Oncological Outcomes

N. of patients

Type of combined treatment

5-year survival rate (%)

Median survival (months)

Garcia-Aguilar J et al. [13]

Multimodal*

Asoglu O et al. [14]

Multimodal

Yamada K et al. [15]

Multimodal

Hahnloser D et al. [3]

394

Multimodal + IORT**

14.1

Hansen MH et al. [4]

577

Multimodal

3.1

Pacelli F et al. [1]

Multimodal + IORT

Kanemitsu Y et al. [16]

101

Multimodal + IORT

Vermaas M et al. [17]

117

Multimodal + IORT

Wieser M et al. [18]

Multimodal

Kakuda J et al. [19]

Multimodal

8.4

You YN et al. [20]

105

Multimodal + IORT

Haddock MG et al. [8]

607

Multimodal + IORT

Total

2245

Mean: 5.32%

Mean: 11.3 months

* Multimodal: adjuvant/neoadjuvant chemotherapy

** IORT: intraoperative radiation therapy

Literature data, however, are quite inconsistent, and several authors demonstrated no difference relative to this parameter. In this sense, the reports of Gagliardi et al. [22], Shoup et al. [23], and Hahnloser et al. [3] showed, at the statistical analysis, that no significant oncological and survival benefit can be demonstrated between microscopically and grossly involved margins and resection [2, 3, 22, 23]. Improvement in OS can be offered to palliative patients by application of multimodal treatment and specifically by intraoperative radiation therapy (IORT): Hahnloser et al. demonstrated that IORT with or without EBRT, performed in 52% of patients with palliative surgery, allowed a 5-year OS of 21% [3]. Literature data confirmed the high complication rate associated with surgery for PRCRC, even in patients who underwent nonradical or palliative resections. For these patients, QoL is of primary importance and is becoming an increasingly appreciated outcome: You et al. [20] demonstrated that while physical well-being was largely preserved over time after curative resection and that it rapidly declined after palliative resection or nonoperative management, reaching borderline significance when curative and palliative resections were compared (P=0.049).

11.4 Multimodal Treatment and Radical Resection

Radical surgical resection with curative intent is the most considered relevant prognostic factor after surgery for PRCRC [1–4]. Statistical significance has been proven in almost all reports published in the literature, and the opinion that survival is greatly increased when a resection with microscopically negative margins is performed has become evident worldwide. However, only a portion of all surgical resections performed for PRCRC presented microscopically negative margins. A literature overview performed by Caricato and colleagues on prognostic factors after surgery for PRCRC, and considering 24 series for a total of 2204 patients (from 1960 to 2000), demonstrated a mean R0 rate of 41.2% (range 9.8–72%) [2]. Table 11.2 summarizes R0 rates of 24 series published in recent decades considering more than 3000 patients, demonstrating an increase in R0 rate (69.8%). This is probably due to an improvement in combined treatment modalities performed before, during, and after surgical resection with the intent to achieve negative margins in an internationally defined multimodal treatment. Haddock et al. [8], in accordance, demonstrated that treatment era (better survival for more recently treated patients) is a strongly significant prognostic indicator of local control and OS. In patients undergoing R0 for carcinoma in situ (CIS), 5-year survival rates are variable, ranging between 15 and 59%, with a mean 5-year survival rate of 34.7% (Table 11.2).

Table 11.2

Oncological outcomes for radical resection

	N. of patients	Type of combined treatment	Curative intent surgery (R0) (%)	5-year survival rate (%)	Re-recurrence rate (%)
Garcia-Aguilar et al. [13]	81	Multimodal*	48	35	33
Lopez-Kostner et al. [24]	117	Multimodal	36.7	49.7
Rodel et al. [25]	35	Multimodal	80		18
Maetani et al. [26]	59	Multimodal		25	76
Melton et al. [27]	29	Multimodal	62	20
Kusters et al. [28]	170	Multimodal + IORT**	54	40.5	46
Asoglu et al. [14]	50	Multimodal	66	35	12.5
Yamada et al. [15]	83	Multimodal	72	18
Hahnloser et al. [3]	394	Multimodal + IORT	77	37
Hansen et al. [4]	577	Multimodal	32.1	55	17.5
Pacelli et al. [1]	58	Multimodal + IORT	56.8	72.4	48.5
Kanemitsu et al. [16]	101	Multimodal + IORT	61	32
Dresen et al. [21]	143	Multimodal + IORT	57.2	48.4	15
Haddock et al. [8]	607	Multimodal + IORT	37	46	28
Sagar et al. [29]	40	Multimodal	50		22.5
Reerink et al. [30]	40	Multimodal	68	19%
Rahbari et al. [31]	107	Multimodal	58	47
Banghu et al. [7]	127	Multimodal	64		35
Vermaas et al. [17]	117	Multimodal + IORT	45.2	21
Wieser et al. [18]	50	Multimodal	95	59	58
Bedrosian et al. [32]	134	Multimodal + IORT	63	36	58
Heriot et al [33]	160	Multimodal + IORT	61	36
Total	3279		Mean: 63% (37–95%)	Mean: 35% (18–72.4%)	Mean: 41% (15–76%)

* Multimodal treatment: adjuvant/neoadjuvant chemotherapy

** IORT: intraoperative radiation therapy

Further treatments on recurrences have been widely explored in order to increase R0 rate and disease-free survival (DFS), disease-specific survival (DSS), and OS. Results of phase II studies considering and analyzing: (1) multimodal treatment and limited resection, (2) extended surgical resections in association with multimodal treatment, and (3) application of IORT are very encouraging and are focused on in this analysis.

11.4.1 Multimodal Treatment and Radical Nonextended Resection

A significant benefit in terms of surgical feasibility has been reported by recent trials of preoperative chemoradiation therapy. Studies on prognosis indicate a predominant role of RT as neoadjuvant therapy: Whereas postoperative therapy (chemo- or radiation therapy) affects outcome in very few reports, preoperative RT strongly affects outcome. In the report by Saito et al. [34], even though statistical significance is not reached, actuarial 5-year survival rates differed widely (RT plus surgery, 61.2%; surgery alone, 29.6%). As demonstrated, patients who received reirradiation or full-course RT as part of PRCRC treatment survived significantly longer, and longer without local recurrence or metastasis (P=0.001) compared with patients who were not reirradiated. Patients who had neoadjuvant radio (chemo)therapy experienced fewer metastases (P=0.001) but did not survive longer (P=0.170) than patients who did not receive neoadjuvant treatment [21]. Dresen et al. showed also that after reirradiation, significantly more radical resection can be performed (64.9 vs. 29.2%, P=0.004), and a significantly better metastasis-free survival (MFS) (at 3 years, 58.7% vs. 17.8%; P=0.001) can be observed compared with surgery alone in patients irradiated for their primary tumor [21].

Other studies report a lower rate of R0 resections when using surgery alone [17, 35]. These findings stress the need for renewed RT in patients who have previously been irradiated. They also suggest that reirradiation, even in combination with chemotherapy, can be safely applied and may result in a considerable survival benefit and even cure rate [21]. The major concern of reirradiation is the fear of toxicity. However, as confirmed by some reports, patients can undergo reirradiation with an additional dose of 30–40 Gy, with acceptable risks, provided that the small intestine is located outside the irradiation field and the interval between previous irradiation and reirradiation is >6 months [20–22]. Other studies found a benefit of the addition of chemotherapy to the neoadjuvant RT [2, 37]. Bedrosian et al. [32], for example, demonstrated that compared with all other modalities (postoperative chemotherapy and/or postoperative RT and/or intraoperative RT and/or brachytherapy), the use of preoperative chemoradiotherapy showed a trend toward improved survival (P=0.07).

11.4.2 Multimodal Treatment and Extended Resection

Extended resections are indicated in the presence of tumoral invasion of at least one of the surrounding pelvic organs (bladder, prostate, uterus, vagina, ureter, iliac vessels, small bowel, ovary, fallopian tube, sacrum). Exenterative procedures are performed when anterior, posterior, anterolateral, posterolateral, or anteroposterior pelvic invasion is preoperatively diagnosed. Extended resection of PRCRC is a technically demanding procedure that poses many intra- and postoperative challenges, which may narrow the therapeutic window. Recent series emphasize the postoperative morbidity and mortality rates, significant blood loss, and transfusion requirements typically associated with these procedures. Multidisciplinary team preparation and cooperation are critical in selecting and supporting these patients perioperatively and over the long term [38].

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