Stage I seminoma surveillance versus treatment

The prognosis for stage I seminoma is excellent, with long-term cure rates approaching 100% [30-33]. Stage I is that most commonly assigned to new presentations of seminoma, making up 70% of all incident cases [34]. Seminoma is highly radiosensitive and chemosensitive. Traditionally stage I disease has been most commonly managed with orchidectomy and adjuvant radiotherapy.

Of clinical stage I disease, a percentage of patients have occult micrometastases undetectable by imaging. This observation is borne out by surveillance series in which 15% to 20 % of patients experience disease relapse [34-39]. A combination of the advent of highly effective salvage chemotherapy for recurrent disease and ethical

Table 1

2002 TNM stage grouping of testicular cancer

Table 1

2002 TNM stage grouping of testicular cancer

Stage

Definition

I

Any T stage, N0, M0

IIA

Any T stage, N1 (<5 lymph nodes <2 cm

maximal diameter), M0

IIB

Any T stage, N2 (lymph nodes >2 cm

but <5 cm maximal diameter), M0

IIC

Any T stage, N3 (lymph nodes >5 cm

maximal diameter), M0

III

Any T stage, any N stage, M1

considerations with regard to the consequences of overtreating 80% to 85% of patients in this group has called the original treatment paradigm into question.

Efficacy of surveillance

No randomized controlled trials exist to compare the outcome of surveillance and salvage treatment if required to adjuvant treatment with radiotherapy or chemotherapy following orchidectomy. Given the excellent prognosis and likely small differences in long-term outcome, such a trial is unlikely to be conducted. There have been several prospective, nonrandomized studies of surveillance published over the last 2 decades with similar results [20,34-38]. The study from Princess Margaret Hospital in Toronto followed 241 patients for a median of 7.3 years and disease-free 5-year survival rates of 86% were reported [34]. The Danish Testicular Carcinoma Study Group (DATECA) had a 19% failure rate at a median of 48 months follow-up [20]. In each study, most recurrences (89% and 82%, respectively) occurred in the retroperitoneum (specifically the para-aortic and interaortocaval lymph nodes) at a median of 12 to 18 months. Late relapses more than 5 years from original diagnosis are well known to seminoma surveillance and protocols generally follow patients for at least 10 years from the point of diagnosis [39]. The Princess Margaret Hospital seminoma surveillance protocol is appended (Table 2).

Patients who have disease relapse from these studies have generally been treated with salvage radiotherapy. Secondary relapse following radiotherapy occurred in 19% in the PMH series and 11% in the DATECA series. Virtually all cases who had relapse beyond the retroperitoneum or following radiation were salvaged with chemo-therapeutic regimens.

Cost

The financial cost of surveillance protocols may be difficult to estimate in a general manner given that expenses vary depending on the protocol used, the local medical economic climate, and regional costs and choices in treating relapse and secondary malignancies. Warde and colleagues [40] evaluated the economic cost of the Princess Margaret Hospital surveillance protocol, including the cost of salvage treatment. Over a 10-year period, surveillance resulted in the expenditure of approximately $2500 Canadian more than adjuvant radiotherapy. A study from the University of Wisconsin estimated the cost of surveillance at $20,487 as opposed to $14,722 for adjuvant radiation [41]. Although the absolute values differ, surveillance seems to be consistently more expensive than adjuvant radiotherapy.

Toxicity issues

The testicular germinal epithelium is exquisitely sensitive to ionizing radiation so that in an effort to maintain hormonal and reproductive function in the remaining testis, scrotal shielding is routinely used. Despite this, some radiation scatter is still experienced and persistent oligo-spermia has been reported in 8% [42]. There seems to be no increase in the incidence of children who have genetic anomalies born to men who have undergone radiation treatment of testic-ular malignancy [43].

Commonly experienced acute side effects of radiation include nausea, vomiting, and diarrhea, whereas late gastrointestinal toxicity, usually in

Table 2

Princess Margaret Hospital stage I seminoma surveillance protocol

Year Month 2 Month 4 Month 6 Month 8 Month 10 Month 12

Table 2

Princess Margaret Hospital stage I seminoma surveillance protocol

Year Month 2 Month 4 Month 6 Month 8 Month 10 Month 12

1

TM, CT

TM, CXR CT

TM, CT

2

TM, CXR CT

TM, CT

TM, CXR CT

3

TM, CT

TM, CT

TM, CXR CT

4

CT

CT, CXR

5

CT

CT, CXR

6

CT

CT, CXR

7

CT

CT, CXR

8

CT, CXR

9

CT, CXR

10

CT, CXR

Abbreviations: CT, computed tomography of the abdomen and pelvis; CXR, chest radiograph; TM, tumor markers.

Abbreviations: CT, computed tomography of the abdomen and pelvis; CXR, chest radiograph; TM, tumor markers.

the form of peptic ulcer disease, occurs in around 5% [43]. Grade II to IV hematologic toxicity is seen in 5% to 15% [44]. Studies of men from early radiation populations have raised concerns of cardiac toxicity and excess risk for death from cardiac events. Risk for events was increased by a factor of 1.8 to 2.4 [44,45]. Although the magnitude of these estimates may not pertain to modern radiotherapy practice, this remains an issue when considering adjuvant treatment.

Although the long-term psychologic effects of the diagnosis and management of seminoma are generally minimal, isolated patients develop significant psychologic symptoms [46]. Comparisons between adjuvant radiation and surveillance are limited; however, it has been suggested that men on surveillance have fewer sexual issues than men who have received adjuvant treatment [47].

Second malignancies

Seminoma patients are already at greater risk for further malignancies, such as contralateral testicular cancers, than the general populace presumably because of a combination of genetic predisposition and environmental exposures [48]. One of the central concerns in the debate between surveillance and adjuvant radiotherapy is the issue of iatrogenically induced late second malignancy following radiation. In the largest study to date, Travis and colleagues [49] looked at 40,576 men surviving more than 1 year following their diagnosis of testicular cancer. Details were extracted from 14 North American and European databases and the mean follow-up was 11.3 years. Overall 2285 solid tumors were observed compared with an expected 1619 (relative risk [RR] = 1.4) and by 10 years the relative risk increased to 1.6. The estimated cumulative risk for developing a second malignancy assuming diagnosis at 35 years of age and follow-up for 40 years was 36% for the semi-noma population, 31% for the NSGCT population, and 23% for the general population. Being diagnosed at 20 years of age added approximately 10% to these figures. Relative risk also varied by type of treatment, whether radiation (RR = 2), chemotherapy (RR = 1.8), or both (RR = 2.9). Cancer rates were higher for organs within radiation fields (eg, bladder, stomach, pancreas, ureter) but also increased for other organs (eg, pleural, esophageal) and leukemias. Although it is difficult to predict with precision the impact of a policy of routine surveillance on these figures, a significant reduction in events would be expected.

Compliance

For surveillance to be a viable option for the management of stage I seminoma following or-chidectomy, patients and medical personnel must be resolved to undertake the rigors of intensive follow-up imaging and outpatient visits. Given that the patient population predominantly consists of young men, this may not necessarily be possible. Changes in study, work, and personal circumstances may lead to relocation, whereas cancer diagnosis denial or perhaps a minimization of perceived risk in the medium to longer term may all contribute to a decline in attendance rates. Hao and colleagues [50] reported compliance with office visits declined from 61% in the first year to 35% in the second and that imaging protocols fared even more poorly with only 25% and 12%, respectively, undergoing all scans. Patients lost to follow-up in the surveillance arm of another study totaled 20.9% by the median follow-up time of 54 months [51]. These data lead to concern about the external validity of widespread surveillance protocols as opposed to those based in cancer centers. They also emphasize the need for, and provide an impetus to, the refinement of patient selection. The impact of poor compliance on overall survival is unknown but would be difficult to quantify given high cure rates in advanced disease.

Patient selection

Warde and colleagues [52] performed a pooled analysis of four published series involving 638 patients who had a median of 7 years surveillance. Only the first two univariate prognostic factors, from tumor size greater than 4 cm, rete testis invasion, lymphovascular invasion, and anaplastic versus classic seminoma, retained significance on multivariate analysis. The estimated 5-year relapse rates were 12%, 16%, and 32% if zero, one, or two factors were present, respectively. Restricting surveillance to only those patients who had one or fewer prognostic variables and irradiating the remainder would eliminate 20% from surveillance but avoid unnecessary treatment in 70%. This plan may present the best compromise for those patients considered to be compliant candidates for surveillance.

Para-aortic strip versus dog-leg radiotherapy

For more than 50 years, the standard of therapy for treatment of men who had Stage I/IIa seminoma was adjuvant irradiation (30 Gy in 15 fractions) of the ipsilateral pelvic and paraaortic nodes. Using this approach, disease-specific survival rates approach 100%. Recent revelation of a 20% failure rate among men placed on surveillance protocols (with their certain salvageabil-ity) coupled with concerns of long-term cardiac toxicity, fertility, and secondary malignancies [44] has led investigators to attempt to minimize exposure to radiation. One such maneuver has been to omit the ipsilateral inguinal radiotherapy. The rationale for this makes logical sense from an embryonic and anatomic point of view. The other change has been to lower doses to as low as 20 Gy in 10 fractions.

The impact of these dose-reduction strategies has been minimal in relapse-free survival and certainly in overall survival. In addition, less hematologic, gastrointestinal, and gonadal toxic-ity have been recognized [53]. Men who have scro-tal violation or prior inguinal or scrotal surgery should not be offered para-aortic strip radiotherapy alone [54]. The EORTC completed a large randomized trial of 30 Gy versus 20 Gy as adjuvant therapy. The long-term results among the 625 randomized subjects revealed the same rate of relapse in both assigned treatment arms [53]. Additional follow-up data among other large cohorts have confirmed these findings [42,54]. Niazi and colleagues [55] reported the McGill University experience using 25 Gy in a paraaortic strip field among 71 patients. At 75-month follow-up, 68 were free of relapse. One patient failed in the ipsilateral pelvic area. The German testicular cancer study group performed a nonrandomized trial of para-aortic-only radiation among 675 patients (26 Gy). At 8 years follow-up, 26 patients relapsed, of which 24 were salvaged. Only 1.6% of patients failed in the ipsilateral pelvis [56]. These data are consistent with those published in other centers [57-59].

Recently some concern has been expressed regarding the long-term success of 20 Gy dose plus para-aortic strip only treatment with case reports of pelvic recurrences with significant clinical sequelae [60,61]. Long-term follow-up will be required at these doses and fields to ensure equivalence to historical norms.

Stage I: emerging role of chemotherapy

One of the more recent controversial topics in the management of patients who have stage I seminoma is the use of chemotherapy as an alternative to radiotherapy among men routinely or among those who do not elect surveillance. The use of one or two cycles of adjuvant carboplatin has been investigated by Oliver and colleagues [62] and other investigators [63-65] for more than a decade.

A recent phase III trial has been completed comparing single-dose carboplatin to radiotherapy (para-aortic strip or dog-leg) among 1477 patients in 14 countries [62]. The primary outcome measure was relapse-free survival with the power to detect a 3% absolute difference. At 4 years median follow-up, relapse rates were the same in both groups (95.9% radiotherapy versus 94.8 % carboplatin). Patients given carboplatin were less lethargic and attended their employment more reliably. Ten new primary testicular tumors were noted among men randomized to radiotherapy versus two among men randomized to carboplatin (P = .04). This study has demonstrated noninfer-iority of carboplatin in relation to radiotherapy and may have an added benefit of sterilizing smaller contralateral tumors. Although this study has greatly increased our understanding of early-stage seminoma we must exercise some caution in using single-dose carboplatin as the new standard of therapy. First, we must recognize that 80% to 85% of these patients never required chemotherapy at all, thus relapse has been decreased from 15% to less than 5% at most. Second, relapses in the retroperitoneum have been reported postchemotherapy, necessitating continuous imaging of the abdomen posttreatment. This finding contrasts to the rare in-field recurrence following dog-leg radiotherapy. Finally, late relapses cannot be excluded as a possibility, although recent data from phase II studies among 243 patients followed over 5 years (including 82 followed over 10 years) suggest that relapse after 3 years does not occur [60]. Finally, the long-term morbidity of subjecting 80% of patients to unnecessary chemotherapy with unknown long-term toxicity must be kept in mind. Adjuvant carboplatin may benefit patients not eligible for surveillance and is a reasonable alternative to standard radiotherapy regimens. A pragmatic approach may represent that taken by the Spanish Germ Cell Cancer group, which advocates surveillance among low-risk patients (<4 cm tumor and no rete testis involvement) and two cycles of adjuvant carboplatin among higher-risk patients. In their experience with 100 men, 13 have relapsed using this strategy [37] and overall survival is 100%. The criticism of this approach is that far too many men who do not require chemotherapy at all do get treated.

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