared to extended field radiation (44 % vs. 4 %). However, these effects were self-limited and there was no significant difference in late serious effects between the two groups (12 % vs. 11 %) (Table 36.2). Updated report after median follow-up of 6.6 years confirmed persistent advantage of chemoradiation therapy over extended field radiation with median survival of 67 % versus 41 % at 8 years respectively and 51 % reduction in risk of recurrence [27]. Interestingly, subgroup analysis showed that patients with stage III–IV who received chemoradiation therapy had significant improvement in progression free survival and trend toward improved survival with no significant difference. However, the trial was not powered to detect difference in outcome in this subgroup of patients.

A third randomized trial conducted by the GOG involving 526 patients with stage IIB–IVA cervical cancer and negative para-oartic nodes by extra-peritoneal staging (GOG-120). Patients in this study were randomized to receive radiation therapy combined with one of three chemotherapy regimens: weekly cisplatin (40 mg/m²) vs. combined cisplatin (50 mg/m²) followed by 5-FU (1 g/m²/day as 96-h infusion) on day 1 and 29 with twice weekly oral hydroxyurea 2 g/m² for 6 weeks vs. oral hydroxyurea (3 g/m² twice weekly) (Table 36.1). This study demonstrated superior progression free survival and overall survival favoring the two platinum containing regimens compared to hydroxyurea only regimen. Furthermore, the rate of pelvic recurrence was significantly lower among platinum containing groups compared to only hydroxyurea group (19–20 % vs. 30 % respectively) (Table 36.2). Patients received cisplatin containing therapy had lower rate of lung metastasis than those who had only hydroxyurea therapy (3–4 % vs. 10 %) respectively. The rate of grade 3 or 4 toxicities was the highest among patients who received the three drug regimen compared to the other two regimens. The cisplatin only regimen was associated with the least severe toxicity [20] (Table 36.2). However, late grade 3 and 4 gastrointestinal and urologic toxicities were not different between treatment groups (4.7 % vs. 0.9 % vs. 2.6 %) (Table 36.2). After median follow-up of 106 months, improvement in PFS and OS continued to be evident in the two cisplatin containing regimen compared with hydroxyurea only regimen. PFS rates at 10 years for the three arms (cisplatin, cisplatin/5-FU/hydroxyurea and hydroxyurea alone) were 46, 43 and 26 % respectively. Similarly, overall survival at 10 years was 53, 53 and 34 % respectively [28]. Further, subgroup analysis was performed to evaluate the impact of cisplatin based chemoradiation therapy on stage IIB and III individually. In each of these stages, progression free survival and overall survival significantly improved with cisplatin based chemoradiation therapy compared to hydroxyurea alone.