Treatment of Oligometastases After Successful Immunotherapy

doi:10.1016/j.semradonc.2005.12.008

Seminars in Radiation Oncology

Volume 16, Issue 2, April 2006, Pages 131-135

https://doi.org/10.1016/j.semradonc.2005.12.008 Get rights and content

Local destruction of individual metastases by any of a number of effective modalities fails as a treatment for most patients with disseminated cancer because of the presence of either undetected micrometastases or simply too many lesions. The availability of a systemic therapy that could reduce the number of metastases to a manageable few would dramatically increase the utility of surgical metastasectomy or other locally ablative measures. Interleukin-2–based immunotherapy can serve exactly this function in some patients with renal cancer or melanoma. We review the effectiveness of surgery in treating limited relapses or residual disease in patients who have responded to systemic immunotherapy. These data indicate that a surprising percentage of such patients can enjoy durable disease-free survival after surgical removal of their oligometastases, and, for a significant minority, it appears to be curative.

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Summary

The failure of resection as a therapeutic modality for metastatic disease is because of a multiplicity of undetected metastases or an excessive number of bulk metastases with no effective means to sterilize enough to make resection reasonable. A systemic adjunct that debulks by incompletely reducing all tumors, large or small, does not contribute to the success of metastasectomy. In contrast to this, a key feature of immunotherapy is the durability of regression when a lesion is rendered

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Cited by (23)

Role of Surgery in Combination with Immunotherapy
2019, Surgical Oncology Clinics of North America
Citation Excerpt :
The reported clinical experience of metastasectomy following immunotherapy has been limited to case reports and small single institutional series. Metastasectomy after IL-2 was first reported in patients with advanced RCC and metastatic melanoma.17 After experiencing a partial response, many patients developed progressive disease and a selected group were salvaged by surgical resection.
Lung Metastases Treated With Stereotactic Ablative Radiation Therapy in Oligometastatic Colorectal Cancer Patients: Outcomes and Prognostic Factors After Long-Term Follow-Up
2017, Clinical Colorectal Cancer
Citation Excerpt :
High local control and good tolerance were observed in this setting. Selected patients with oligometastastic state and expected long survival have been considered candidates for curative treatments.10,11 To date, there are several reports in the literature regarding the outcomes of stereotactic body radiotherapy (SBRT) for metastatic lung tumors, but still no standard treatment regimens, optimal dose, and fractionation schedule have been defined.11
We evaluated a series of oligometastatic colorectal cancer (CRC) patients treated with stereotactic ablative body radiotherapy (SABR) delivered in all active lung metastases.
Forty-four patients with 69 lung metastases were treated with SABR. Eleven patients presented with other sites of metastases before stereotactic body radiotherapy (SBRT), even though they had controlled/cured systemic disease.
The median follow-up was 36 months. The median overall survival (OS) was 38 months and 2 years, 3-year OS rates were 67.7% and 50.8%, respectively. The median progression-free survival (PFS) was 10 months and 2 years, 3-year PFS rates were 20.3% and 16.2%, respectively. Local recurrence occurred in 16 patients (36%).The first site of failure was local only in 22%, distant only in 35%, and local and distant in 14% of the patients. The 1-year, 2-year, and 3-year local PFS (LPFS) were 68.8%, 60.2%, and 54.2%, respectively. No Grade ≥ 3 toxicities were recorded in the univariate analysis; multiple lung metastases and synchronous oligometastatic disease were significantly associated with worse PFS (P = .04, and P < .001, respectively) and worse metastases-free survival (MFS; P = .04, and P < .001, respectively). The type of response was identified as a significant prognostic factor for OS (P = .014), PFS (P = .006), and LPFS (P < .001). In multivariate analysis single lung metastases treated with SBRT was associated with better MFS (P = .015). Metachronous oligometastatic disease and type of response were associated with significantly better PFS.
Stereotactic body radiotherapy is a valid therapy in the treatment of lung metastases for oligometastatic CRC patients presenting long survival. The rate of local control remains lower compared with other primaries. Further prospective cohorts would better evaluate effective fractionation for patients with oligometastatic CRC.
Immunotherapy for Resected Pulmonary Metastases
2016, Thoracic Surgery Clinics
Citation Excerpt :
Removing these resistant sites would allow elimination of the disease. Yang and colleagues23 reported that among patients with melanoma with partial responses to high-dose IL-2, surgical salvage results in approximately 20% of patients seeming to be cured and 36% surviving for at least 5 years after salvage surgery. In summary, because pulmonary metastasectomy of melanoma is associated with longer survival but a significant risk of extrapulmonary visceral relapse, adjuvant systemic therapies (or local plus systemic therapies) will likely be necessary.
Metastasectomy for stage IV melanoma
2015, Surgical Oncology Clinics of North America
Citation Excerpt :
Surgery is also a component of some adoptive immunotherapy strategies in which tumor is resected and the responsive immune cells within the lesion are isolated and amplified to produce a cell product that can be returned to the patient. This strategy has been successfully used, initially at the National Cancer Institute, and now at several other centers around the world.69,70 Overall, this new, complex situation, although confusing, is an important opportunity for continued progress in the treatment of metastatic melanoma.
Stereotactic Body Radiotherapy for Oligometastatic Lung Tumors
2008, International Journal of Radiation Oncology Biology Physics
Since 1998, we have treated primary and oligometastatic lung tumors with stereotactic body radiotherapy (SBRT). The term “oligometastasis” is used to indicate a small number of metastases limited to an organ. We evaluated our clinical experience of SBRT for oligometastatic lung tumors.
A total of 34 patients with oligometastatic lung tumors were included in this study. The primary involved organs were the lung (n = 15), colorectum (n = 9), head and neck (n = 5), kidney (n = 3), breast (n = 1), and bone (n = 1). Five to seven, noncoplanar, static 6-MV photon beams were used to deliver 48 Gy (n = 18) or 60 Gy (n = 16) at the isocenter, with 12 Gy/fraction within 4–18 days (median, 12 days).
The overall survival rate, local relapse-free rate, and progression-free rate at 2 years was 84.3%, 90.0%, and 34.8%, respectively. No local progression was observed in tumors irradiated with 60 Gy. SBRT-related pulmonary toxicities were observed in 4 (12%) Grade 2 cases and 1 (3%) Grade 3 case. Patients with a longer disease-free interval had a greater overall survival rate.
The clinical result of SBRT for oligometastatic lung tumors in our institute was comparable to that after surgical metastasectomy; thus, SBRT could be an effective treatment of pulmonary oligometastases.
Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma
2008, Molecular Therapy
Citation Excerpt :
Even though this study was carried out in a small group of patients who may have benefited from any type of immunotherapy, it is interesting to mention that, after this study, three responders (patients 22, 25, and 29), as well as one patient with local and distant stabilization (patient 30) underwent surgery to remove residual oligometastases in a selective manner, and are since then disease-free and alive (additionally, patient 29 underwent removal of one new metastasis in November 2007). Yang et al. have recently pointed out that surgical (oligo)metastasectomy can be quite beneficial in patients who have responded to systemic immunotherapy by providing them with longer disease-free periods, while some even appear to be cured.25 Other types of cancer treated in this study did not respond to intralesional TG1024 injections, which is not surprising given the less than convincing responses obtained with recombinant IL-2 in various cancers, other than melanoma and renal cell carcinoma (reviewed in refs. 26,27).
Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 × 10⁸ to 3 × 10¹¹ viral particles (vp). Intratumoral TG1024 injections in combination with dacarbazine (DTIC) were tested in metastatic melanoma in one cohort. No clinical responses were observed at doses below 3 × 10¹¹ vp. Six local objective responses were recorded in patients receiving 3 × 10¹¹ vp per treatment [five in metastatic melanoma and one in metastatic squamous cell carcinoma (SCC) of the skin], of which two were complete responses (CRs). Most of the common side effects were injection site reactions and flu-like syndrome. TG1024 dose intensification across cohorts resulted in increased serum IL-2 levels after the injection. Intratumoral TG1024 injection induced pronounced inflammation of the treated lesion, with predominant CD8⁺, TIA+ lymphocytic infiltrate. Our results show that intratumoral injections of TG1024 are safe and well tolerated. The clinical activity of TG1024 observed in this study warrants further investigations.

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Treatment of Oligometastases After Successful Immunotherapy

Section snippets

Summary

Adv Cancer Res

Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer

N Engl J Med

Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2

JAMA

Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2

Ann Surg

Tumor antigens recognized by cytotoxic lymphocytes

Identification of fibroblast growth factor-5 as an overexpressed antigen in multiple human adenocarcinomas

Cancer Res

Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells

J Exp Med

Receptors for HLA class-I molecules in human natural killer cells

Annu Rev Immunol

Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2

Science