American Brachytherapy Task Group Report: A pooled analysis of clinical outcomes for high-dose-rate brachytherapy for cervical cancer

Abstract

PURPOSE

Advanced imaging used in combination with brachytherapy (BT) has revolutionized the treatment of patients with cervical cancer. We present a comprehensive review of the literature for definitive radiation with high-dose-rate (HDR) BT. In addition, we investigate potential outcome improvement with image-based brachytherapy (IBBT) compared to studies using traditional Point A dosing. This review extensively investigates acute and late toxicities.

METHODS AND MATERIALS

This study reviews the literature from 2000 to 2015 with an emphasis on modern approaches including concurrent chemotherapy (chemoRT), radiation, and HDR BT and IBBT. Descriptive statistics and pelvic control (PC), disease-free survival (DFS), and overall survival (OS) outcomes were calculated using weighted means to report pooled analysis of outcomes.

RESULTS

Literature search yielded 16 prospective, 51 retrospective studies that reported survival outcomes, and 13 retrospective studies that focused on acute and late toxicity outcomes regardless of applicator type. There are 57 studies that report Point A dose specification with 33 having chemoRT, and 10 studies that use IBBT, 8 with chemoRT. Patients receiving radiation and chemoRT with HDR BT in the prospective studies, with >24 months followup, rates of PC were: for RT: 73%, SD: 11; CRT: 82%, SD: 8; DFSdRT: 55%, SD: 10; CRT: 65%, SD: 7; OSdRT: 66%, SD: 7; CRT: 70%, SD: 11. In the retrospective studies, the PC rates (weighted means) for the radiation and chemoradiation outcomes are 75% vs. 80%, and for DFS, the values were 55% vs. 63%, respectively. Comparing patients receiving chemoRT and IBBT to traditional Point A dose specification, there is a significant improvement in PC (p < 0.01) and DFS (p < 0.01) with IBBT. The range of genitourinary late toxicity reported for radiation was Grade 3: 1–6% and for chemoRT 2–20%. The range of late gastrointestinal toxicity for radiation was Grade 3: 4–11% and for chemoRT, 1–11%. For the late gynecologic toxicity, only 1 of the 16 prospective trials report a Grade 1–2 of 17% for radiation and 9% for chemoRT effects.

CONCLUSIONS

We present concise outcomes of PC, DFS, OS, and toxicity for cervical cancer patients treated with chemoradiation and HDR BT. Our data suggest an improvement in outcomes with the use of IBBT compared with traditional Point A dose prescriptions. In conclusion, HDR BT is a safe, effective modality when combined with IBBT.

Introduction

Cervical cancer affects over 12,000 women in the United States and accounts for more than 4200 deaths annually. Advanced stage disease (Stage ≥ IIB) continues to be an important cause of morbidity and mortality (1). Definitive irradiation, with both external beam radiation and brachytherapy (BT), has been the mainstay of curative treatment of locally advanced cervical cancer for more than half of a century. BT is a key component in the treatment of cervical cancer as it allows for dose escalation to the tumor while minimizing the dose to surrounding critical organs at risk (OAR) such as the sigmoid, bladder, and rectum. Patterns of care studies established the essential role of BT in the management of cervical cancer and linked its use to improvements in pelvic control (PC) and disease-free survival (DFS) (2).

In 1999, the National Cancer Institute issued a practice changing statement mandating that the new standard of care includes the addition of concurrent chemotherapy (chemoRT) to radiation therapy due to significant outcome improvements. This consensus statement revolutionized the management and clinical outcome of locally advanced cervical cancer (3–8). While the integration of systemic therapy in the treatment paradigm of locally advanced cervical cancer has evolved, radiation treatment options have also significantly progressed over time. In the late 1990s, radiation therapy centers around the globe started a major transition from the routine use of low-dose-rate BT to high-dose-rate (HDR) BT (9). Furthermore, within the last decade, the advent of image-based brachytherapy (IBBT) for both applicator insertion and treatment planning has increased the procedural implantation and treatment planning options for the treatment of cervical cancer (10). With the widespread use of sophisticated imaging modalities in radiation oncology departments, the use of three-dimensional (3D) imaging for contouring and treatment planning for gynecologic BT is increasing (11–17). In 2008, the American Brachytherapy Society published a practice patterns survey regarding 3D imaging in gynecologic BT (18). Of the survey responders, 70% obtained a CT scan during the implantation process (18) whereas in 2014, 95% report using CT (Grover et al. IJROBP accepted, personal communication). An increasing number of radiation centers have switched over the past decade from two-dimensional (2D) treatment planning to IBBT (11, 13–22). Use of image guidance is more complex and time consuming and, resultantly, has not been universally adopted (23, 24). The use of MRI-based BT has also increased to 34% compared to the 2007 survey (Grover et al., IJROBP accepted). The benefit of MRI in the planning process is the superior soft tissue delineation that permits targeting of the residual tumor volume with BT. In addition, MRI-based BT is used to determine the parametrial involvement or areas of gross tumor response known as the “gray zones” that are not in the gross tumor volume but need to be included in the high risk clinical target volume. This delineation can allow for dose escalation to the primary tumor and targeting of response after chemoRT with external beam (13–15).

Unfortunately, with the advent of more sophisticated external beam radiation modalities, the increasing use of image-based radiation requiring advanced technical skills for competency, and the increased complexity with HDR, the use of BT for cervical cancer has declined. In a recent SEER review, the BT utilization rate for cervical cancer has decreased from 83% in 1988 to 58% in 2009 (p < 0.001), with a corresponding decline in overall survival (OS) (25).

There is a plethora of data reporting outcomes in cervical cancer after definitive radiation. The purpose of this comprehensive review is to present the recent PC, DFS, and OS outcomes in the era of chemoRT and HDR BT for locally advanced cervical cancer. Furthermore, we sought to explore potential outcome differences that exist between IBBT and traditional Point A dosing and 2D planning in the available literature with chemoRT. In addition, we also examine acute and late gastrointestinal (GI), genitourinary, and gynecologic toxicity outcomes after definitive therapy.

Methods and materials

We define inclusion criteria for the literature search using the Population, Intervention, Control, Outcome, Study Design (Table 1) approach (26). We searched the published English medical literature from January 2000 until May 2015 in MEDLINE and PubMed using the terms “cervical cancer,” “high-dose-rate,” “radiation,” and “brachytherapy.” This search yielded 649 published articles. Of those, both prospective and retrospective studies with at least 40 patients with at least 24 months of reported followup (FU) were included for this analysis. Case reports, abstracts, dosimetric studies, special populations, low-dose-rate, MDR, small studies less than 40 patients, short FU <24 months reported, redundant study populations, chemoRT/study drug objectives, posthysterectomy, review article, non–cervical cancer studies, and specific studies on applicator molding were excluded. The abstract refinement then yielded 150 full text articles. Eighty-seven articles met the inclusion criteria: 16 prospective outcomes, 0 prospective toxicity, 51 retrospective outcomes, and 13 retrospective toxicity studies as shown in Fig. 1. We then performed an in-depth review for analyses of primary clinical outcomes PC, DFS, OS, and acute and late toxicities. For the IBBT group, there were 10 prospective and retrospective studies and 57 that used Point A dosing. We then examined the eight studies that used chemoRT and IBBT, and 33 investigations that report on chemoRT outcomes using Point A prescriptions.

Table 1.

Population, Intervention, Control, Outcome, Study Design (PICOS) inclusion criteria

Population	Females with FIGO stage IB1–IVA cervical cancer
Intervention	Primary radiation or chemoradiation followed by HDR brachytherapy, defined as radiation that is delivered as 1–6 fractions (typically, 4–5), at 5.5–7 Gy per fraction after EBRT
Control	Either no control group (i.e., HDR BT as a single-arm study) or a multiarm study that contains an HDR BT arm
Outcomes
Efficacy	Primary clinical (surrogate outcomes) for all studies: local control, disease-free survival, and overall survival
Toxicity	Late LENT/SOMA, RTOG, CTCAE v 4: GU, GYN, GI toxicities; sexual toxicity
Study design
Efficacy	All prospective and retrospective studies, >40 patients, with one or more arms, >24 month FU
Toxicity	All prospective and retrospective studies, >40 patients, with one or more arms, >24 month FU

BT = brachytherapy; EBRT = external beam radiation therapy; HDR = high-dose-rate; FU = followup; GI = gastrointestinal; GU = genitourinary; GYN = gynecologic; RTOG = radiation therapy oncology group; LENT = Late Effects Normal Tissue Task Force; SOMA = Subjective, Objective, Management, Analytic; CTCAE = Common Terminology Criteria for Adverse Event.

Fig. 1.

Search results. LDR = low-dose-rate; MDR = medium-dose-rate.

Given the heterogeneity of the patients reported, some studies describe a percentage of patients being treated with radiation vs. chemoRT. We therefore report the outcomes of radiation and chemoRT patients separately in the descriptive tables. In addition, for the toxicity results, several studies do not specify a toxicity scale. Most of the acute and late toxicity reports use the radiation therapy oncology group (RTOG), Common Terminology Criteria for Adverse Events version 3 or 4, European Organisation for Research and Treatment of Cancer, or Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA) scales. We combined rectal and bowel toxicity to report GI toxicities together. For a comprehensive analysis of outcomes and creation of figures, we included all retrospective and prospective studies. The outcomes in terms of PC, DFS, or OS are reported as actuarial or median FU time. For the acute and late toxicities, we constructed graphs of median number with toxicity outcomes and severity using a toxicity scoring system. In the data analysis of toxicity, we note that most studies use RTOG criteria for grading late toxicity. For the IBBT group, we include studies that use CT- or MR-based planning as a comparison to the group that prescribed dose to Point A.

Statistical analysis

For comprehensive analysis of outcomes and creation of figures, we include all retrospective and prospective studies. Descriptive statistics were calculated using SAS 9.4 (Cary, NC). We note that reported DFS, OS, and PC rates differ among those treated with radiation (RT) vs. chemoRT (CRT), and several studies have a combination of treatment groups. The outcomes in terms of PC, DFS, or OS are reported at an actuarial or a median FU time. We construct plots of PC, DFS, and OS around a weighted mean of outcome. Using a pooled analysis and patient numbers in the studies examined, we provide weighted means calculated using the statistical software, R version 3.2.1 (open source) and corresponding Forest plots with the pooled SD and 95% confidence intervals (CIs). Time points chosen for the weighted means calculation were greater than 24 months as reported study outcomes. Ideally, we would be able to report outcomes at various specific time points, but the data set did not allow for this specification. The reported FU time in the data set is actually the mean of all subjects’ FU times in the included studies. To compare the IBBT and the Point A prescription studies using chemoRT, we compared the weighted means, with the 95% CI, calculated as each individual study. To compare the results, a Student’s t-test was used with the SD representing the SD for the sample mean. For the Forest plots, the width of the line shows the confidence, with the area of the horizontal box representing the weight given to the studies included. For the acute and late toxicities, we constructed graphs of median number of articles with toxicity outcomes and severity using a toxicity scoring system with weighted means. In data analysis of toxicity, we note that most studies use RTOG criteria for grading toxicity. Given the variation in the scoring scale and time points reported of the studies, we report crude toxicity percentages vs. a weighted mean analysis.

Pelvic control

The literature search yielded 16 prospective studies reporting on local control for radiation or chemoRT and HDR BT for cervical cancer (10, 27–41). Local control is defined as no recurrence in the pelvis. Of the studies, six report outcomes with radiation and 12 report chemoRT outcomes. For those patients, the weighted mean PC at ≥24 months for RT: 74%, SD: 11 (95% CI: 52, 95) and CRT: 81%, SD: 9 (95% CI: 64, 99). For the 51 retrospective studies reviewed that met our criteria, 28 studies reported PC outcomes for radiation and 28 for chemoRT with HDR BT (42–92). The weighted mean PC rate at ≥24 months for RT was 75%, SD: 18 (95% CI: 40, 110) and for CRT was 81%, SD: 16 (95% CI: 49, 112).

Disease-free survival

Nine prospective studies report DFS outcomes for cervical patients treated with HDR BT with radiation and chemoRT. The weighted DFS means at ≥24 months for the patients treated with RT: 55%, SD: 9.6 (95% CI: 36, 74) and CRT: 65%, SD: 7 (95% CI: 51, 80). For the retrospective studies, the weighted DFS means at ≥24 months for the patients treated with RT: 56%, SD: 20 (95% CI: 16, 96) and CRT: 63%, SD: 21 (95% CI: 22, 104).

Overall survival

For the prospective studies, the weighted mean at ≥ 24 months for OS for the RT: 66%, SD: 7 (CI: 52, 80) and CRT: 65%, SD: 7 (CI: 51, 80). For the retrospective series, there are 37 studies provide a weighted mean OS for the RT: 54%; SD: 18 (18, 90) and CRT: 66%, SD: 17 (33, 99).

Tables 2 and 3 display the prospective and retrospective studies, respectively, with the study characteristics and outcomes for PC, DFS, and OS for the radiation and chemoRT patients. Table 6 depicts the weighted means and outcomes for the prospective and retrospective studies with a corresponding forest plots in Figs. 2 and 3.

Table 2.

Prospective outcomes for HDR brachytherapy

Author	Reference	No pts	Phase	Arms	Stage	WPRT	PM boost	HDR dose/fx	Fx #	Total HDR	HDR Rx	Median f/u	F/u mo	Stage	Pelvic control (RT)	Pelvic control (CRt)	DFS (RT)	DFS (CRT)	OS (RT)	OS (CRT)
Pearcey et al., 2002	(37)	259	3	RT vs. CRT (cis)	Ib–IVa	45		8	3	24	A	82	36				65	68	66	69
													60		57	65	60	70	58	62
Lorvidhaya et al., 2003, 2000	(35, 69)	926	3	RT vs. RT (MMC 5 FU)	2B–4a	50	10–16	7–7.5	4	28	A	89	60		75	86	48	65	71	83
				4 arms, reporting 2
Garipagaoglu et al., 2004	(27)	44	3	RT vs. CRT (cis)	2b–3b	46–50		10	2	20	A	40	60		69	64	67	59	52	49
Lanciano et al., 2005	(33)	316	3	CRT (cis) vs. CRT (5 FU)	2b–4a	45	4–9	6	5	30	A	40	48					57		64
Yoon et al., 2006	(40)	43	1, 3	CRT (cis and 5 FU) (RT 6 days/wk)	1b–3b	45	5.4	4	6	24	A	37	36			88		85		75
Kim et al., 2005, 2008	(31, 32)	158	3	CRT (wk cis) vs. CRT (cis 5 FU month)	2B–4a	40–50		5	6–7	30–35	A	39	48			87		66		67
Toita et al., 2012	(39)	72	2		3–4a	30–40.1		5.5–6	2	11	A	28	24			73		70		90
Huang et al., 2013	(29)	267	3	CRT 2 HDR fx schema	Ib–4a	39.6–45		4.5–6	4–6	24	A	57	60			80				66
Kato et al., 2013, 2010	(30, 60)	120	2		2b–3b	30–40	10	6–7	4	24–28	A	64	60			77				55
Zuliani et al., 2014, 2010	(41, 92)	147	3	RT vs. CRT	3b	45					A	43	36						64	68
													60				49	54	54	56
Hareyama et al., 2002	(28)	151	3	RT LDR vs. RT HDR	2–3b	30–50		5.8	5	29	A		60	2	89		69
								5.75–7.6	3, 4	23				3	69		51
								8.65–5.76	2, 3	17.5
Potter et al., 2011, 2006, 2007, 2000	(10, 14, 81, 82)	156	2	RT HDR plus CT		45–50.4		7	4	28	IGBT	42	36			91		74		68
Lertsanguansinchai et al., 2004	(34)	112	3	RT (LDR vs. HDR)	1b1–3b	45–50	4–9	7.5	3	22.5	A	37	36		86		70		68
								8.3	2	16.6
Nam and Ahn, 2004	(36)	46	3	HDR fx schema	1b1–4a	45		3	10	30	A	46	36					88		76
								5	5	25
Kim et al., 2005, 2008	(31, 32)	61	3	CRT 5 FU cis vs. CRT cis	2b–41	41.4–50.4		6	5	30	A	44	48			89	59			70
								7	5	35	A
Sharma et al., 2011	(38)	42	2	CRT (interstitial)	2b–4a	40		10	2	20	CT	23	36			62		55		47
Huang et al., 2013	(29)	267	3	HDR fx schema (CRT and RT)	1b–4a	39.6	5.4	6	4	24	A	57	60			80				65

HDR = high-dose-rate; DFS = disease-free survival; OS = overall survival; FU = followup; WPRT = whole pelvic radiation therapy; PM = parametria; CRT = chemoradiation; RT = radiation; CRt = chemoradiation; MMC = Mitomycin C.

Table 3.

Retrospective outcomes for HDR brachytherapy

Author	Reference number	No pts	Phase	Arms	Stage	WPRT	PM boost	HDR dose/fx	HDR fx	Total HDR	Rx HDR	Median f/u	F/u mo	Stage	Pelvic control (RT)	Pelvic control (CRT)	DFS (RT)	DFS (CRT)	OS (RT)	OS (CRT)
Lorvidhaya et al., 2003, 2000	(35, 69)	2063		RT	Ia–4a	30–50		5.5–7.5	4–6	30 Jan	A	96	60				54		68
Potter et al., 2011, 2006, 2007, 2000	(10, 14, 81, 82)	189		RT	1–4	48.6–50		7	3–4	21–28	A	34	36		78		69		58
Ferrigno et al., 2001, 2005	(52, 53)	138		RT		45	9	6	4	24	A	38	60		62		53		54
Hama et al., 2001	(56)	124		RT HDR fx	1–4	50		4.5–7	3–6	21–27	A		60		76		63		65
Kucera et al., 2001	(64)	189		RT HDR	1 –4b	42	6–8	7	5–6	35 or 42	A	70	36						58
Chen et al., 2006	(48)	295		RT elderly	1b–4b	40–45	5–13	7.2	4	28
								6		24
Ogawa et al., 2003	(74)	442		RT		44–53		6	5	30	A	60	60				63		60
Okkan et al., 2003	(75)	293		RT		54		8	3	24	A	60	60		73		53		45
Sood et al., 2003	(85)	54		RT	1b–3b	45	9	8	3	24	A	28	36		100	90			90	78
								9.6	1	9.6
								10	1	10
Mayer et al., 2004	(70)	210		RT	2a–3b	30		8	4	32	A	40	60			69				89
								6	5	30
Okuda et al., 2004	(76)	146			1–4a	45		6	5	30	A	82	58				71		62
Ferrigno et al., 2001, 2005	(52, 53)	118			1–3	40–50		6	4	24	A	70	60		65		56		55
Nakano et al., 2005	(71)	1148			1b–4b	40–50		6	4	24	A	264	120		78				Stage 1b–74%	Breaks down by stage
								5	3	15									Stage 2–52%
																			Stage 3–42%
																			Stage 4a–17%
Patel et al., 2005	(79)	121		RT	1b–4b	40–46		9	2	18	A	60	60
															75		62		62
Souhami et al., 2005	(87)	282		RT	1b–4a	45		8	3	24	A	50	60						57
													120						52
													180		85				47
Chen et al., 2015	(47)	171		RT vs. CRT (weekly cisp)	2b–3	45	6–12	6	4	24	A	52	48		85	87			68	74
Falkenberg et al., 2006	(51)	57		LDR vs. HDR	2b–3	45		6	4	24	A	59	36		76		59		55
								6	5	30
Gerszten et al., 2006	(54)	107	(44% RT got chemo)	LDR vs. HDR	1b–3b	45–50		5	5	25	A		60		95		54		53
Atahan et al., 2007	(43)	183	49% chemo	RT vs. CRT (weekly cisp)	2b–3b	45						45	60		71		51		55
Jain et al., 2007	(57)	214		RT	1-4	50–54.4		7.5	2	15	A	59	60	1	42		58		58
														2			44		49
														3			33		37
														4			15		23
Khor et al., 2007	(61)	106		RT	2–4	45–50.4		6	3	18	A	59	60		81		71		69
Novetsky et al., 2007	(73)	77		CRT (cisp)	1b2–4	45	9–14	9	2	18	A	42	60			83		74
Ozsaran et al., 2007	(77)	76		CRt (weekly cisp)	1b2–4a						A	42	60			82		77		69
Potter et al., 2011, 2006, 2007, 2000	(10, 14, 81, 82)	145		RT and CRT (55% weekly cispl)	1b–4a	45–50.4		7	4	28	MRI	51	36		82	85	85	85	58	58
Kim et al., 2005, 2008	(31, 32)	158		CRT 3 monthly 5FU plus 5 days of cisplatin vs. weekly cisplatin	2b–4a	41.4–50.4		5	6	30	A	39	48					69		66
								5	7	35
Liang et al., 2008	(68)	148		CRT weekly cisp	1b2–4a	45	9–12.6	5	6	30	A	49	48	1b2–2a		100		92		82
								6	5	30				2b		92		78
														3		81		51
Sakata et al., 2008	(83)	226		CRT vs. RT	1b2–4	30				24	A			Ib2–2	91	100	76	74	81	82
														3–4	71	83	52	59	43	66
Kim et al., 2009	(62)	51		CRT (weekly cisp)	1b1–4a	40–50.4		7	4	28	MRI	24	24			96		73		86
											CT									72
Parker et al., 2009	(78)	92		CRT (weekly cisp)	1b2–4a	45		6	4	24	A		24			76				55
													60			67
Azad and Choudhary, 2010	(44)	342		CRT	1–4	45		6.5	3	19.5	A	36	36	1				82		82
														2				70		78
														3		47		40		54
														4				12		41
Kato et al., 2013, 2010	(30, 60)	84		RT		50		6	4	24	CT	44	60		90				78
Niibe et al., 2010	(72)	61		RT and CRT	3b	40–59.4		6	5	30	A		60		36	36	13	13	20
Sorbe et al., 2010	(86)	131		CRT (weekly cis) some without chemo	1–4	50–60		6	5	30	A		60					70		65
								6	3	18										50
Teh et al., 2010	(88)	120		CRT (cispl weekly)	1b2–4a	46–50.4		6	3	18	A		60			82		57		65
								5	4	20
Zuliani et al., 2014, 2010	(41, 92)	155		CRT	3b	40–50.4		7	4	28	A		60					60		65
Beriwal et al., 2011	(45)	44		CRT (weekly cisp	1b1–3b	45–50.4		5	5	25	MRI	8	24			88		85		86
								6	5	30
Das et al., 2011	(49)	286		RT	2b–4a	40	10–20	7	3	21	A		24		75
Schmid et al., 2011	(84)	265		CRT and RT								17				90
Kannan N., 2012	(59)	47		CRT (interstitial only)	2b–4a	45		3.75	5	18.75	CT	14.6	24			61		43		59
												30
Kim et al., 2012	(63)	174		CRt (weekly cis, or cis FU, or cis paclitaxel))	1b1–4a	45	5.4	5	6	30	A		60	1b1–2a						92
														2b						72
														3						45
														4a						20
Kuroda et al., 2012	(66)	131		CRT (weekly cisp)	3b	40–60		5	6	30	A	44	60			80		60		52
Lee et al., 2013, 2012	(67, 93)	209		CRT (cispl)	1b2–4a	41.4–50.4	10–15	5	6	30	A	52	60					74		67
Al Asiri et al., 2013	(42)	74		CRT	1b2–4a	45		7	4	28	A	60	60			84		76		65
Kudaka et al., 2013	(65)	99		CRT (weekly cisp vs. q 3 cisplatin)	3–4a	50	6–10					58	60			83		69		72
Pinn-Bingham et al., 2013	(80)	116		CRT (interstitial only)	2b–4a	50.4		6	6	36	CT	35	36			85		68		58
													60					60		44
Yamashita et al., 2013	(90)	118		CRT (<40 yo)	1b–4a	30.6–50.4		6	4	24	A	48	60			61				65
Chatani et al., 2014	(46)	218		RT diff HDR (A vs. B)	1b–4a	20–40		6	4	24	A		60	1	86		81
								5	4	20				2	7		89
								5	5	25				3			52
								7.5	5	37.5				4			15
								6	6	36
Zhang et al., 2014	(91)	45		EFRT IMRT	1b2–3b	50.4	5.4–9	6	4	24	A	28						69		85
								6	5	30
Chen et al., 2015	(47)	125		IMRT (weekly cis)	1b2–3	45–54				20–33.5	A	42	48			92		67		74
Gill et al., 2015	(55)	128		CRT	1b1–4a	45		5	6	30	A	24	24			92		82		88
								5	5	25
Wong et al., 2003	(89)	220		RT	1b–4a	40		7	3	21	A	56	60	1b	88		88		72
								6	4	24				2a	90		85		80
														2b	80		67		67
														3b	76		45		45
														4a	74		0		25
Kang et al., 2010	(58)	97		CRT (weekly cis)	1b–4b	36–45		5	6	30	CT		36			97
								7	4	28
								6	4	24

HDR = high-dose-rate; DFS = disease-free survival; FU = followup; LDR = low-dose-rate; EFRT = extended field radiation therapy; IMRT = intensity modulated radiation therapy.

Table 6.

Weighted means and outcomes for the prospective, retrospective, IBBT, and non-IBBT studies

Treatment	Prospective				Retrospective				IBBT with chemoRT				Point A dose chemoRT
	Mean	SD	Lower bound	Upper bound	Mean	SD	Lower bound	Upper bound	Mean	SD	Lower bound	Upper bound	Mean	SD	Lower bound	Upper bound
Pelvic control (RT)	73.49	11.17	51.59	95.39	74.82	17.70	40.13	109.51
Pelvic Control (CRT)	81.27	8.84	63.95	98.59	80.51	16.08	49.00	112.03	86.00	11.27	63.90	108.10	83.84	9.17	65.88	101.80
DFS (RT)	55.23	9.60	36.41	74.05	55.72	20.46	15.62	95.82
DFS (CRT)	65.44	7.37	50.99	79.89	63.02	20.94	21.98	104.06	72.46	13.26	46.47	98.46	69.51	9.26	51.35	87.66
OS (RT)	66.06	7.26	51.84	80.28	54.05	18.14	18.49	89.61
OS (CRT)	70.15	10.58	49.41	90.89	66.19	16.72	33.43	98.96	64.33	12.06	40.69	87.97	73.36	10.64	52.49	94.23

IBBT = image-based brachytherapy; DFS = disease-free survival; OS = overall survival.

Fig. 2.

Forest plot for the outcomes for the prospective studies. DFS = disease-free survival; OS = overall survival.

Fig. 3.

Forest plot for the outcomes for the retrospective studies. DFS = disease-free survival; OS = overall survival.

IBBT vs. Point A dose prescription

We examined the eight studies using chemoRT and IBBT with the 35 studies using chemoRT and Point A dose prescriptions. Table 6 shows the weighted means and comparisons of PC, DFS, and OS between the groups. PC and DFS were significantly increased in the IBBT studies, p < 0.01 and p < 0.01, respectively. The mean improvement in PC and DFS in the era of chemoRT is 3%. The OS of the groups were statistically different, with the mean OS better in the Point A dose group vs. the IBBT group, p < 0.01. The weighted means and comparisons are shown in Table 6 with corresponding comparison of the standardized mean differences in Fig. 4.

Fig. 4.

Forest plot comparison for the IBBT and non-IBBT studies. Comparison of chemoRT mean differences of the IBBT vs. Point A dosing studies for pelvic control (Study 1), DFS (Study 2), and OS (Study 3). IBBT = image-based brachytherapy; CI = confidence interval; DFS = disease-free survival; OS = overall survival; SMD = standardized mean difference.

Toxicity

From our review, of the 16 prospective studies, only six report acute toxicity outcomes using the RTOG scale (n = 4), NCIC (n = 1), or the LENT/SOMA (n = 1). There is little data reporting for Grade 3 or higher toxicity in the prospective studies for GU toxicity for RT alone patients. For the late effects, the 14 of the 16 prospective studies report toxicity scales using the RTOG (n = 9), NCIC (n = 2), or not specified (n = 3). Of the 64 retrospective studies reviewed, 13 have a primary outcome of late toxicity reporting. Forty of the 51 retrospective outcome series report late effects after RT or CRT.

Acute toxicity

For radiation and chemoradiation treatment, in the prospective and retrospective series, the range of GU acute toxicity reported is RT: Grade 2: 1–54%, Grade 3: 1–3%, and Grade 4: 0%; CRT: Grade 2: 2–53%, Grade 3: 1–3%, and Grade 4: 0%. The range of acute GI toxicity is RT: Grade 2: 15–48%, Grade 3: 3–11%, and Grade 4: 5%; CRT: Grade 2: 5–62%, Grade 3: 1–25%, and Grade 4: 1–2%. As seen in Tables 4 and 5, only two of the IBBT studies report acute toxicity.

Table 4.

Prospective and retrospective series acute and late effects

Author	Reference	No pts	Phase	Arms	Stage	WPRT	PM boost	HDR dose/fx	Fx #	Total HDR	HDR Rx	Median f/u	F/u mo	Scale
Pearcey et al., 2002	(37)	259	3	RT vs. CRT (cis)	Ib–Iva	45		8	3	24	A	82	36	NCIC CTG
													60
Lorvidhaya et al., 2003, 2000	(35, 69)	926	3	RT vs. RT (MMC 5 FU)	2B–4a	50	10–16	7–7.5	4	28	A	89	60
				4 arms, reporting 2
Garipagaoglu et al., 2004	(27)	44	3	RT vs. CRT (cis)	2b–3b	46–50		10	2	20	A	40	60
Lanciano et al., 2005	(33)	316	3	CRT (cis) vs. CRT (5 FU)	2b–4a	45	4–9	6	5	30	A	40	48
Yoon et al., 2006	(40)	43	1, 3	CRT (cis and 5 FU) (RT 6 days/wk)	1b–3b	45	5.4	4	6	24	A	37	36	RTOG
Kim et al., 2005, 2008	(31, 32)	158	3	CRT (wk cis) vs. CRT (cis 5 FU month)	2B–4a	40–50		5	6–7	30–35	A	39	48	RTOG
Toita et al., 2012	(39)	72	2		3–4a	30–40.1		5.5–6	2	11	A	28	24	NCI CTCEA v3
Huang et al., 2013	(29)	267	3	CRT 2 HDR fx schema	Ib–4a	39.6–45		4.5–6	4–6	24	A	57	60
Kato et al., 2013, 2010	(30, 60)	120	2		2b–3b	30–40	10	6–7	4	24–28	A	64	60
Zuliani et al., 2014, 2010	(41, 92)	147	3	RT vs. CRT	3b	45					A	43	36	RTOG
													60
Hareyama et al., 2002	(28)	151	3	RT LDR vs. RT HDR	2–3b	30–50		5.8	5	29	A		60
								5.75–7.6	3, 4	23
								8.65–5.76	2, 3	17.5
Potter et al., 2011, 2006, 2007, 2000	(10, 14, 81, 82)	156	2	RT HDR plus CT		45–50.4		7	4	28	IGBT	42	36	LENT/SOMA
Lertsanguansinchai et al., 2004	(34)	112	3	RT (LDR vs. HDR)	1b1–3b	45–50	4–9	7.5	3	22.5	A	37	36
								8.3	2	16.6
Nam et al., 2004	(36)	46	3	HDR fx schema	1b1–4a	45		3	10	30	A	46	36
								5	5	25
Kim et al., 2005, 2008	(31, 32)	61	3	CRT 5 FU cis vs. CRT cis	2b–41	41.4–50.4		6	5	30	A	44	48	RTOG
								7	5	35	A
Sharma et al., 2011	(38)	42	2	CRT (interstitial)	2b–4a	40		10	2	20	CT	23	36
Huang et al., 2013	(29)	267	3	HDR fx schema (CRT and RT)	1b–4a	39.6	5.4	6	4	24	A	57	60
Lorvidhaya et al., 2003, 2000	(35, 69)	2063		RT	Ia–4a	30–50		5.5–7.5	4–6	30 Jan	A	96	60	Not spec
Potter et al., 2011, 2006, 2007, 2000	(10, 14, 81, 82)	189		RT	1–4	48.6–50		7	3–4	21–28	A	34	36
Ferrigno et al., 2001, 2005	(52, 53)	138		RT		45	9	6	4	24	A	38	60
Hama et al., 2001	(56)	124		RT HDR fx	1–4	50		4.5–7	3–6	21–27	A		60	Not spec
Kucera et al., 2001	(64)	189		RT HDR	1–4b	42	6–8	7	5–6	35 or 42	A	70	36
Chen et al., 2006	(48)	295		RT elderly	1b–4b	40–45	5–13	7.2	4	28
								6		24
Ogawa Y., 2003	(74)	442		RT		44–53		6	5	30	A	60	60	RTOG/EORTC
Okkan S., 2003	(75)	293		RT		54		8	3	24	A	60	60	Not spec
Sood et al., 2003	(85)	54		RT	1b–3b	45	9	8	3	24	A	28	36	Not spec
								9.6	1	9.6
								10	1	10
Mayer et al., 2004	(70)	210		RT	2a–3b	30		8	4	32	A	40	60	Not spec
								6	5	30
Okuda et al., 2004	(76)	146			1–4a	45		6	5	30	A	82	58
Ferrigno et al., 2001, 2005	(52, 53)	118			1–3	40–50		6	4	24	A	70	60
Nakano et al., 2005	(71)	1148			1b–4b	40–50		6	4	24	A	264	120
								5	3	15
Patel et al., 2005	(79)	121		RT	1b–4b	40–46		9	2	18	A	60	60
Souhami et al., 2005	(87)	282		RT	1b–4a	45		8	3	24	A	50	60
													120
													180
Chen et al., 2015	(47)	171		RT vs. CRT (weekly cisp)	2b–3	45	6–12	6	4	24	A	52	48
Falkenberg et al., 2006	(51)	57		LDR vs. HDR	2b–3	45		6	4	24	A	59	36
								6	5	30
Gerszten et al., 2006	(54)	107	(44% RT got chemo)	LDR vs. HDR	1b–3b	45–50		5	5	25	A		60
Atahan et al., 2007	(43)	183	49% chemo	RT vs. CRT (weekly cisp)	2b–3b	45						45	60	RTOG/EORTC
Jain et al., 2007	(57)	214		RT	1–4	50–54.4		7.5	2	15	A	59	60
Khor et al., 2007	(61)	106		RT	2–4	45–50.4		6	3	18	A	59	60
Novetsky et al., 2007	(73)	77		CRT (cisp)	1b2–4	45	9–14	9	2	18	A	42	60
Ozsaran et al., 2007	(77)	76		CRt (weekly cisp)	1b2–4a						A	42	60
Potter et al., 2011, 2006, 2007, 2000	(10, 14, 81, 82)	145		RT and CRT (55% weekly cispl)	1b–4a	45–50.4		7	4	28	MRI	51	36
Kim et al., 2005, 2008	(31, 32)	158		CRT 3 monthly 5Fu plus 5 days of cisplatin vs. weekly cisplatin	2b–4a	41.4–50.4		5	6	30	A	39	48	Not spec
								5	7	35
Liang et al., 2008	(68)	148		CRT weekly cisp	1b2–4a	45	9–12.6	5	6	30	A	49	48
								6	5	30
Sakata et al., 2008	(83)	226		CRT vs. RT	1b2–4	30				24	A			ctc v2
Kim et al., 2009	(62)	51		CRT (weekly cisp)	1b1–4a	40–50.4		7	4	28	MRI	24	24	ctc v3
											CT
Parker et al., 2009	(78)	92		CRT (weekly cisp)	1b2–4a	45		6	4	24	A		24
													60
Azad and Choudhary, 2010	(44)	342		CRT	1–4	45		6.5	3	19.5	A	36	36
Kato et al., 2013, 2010	(30, 60)	84		RT		50		6	4	24	CT	44	60
Niibe et al., 2010	(72)	61		RT and CRT	3b	40–59.4		6	5	30	A		60
Sorbe et al., 2010	(86)	131		CRT (weekly cis) some without chemo	1–4	50–60		6	5	30	A		60	RTOG/EORTC
								6	3	18
Teh et al., 2010	(88)	120		CRT (cispl weekly)	1b2–4a	46–50.4		6	3	18	A		60
								5	4	20
Zuliani et al., 2014, 2010	(41, 92)	155		CRT	3b	40–50.4		7	4	28	A		60
Beriwal et al., 2011	(45)	44		CRT (weekly cisp	1b1–3b	45–50.4		5	5	25	MRI	8	24
								6	5	30
Das et al., 2011	(49)	286		RT	2b–4a	40	10–20	7	3	21	A		24
Schmid et al., 2011	(84)	265		CRT and RT								17
Kannan et al., 2012	(59)	47		CRT (interstitial only)	2b–4a	45		3.75	5	18.75	CT	14.6	24
												30
Kim et al., 2012	(63)	174		CRt (weekly cis, or cis FU, or cis palitaxel))	1b1–4a	45	5.4	5	6	30	A		60
Kuroda et al., 2012	(66)	131		CRT (weekly cisp)	3b	40–60		5	6	30	A	44	60
Lee et al., 2013, 2012	(67, 93)	209		CRT (cispl)	1b2–4a	41.4–50.4	10–15	5	6	30	A	52	60
Al Asiri et al., 2013	(42)	74		CRT	1b2–4a	45		7	4	28	A	60	60
Kudaka et al., 2013	(65)	99		CRT (weekly cisp vs. q 3 cisplatin)	3–4a	50	6–10					58	60
Pinn-Bingham et al., 2013	(80)	116		CRT (interstitial only)	2b–4a	50.4		6	6	36	CT	35	36
													60
														CTCAE v 3
Yamashita et al., 2013	(90)	118		CRT (<40 yo)	1b–4a	30.6–50.4		6	4	24	A	48	60	Not spec
Chatani et al., 2014	(46)	218		RT diff HDR (A vs. B)	1b–4a	20–40		6	4	24	A		60
								5	4	20
								5	5	25
								7.5	5	37.5
								6	6	36
Zhang et al., 2014	(91)	45		EFRT IMRT	1b2–3b	50.4	5.4–9	6	4	24	A	28		RTOG
								6	5	30
Chen et al., 2015	(47)	125		IMRT (weekly cis)	1b2–3	45–54				20–33.5	A	42	48	CTCAE v 3
Gill et al., 2015	(55)	128		CRT	1b1–4a	45		5	6	30	A	24	24
								5	5	25
Wong et al., 2003	(89)	220		RT	1b–4a	40		7	3	21	A	56	60
								6	4	24
Kang et al., 2010	(58)	97		CRT (weekly cis)	1b–4b	36–45		5	6	30	CT		36
								7	4	28
								6	4	24
Noda et al., 2007	(94)	93	RT	1b–4b	49.8–50.6		6	4	24	A
Fujikawa et al., 2001	(95)	232	RT–GI and GU tox	1–4	45–60			3–5	15–29	A		24+
Huh et al., 2002	(96)	228	RT–pelvic insuff	1b–3b	50.4–55.8		4	6	24	A
Cheng et al., 2003	(97)	62	RT–rectal toxicity	1a–4a	40–45		5	4	20	A
Chun et al., 2004	(98)	213	RT–rectal tox	1b1–4a	45	6–8	4	7	28	A	39
							5	6	30
Chen et al., 2006, 2010	(48, 99)	451	RT GU and GI tox	1b1–3b	45	5–14.4	6	4	24	A
							7.2	3	21.6
Tokumaru et al., 2012	(100)	59	RT–pelvic insufficency	1b1–32b	50		6	4	24	A	24
Trifiletti et al., 2015	(101)	85	CRT–GI toxicity	1b2–2b	45	9–10	5.5	5	27.5	CT	15
Yang et al., 2012	(102)	1518	RT–GU and GI toxicity	1b–3b	32–36	12–15	5	6	30	A
Yoshida et al., 2015	(103)	57	HDR–interstitial and T R	1b–4a	30	20	7.5	4	30		36
							6	5	30
Kirchheiner et al., 2014	(104)	588	CRT–vaginal stenosis	1b–4a	45		7	4	28	MRI	15	24
Bohr Mordhorst et al., 2014	(105)	134	CRT	1–4	50–60		6	5	30	A		60	RTOG
Georg et al., 2013	(106)	225	CRT	1b–4a	45–50.4		7	4	28	MRI	44	60

HDR = high-dose-rate; FU = followup; RTOG = radiation therapy oncology group; LDR = low-dose-rate; CTCAE = Common Terminology Criteria for Adverse Event; GI = gastrointestinal; GU = genitourinary; LENT = Late Effects Normal Tissue Task Force; SOMA = Subjective, Objective, Management, Analytic; NCIC CTG = National Cancer Institute of Canada Clinical Trials Group; EORTC = European Organisation for Research and Treatment of Cancer.

Table 5.

Prospective and retrospective series acute and late effects with scale toxicities

Author	Scale	Toxicity grade (acute)	GU (RT)	GU (CRT)	GI (RT)	GI (CRT)	GYN (RT)	GYN (CRT)	Scale	Toxicity scale (late)	GU (RT)	GU (CRT)	GI (RT)	GI (CRT)	GYN (RT)	GYN (CRT)
Pearcey 2002	NCIC CTG	3	3	1	11	1			NCIC CTG	3	5	14	6	1
		4	0	0	5	0				4	5	3	7	5
Lorvidhaya V.,2003, 2000									RTOG	3	4	3	4	3
										4
Garipagaoglu M., 2004
Lanciano R., 2005
Yoon S. M., 2006	RTOG	2		12		33			RTOG	2				7
		3		0		1				3		2		2
Kim Y. S., 2005, 2008	RTOG	2		7		20			RTOG	2		2		4
		3		0		0				3		1		2
Toita T., 2012	NCI CTCEA v3	Not spec							NCI CTCEA v3	2		7		8
										3		2		0
Huang E. Y., 2013									Not spec	2–4 (est)		7		22
Kato S., 2013, 2010									Not spec	2–4 (est)		12		26
Zuliani A. C., 2014, 2010	RTOG	1–2	54	33	43	31	4	10	RTOG	Grades 1 and 2	22	25	69	58	17	9
Hareyama M., 2002									RTOG	≥Grade 3	4		6
Potter 2011, 2006, 2007, 2000	LENT/SOMA	2		2		5		Spec Vagina: 28
Lertsanguansinchai P., 2004									RTOG	2	8		6
										3	1		5
Nam T. K., 2004									RTOG	2–4		7		13
Kim Y. S., 2005, 2008	RTOG	2		5		51			RTOG	2		0		0
		3		0		2				3		2		2
		4		0		0				4		0		0
Sharma D. N., 2011
									Not spec	2
										3				5
										4		1
Huang E. Y., 2013									RTOG	2 to 3				HDR 4: 19 vs. HDR 6: 10
Lorvidhaya V., 2003, 2000	Not spec								RTOG	Grade 3/4		3.5		4.8
Potter R. 2011, 2006, 2007, 2000
Ferrigno R., 2001, 2005									RTOG	Grade 3/4		0		11
Hama Y., 2001	Not spec								Not spec	2		3		12
Kucera H., 2001
Chen S. W., 2006
Ogawa Y., 2003	RTOG/EORTC								RTOG/EORTC	1–2		2		6
										3–4		0.2		2
										5		0		0.2
Okkan S., 2003	Not spec								Not spec	2–4		21		21
Sood B. M., 2003	Not spec
		3				25
Mayer A., 2004	Not spec	Not spec		3		7			Not spec	Not spec			13		25
Okuda T., 2004									RTOG	2	3
										3	1
										4	2
Ferrigno R., 2001, 2005									RTOG/EORTC	2
										3
										4				2
										5				1
Nakano T., 2005									RTOG	3–5		1		7
Patel F. D., 2005
									RTOG	2		2		1
										3		2		0
Souhami L., 2005
									RTOG	3		3		1.5
Chen S. W., 2015										4		0.5		5
Falkenberg E., 2006									Not spec	4				4
Gerszten K., 2006									Not spec	3 and 4	4
Atahan I. L., 2007	RTOG/EORTC	2	15		48				RTOG/EORTC	2		2		13
		3	1		3					3		8		4
		4								4		2		2
Jain V. S., 2007									RTOG	1–4		7		9
Khor T. H., 2007									RTOG	4				1
Novetsky A. P., 2007									RTOG	3 and 4	6
Ozsaran Z., 2007									RTOG	2					2
										3
Potter R., 2011, 2006, 2007, 2000									LENT/SOMA	3 and 4		4	4	4	4	3
Kim Y. S., 2005, 2008	Not spec	2		9		26			Not spec	2			4		4
		3		1		2.5				3			0		2
		4		0		1				4			0		0
Liang J. A., 2008
Sakata K., 2008	ctc v2	2	1	0	15	0			Not spec	2–4	15 (RT)
		3	0	0	0	0					35 (CRT)
		4	0	0	0	0
Kim D. H., 2009	ctc v3	2		15		10		0	ctc v3	2			4		7
		3		0		0		0		3			0		2
		4		0		0		0		4			0		0
Parker K., 2009									ctc v3	3–4			1		1
Azad S. K., 2010									RTOG	2			5		5
										3			1		1
										4			0		0
Kato S., 2013, 2010									RTOG/EORTC	2				8
										3				0
										4				0
Niibe Y., 2010
									Not spec	2–4	13
Sorbe B., 2010	RTOG/EORTC	2	2	1					RTOG/EORTC	2			5		18
										3			3		5
										4			6		6
Teh J., 2010									RTOG/EORTC	2			0
										3			0		3
										4			0		1
Zuliani A. C., 2014, 2010									RTOG/EORTC	2					4
Beriwal S., 2011
Das D., 2011									RTOG	2		2		2
										3		2		2
Schmid M. P., 2011
Kannan N., 2012									RTOG	3					1
										4					1
Kim T. E., 2012									ctc v3	Not spec			15		18
Kuroda Y., 2012
Lee H. J., 2013, 2012									Not spec	3	5
Al Asiri M., 2013
Kudaka W., 2013									RTOG	3			1
										4					2
Pinn-Bingham M., 2013
	CTCAE v 3	2	3	8					ctc v3	2			3		8
		3	0	1						3			6		10
										4			1		1
Yamashita H., 2013	Not spec	2	0	5					Not spec	2			2		2
		3	3	3						3			4		9
		4	0	2						4			0		0
Chatani M., 2014
Zhang G., 2014	RTOG	2	53	62					RTOG	2			2		4
		3	2	7						3			0		6
		4	0	0						4			0		0
Chen C. C., 2015	CTCAE v 3	2		10					CTCAE v 3	2			11		6
		3		2						3			1		2
		4		1						4			4		4
Gill B. S., 2015									Not spec	3	1
Wong F. C., 2003
Kang H. C., 2010									RTOG	3–4					2
Noda S. E., 2007									RTOG	2				4		RTOG
										3				0
										4				0
Fujikawa K., 2001									Not spec	3–4		20		15
Huh S. J., 2002									Not spec
Cheng J. C., 2003									RTOG	2 or higher					23
Chun M., 2004									LENT.SOMA	2				8
										3				1
										4				0
Chen S. W., 2006, 2010										2–4	5	15	10	15
											6		14
Tokumaru S., 2012										ctc v3	2	10
										3	5
Trifiletti D. M., 2015									ctc v4	3–4					6
Yang L., 2012										3		2.3		3.8
Yoshida K., 2015									Not spec	2						61
										3						7
Kirchheiner K., 2014									EORTC/RTOG	2						29
										3						4
Bohr Mordhorst L., 2014	RTOG	2				1			RTOG	2			5		18
										3			11		5
										4			11		3
Georg P., 2013										LENT.SOMA	2			8.9		6.2

HDR = high-dose-rate; RTOG = radiation therapy oncology group; CTCAE = Common Terminology Criteria for Adverse Event; GI = gastrointestinal; GU = genitourinary; GYN = gynecologic; LENT = Late Effects Normal Tissue Task Force; SOMA = Subjective, Objective, Management, Analytic; NCIC CTCEA = National Cancer Institute Common Terminology Criteria for Adverse Events.

Late toxicity

For radiation and chemoRT treatment, in the prospective and retrospective series, the range of GU late toxicity reported is RT: Grade 2: 3–8%, Grade 3: 1–5%, and Grade 4: 2–5%; CRT: Grade 2: 2–7% and Grade 3: 1–14%, with heterogeneity of the grouping of Grade 4 toxicity per Table 2. The range of late GI toxicity is RT: Grade 2: 4–6%, Grade 3: 3–11%, and Grade 4: 0–11%; CRT: Grade 2: 1–13%, Grade 3: 1–4%, and Grade 4: 1–5%. For the late gynecologic (GYN) toxicity, only 1 of the 16 prospective trials report a Grade 1–2 of 17% for radiation and 9% for chemoRT effects. For the retrospective studies, seven studies report GYN vaginal late toxicity. The range of late GYN toxicity is RT: Grade 2: 2–23%, Grade 3: 1–10%, and Grade 4: 0–6%; CRT: Grade 2: 29–61%, Grade 3: 3–7%, and Grade 4: 3% and otherwise unspecified from other studies. For the IBBT studies, nine report late toxicity. The range of late GU toxicity is Grade 4: 1–4%; late GI toxicity Grades 3–4: 2–4%; and late GYN toxicity Grades 3–4: 3%.

The acute and long-term GI, GU, GYN toxicity with scale for radiation and chemoRT patients are illustrated in Tables 4 and 5 (93, 95–100, 102–105), with nine of the IBBT reporting late toxicity.

Discussion

Outcomes in cervical cancer are shaped by several clinical and pathologic risk factors. This pooled analysis demonstrates the improvement in PC and DFS seen in the era of chemoRT with IBBT compared to the Point A dose reports. Therefore, our article suggests that with refinement in technique that is offered with IBBT, there is a reasonably small, but probably still significant, marginal improvement in cervical cancer outcomes. Historically, cervical cancer risk stratification is largely based on International Federation of Gynecology and Obstetrics (FIGO) staging, presence of pelvic or para-aortic lymphadenopathy, and patient performance status. Various definitions of risk factors and the use of the nonspecific FIGO system to stratify patients explain a wide variation in outcome results across the studies we report. In addition, there may be selection bias for treatment or other confounders in the articles reviewed. The main goal of our review is to define a summary result for chemoRT and HDR BT and to compare IBBT to non-IBBT series in the era of chemoRT.

Image-based BT

This investigation of pooled data analysis augments the individual outcomes reports in the literature that IBBT improves local control and DFS. This analysis reported a mean improvement in PC of 3% for patients treated with CRT. For DFS, studies with IBBT showed a mean increase in the CRT group of 3%. The difference in PC and DFS with IBBT is noteworthy, as estimates of the impact of concurrent systemic therapy which lead to the NCI statement in 1999 are 9% and 8%, respectively. To reflect on series in the literature that was used in our analysis, mono-institutional IBBT series of 156 and 140 patients from the Medical University of Vienna and Aarhus University Hospital, respectively, have demonstrated excellent outcomes with 3-year actuarial local control rates of >90% (10). Pötter et al. (10) reported local control rates of 100% for Stage IB, 96% for Stage IIB, and 86% for Stage IIIB cervical cancers. Compared with earlier patients treated without image guidance, patients treated with IBBT appeared to have higher survival rates and less major morbidity (10). In addition, in a prospective trial of locally advanced cervical cancer with chemoradiation and low-dose-rate or pulse-dose-rate BT to either 2D vs. 3D treatment planning, there was an improvement in local control with half the toxicity observed with 3D image guidance for treatment planning (107). Our analysis of the studies shows a higher OS in the Point A group vs. the IBBT group in patients treated with chemoRT. The difference could be related to a multitude of factors including various stages of patients in the studies and cofounding of systemic failure in patients with locally advanced cervical cancer.

Furthermore, IBBT is an advancement and technological augmentation of an existing treatment with BT. Therefore, the increase in outcome improvements is likely due to advancement in imaging sophistication to better and more appropriately define the target volume, treatment planning, and dose escalation. Importantly, much of the benefit of IBBT is likely related to enhanced target volume coverage and further escalating that dose, if need be, with the addition of needles, in the case of interstitial BT. With the advent of IBBT techniques and delivery, a major advantage is better assessment of the surrounding OAR such as the bladder, sigmoid, rectum, and vagina. IBBT allows for more precise placement of the applicator and optimization of the dose to avoid in part the OAR to decrease serious late effects. The Groupe Européen de Curiethérapie and the European SocieTy for Radiotherapy & Oncology (GEC-ESTRO) has studied the relationship between volume-based dose constraints and long-term outcomes using a model system (10). The International Commission on Radiation Units and Measurements Report 38 advocated a standardized system of dose reporting using critical organ doses at specified reference points. However, in the era of IBBT, a more detailed volumetric and dosimetric account is appreciated during the treatment planning phase to potential avoid high-grade toxicity (94, 101, 106). In addition, GEC-ESTRO sponsored a trial entitled “A European Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer” known as the EMBRACE Trial. The name was later changed to “An International Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer,” as international institutions began participating. As the study results develop from this trial, we will continue to enrich our understanding of IBBT and cervical cancer outcomes.

Toxicity outcomes

There are various reporting systems for acute and late toxicity. The majority of studies report acute toxicity using the clinical trials Common Terminology Criteria for Adverse Events and the LENT/SOMA or RTOG/European Organisation for Research and Treatment of Cancer toxicity scales. For acute effects, cervical cancer patients face genitourinary symptoms such as cystitis, urethritis, hematuria, dysuria, and increased risk of urinary tract infections. For gastrointestinal acute effects, there is a risk of bleeding, pain, mucus discharge, irregular bowel habits, food intolerances, nausea, and vomiting. Among late adverse events, the most feared complication is fistula between the bladder, vagina, or rectum requiring surgical repair. In addition, vaginal toxicity may include vaginal dryness, vaginal narrowing, foreshortening, ulceration, potential necrosis, and pain with intercourse. In our study, we found a mean acute late GU toxicity for the CRT studies as 3% and 5%, with a mean GI acute and late toxicity of 5% and 5%. The mean late GYN toxicity was 16% in the RT treatment and 3% in those treated with chemoRT. There is a lack of acute toxicity reporting in the IBBT studies, with more reporting of late toxicity. Therefore, as BT programs grow in IBBT, prospective outcome toxicity reporting and patient reported toxicity outcomes are needed.

Conclusions

We present modern era outcomes of PC, DFS, OS, acute, and late toxicities in the era of chemoradiation and image-based techniques for HDR BT. Our study suggests that IBBT improves PC and DFS compared to studies with conventional 2D-based imaging technology in patients treated with chemoRT. Although IBBT is not a treatment of itself for cervical cancer, the advance in imaging may lead to improved outcomes. We need to develop more user friendly techniques to incorporate IBBT for centers with even a low volume of cervical cancer patients. This review presents a summary of reported outcomes to aid the clinician in discussions regarding efficacy and prognosis after HDR BT, as the adoption of IBBT increases.