Brachytherapy for Cervical Cancer

AC presents on complications of brachytherapy for cervical cancer.

Reviews the treatement of a IIIB cervical cancer (invovlement of the sidewall).

Treat to 45Gy with 1.8 Gy/day and 40mg/m2 CDDP weekly.  Follow by a T&O boost to an additional 40 Gy to point A.  Sidewall boost to an additional 5-10Gy (with a goal of 60-65Gy to point B).  

For dosimetry, patients regularly undergo CT after implant.  Occaisionally one can see a perforation of the superior aspect of the uterus.  The Uterus usually sounds to around 8cm maximum, and one usually will set the flange to just below the sound.  

DPB makes the point that often perfs are created during the sounding process, and emphasises that the sound should be held lightly with 2 fingers and the thumb to reduce the risk of perforation.

Risks: Hemmorhage, Infection, and Irradiation of adjacent structures.

Clinically Detecting a Perforation: 

• Loss of resistance during instrumentation
  
• Extension into the uterus for greater than expected distance
  
• Severe caginal bleeding
  
• Perioperative Hypotension
  
• Signs of infection
  

Detection on plain films can be challenging due to indivdual variation in anatomy.

U/S may be used per Fox Chase - with a full bladder a transabdominal u/s may be used throughout the placement of the tandem.

Granai Ob Gyn 1990 75(1):110.  50 placements.  10% frank perforation per u/s, 24% with myometrial penetration, and 34% with suboptimal positioning of the tandem.  U/S affected management in 21/50 placements.  In follow up 73 placements were performed with real-time U/S guidance, and only 1 was suboptimally placed.

Barnes Int J Gyn Cancer 2007;17:821.  CT detection series.  124 LDR insertions - compared Rad Oncs clinical impression with CT findings.  14% had perfed by CT.  MD concern sensitivity 53%, specificity 84%.  MD concern, >=60yo, tumor size.

Irvin 2003; Gyn Onc 90:113.  Laparoscopic series from UVA to ensure correct tandem placement.  

Kim 1983; Radiology 147:249.  622 pt 1971-1981, UAB.  14 perforations, managed by halting the application, and close monitoring.  1 had pelvic abscess, 1 had pyometria.  Only 7 were given prophylactic antibiotics, and none of these had complications.

Jhingran & Eifel.  2000;IJROBP 46(5):1177.  4043 pt undergoing LDR.  113 (3%) had perforation, in 50% tandem was repositioned and treatment proceeded, 41% had the tandem removed and successfully reinserted later.  9% were unable to undergo brachytherapy.  Demonstrated that there were increased risks with older age.   Thromboembolisms seen in 0.3% (11pts).  

What about HDR - 169pt from Wisconsin, Petereit 1998;IJROBP 42(5):1025. 822 placements.  19 perforations seen by US (2% of insertions, 11% of patients). Routine antibiotic prophylaxis was not used.  Age and PS were associated with complications

In Summary: Perforation occurs in 2-4% of insertions, with an increase of up to 10-15% with prospecitive imaging surveillance.  Age >60 is a risk factor.  Conservative repositioning may be performed without clinically relavent complications.  For limited fundal perforations, based on experience from Dr. Montana at Duke, the tandem may be loaded with a spacer at the superiormost location without repositioning, provided that dosimetry is accpetable.

  

History of Cervical Cancer Treatment

Dr. Montana presents on the history of cervical cancer treatment.

Timeline:

1895 Roentgen discovers x-rays

1896 Becquerel discovers natural radiation

1898 Polonium and Radium discovered by Marie and Pierre Curie

Polonium is named after Marie's native Poland.

1934 Discovery of artificial or induced radioactivity Irene and Frederic Joliot-Curie

1903 intracavitary brachytherapy was first used for treatment of a gynecologic cancer - Margaret Cleaves

1903 Alexander Graham Bell proposes interstitial brachytherapy as a treatment for neoplasm

Aspects of Cervical Cancer which make it ideal for brachytherapy : Accessibility, Radiosensitive, Tolerance of normal tissues, and an Orderly pattern of Spread.

Competing systems of Brachytherapy.

Paris  - tandem of rubber, colpostats fabricated of cork with paraffin coating.  tandem loading 6.66 13.33 13.33, colpostats 13.33 and 13.33.  120 hour insertion - dose was 7200 mg*hrs.

Stockholm - metal tandem and colpostats.  tandem as ~40mg, vaginal plaque was loaded at 70mg.  Applications of 20-30hrs of 3 applications over 3 weeks.  6844 - 7266 mg*hrs.

Manchester - rubber tandem and ovoids.  units of radium 1unit=5mg radium.  tandem was 2-2-1, ovoids 3-5 depending on size.  7200 r were prescibed to point A (2cm superior to the flange or top of the ovoids, along the axis of tandem, 2cm laterally to the axis of the tandem).  Packing was used to distance critical normal tissues. 

Significant cure rates began occuring in the late 1910s to mid 1920s.  By the 1940s 5 year OS was ~35%.

MD Anderson - Fletcher grew up in France - initially came to Memorial for practice, and gathered experience at Stockholm and Manchester system.  Developed the a preloaded applicator, which forms the basis of our current system.  Fletcher was a big proponent of the mg*hrs system, though point A began to dominate Rx points.   Loading was 1.2 to 1 ratio of uterine to vaginal cavity activity.  Introduced vaginal mucosa, bladder, and rectal dose tolerance.  Also tailored mg*hours in combination with EBRT to stage of disease.

Herman Suit - Introduced afterloaded applicator to reduce exposure to physicians. 

1963 - afterloading brachytherapy

1974 - HDR brachytherapy

1976 - afterloading transperineal

1977 - 3D treatment planning

1996 - IMRT 

Future Directions should be geared towards reducing cost of current state of the art treatments (vaccines - concurrent chemotherapy) so that these innovations can be disseminated to the developing world. 

Locally Advanced Cervical Cancer

AC presents a case of Locally Advanced Cervical Cancer.

Case: 42yo G4P3 woman presenting with hx of 3mo vaginal bleeding, and discharge. Biopsy positive for moderately differentiated SCC of the cervix. On exam, 5cm exophytic mass noted with parametrial involvement; cervix was fixed the sidewall. On PET, multiple Pelvic nodes were positive.

2nd most common cancer worldwide, with a predominance in south america, africa and south asia. In the US, it is the 6th most common (11,150 new cases in 2007), largely due to the widespread implementation of Pap testing.

Risk factors: HPV 16, 18 (E6 and E7 act on p53 and the Rb protein). Smoking, immunosuppression also associated. Prenatal DES is associated with clear cell adenocarcinoma.

Likely the incidence of cervical cancer will decrease with the increasing penetrance of the HPV vaccines.

Brief FIGO Staging Basics: IA microscopic, IB1 visible <=4cm, IB2 >4cm, IIA proximal vagina, IIB parametrium, IIIA distal 1/3 vagina, IIIB pelvic sidewall (including hydronephosis), IV involvement of bladder or rectum. Primarily a clinical staging system. Only exam and IVP may be used to stage, though hydronephrosis on CT can also be used to obtain IIIB. Stage IV diagnosis can only be arrived at after cysto or procto with biopsy proven involvement.

Of course, when determining treatment, one uses all of the information available including PET, CT, MRI and other modalities not included in the FIGO system.

1. Hreshcyshyn IJROBP 1979: IIIB, IVa, n=104, randomized to XRT+brachy +/- HU. Improved median survival 20 vs 11mos.

2. GOG85 IIB-IVa n=388 Whitney JCO 1999, XRT+brachy with HU vs 5FU/CDDP. All patients had operative nodal evaluations. PFS 57 vs 47%, OS 55 vs 43%, SS with one-tailed test.

3. RTOG 9001: Eifel JCO 2004 (update). IIB-IVA or IB-IIA >=5cm or positive nodes. EFRT (WPRT + PA nodes) vs WPRT with CDDP(75mg/m2)/5FU x 2, n=405. 8yr OS benefit: 67 vs 41% (SS), including local control, and DFS.

4. GOG 120: Rose JCO 2007 (update). IIB-IVA, n=526. XRT with CDDP (40 mg/m2) weekly, CDDP(50 mg/m2)/5FU/HU x 2, or HU twice weekly. Both CDDP arms were superior with 10yOS 53% vs 34% in HU arm, PFS and LC similarly improved (all SS).

5. GOG 109/Intergroup: Peters JCO 2000. IA2-IIA n=268, undergoing Rad Hyst and LND, with +LN, +parametrium, +margins randomized to RT vs RT+CDDP/5FU. 4yOS 71 vs 81%, with PFS benefit as well 63 vs 80%, all SS.

6. GOG 71: Keys 2003. IB2 (n=256) all underwent CTRT, randomized to observation vs TAH (doses of RT were slightly different between arms, 40Gy WPRT + 40Gy to pt A in the non-operative arm, 45Gy WPRT then 30Gy to pt A in the operative arm). 5y LC 27 vs 14% (no statistical significance). No PFS or OS advantage.

7. GOG 123: Keys NEJM 1999. IB2 (n=369), RT vs RT/CDDP then TAH. CDDP improved, OS (3yr 74 vs 83%), DFS, LC, all SS.

8. NCIC (Pearcey JCO 2002): n=253 IB-IVA. RT vs RT+CDDP (40mg/m2 weekly). 5yr OS 62 vs 58% (NS), no difference in PFS or LC. This is the outlier and reasons for why this trial is divergent remains a subject of debate.

Probably, however, it's simply due to a power issue as described during conference by DK and DB. I'm going to describe this in a separate post.

The approach at Duke is to treat with WPRT to 45Gy in 1.8Gy/fx, with weekly CDDP at 40mg/m2. This is followed by a brachytherapy boost via T&O to a total dose to point A of 75-85Gy. In this patient the PA nodes were treat in the initial fields (4field) and the boost was followed by a side wall boost of an additional 9 Gy.