INTRODUCTION
Poor risk nonseminomatous germ cell tumor (NSGCT) merit high orchiectomy followed by chemotherapy (CT). Response to CT can be categorized into (1) complete radiographic and serum marker decline complete response (CR), (2) partial radiographic response and complete/incomplete marker decline partial response (PR), (3) progressive disease (PD). Guidelines suggest that CR should be kept on observation, PR should be treated by excision of residual and PD should be treated with second-line CT.[ 1 ] Can the PR/unresectable be treated with consolidation radiotherapy (RT) instead of surgery? This approach not evaluated earlier will allow avoidance of surgical morbidity and be an additional tool for treatment. We have reported a series of five cases with poor prognosis NSGCT, who were treated with consolidation RT after PR/unresectable disease and complete serum marker decline.
METHODS
Between 2008 and 2020, among 24 patients of germ cell tumor (GCT) registered under SA, 17 were seminomatous GCT and 7 were NSGCT (2 mediastinal and rest 5 testicular with Stage III). The median age of patients was 28.8 years. Patient characteristics are summarized in Table 1 . After high inguinal orchiectomy, all were initiated on first-line CT (Bleomycin , etoposide , cisplatin [BEP] × 4 cycles) and showed normalization of serum tumor markers (beta-human chorionic gonadotropin and serum alpha protein), except raised lactate dehydrogenase (LDH). A PET-CT was done to evaluate the radiographic response and the avidity of residual disease among which residual disease was more than 1 cm and fluorodeoxyglucose (FDG) avidity found.
Table 1: Patient characteristics and treatment
Patient 1 was followed up on observation after 4 cycles BEP and 2 cycles etoposide , cisplatin and within 4 months showed evidence of increase in size and FDG avidity of residual mass in inguinal region, further given 4 cycles of second-line CT (TIP regime). Three months later, the residual disease in inguinal region still had viable malignant cells on fine-needle aspiration cytology and was adherent to the abdominal wall and was given palliative RT of 20 Gy in 5 fractions in 1 week, presently on 51 months’ follow-up with normal markers and resolution of inguinal mass.
Patient 2: The residual mass (after 2 months of first-line CT) was 3 cm size encasing aorta and considered unresectable by urologists. So RT was given to the residual retroperitoneal mass to a dose of 30 Gy/10 fractions and is now on 65 months follow-up with normal markers and resolution of mass.
Patient 3, who did not have residual disease after first-line CT but showed recurrence after 10 years in retroperitoneum with raised tumor markers, was re-initiated on first-line CT (BEP) after which residual disease was 2 cm size, FDG avid, encasing vessels with raised LDH and hence unresectable and was given 20 Gy/5 fractions to the residual disease presently on 112 months’ follow-up with normal markers with partial resolution of mass.
Patient 4 had lung oligometastatic disease at presentation, and after first-line CT had stable disease in oligometastases, normal tumor markers except raised LDH. In view of right lung oligometastases, stereotactic RT to a dose of 55 Gy in 5 fractions was delivered presently on 24 months’ follow-up with normal markers and partial resolution of mass.
Patient 5 had normalization of markers after first-line CT except serum LDH with radiographic residual in para-aortic LN of more than 1 cm with FDG avidity and was given 30 Gy/10 fractions to the residual mass.
All except one underwent RT by three-dimensional conformal radiation therapy with 6–10 MV photons [Figure 1 ].
Figure 1: Patient 3: NSGCT posthigh inguinal orchiectomy, postchemotherapy para-aortic node recurrence (a) axial fused PET/CT image showing metabolic para-aortic lymphnode measuring about 2.5 cm in diameter with SUVma× 10 prior to re-treatment, (b) axial fused PET/CT image showing metabolic para-aortic lymphnode measuring about 2 cm in diameter with SUVma× 4 after RT, (c and d) sagittal and axial 3D-CRT planning 95% dose colour wash of para-aortic lymph-node (GTV-Green; CTV-Red; PTV-Cyan colour). NSGCT = Nonseminomatous germ cell tumour, PET/CT = Positron Emission Tomography/Computed tomography, SUVmax = Maximum standardized uptake value, 3D-CRT = Three-dimensional conformal radiation therapy, RT = Radiotherapy
No patient had any gastro-intestinal or renal morbidity on follow-up.
DISCUSSION
Twenty to fifty percentage of patients who undergo standard CT for advanced GCT have a significant residual retroperitoneal disease. Residual masses after CT have necrosis in 50%, teratoma in 35%, and viable tumor in 10%–15% cases.[ 1 , 2 ] Normalisation of serum markers after first-line CT with PR requires resection of residual masses more than 1 cm. This is not always feasible because of the encasement of major vessels or adjacent structures or medical reasons. The presence of viable malignant cells on resection merits postoperative administration of further 2 cycles of CT. This has shown benefit in the intermediate risk group only, but not in poor prognostic group. With no option left for the poor prognostic group, we sought to use a noninvasive modality to consolidate achieved response. A noninvasive modality such as RT can prove to be a successful strategy in the armamentarium of treatment modalities and requires further exploration. In our series, though the serum tumor markers were normalized after CT, serum LDH was raised in all cases, and all had residual mass more than 1 cm.[ 3 ] In view of the encasement of vessels (n = 3), proximity of residual mass to anterior abdominal wall (n = 1), lung oligometastases (n = 1) these residual masses were unresectable. We sought to the un-conventional modality of RT with palliative dose (20 Gy/5 fractions) in 3 patients, rather than keeping the patients on further surveillance or initiating second-line CT. Our results revealed that dose schedules 20 Gy/5 fractions and 30 Gy/10 fractions seem to be equally effective, as the patients are on a follow-up of 21 months to 112 months and have normal markers on follow-up. However, patients with unresectable disease may have better outcomes with higher doses to prevent recurrences as is evident from the case series available in literature [Table 2 ] cases with recurrent NSGCT (occult lumbar vertebral body metastasis) were successfully eliminated by radiation with a total dose of 61 Gy or Stereotactic ablative body radiotherapy (SABR) (45/6 fractions) [Table 2 ].[ 4 , 5 ] Another case of recurrence (3 lung metastases) and spinal metastases were also successfully eliminated with a stereotactic RT dose of 54 Gy/3fractions or conventional RT of 61 Gy [Table 2 ].[ 6 , 7 ] The role of stereotactic body RT in oligo-metastatic disease is gradually emerging and has shown durable local control and survival benefit in few randomized trials.[ 8 ]
Table 2: Review of literature
To the best of our knowledge, ours is the only case series on role of RT in this subset of NSGCT. Though Kersh et al . showed that radiation therapy with a mean dose of 40 Gy was not effective in NSGCTs, their series was of extragonadal NSGCT (predominantly mediastinal NSGCT) where patients were treated with old RT techniques. Furthermore, patients with mediastinal NSGCT have the poorest prognosis and cannot be compared with non-mediastinal NSGCT.[ 9 ] Based on our experience, we opine that a dose ranging from 20 Gy/5 fraction to 30 Gy/10 fractions is effective for consolidation RT irrespective of the histology of NSGCT. Based on this sparse literature and our limited series, it is difficult to conclude whether conventional RT or SABR can salvage such cases. Perhaps small tumors should be treated with SABR, and large residual or recurrent disease should be treated with conventional RT with dose ranging from 30 to 60 Gy. A large study is needed for the validation of these results.
CONCLUSION
External RT seems to be an effective non-invasive modality for PR/unresectable residual and should be explored further for confirming its efficacy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Honecker F, Aparicio J, Berney D, Beyer J, Bokemeyer C, Cathomas R, et al. ESMO Consensus Conference on testicular germ cell cancer:Diagnosis, treatment and follow-up. Ann Oncol 2018;29:1658–86.
2. Daneshmand S, Djaladat H, Nichols C. Management of residual mass in nonseminomatous germ cell tumors following chemotherapy. Ther Adv Urol 2011;3:163–71.
3. Oldenburg J, Alfsen GC, Lien HH, Aass N, Waehre H, Fossa SD. Postchemotherapy retroperitoneal surgery remains necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses. J Clin Oncol 2003;21:3310–7.
4. Kita Y, Imamura M, Mizowaki T, Norihisa Y, Yoshimura K, Hiraoka M, et al. Late recurrence of non seminomatous germ cell tumor successfully treated with intensity-modulated radiation therapy. Jpn J Clin Oncol 2013;43:835–7.
5. Gulia A, Anand AK, Punnakal AU, Kumar A, Patro CK, Bansal AK. Stereotactic ablative body
radiotherapy (SABR) for inoperable, chemorefractory retroperitoneal lymph node relapse from non seminomatous germ cell tumour of testis:A case report. BJR Case Rep 2018;4:20160114.
6. Satyanarayan A, Mooney R, Bhanvadia RR, Iyengar P, Margulis V, Desai NB, et al. Stereotactic Ablative
Radiotherapy (SAbR) in the setting of metastatic
nonseminomatous germ cell tumor of testis. Clin Genitourin Cancer 2019;17:e768–71.
7. Kanto S, Tokuyama S, Numahata K, Nakagawa H, Saito S, Arai Y. Occult lumbar vertebral body metastasis of non-seminomatous germ cell tumor eradicated by radiation and salvage surgery 9 years after initial onset. Nihon Hinyokika Gakkai Zasshi 2007;98:634–7.
8. Kersh CR, Constable WC, Hahn SS, Spaulding CA, Eisert DR, Jenrette JM, et al. Primary malignant extragonadal germ cell tumors. An analysis of the effect of the effect of
radiotherapy . Cancer 1990;65:2681–5.
9. Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, et al. Stereotactic ablative
radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET):A randomised, phase 2, open-label trial. Lancet 2019;393:2051–8.
