CASE 2: PRIMARY CUTANEOUS MARGINAL ZONE B-CELL LYMPHOMA

Treatment

He had 6 febrile responses (38° to 39.2°C) between days 5 and 87. There were no signs of concomitant infection. After IT injections, the lymphoma lesion each time showed a similar response pattern of inflammatory swelling and erythema for up to 2 days, then resolution. The lesion increased in size over the first month to 4 × 5 cm, then remained unchanged for 3 months, and after the IT dose was increased to 100 mg ME, the lesion steadily diminished to become impalpable at 8.5 months (Table 2). This complete response (CR) was clinically verified by 3 clinicians in 2 separate institutions, including the ARI. The ITs were ceased in April 2009, and SC and IV treatment was continued until November 2010. A CT scan in March 2010 was unre-markable. The patient was last reviewed in December 2011 and was doing well and in remission; no new lesions had developed.

Tolerability

Patient's Description of Treatment

When I was offered chemo-/radiotherapy, this seemed aggressive to me like a sledge hammer [sic] to crack a nut. My understanding of mistletoe therapy felt gentler and simply like the right thing to do. The treatment itself, whilst challenging, confirmed my feeling that it was the bedrock, the main stay [sic] of being healed.

DISCUSSION

With high dosage, especially local ME applications, tumor remissions have been reported repeatedly in a number of tumor types, including breast cancer, Merkel cell cancer, primary liver cancer, pancreatic cancer, and cutaneous squamous cell cancer.^25–27 Still, high-dose and combined IT, IV, and SC administration that aims to elicit febrile induction is uncommon and underreported.

The literature on ME treatment of lymphoma is limited compared to that of other tumor types. One retrospective study describes favorable outcomes, including a few remissions in a group of 61 patients with follicular non-Hodgkin's lymphoma treated with a lowlectin ME (Iscador Pini) either alone or combined with or on completion of chemotherapy.³⁰ Another retrospective study primarily investigated safety aspects of ME treatment in Hodgkin's and non-Hodgkin's lymphoma and found no risks.³¹ Some case reports describe remission of non-Hodgkin's lymphoma under ME monotherapy,^32–35 including 2 in cutaneous T-cell lymphoma in children.^36,37 In these cases, the dosage was lower than in the cases reported here and applied mainly subcutaneously and only partly intravenously and intratumorally. At least one fever reaction was reported.

Preclinical studies with lymphoma cells and murine lymphoma models treated with ME, isolated MLs, recombinant ML, and other ME peptides have consistently shown antitumoral effects with tumor inhibition, inhibition of metastases, and survival benefit.^19,38–42 ME contain several cytotoxic ingredients, among them lectins and viscotoxins, which are particularly abundant in Abnobaviscum fraxini. When lec-tins are applied systemically, their cytotoxicity is moderated by serum proteins⁴³ and later by the occur-rence of anti-ML antibodies;⁴⁴ hence, their cytotoxicity is to be expected, primarily with IT administration. However, a disease response could also be effected by an immunological mechanism, as has been demonstrated for ME repeatedly.^19,20 Furthermore, fever seems to have a role in tumor defense.⁴⁵ The impact of ME treatment cannot be easily ascertained when used concurrently with mainstream cancer therapy. Occasionally, however, patients postpone or decline recommended conventional treatment in favor of ME, and such cases allow evaluation of ME treatment alone. Two of these patients are described above; these are the only two cutaneous lymphoma cases treated at PAC with ME alone and are therefore unselected. The cases of 2 other patients from PAC who had cancer at other sites and were treated with ME monotherapy have been published previously.²⁷

In lymphoma, spontaneous remission is estimated to occur in 5% to 20% of cases. It is sometimes of long duration^16,17,46,47 and often is associated with reducing an immunosuppressive treatment or condition; following fever, viral or bacterial infections, or vaccination; or after biopsy and following eradication of helicobacter in gastric lymphoma.¹⁷ In a small follow-up study observing patients over many years, spontaneous remissions were reported in 4 of 16 patients with PCFCL (one of them complete) and in 4 of 8 patients with PCMZL (none of them complete), all of whom had a relapse.⁴⁸ Although spontaneous remission could have played a role in the cases presented here, in the first of the cases presented, the lesions had grown progressively until commencement of ME treatment and then steadily decreased, with fluctuating treatment-related inflammatory responses. In the second case, the lesion resolved after initial treatment-related increase and with some delay, which is a known response pattern in ME-associated tumor remissions.^26,30 Therefore, a mere coincidence is unlikely, especially as the 2 cases are unselected (meaning that they were not selected from a larger group of patients with cutaneous lymphomas treated with ME but were the only patients with cutaneous lymphonas treated in this way) and represent the only patients with PCBCL from PAC that had been treated with ME monotherapy. One also has to consider that the fever-induction ME treatment is likely to upregulate just those mechanisms implicated in the frequent spontaneous remission described for lymphoma.

Two further case publications on ME treatment of a related entity, CD30+ T-cell lympho-proliferation, reported complete regression of multiple and active cutaneous and nodal disease.^37,38 In one case, treatment consisted of low-dose IV (3 infusions of 0.02 mg, 0.2 mg, and 2 mg) and SC (up to 2 mg twice a week) without fever or site responses, with a noticeable disease response within 1 week and durable (30 months) complete response (CR) within 4 weeks. The second case was treated with primary fever intent (38°C), IT, and SC, and had a dose-dependent partial response and CR that relapsed with a lower-dose ME but regressed again with dose increase.

A differentiated appreciation of the singular components of the combined ME treatment—the specific role of fever and each of the specific contributions of SC, IT, and IV—and of the synergies is not possible given the current knowledge and require further research.

Although treatment was well tolerated and the safety observed is in accordance with other investigations on the safety of ME treatment in higher dosage,²⁸ this treatment should be reserved for use by physicians who have experience with ME application in higher dosages and IT/IV until further investigations have explored the role of high-dose, fever-inducing ME in cancer and its safety in more detail.