This intra-arterial approach was a part of the 1991 report of Dexeus et al. [6], and is the subject of later series as well. The anatomy of the perineum, particularly being distal to the renal and most of enteric circulation, does allow for potential use of intra-arterial cisplatin or other conventional chemotherapy in a way that bypasses renal arterial first-pass exposure. Roth and colleagues describe the position as a femoral artery approach, with the tip beyond the inferior mesenteric artery, above the aortic bifurcation [17]. Roth and colleagues described the treatment of eight penile cancer patients (as well as eight anal cancer patients, by the same approach), using a five-part combination (cisplatin; 5-FU; methotrexate; mitomycin C; and bleomycin), with three each of penile and anal cancer having CR; and additional partial responses.

Clearly, for most medical oncology contexts, a reliance on intra-arterial therapy does involve coordination of the infusion process with interventional radiologist, for the placement of the intra-arterial catheter, and the administration of the chemotherapy which may be in a setting very different from a typical infusion center. Myelotoxicity or nausea risks would be expected to not be different.

An additional five patients treated in Japan with intra-arterial chemotherapy (same five drugs, one patient had carboplatin instead) were reported by Chen and colleagues. Among these neoadjuvant patients who had refused up-front surgery, were observed one CR and four PR [18]. Overall, however, the experience with this route of administration remains quite limited. Huang et al. reported one CR and two PR among three patients receiving monthly intra-arterial cisplatin methotrexate and bleomycin, reported in 1999 [19].

A Chinese series describing outcomes for 12 subjects with intra-arterial gemcitabine and cisplatin treatment of locally advanced penile cancer, over a period of 12 years, was reported by Liu and colleagues in [20]. Ten had major response, and three were long-term survivors. Overall, despite the long term of the experience, the base of intra-arterial treatments and the logistics remain limiting, although the rationale and particularly the potential for organ preservation do present a key appeal. Further formal study and standardization of protocols to accommodate prospective testing are lacking.

While there are few data to guide which chemotherapy to use, notwithstanding the above experiences of a couple hundred patients over a few decades, there are even less data to guide a uniform recommendation on treatment before, during, or after other modalities. A treatment for advanced disease that is metastatic and not potentially surgically resectable to potential cure is the most straightforward medical context; recurrent metastatic disease after surgery is a similar context, although it is logical to define a distinction between small-volume, longer-latency cancers as compared to widely metastatic, rapid early regrowth. Similarly to those patients with a demonstrable metastatic pattern, a penile cancer that at presentation technically unresectable but only apparently locally spread presents a situation for which initial medical therapy (the neoadjuvant schedule) is a relatively rational recommended consideration for initial treatment.

On the other hand, the period time immediately after potentially or apparently definitive resection of the primary cancer is one for which treatment decisions are further less well-defined. Clearly there will be some patients for whom the recurrence risk defined by the [residual] cancer in the resected specimen appears minimal—small volume, single superficial node area, for example. And at the other end of the risk spectrum will be patients (still technically resected to no evident disease) with features such as were identified as adverse by Pagliaro and colleagues [11]: Large volume of nodal disease, bilateral pattern, extranodal pattern, and skin-extension pattern. For the latter group, the balance of risk would be to favor immediate action to escalate treatment intensity, to try to tip the balance to prevent recurrence.

Thus is framed the question of how much disease risk should be present before a recommendation of adjuvant treatment, whether regional radiotherapy, radiotherapy with concurrent chemotherapy, or single- or multi-agent chemotherapy systemic treatment. In a small series (cisplatin/bleomycin/methotrexate) that includes some adjuvant patients, Hakenberg et al. describe the risk of treatment-related death in plain terms [21]. Adjuvant use of cytotoxic chemotherapy in most other cancer has been approached cautiously, recognizing that the incident population represents an uncertain ratio of patients who could not benefit and those who might benefit. (The former include a proportion who would have been cured anyway, or whose disease was absolutely insensitive to the treatment planned, or died first of other causes before the disease in question, or died from treatment-related toxicity; the latter are those for whom the disease is sensitive, and eventual progression is substantially delayed or actually prevented.) The situation for penile cancer therapy is that there are no generalized trial results to interpret. This risk:benefit ratio is left for the judgment of the treating physician and the patient’s own interpretive perspective. The NCCN guidelines identifies a key tipping point for greater than pathological N1 (that is pN2 or pN3; or cN3 [pelvic LN]; or pM1) for adjuvant chemotherapy, or for lymph node dimension over 4 cm for neoadjuvant chemotherapy [22].

Overall, any regimen known to show activity in advanced disease could reasonably be discussed in this adjuvant context; however this adjuvant timing for chemotherapy, as well as the choice of medications, are ones that are not amenable for description as a standardized intervention. Nicolai and colleagues present what is probably the largest specific neoadjuvant and adjuvant experience, using a taxane (paclitaxel or docetaxel), cisplatin and 5-FU for 28 neoadjuvant patients and 19 adjuvant patients with N2M0 or N3M0 pattern of regional spread. Over the 8 years in which this non-randomized series accrued (2004–2012), they describe a practice pattern shift toward neoadjuvant treatment. Among the neoadjuvant treatment patients were recorded 43 % “clinical responses” and 14 % complete pathologic remissions. Response was not associated with survival; however, associations of worse outcomes for N3 disease, and for p53 status, and for bilateral disease were observed [23].

Practically speaking the key decision for pursuing a neoadjuvant approach will be based on the clinical assessment of the extent to which the disease could be completely resected. Conversely, the key decision point on adjuvant therapy, whether as chemotherapy alone or concurrent with radiation therapy, will be on the clinical and pathologic assessment of the extent of remaining or metastatic disease.

Radiation therapy is not per se a systemic treatment, but there are few points that can be mentioned in the interface of radiation treatment and systemic therapies. The first relates to timing in relation to other modalities of treatment. Extrapolating from the experience of other cancer diagnoses, an induction multiagent chemotherapy treatment could be used prior to a definitive-intent radiation therapy approach. While certainly rationale in favor or opposed to this for a given penile cancer, patient could be developed along lines exactly parallel to those for neoadjuvant chemotherapy before surgery; the data for this diagnosis quite limited. Extrapolating from experiences, for example, in head and neck cancer, a phase III trial adding TPF induction before definitive radiotherapy did not improve outcomes [24], although a prior meta-analysis did show better outcomes [25].

The two key interactions of radiation therapy with systemic treatments relate to concurrent use of radiosensitizing chemotherapy, and to the role of local tissue destruction as a potential priming event of an immune response [26, 27]. The former is not the subject of any series particularly devoted to penile cancer, but approaches extrapolated from experiences for therapy of other squamous cancers, such as weekly cisplatin (squamous cervical cancer, e.g. [28]; head and neck cancer, e.g. [29]) or mitomycin and 5-FU (squamous anal cancer, e.g. [30]; muscle invasive urothelial bladder cancer, e.g. [31]).

The latter concept, to leverage tumor and stromal changes from radiotherapy to cause a better anticancer immune response is among many in development in conjunction with checkpoint inhibitor treatments. Some of the latter may ultimately include penile cancer patients not as a separate cohort, but rather as part of a multi-diagnosis immunotherapy development process, particularly in early-phase clinical trials.