RPLND for chemo-resistant disease: Examining different options for different patients

Patients with persistent or relapsing elevated serum tumour markers (STMs) following induction chemotherapy are considered to have residual germ cell tumour elements and second-line chemotherapy is the standard management of choice.[1] Following salvage chemotherapy, patients have a higher rate of malignancy in residual tumour specimens so that a postsalvage chemotherapy retroperitoneal lymph node dissection (RPLND) is recommended for all patients with residual lesions independent of their size. Still the overall long-term survival rates are poor at 15–40%. [2,3]

Surgery of patients with rising or STM persistence following second or third-line chemotherapy indicates the presence of chemorefractory disease and complete surgical resection will result in long-term cure rates of 35–75%. [2,3] When referring to salvage surgery in mTGCT, one has to differentiate the terms salvage, late relapse and desperation surgery.

Salvage RPLND
Salvage RPLND usually defines a patient with an enlarged mass and normalized STMs following salvage chemotherapy. All patients with enlarged residual masses should undergo salvage RPLND due to the 55% frequency of active cancer. [4] Salvage RPLND is always performed with a curative intent so that even in the presence of multiple sites, all efforts should be taken to resecting all residual disease.

There is a histological discordance between the histology of the RP and extraretroperitoneal sites in about 30% of cases indicating that all residual masses need to be resected. [4,5] There is, however, a 90% histological concordance between RP and lung lesions so that expectant management can be considered in patients with necrosis/fibrosis in the RP specimen in order to reduce treatment associated morbidity. Salvage surgery by itself is more complicated and it requires a higher frequency of adjunctive procedures such as vascular, intestinal or even skeletal surgeries so that it should only be performed in highly experienced centers only. [6,7] Long-term survival is reported in the range of 75% following salvage chemotherapy and about 65% following high-dose chemotherapy [1,4,7].

There are reliable predictive markers associated with viable cancer or teratoma although persistently elevated STMs have a higher chance of finding active cancer in the resected specimens. It also has been demonstrated that basically all patients with high elevated ß-hCG levels will relapse after salvage RPLND and that high ß-hCG levels represent a predictor for disease-free survival. [8-10] Especially for patients with elevated ß-hCG salvage, RPLND should only be performed if the residual masses are completely resectable.

Furthermore, the location of the masses seems to be associated with oncological outcome: 82 and 57% with retroperitoneal/mediastinal masses and visceral disease achieved complete resection, respectively. [10] Postoperative normalization of STMs has a long-term prognostic value so far, that STM persistence results in 5-year survival of 8% as compared to 95% in normalized STMs. [11]

Desperation surgery or RPLND
This describes the clinical situation of elevated or rising STMs during or within 4 weeks after completion of systemic therapy and those patients harbour chemorefractory GCT, which only can be cured by complete surgical resection.

Despite the fact that STMs are rising, about 50% of patients harbour teratoma or necrosis only in the final specimen. [2,3, 12-14] Therefore, all men with completely resectable lesions should undergo surgery resulting in a partial remission rate and long-term cure rate of 50–60% and 20–30%, respectively. However, there are several criteria to identify those patients who might benefit most from desperation surgery. The 5-year OS is 93, 60, and 23% in men with normalized, stable or rising STMs, respectively. [14] In addition, slowly rising STMs are associated with the long-term cure, especially if only alphafetoprotein (AFP) is involved. Resectable masses in less than three sites are additional criteria predicting long-term benefit from surgery. Respectively. [11] Postoperative normalization of STMs has a long-term prognostic value so far, that STM persistence results in 5-year survival of 8% as compared to 95% in normalized STMs.[12] In recent series, increasing preoperative ß-hCG, elevated AFP, redo RPLND and incomplete resection had been identified as negative risk factors associated with poor survival. [13, 14]

Late relapse surgery
This kind of surgery is defined for patients with relapses > 2 years after completion of first line chemotherapy and it is observed in about 3.2% and 1.4% of patients with nonseminomas or seminomas, respectively. [15,16] The majority of relapses develops in the retroperitroneum only and 80% harbor viable GCT with yolk sac tumour elements representing the most common histology. [17] In addition, many lesions contain somatic malignant transformation so that surgery remains the therapeutic approach of choice if the mass is completely resectable.

Systemic chemotherapy is associated with an inferior oncological outcome because a complete remission can only be achieved in 26% and relapse-free survival without surgery of only 3%. [17,18] In patients with extensive disease at the time of late relapse not amenable for upfront surgery, systemic chemotherapy followed by surgical resection will result in complete remission of 50% and a median overall survival of 23.9 months. [18]

Repeat RPLND after previous retroperitoneal surgery
Although rare, a subset of patients’ needs repeat RPLND due to metastatic tumour recurrence after primary RPLND or PC-RPLND because of incomplete tumour resection during initial surgery. [19-25]

Repeat RPLND itself represents a poor risk factor associated with a significantly lower 5-year survival rate of only 55% as compared to 86% in the group of patients undergoing adequate PC-RPLND. The long-term outcome after repeat RPLND relies on the complete resection of all residual retroperitoneal masses, which will harbour viable cancer and mature teratoma in 20–25 and 35–40%, respectively. Whereas the cure rate for those with mature teratoma only approaches 100%, it decreases significantly to 44% and 20% in the presence of viable cancer and teratoma with malignant transformation, respectively.

Repeat RPLND is a challenging surgical procedure associated with higher rates of adjunctive surgical procedures, with ipsilateral nephrectomy and vascular procedures being the most frequent adjunctive surgeries.

Repeat RPLND often represents the last chance of cure for patients with in-field recurrences and it usually can be performed with acceptable morbidity. Repeat RPLND will result in long-term survival of 67–75%; if patients present with in-field recurrences and elevated markers, systemic chemotherapy followed by PC-RPLND should be initiated. In patients with negative markers, immediate RPLND should be performed since most masses will harbour mature teratoma only.

Adjunctive surgery in patients undergoing
PC-RPLND Additional surgical procedures of adjacent vascular or visceral structures might be necessary in up to 25% of the patients undergoing PC-RPLND in order to achieve complete resection of the residual masses. [26] En-bloc nephrectomy represents the most common type of adjunctive surgery for complete tumour clearance. Additional vascular procedures such as aortic replacement and resection of the inferior vena cava due to tumour infiltration will be necessary for about 1.5 and 10%, respectively.

Our group compared the outcome of standard PC-RPLND versus complex PC-RPLND with a variety of adjunctive vascular, visceral or skeletal surgeries. [27] It was demonstrated that the extensive surgeries resulted in an identical high cure rate as compared to the standard PC-RPLND. Besides, in patients undergoing pancreaticoduodenal surgeries, we did encounter a significantly increased frequency or severity of surgery-related complications.

Preoperative imaging studies
All types of salvage surgery are more complicated and require more adjunctive surgeries than a typical post-chemotherapy RPLND. [1,2] Therefore, a complete metastatic workup is mandatory, using different imaging modalities to identify potential pitfalls of the intended resection and in order to allow early identification of multidisciplinary teams. Especially in patients with large residual masses, imaging studies should allow an adequate assessment of the retroperitoneal vascular structures since the involvement of the inferior vena cava (IVC) and the abdominal aorta can be expected in about 6–10 and 2%, respectively. [28]

Magnetic resonance imaging represents the most appropriate imaging technique to predict infiltrations of the vessel wall and the presence of an intracaval tumour thrombus. Infiltrations of the IVC wall or IVC thrombi should be completely resected since about two thirds of the patients harbor vital cancer or mature teratoma in the infiltrating masses. Usually, intraoperative reconstruction or replacement of the IVC is not necessary since chronic venous sequelae are to be expected in less than 5% of all patients. [28] The necessity for aortic replacement is rare and usually accompanied by large residual masses involving additional adjacent structures and making additional surgical procedures necessary such as nephrectomy, IVC resection, small bowel resection and hepatic resection. In the majority of cases, mature teratoma or vital carcinoma was identified in the aortic wall.

Summary
Depending on the International Germ Cell Cancer Classification Group risk classification, 10–50% of metastatic testis cancer patients relapse. Tumour marker negative late relapses are best treated by a surgical approach when complete resection of metastatic sites is possible. Tumour marker positive relapses are initially managed by systemic salvage second-line or high dose chemotherapy depending on the prognostic risk score.

All patients with residual lesions need to undergo post-chemotherapy residual tumour resection of all residual lesions. Patients with early rising markers during or within 4 weeks after completion of salvage chemotherapy are best treated by desperation surgery if the masses can be resected completely. All those systemic and surgical are reserved for specialised centres only.

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