Authors' reply.

Sir,

I would like to thank Ghanie et al. for their interest in the editorial, Surgery in limited-disease small-cell lung cancer.[1] They have raised some interesting points.

They discuss that surgery may have a role in the treatment of lung cancer solely for reduction in cells capable of inactivation of Gc protein macrophage-activating factor (Gc MAF) because cancer cells elaborate an enzyme alpha-N-acetylgalactosaminidase (Nagalase) that is capable of deglycosylation and inactivation of human group-specific component (Gc) protein, which in turn is important for enhancement of humoral and cellular immunity. As a result, cancer cells are able to protect themselves against activated macrophages. Since Nagalase activity is related to tumor load, they suggest that there could theoretically be a role for cancer cell load reduction surgery even in cases of advanced lung cancer.

Gc protein (also called Vitamin-D binding protein) is an interesting molecule, which becomes the molecular switch to activate macrophages when it is converted to its active form, Gc-MAF. Gc protein is normally activated by conversion to Gc-MAF with the help of the B and T cells. Cancer cells secrete alpha-Nacetylgalactosaminidase that completely blocks conversion of Gc protein to Gc-MAF, preventing tumor-cell killing by the macrophages. In addition Gc protein has other pleotropic effects that include macrophage activation, antiangiogenic activity and anti-tumor activity.[2] GcMAF has recently shown notable clinical value as a potent immunotherapy against human breast, prostate, and colorectal cancer.[34] Studies in cancer patients have indeed shown that high-serum levels of α-N-acetylgalactosaminidase activity correspond in linear fashion to both tumor burden[56] (in mice and humans) and, inversely to GcMAF “precursor activity” in humans.[47] This “precursor activity” has been assigned (without direct structural evidence) as the quantity of O-linked trisaccharide glycosylated DBP available in patient plasma, and is reported to be significantly depleted or even eliminated in cancer patients based on activity studies. Hence, theoretically debulking surgery could be utilized for benefits on Gc MAF formation. However, the concept shall have to stand the test of intense scientific scrutiny. Nonetheless, there is a lot of interest in the scientific community about the potential immunotherapeutic role of the molecule in various types of cancers.

The authors also suggest that advanced age is a risk for adverse outcome for surgery. Published data has demonstrated that elderly patients are denied potentially beneficial treatment and participation in clinical trials solely because of chronological age and because of the physician perception that they are too frail to withstand treatment. On the contrary, the benefit of active therapy is well demonstrated in the elderly population in general and is comparable to the benefit obtained by younger patients.[89] However, presence of age-related co-morbidities strongly advocate for a careful selection of the patients for any kind of invasive or aggressive therapy.

Lastly, the contention of the authors that role of surgery needs to be re-looked at in patients with advanced lung cancer cannot but be emphasized as majority of the patients are present in this stage of cancer. Rostad et al.[10] have recommended that more patients with peripherally located Stage IA and IB SCLC should be referred for surgery, and others[11] have reported promising results for Stage 1 and II SCLC with primary surgery and adjuvant chemotherapy and radiation. However, they suggest that in more advanced stages like Stage II and III, surgery should be undertaken as a part of controlled clinical trials.