Radiation Oncology/Cervix/Radiation Technique

Radiotherapy technique

Overall treatment time

• Total treatment time (EBRT + brachy) should not exceed 8 weeks; target 85 Gy to Point A. However, concurrent chemotherapy may negate this time effect

• University of Wisconsin; 2013 PMID 23561652 -- "Effects of treatment duration during concomitant chemoradiation therapy for cervical cancer." (Shaverdian N, Int J Radiat Oncol Biol Phys. 2013 Jul 1;86(3):562-8. doi: 10.1016/j.ijrobp.2013.01.037. Epub 2013 Apr 2.)
  • Retrospective. 372 patients (RT 206, CRT 166). Median F/U 4.2 years
  • Outcome: Treatment duration RT 55 days versus CRT 51 days (SS). In RT cohort, treatment duration ≥ 62 days trended to worse DFS (HR 1.4, p=0.08). No difference for treatment duration in CRT cohort
  • Conclusion: With addition of concomitant chemotherapy, extended TD has no effect on treatment efficacy

• Washington University; 1995 (1959-89) PMID 7635767, 1995 -- "Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy." Perez CA et al. Int J Radiat Oncol Biol Phys. 1995 Jul 30;32(5):1275-88.
  • Usual treatment including EBRT and 2 intracavitary insertions lasts 42-48 days (less than 7 weeks). For Stage IB, the cause specific survival was 86% for 7 weeks or less, 78% (7-9 weeks), and 55% (>9wks). For IIA, 73% / 41% / 43%. For Stage III (and dose >=85), 46% for <9 wks vs 38% for longer. No effect of treatment time for Stage IB tumors < 3 cm (IB1).

• Patterns of Care; 1993 (1973-1978) PMID 8436516, 1993 -- "The influence of treatment time on outcome for squamous cell cancer of the uterine cervix treated with radiation: a patterns-of-care study." (Lanciano RM, Int J Radiat Oncol Biol Phys. 1993 Feb 15;25(3):391-7.)
  • Retrospective. 837 patients. Time bins <6 weeks, 6-8, 8-10, >10 weeks
  • Multivariate for in-field recurrence: stage, total treatment time, age (50)
  • Stage III cancers: total treatment time independent predictor; not in Stage I-II
  • Conclusion: Significant adverse effect in Stage III patients

• Gustave-Roussy; 1993 (France)(1973-1983) PMID 8262826 -- "Overall treatment time in advanced cervical carcinomas: a critical parameter in treatment outcome." Girinksy T et al.
  • Retrospective. 386 patients. Stage IIB and III. Loss of local control and overall survival when treatment extended beyond 52 days. 1% loss of LC and OS per day.

• Princess Margaret; 1992 PMID 1480773 -- "The effect of treatment duration in the local control of cervix cancer." (Fyles A, Radiother Oncol. 1992 Dec;25(4):273-9.)
  • Retrospective. 830 patients.
  • Loss of control: 1% per day beyond 30 days, predominately in Stage III/IV

Classic pelvic fields

• Fox Chase; 1996 PMID 12118547 — "Bony landmarks are not an adequate substitute for lymphangiography in defining pelvic lymph node location for the treatment of cervical cancer with radiotherapy." Bonin SR et al. Int J Radiat Oncol Biol Phys. 1996 Jan 1;34(1):167-72.
  • Used lymphangiograms to determine the adequacy of lymph node coverage by standard GOG pelvic fields.
  • Great variability in lymph node location. Bony landmarks are a poor substitute for lymph node location. Poor coverage of lateral external iliac lymph nodes.

Target Volume Delineation

• Gyn IMRT Consortium: Definitive Treatment; 2011 PMID 20472347 -- "Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer." (Lim K, Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):348-55. Epub 2010 May 14.)
  • Guidelines for CTV definition in definitive therapy setting

• Gyn IMRT Consortium: Postoperative Treatment; 2008 PMID 18037584 -- "Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy in postoperative treatment of endometrial and cervical cancer." (Small W, Int J Radiat Oncol Biol Phys. 2008 Jun 1;71(2):428-34. Epub 2007 Nov 26.)
  • Guidelines for CTV definition in postoperative therapy setting
  • RTOG Atlas

Image Guided IMRT

• PARCER Clinical Trial (2011-2019) -- 3D vs IMRT
  • Randomized Phase III. 300 patients with indication for PORT alone (two of three: tumor >= 4 cm, deep stromal invasion, LVI+). Concurrent chemo (cisplatin 40 mg/m2 weekly) if parametrial involvement, LN+, or surgical margin positive. Arm 1) 3D using 4-field box, goal PTV 95% to 95%. vs Arm 2) IG-IMRT, small bowel V15 <190cc and V40 <100 cc.
  • Late Toxicity; 2021 PMID 34506246 -- "Late Toxicity After Adjuvant Conventional Radiation Versus Image-Guided Intensity-Modulated Radiotherapy for Cervical Cancer (PARCER): A Randomized Controlled Trial" (Chopra S, J Clin Oncol. 2021 Nov 20;39(33):3682-3692. doi: 10.1200/JCO.20.02530. Epub 2021 Sep 10.). Median F/U 3 years
    • Toxicity: Late grade 2+ GI: 3D 42% vs IMRT 21% (ss). Any grade 2+ 49% vs 28% (SS).
    • Outcome: 3-year pelvic RFS 84% vs 82% (NS). 3-year DFS 81% vs 77% (NS)
    • Conclusion: Image guided IMRT resulted in reduced toxicity, with no difference in disease outcome
  • Longitudinal Costs; 2024 PMID 38484193 -- "Longitudinal Costs of Image-Guided Intensity-Modulated Radiation Therapy Versus Three-Dimensional Conformal Radiation: Lessons From Phase III PARCER Trial for Shaping Resource-Stratified Guidelines in Low- and Middle-Income Countries" (Hande V, JCO Glob Oncol. 2024 Mar:10:e2300478. doi: 10.1200/GO.23.00478.)
    • Estimate of overall financial impact, extrapolated nationally in India
    • Toxicity: Time in toxicity 3D 2.4 years vs IMRT 2.0 years. Financial impact 1.4x higher in trial. Financial impact 2.9x higher nationally
    • Conclusion: Initial costs of IG-IMRT higher, but longitudinal costs lower than 3D. Guidelines should include longitudinal health costs, rather than just initial costs.

Parametrial Boost

• Batticoloa, Sri Lanka; 2012 PMID 23027037 -- "Reviewing the role of parametrial boost in patients with cervical cancer with clinically involved parametria and staged with positron emission tomography." (Rajasooriyar C, Int J Gynecol Cancer. 2012 Nov;22(9):1532-7. doi: 10.1097/IGC.0b013e31826c4dee.)
  • Retrospective. 193 patients, locoregionally advanced cervical cancer. Whole pelvis 40 Gy, PET positive nodes boosted to 46-50 Gy, no parametrial boost. Group A (IB-IIA) versus Group B (IIB-IIIB)
  • Outcome: No difference in pelvic failure or extrapelvic failure between Group A and Group B. Pelvic failure predicted by tumor volume, extrapelvic failure predicted by nodal disease. Parametrial involvement with no parametrial boost not related to either pelvic or extra-pelvic failure. No isolated pelvic nodal failures
  • Conclusion: Cervical cancer with clinical parametrial involvement can be adequately treated without parametrial boost. Dose 46-50 Gy adequate to avoid isolated pelvic nodal failure

Para-aortic Lymph Nodes

• UC San Diego; 2013 (2003-2010) PMID 23262521 -- "Outcomes for patients with cervical cancer treated with extended-field intensity-modulated radiation therapy and concurrent cisplatin." (Jensen LG, Int J Gynecol Cancer. 2013 Jan;23(1):119-25. doi: 10.1097/IGC.0b013e3182749114.)
  • Retrospective. 21 patients. treated with EFRT IMRT and concurrent weekly cisplatin. Positive PA nodes in 14, positive pelvic nodes in 20. Median F/U 22 months
  • Outcome: 18 month OS 60%, DFSS 43%. LR 9%, DM 43%.
  • Toxicity: Grade 3+ GU 5% and GI 0%
  • Conclusion: Low rates of late toxicity; high rates of distant failure

• Shadong University, China; 2012 PMID 22854654 -- "Extended-field intensity-modulated radiotherapy and concurrent cisplatin-based chemotherapy for postoperative cervical cancer with common iliac or para-aortic lymph node metastases: a retrospective review in a single institution." (Zhang G, Int J Gynecol Cancer. 2012 Sep;22(7):1220-5. doi: 10.1097/IGC.0b013e3182643b7c.)
  • Retrospective. 58 patients, EF-IMRT and concurrent cisplatin. Median F/U 2.8 years
  • Outcome: in-field recurrence 3.4%, distant recurrence 31%
  • Toxicity: Late grade 3 toxicity 5%; 77% of patients with ovarian transposition maintained ovarian function
  • Conclusion: Concurrent cisplatin with postoperative ER-IMRT is safe; locoregional control rates are hopeful, but distant metastases the primary mode of failure

Dose

• Patterns of Care Study, 1991 - PMID 2004942
  • Dose response demonstrated only for Stage III with improved conrol with Pt A dose of 85 Gy.

Circadian variation

• Lucknow, India -- morning RT vs evening RT
  • Randomized. 229 patients, cervical CA. Arm 1) morning (8-10 AM) vs Arm 2) evening (6-8 PM) RT. Primary outcome mucositis
  • 2010 PMID 20162717 -- "Circadian variation in radiation-induced intestinal mucositis in patients with cervical carcinoma." (Shukla P, Cancer. 2010 Feb 16. [Epub ahead of print])
    • Outcome: Overall diarrhea AM 87% vs PM 68% (SS), Grade 3-4 diarrhea 14% vs 5% (SS)
    • Conclusion: Significant difference between morning and evening arms suggest influence of circadian rhythms

Brachytherapy

• Image-guided brachytherapy working group
  • 2004 PMID 15519788 — "Proposed guidelines for image-based intracavitary brachytherapy for cervical carcinoma: Report from Image-Guided Brachytherapy Working Group." Nag et al. Int J Radiat Oncol Biol Phys. 2004 Nov 15;60(4):1160-72.