American Head & Neck Society

Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.

Published on by Aviram Mizrachi

Cutaneous Malignancies in the Organ Transplant Population

Case

A 68 y/o man with a history of kidney transplantation on Tacrolimus and prednisone treatment.

Several months prior to his presentation he underwent excision of a Rt temple skin lesion by a plastic surgeon. Pathology revealed a 4 mm SCC with evidence of PNI and free surgical margins. No further treatment or follow-up was recommended.

The patient presents now after noticing a weakness of Rt eyebrow for the last two months. He was seen at the Ophthalmology clinic and diagnosed with complete paralysis of the Rt temporal branch of CN-VII. In addition, there was a 2 cm firm subcutaneous painless mass on the Rt temple, deep to the surgical scar. Biopsy of the Rt temple lesion showed SCC. The patient was then referred to the head and neck clinic for further evaluation and treatment. There were no additional findings on physical examination and imaging studies did not show evidence of regional or distant disease (Figures 1, 2).

Figure 1
Figure 2: PET-CT

 

 

 

 

 

 

Risk of recurrence or metastases

The above case depicts a patient with a high risk for disease recurrence and/or metastases due to chronic immunosuppression. A recent review summarizes the role of the immune system in cutaneous SCC (Figure 3). In this paper the authors illustrate the effect of immunosuppressive drugs on several carcinogenic mechanisms including DNA repair, synergism with UV-related DNA damage, angiogenesis and invasiveness.  The NCCN guidelines address the group of high-risk patients with skin SCC and specify the risk factors that warrant close follow-up. Pay attention to “Area H” that includes the “Mask areas” of the face and is considered a high-risk feature (Figure 4).

Management

Every attempt should be made to achieve complete excision of the primary lesion with negative margins. Modification or reduction of immunosuppression should be considered and consulting the appropriate discipline (nephrologist, hepatologist etc.) is strongly encouraged. Adjuvant radiation may be recommended in cases of perineural involvement of large nerves. However, it should be noted that the definition of large nerves by AJCC 8th edition for skin SCC of the head and neck is above 0.1 mm and most nerves deep to the dermis are above 0.1 mm. Moreover, the survival benefit of adjuvant radiation following complete resection of the primary lesion remains unclear (Figure 5).

Outcomes

Several studies addressed the differences in survival outcomes between immunosuppressed and immunocompetent patients with skin SCC. A recent multi-center study reported on 67 immunosuppressed patients, most of them solid organ recipients, and compared them with 138 immunocompetent patients (Figure 8). They found better progression free survival and locoregional control in the immunocompetent patients group. However, no difference in overall survival between the two groups was noted. Another study by Ritter et al. compared 177 solid organ recipients with 177 immunocompetent patients with skin SCC. They found a significantly higher recurrence rate and worse overall survival in the solid organ recipients group (Figure 6).

Checkpoint inhibitors 

Immunocompromised patients have been traditionally excluded from the major clinical trials on checkpoint inhibitors. Solid organ recipients and patients with chronic viral infections (HIV, HBV, HCV) are considered poor candidates for checkpoint inhibitors due to the risk of allograft rejection and disease flare-up respectively. A multi-center European study reported on 46 patients treated with anti-PD-1/PD-L1 agents. Of them 6 were solid organ recipients and the remaining had chronic viral infections. They concluded that while patients with chronic viral infection may be safely treated with anti-PD-1/PD-L1 drugs, in solid organ recipients the risk of allograft rejection needs to be carefully weighed against the benefit of immunotherapy (Figure 7).

 

“CONCLUSION: Patients with HIV or hepatitus B/C infection treated with anti-PD-1/PD-L1 immunotherapy may respond to treatment without increased toxicity. Given the risk of graft rejection in solid organ transplant patients and also the potential for response, the role of anti-PD-1/PD-L1 immunotherapy needs to be carefully considered.”

 

Another study from MD Anderson Cancer Center reported on 37 solid organ recipients treated with checkpoint inhibitors. They found that 41% of patients experienced allograft rejection with a median time to rejection of 21 days from the initiation of immunotherapy. Furthermore, patients with allograft rejection had a significantly worse overall survival (Figure 8).

There is certainly a need for prospective trials in order to optimize the use of checkpoint inhibitors in immunosuppressed patients. A recently opened trial is enrolling kidney transplant recipients with advanced cancers, with an aim to treat them with Tacrolimus, Nivolumab and Ipilimumab. Additional details on this topic and the trial can be found in the following link:

https://ascopost.com/issues/march-10-2020/immune-checkpoint-inhibitors-in-solid-organ-transplant-recipients/

References

  • Bottomley MJ, Thomson J, Harwood C, Leigh I. The Role of the Immune System in Cutaneous Squamous Cell Carcinoma. Int J Mol Sci. 2019 Apr 24;20(8):2009. doi: 10.3390/ijms20082009. PMID: 31022866; PMCID: PMC6515307.
  • National Comprehensive Cancer Network. Squamous Cell Skin Cancer (Version 2.2020). https://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf
  • Manyam BV, Garsa AA, Chin RI, Reddy CA, Gastman B, Thorstad W, Yom SS, Nussenbaum B, Wang SJ, Vidimos AT, Koyfman SA. A multi-institutional comparison of outcomes of immunosuppressed and immunocompetent patients treated with surgery and radiation therapy for cutaneous squamous cell carcinoma of the head and neck. Cancer. 2017 Jun 1;123(11):2054-2060. doi: 10.1002/cncr.30601. Epub 2017 Feb 7. PMID: 28171708.
  • Ritter A, Badir S, Mansour M, Segal Z, Ad-El D, Bachar G, Shpitzer T, Popovtzer A, Mizrachi A. Solid organ transplantation worsens the prognosis of patients with cutaneous squamous cell carcinoma of the head and neck region-Comparison between solid organ transplant recipients and immunocompetent patients. Head Neck. 2020 Nov 27. doi: 10.1002/hed.26546. Epub ahead of print. PMID: 33247523.
  • Tio M, Rai R, Ezeoke OM, McQuade JL, Zimmer L, Khoo C, Park JJ, Spain L, Turajlic S, Ardolino L, Yip D, Goldinger SM, Cohen JV, Millward M, Atkinson V, Kane AY, Ascierto PA, Garbe C, Gutzmer R, Johnson DB, Rizvi HA, Joshua AM, Hellmann MD, Long GV, Menzies AM. Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection. Eur J Cancer. 2018 Nov;104:137-144. doi: 10.1016/j.ejca.2018.09.017. Epub 2018 Oct 20. PMID: 30347289.
  • Abdel-Wahab N, Safa H, Abudayyeh A, Johnson DH, Trinh VA, Zobniw CM, Lin H, Wong MK, Abdelrahim M, Gaber AO, Suarez-Almazor ME, Diab A. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J Immunother Cancer. 2019 Apr 16;7(1):106. doi: 10.1186/s40425-019-0585-1. Erratum in: J Immunother Cancer. 2019 Jun 24;7(1):158. PMID: 30992053; PMCID: PMC6469201.
Aviram Mizrachi

Aviram Mizrachi

Dr. Aviram Mizrachi is a surgeon-scientist at the Department of Otolaryngology – Head and Neck Surgery of Rabin Medical Center in Israel. He has an active research laboratory focusing on tumor and radiation biology in head and neck cancer as well as targeted drug delivery. Furthermore, he investigates both radiation and chemotherapy mechanisms of action and their effect on tumor and normal tissue including the utility of novel radio-sensitizing and radio-protective agents. In addition, Dr. Mizrachi conducts clinical research on outcomes in head and neck, skin and thyroid cancers.

Published on by Aviram Mizrachi

AHNS Basic Science/Translational Newsletter Vol 2

Phase 2 Trial of Neoadjuvant Chemotherapy and Transoral Endoscopic Surgery With Risk-Adapted Adjuvant Therapy for Squamous Cell Carcinoma of the Head and Neck

Weiss JM, Grilley-Olson JE, Deal AM, Zevallos JP, Chera BS, Paul J, Knowles MF, Usenko D, Weissler MC, Patel S, Hayes DN, Hackman T.

From Clinical Trial. Cancer. July 2018; 124(14):2986-2992.

Article Review by Aviram Mizrachi, MD

Background / Hypothesis
In this phase II clinical trial the authors attempt to stratify patients with head and neck squamous cell carcinoma (HNSCC) undergoing trans oral surgery and select them for adjuvant treatment according to the response to neoadjuvant chemotherapy. The main endpoint of this study was response to neoadjuvant chemotherapy that may lead to de-intensification of adjuvant radiation treatment. Other endpoints were feasibility and safety of this protocol. The induction protocol success was set at >75% response rate. Furthermore, the study looked at the percentage of patients, who “avoided” adjuvant radiation, which they were eligible for by having stage III/IV disease at enrolment.

Design
The study included patients with newly diagnosed resectable HNSCC of the oral cavity, oropharynx (HPV+ and HPV-), larynx and hypopharynx. Patients with T1N0 and T2N0 disease were excluded. The neoadjuvant regimen consisted of weekly carboplatin and paclitaxel and daily lapatinib for 6 weeks. Imaging was obtained 2-5 weeks following the completion of neoadjuvant treatment for evaluation of clinical response. Subsequently the patients underwent trans oral surgical resection of the primary tumor and neck dissection. Patients with pN0 and pN1 disease were observed. Adjuvant treatment included concomitant radiation plus cisplatin and was given to patients with adverse features.

(Figure 1).

Summary of Results
A total 40 patients were accrued for the trial and 37 completed the full protocol.
The majority of patients had oropharyngeal cancer (75%) however only 17 had RTOG low-risk HPV+ cancer. The clinical response rate for all patients was 93% with 40% achieving complete clinical response. Pathological complete response was observed in 36% of patients with no correlation between clinical and pathological responses. Overall, 30 patients (77%) successfully avoided adjuvant radiation. At a median follow up of 2.4 years none of the patients had recurred or died.

Toxicity in general was mild with diarrhea being the most common adverse event (lapatinib) and neutropenia being the most severe, accounting for grade 3 and 4 toxicity in 38% of patients. Finally, the functional outcomes reported in the study were excellent in terms of speech and swallowing.

Strengths

  • The study demonstrated high clinical and pathological response rates to neoadjuvant
    chemotherapy in patients with advanced stage resectable HNSCC.
  • The majority of patients successfully avoided adjuvant radiation therapy.
  • None of the patients experienced recurrence or death during follow-up.
  • Toxicity profile for this neoadjuvant regimen was relatively modest and well tolerable.
  • Functional outcomes were good, probably due to the fact that most patients did not

 Weaknesses

  • Small number of participants.
  • Heterogeneity of tumor sub-sites and especially the inclusion of HPV+ oropharyngeal
    cancer.
  • The majority of patients were RTOG low and medium risk.
  • The choice of lapatinib as a neoadjuvant agent while there is not enough evidence to
    support its use in HNSCC.

Key Points

  • Neoadjuvant regimens are emerging and may play an important role in the stratification
    and management of patients with HNSCC.
  • Specifically, the neoadjuvant regimen of Carboplatin and Paclitaxel achieved excellent
    clinical and pathological response rates.
  • The ability to de-intensify treatment by avoiding adjuvant radiation is made possible
    with neoadjuvant therapy followed by surgery, which provides valuable clinical and
    pathological insights.
  • De-intensification of adjuvant treatment may result in better functional outcomes and
    improved quality of life without compromising survival.
  • Ongoing clinical trials combining immunotherapy in neoadjuvant regimens are showing
    promising preliminary results.

From the Basic Science/Translational Service
Jeffrey C. Liu MD Vice Chair
Richard Wong MD Chair

Aviram Mizrachi

Aviram Mizrachi

Dr. Aviram Mizrachi is a surgeon-scientist at the Department of Otolaryngology – Head and Neck Surgery of Rabin Medical Center in Israel. He has an active research laboratory focusing on tumor and radiation biology in head and neck cancer as well as targeted drug delivery. Furthermore, he investigates both radiation and chemotherapy mechanisms of action and their effect on tumor and normal tissue including the utility of novel radio-sensitizing and radio-protective agents. In addition, Dr. Mizrachi conducts clinical research on outcomes in head and neck, skin and thyroid cancers.